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Product Details of [ 5452-37-9 ]

CAS No. :5452-37-9 MDL No. :MFCD00001748
Formula : C8H17N Boiling Point : -
Linear Structure Formula :- InChI Key :HSOHBWMXECKEKV-UHFFFAOYSA-N
M.W : 127.23 Pubchem ID :2903
Synonyms :

Calculated chemistry of [ 5452-37-9 ]

Physicochemical Properties

Num. heavy atoms : 9
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 : 41.16
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) : -6.13 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.1
Log Po/w (XLOGP3) : 1.33
Log Po/w (WLOGP) : 2.06
Log Po/w (MLOGP) : 1.83
Log Po/w (SILICOS-IT) : 1.85
Consensus Log Po/w : 1.83

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.47
Solubility : 4.34 mg/ml ; 0.0341 mol/l
Class : Very soluble
Log S (Ali) : -1.48
Solubility : 4.23 mg/ml ; 0.0333 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.48
Solubility : 4.26 mg/ml ; 0.0335 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.16

Safety of [ 5452-37-9 ]

Signal Word:Danger Class:8
Precautionary Statements:P280-P305+P351+P338-P310 UN#:2735
Hazard Statements:H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 5452-37-9 ]

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

  • Downstream synthetic route of [ 5452-37-9 ]

[ 5452-37-9 ] Synthesis Path-Downstream   1~85

  • 1
  • [ 13726-16-4 ]
  • [ 5452-37-9 ]
  • [ 769062-56-8 ]
  • 2
  • [ 2494-79-3 ]
  • [ 5452-37-9 ]
  • [ 59815-68-8 ]
YieldReaction ConditionsOperation in experiment
In thionyl chloride; a. 4-Chloro-3-cyclooctylsulfamoylbenzoyl chloride 25.5 g of 4-chloro-3-chlorosulfonylbenzoic acid were reacted as prescribed in Example 75a) with 45 g of cyclooctyl amine and worked up. The crystallized 4-chloro-3-cyclooctylsulfamoylbenzoic acid so obtained was dried end reacted without further purification in thionyl chloride as prescribed in Example 74a). Colorless crystals, melting point: 134 C.
  • 3
  • [ 5452-37-9 ]
  • [ 35511-15-0 ]
  • [ 35511-11-6 ]
  • 4
  • [ 29547-04-4 ]
  • [ 5452-37-9 ]
  • [ 62664-92-0 ]
  • 5
  • [ 5452-37-9 ]
  • [ 59486-73-6 ]
  • [ 137795-74-5 ]
  • 7
  • [ 3056-18-6 ]
  • [ 5452-37-9 ]
  • (2R,3R,4S,5R)-2-(2-Chloro-6-cyclooctylamino-purin-9-yl)-5-hydroxymethyl-tetrahydro-furan-3,4-diol [ No CAS ]
  • 8
  • [ 5452-37-9 ]
  • [ 207557-35-5 ]
  • (S)-1-(2-Cyclooctylamino-acetyl)-pyrrolidine-2-carbonitrile [ No CAS ]
  • 9
  • [ 67-56-1 ]
  • [ 5452-37-9 ]
  • [ 17630-21-6 ]
YieldReaction ConditionsOperation in experiment
100% at 100℃;
90% With (C5(CH3)5)IrCl2(1,3-diisoptopylimidazole); potassium carbonate at 60℃; for 17h; Inert atmosphere; Schlenk technique; Sealed tube; N,N-Dimethylation of a Variety of Aliphatic Amines with Methanol Catalyzed by 2c Shown in Table 2; General Procedure General procedure: In a stainless reactor bomb, the corresponding aliphatic amine (1.0mmol), 1c (0.50 mol%), K2CO3 (5.0 mol%), and MeOH (1.0 mL) were placed. Then, the reactor was sealed with a stainless stopper, and the mixture was stirred under indicated conditions. After removing MeOH under reduced pressure, the products were isolated by silicagel column chromatography.
72 %Chromat. With platinum on carbon; sodium hydroxide at 150℃; for 48h; Inert atmosphere; Autoclave; 2.4. Typical procedures of catalytic reactions General procedure: After the reduction under a flow of H2 at 300°C for 0.5h, we carried out catalytic tests without exposing the catalyst to air as follows. Methanol (30mmol) was injected to the reduced catalyst inside the glass tube through a septum inlet, thus the catalyst was covered with a layer of methanol to restrict it from air exposure. After removal of the septum under air, amine (1mmol), solid NaOH (1mmol), n-dodecane (0.25mmol) and a magnetic stirrer bar were placed in the tube. The tube was inserted into a stainless-steel autoclave (28cm3) and purged with N2 gas. Finally, the resulting mixture was heated at 150°C and stirred under 1barN2. For the model reaction of n-octylamine, the catalyst screening, optimization of reaction conditions, kinetic studies and control reactions, the conversion of n-octylamine and yields of products were determined by GC analyses, using n-dodecane as an internal standard by applying the GC sensitivity of the isolated or commercial products. For the substrate scope study, the products were isolated by column chromatography with silica gel 60 (spherical, 60-100μm, Kanto Chemical Co., Ltd.) using hexane/ethyl acetate or ethyl acetate/methanol as the eluting solvent. The yields of the isolated amine derivatives were determined and identified by 1H and 13C NMR and GC-MS methods.
  • 10
  • [ 18698-97-0 ]
  • [ 5452-37-9 ]
  • 1-cyclooctyl-1,3-dihydroindol-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
30% Stage #1: ortho-bromophenylacetic acid; cyclooctylamine at 150℃; for 0.5h; microwave irradiation; Stage #2: With sodium hydroxide; XPhos In water; toluene at 100℃; for 0.5h; microwave irradiation;
  • 11
  • [ 502-49-8 ]
  • [ 5452-37-9 ]
YieldReaction ConditionsOperation in experiment
98% With ammonium formate; C25H31ClIrN2OP at 50℃; for 18h; Sealed tube;
81% With N,N'-bis(salicylidene)-1,2-phenylene-diaminocobalt(II); ammonia; hydrogen In tetrahydrofuran; water at 130℃; for 24h; Autoclave;
Multi-step reaction with 2 steps 2: ethanol; sodium
47 %Spectr. Stage #1: cycloactanone With choline chloride; ammonium acetate; urea at 70℃; for 0.0833333h; Stage #2: With sodium cyanoborohydride at 70℃; for 1h; General procedure for the reductive amination of ketones in DES General procedure: In a 10-mL round-bottom flask with a magnetic stirrer, 1.20 g of choline chloride and1.00 g of urea (ChCl/urea 1:2) were added. The mixture was stirred at 70 C until completemelting was achieved. Then, 1.00 mmol of the ketone, 0.825 g of NH4OAc(10.7 mmol) and, after 5 min, 70 mg (1.10 mmol) of NaBH3CN were added. The mixturewas maintained at 70 C for 60 min. Subsequently, 5mL of HCl (1 mol L1) was addedto the reactional mixture, and the aqueous layer was washed with dichloromethane(3x15 mL). Five milliliters of NaOH (1 mol L1) was added to the aqueous layer, andthe amine product was extracted into dichloromethane (3 x 15 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. All of the productsin this study were known compounds and were identified based on matching their1H NMR spectra with those in the literature cited.

  • 12
  • [ 5452-37-9 ]
  • [ 175357-98-9 ]
  • Cyclooctyl-(6-fluoro-pyrido[3,4-d]pyrimidin-4-yl)-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
27% With N-ethyl-N,N-diisopropylamine In dichloromethane at 5 - 20℃; for 18h; 11 Preparation 11, Cyclooctyl-(6-fluoro-pyrido[3,4-d]pyrimidin-4-yl)-amine Preparation 11 Cyclooctyl-(6-fluoro-pyrido[3,4-d]pyrimidin-4-yl)-amine Cyclooctylamine (692 mg, 5.4 mmol) was added to a stirred solution of 4-chloro-6-fluoro-pyrido[3,4-d]pyrimidine (0.5g, 2.7 mmol) and diisopropylethylamine (0.95 ml, 5.4 mmol) in dichloromethane (13 ml) at 5° C. The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was partitioned between water and dichloromethane. The organic layer was concentrated in vacuo to yield an off white solid which was recrystallized in acetonitrile to yield the title compound as a tan solid (0.2g, 27%). 1H NMR(CDCl3, 400 MHz): 1.55-1.80(m, 12H), 2.00(m, 2H), 4.50(m, 1H), 5.70(brs, 1H), 7.10(s, 1H), 8.65(s, 1H), 8.95(s, 1H). MS (APCl+) m/z 275 [MH]+.
  • 13
  • [ 5452-37-9 ]
  • [ 539-88-8 ]
  • [ 913731-01-8 ]
YieldReaction ConditionsOperation in experiment
93.34% With hydrogen at 25 - 150℃; for 1h; 21 EXAMPLES 1-22 Preparation of 5-Methyl-N-Alkyl-2-Pyrrolidone; Ethyllevulinate (EtLA) and the indicated alkyl amine (R-NH2) were mixed in approximately equal molar equivalents at room temperature (25° C.) to prepare a solution. To this solution was added the unsupported (Platinum black) or supported metal catalyst. The reactor was pressurized with hydrogen at the indicated pressure and heated for the indicated time. At the end of the reaction, the reactor was cooled, vented and the product analyzed by GC-MS using an HP 6890 (Agilent; Palo Alto, Calif.) equipped with a WCOT fused silica column, 25 m×0.25 MM ID, coating CP-wax 58 (FFAP)-CB DF=0.2 (Varian, Palo Alto, Calif.).
  • 14
  • [ 13726-16-4 ]
  • [ 5452-37-9 ]
  • N-cyclooctyl-3-methoxy-4-chloro-benzylamine-hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 34 Starting from 9.9 g of <strong>[13726-16-4]3-methoxy-4-chlorobenzaldehyde</strong> and 6.35 g of cyclooctylamine, there were obtained according to the method described in Example 1 7.2 g of N-cyclooctyl-3-methoxy-4-chloro-benzylamine-hydrochloride. Melting point 222°-223° C (from ethanol).
  • 15
  • [ 5452-37-9 ]
  • [ 158966-92-8 ]
  • [ 947370-34-5 ]
YieldReaction ConditionsOperation in experiment
94% In toluene at 25℃; for 1h; Heating / reflux; 14 EXAMPLE 14A reaction vessel equipped with a thermometer, a reflux condenser and a magnetic stirrer was charged with 3 g (0.0051 moles) of montelukast acid in 45 ml of toluene. The mixture was stirred and heated to reflux to afford a solution. 0.763 g (0.0060 moles) of cyclooctylamine was added, and the mixture was cooled to 25 C, causing the montelukast cyclooctyl ammonium salt to separate and the resulting suspension was stirred for 1 hour at 25 C. The thus formed crystals were filtered, washed with cold toluene and dried under vacuum at 40 C to obtain 3.42 g (94% yield) of crystalline montelukast cyclooctyl ammonium salt form VIII, having a purity of 98.5% (by HPLC).
70% In ethyl acetate 1 A three-necked flask equipped with a thermometer, a nitrogen inlet and a magnetic stirrer was charged at room temperature with 9 g (0.0198 moles) of 2-(2- (3(S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(hydroxylpropyl)phenyl)-2- propanol (compound (H)) in 48 mL of anhydrous THF under stirring and cooled to about -20°C. N,N-diisopropylethylamine (DIPEA) (7.8 mL; 0.045 moles) was added in portions followed by addition of 3 mL (0.039 moles) of methanesulfonyl chloride in portions, and stirring was maintained at about -20°C for about 2 hours. An aliquot was checked by HPLC, which contained less than 1% of the starting material, and about 1.5% of compound (VI) in the reaction mixture. The cold suspension containing the product 2-(2-(3S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3- (methanesulfonyloxypropyl)phenyl-2-propanol (compound (III)) was filtered at -20°C and washed with cold anhydrous THF.[0049] Another three-necked flask equipped with a thermometer, a nitrogen inlet and a magnetic stirrer was charged at room temperature with 7.3 g (0.04 moles) of 1- (mercaptomethyl)cyclopropaneacetic acid (compound (VII)) and 48 mL of N-methyl- 2-pyrrolidone (NMP) under stirring and under nitrogen atmosphere to obtain a solution. Sodium hydroxide flakes (0.0112 moles; 4.5 g) was added in one portion at room temperature followed by addition of 2.4 mL of water, and stirring was maintained for 1 hour to afford a suspension. A solution of compound (III) in about 50 mL THF, at -2O0C, was added in portions to the solution of compound (VII) at room temperature. After completing the addition, the mixture was stirred for 2 hours and reaction completion was checked by HPLC. Ethyl acetate (130 mL) and 5% sodium chloride solution (130 mL) were added to the reaction mixture, and the mixture was stirred for 20 minutes.[0050] The layers were separated and the upper organic layer was washed with 130 mL of 5% sodium chloride solution, and the layers were separated. Tartaric acid (84 mL of 0.5 M solution) was added to the upper layer and the layers were separated. The upper layer was washed with 40 mL of water and again separated. The organic layer was distilled to dryness to afford an oily residue. Ethyl acetate (90 mL) was added to the residue and the mixture was distilled to dryness to afford 12.5 g of an oily residue. Ethyl acetate (90 mL) was added to the residue under stirring to obtain a solution. Cyclooctylamine (3.1 mL) was added and stirring was maintained for few minutes and the solution was seeded with crystalline montelukast acid cyclooctyl ammonium salt. Stirring was maintained at room temperature to afford a suspension, which was filtered off to obtain a cake. The cake was washed with ethyl acetate and dried at 400C in vacuum to afford 9.1 g of dry crude montelukast acid cyclooctyl ammonium salt in 70% yield. The HPLC purity was 90.4% (containing 1.7% compound (VII)). The crude montelukast acid cyclooctyl ammonium salt was crystallized from toluene to obtain a product having 97% purity and containing 1.4% of the methylene impurity. Ethyl acetate (25 mL) was added followed by addition of 17 mL of 0.5M tartaric acid solution. The mixture was stirred at room temperature for half an hour to afford a two phase system. The layers were separated and the upper ethyl acetate layer (containing the montelukast acid) was washed with 10 mL water. A solution of 0.15 g of solid sodium hydroxide in 25 mL of water was added in portions to the organic phase, and the layers were separated. The aqueous layer (containing the desired end product) was transferred into a three-necked flask equipped with nitrogen inlet, a stirrer, and a distillation head, and the solution was concentrated under vacuum at about 40°C. Acetonitrile was added and the mixture was allowed to cool to ambient temperature and seeded with crystalline montelukast sodium. The crystalline product was obtained by filtration and washed with acetonitrile.
70% In water; toluene for 1.5h; 3 A dry reactor was charged at room temperature with 1.21 kg (2.66 mol) compound (H) and 6 L of anhydrous THF, cooled to 0°C while stirring. DIEA (650 mL, 3.25 mol; 1.22 equiv.) was added in portions. A solution of methansefulonyl chloride (250 mL, 3.25 mol, 1.22 equiv.) in 500 mL THF then was added to the stirred reaction mixture over a hour, while the temperature of the reaction mixture was maintained at or around 0°C for about 3 hours. A sample of the reaction mixture was checked by HPLC, and indicated there was 0.74% of the starting material (compound (H)), and 0.3% of compound (VI). The cold reaction mixture then was filtered at O0C and the cake washed with 1 L anhydrous THF, then 2 L THF. The solution, containing the product (compound (III)) was then transferred to a clean and dry container. [0054] Compound (VII) (480 g, 3.29 mol) was added to a clean and dry reactor at room temperature, followed by NMP (6.48 L) to form a solution. Next, NaOH (a 46% solution, 370 mL, 6.3 mol) was added in one portion at room temperature. Then, the solution of compound (III), prepared above, was added drop- wise at room temperature. Then, the reaction mixture was stirred at room temperature for 3 hours and monitored for completion via HPLC. Toluene (12.1 L) and 5% NaCl solution (17.4 L) were added to the reaction mixture and the resulting mixture was stirred for 20 minutes. The layers were separated and the organic layer was washed with water (5.7 L). Cyloocylamine (420 mL) was added to the organic layer. Water was distilled out of the organic layer by azeotropic distillation over about 1.5 hours. The reactor was then cooled to about 40°C, and the solution seeded with crystalline montelukast cycloocyl ammonium salt. The solution was then cooled to room temperature, whereupon a suspension was formed. The suspension was filtered to obtain a cake. The cake was washed with toluene (550 mL) and dried to afford montelukast cycloocyl ammonium salt (1.13 g, 70% yield). The HPLC purity of the montelukast cycloocyl ammonium salt was 97.7%, and contained 0.25% compound (VI) and 0.46% compound (VIII). The montelukast cycloocyl ammonium salt then was crystallized from toluene having about 2% methanol to obtain montelukast cycloocyl ammonium salt in 85% yield having 99.5% purity and having 0.17% compound (VI) and 0.03% compound (VIII). The product was re-crystallized to obtain 99.7% purity and 0.17% compound (VI) and no detectable compound (VIII).[0055] The re-crystallized montelukast cycloocyl ammonium salt (690 g) was placed in a clean, dry reactor with dichloromethane (5.8 L) and stirred for 15 minutes at room temperature. A 5M citric acid solution (3.45 L) was added and the mixture stirred for 30 minutes at room temperature to afford a two-phase system. The layers were separated and the organic layer (containing the montelukast acid) was washed three times each with 3 liters of water. Water (4.7 liters) then was added to the organic phase and a solution IM NaOH (785 mL) was added drop-wise. The organic solvent was distilled off. The pH of the resulting aqueous layer was measured at 8.65. The aqueous layer was spray-dried to obtain montelukast sodium salt having a purity of 99.8% and containing less than 0.1% of compound (VI) (as measured by HPLC). No traces of compound (VIII) were detected in the sample.
68% In toluene 2 A three-necked flask equipped with a thermometer, a nitrogen inlet and a magnetic stirrer was charged at room temperature with 9 g (0.0198 moles) of compound (II) in 48 mL of anhydrous THF under stirring and cooled to about -200C. N,N-diisopropylethylamine (DIPEA; 4.8 mL; 0.028 moles) was added in portions followed by addition of 1.86 mL (0.024 moles) of methanesulfonyl chloride in portions, and stirring was maintained at about -200C for about 2 hours. A sample was withdrawn and checked by HPLC, which contained about 5% of the starting material, and about 0.5% of compound (VI) in the reaction mixture. The cold suspension containing the product compound (III), was filtered at -200C and the cake was washed with cold anhydrous THF.[0052] Another three-necked flask equipped with a thermometer, a nitrogen inlet and a magnetic stirrer was charged at room temperature with 7.3 g (0.05 moles) of compound (VII) and 48 mL of NMP under stirring and under nitrogen atmosphere to obtain a solution. NaOH flakes (4.5 g; 0.0112 moles) was added in one portion at room temperature followed by addition of 2.4 mL of water, and stirring was maintained for 1 hour to afford a suspension. The solution of compound (III) in about 50 mL THF, which was kept at -200C, was added in portions to the solution of compound (VII) at ambient temperature. After completing the addition, the mixture was stirred for half an hour and reaction completion was checked by HPLC. Toluene (130 mL) and 130 mL of a saturated sodium chloride solution (brine) were added to the reaction mixture and mixing was maintained for 20 minutes. The layers were separated and the organic layer was washed with 130 mL of brine, and the layers were separated. Tartaric acid (84 mL of 0.5 M solution) was added to the upper layer and the layers were separated. The upper layer was washed with 40 mL of water and again separated. The organic layer was distilled to dryness to afford an oily residue. Toluene (90 mL) was added to the residue and the mixture was distilled to dryness to afford 11 g of an oily residue. Toluene (90 mL) was added to the residue under stirring to obtain a solution. Cyclooctylamine (3.1 mL) was added and stirring was maintained for few minutes and the solution was seeded with crystalline montelukast acid cyclooctyl ammonium salt. Stirring was maintained at room temperature to afford a suspension, which was filtered off to obtain a cake. The cake was washed with toluene and dried at 40°C in vacuum to afford 8.14 g of dry crude montelukast acid cyclooctyl ammonium salt in 68% yield. The HPLC purity was 98% (containing 0.23% compound (VI)). The crude montelukast cyclooctyl ammonium salt was crystallized from toluene containing about 2% of methanol to obtain a product having 99% purity and containing 0.1% compound (VI). Ethyl acetate (100 mL) was added followed by addition of 17 mL of 0.5M tartaric acid solution. The mixture was stirred at room temperature for half an hour to afford a two-phase system. The layers were separated and the ethyl acetate layer (containing the montelukast acid) was washed with 3 x 70 mL of water and concentrated by distillation to about half of its volume. A solution of 0.15 g of solid NaOH in 25 mL water was added in portions to the organic phase, and the layers were separated. The aqueous layer (containing the desired end product) was spray-dried to obtain the desired product having a purity of 99.8% and containing less than 0.1% of compound (VI) (according to HPLC).
In toluene at 20℃; 5 Another three-necked flask equipped with a thermometer, a nitrogen inlet and a magnetic stirrer was charged at room temperature with 6.7 g (0.0459 moles) of 1-(mercaptomethyl)cyclopropaneacetic acid and 48 ml of NMP under stirring and under nitrogen atmosphere to obtain a solution. 4.5 g of NaOH flakes (0.1125 moles) was added in one portion at room temperature followed by addition of 2.4 ml of water, and stirring was maintained for 1 hour to afford a suspension. The solution of compound (III) in about 50 ml THF, which was kept at 5° C., was added in portions at ambient temperature. After completing the addition, the mixture was stirred for 2 hours and reaction completion was checked by HPLC. 130 ml of toluene was added to the reaction mixture along with 130 ml of 5% sodium chloride solution, and the mixture was stirred for 20 minutes. Then, the layers were separated and the upper organic layer was washed with 130 ml of 5% sodium chloride solution, and the layers were separated. 84 ml of 0.5 M tartaric acid solution was added to the upper layer and the layers were separated. The upper layer was washed with 40 ml of water and again separated. The organic layer was distilled to dryness to afford an oily residue. 90 ml of toluene was added to the residue under stirring to obtain a solution. 3.1 ml of cyclooctylamine (0.0226 moles) was added and stirring was maintained for few minutes and the solution was seeded with crystalline montelukast acid cyclooctyl ammonium salt. Stirring was maintained at room temperature to afford a suspension, which was filtered off to obtain a cake. The cake was washed with toluene and dried at 40° C. in vacuum to afford 9.88 g of dry crude montelukast acid cyclooctyl ammonium salt in 70% yield, having 98% purity (according to HPLC). The crude montelukast cyclooctyl ammonium salt was crystallized from toluene containing about 2% of methanol to obtain a product having 99% purity (according to HPLC). 30 ml of dichloromethane was added followed by addition of 17 ml of 0.5M citric acid solution. The mixture was stirred at room temperature for half an hour to afford a two phase system. The layers were separated and the organic layer (containing the montelukast acid) was washed with 3×15 ml water, the layers were separated and the aqueous layer was removed. 20 ml of water was added under stirring followed by addition of 4 ml of 1M NaOH solution and stirring was maintained for about 5 minutes. The dichloromethane was distilled off at a temperature lower than 35° C. The pH was checked and 1 M NaOH solution was added drop-wise until the pH value was about 10.5. The aqueous layer (containing the desired end product) was freeze-dried to obtain 8.3 g of montelukast sodium in 99% yield having a purity of 99.8% (according to HPLC).
In toluene at 20℃; Heating / reflux; 2 Step 2: Preparation of compound (IX): A three-necked flask equipped with a thermometer, a nitrogen inlet, and a magnetic stirrer was charged at room temperature with compound (VII) (6.41 g, 0.0408 moles) and NMP (50 mL). The mixture was stirred under a nitrogen atmosphere to obtain a solution. 50% NaOH (w/w) solution (4.73 ml, 0.0902 moles) were added in portions at room temperature. The reaction mixture was stirred for 1 hour at room temperature to afford a suspension. A solution of compound (III), prepared in Step 1, in THF (about 50 mL), was maintained at about -20°C and added in portions to the dianion mixture of compound (VII) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. Reaction completion was checked by HPLC. Toluene (133 mL) and brine (133 mL) were added to the reaction mixture in portions at room temperature, and the resulting solution was stirred for 1 hour. Then, the layers were separated, and the organic layer was washed with brine (133 mL). The layers were separated again. A tartaric acid solution (87 mL of 0.5 M solution) was added to the organic layer, and the layers were separated. The organic layer was washed with water (43 mL) and again the layers were separated. To the organic layer was added cyclooctylamine (3.19 ml, 0.0233 moles) in portions at room temperature. The mixture was heated to reflux and maintained at reflux in order to remove the water by azeotropic distillation. Toluene (40 ml) was distilled out at atmospheric pressure. The mixture was cooled to room temperature and the resulting solution was seeded with crystalline montelukast cyclooctylammonium salt. Stirring was maintained at room temperature to afford a suspension, which was filtered off to obtain a cake. The cake was washed with toluene and dried at 40°C in vacuum to afford 7.6 g of dry crude (R)-montelukast cyclooctylammonium salt in 52% yield containing 2.0% by weight of the (S) isomer. The HPLC purity of (R)-montelukast cyclooctylammonium salt was 99.3%. The crude montelukast cyclooctylammonium salt was crystallized twice from toluene containing about 0.5% by volume methanol to afford 5.9 g of dry crystalline (R)-montelukast cyclooctylammonium salt in 78% yield with 99.7% HPLC purity and less than 0.1% by weight of the (S) isomer.

  • 16
  • [ 5452-37-9 ]
  • [ 62-53-3 ]
  • [ 13310-25-3 ]
YieldReaction ConditionsOperation in experiment
99% In tert-Amyl alcohol at 150℃; for 24h;
  • 17
  • [ 5452-37-9 ]
  • [ 102-83-0 ]
  • [ 245421-04-9 ]
  • [ 1018478-84-6 ]
  • 18
  • [ 1034925-97-7 ]
  • [ 5452-37-9 ]
  • [ 1034925-72-8 ]
YieldReaction ConditionsOperation in experiment
51% With caesium carbonate In toluene at 20 - 110℃; 1.88.b The product of step (a) (120 mg, 0.34 mmol) was dissolved in dry toluene (10 mL) under N2 atmosphere. To the stirring solution were added Pd(OAc)2 (7.6 mg, 0.034 mmol), BINAP (23 mg, 0.037 mmol) and cesium carbonate (138 mg, 0.43 mmol) and the reaction mixture was stirred at rt for 20 min. Cyclooctylamine (65 mg, 0.50 mmol) was added and the mixture was stirred at rt for 10 min. Stirring was continued at HO0C under N2 atmosphere for 6 hours, cooled and allowed to proceed overnight at rt. The mixture was filtered through a small pad of silica gel on a sinter glass, eluted with additional amount of 30 mL toluene and then 50 mL EtOAc. 178 mg of yellowish crude oil obtained which was further purified usingCombiflash (PE - THF) affording the clean desired product as a yellow oil (70 mg, 51% yield).1H NMR: (CDCl3) δ 7.98 (d, IH, CH); 6.97 (bs, IH, CH); 6.69 (bd, IH, CH); 4.64 (bs, IH, NH); 3.57 (sextet, IH, CH); 2.80 (t, 2H, CH2N); 1.97-1.47 (m, 14H, CH2); 0.89 (m, IH, CH); 0.48 (m, 2H, CH2); 0.10 (m, 2H, CH2).MS: m/z 405.10 (MH+).
  • 19
  • [ 5452-37-9 ]
  • [ 292638-85-8 ]
  • [ 1040363-41-4 ]
YieldReaction ConditionsOperation in experiment
99% With bismuth triflate In acetonitrile for 18h; Heating / reflux; 5.17.17 Cyclooctylamine (HA, 155g, 1218.5mmol, Sigma- Aldrich) was dissolved in acetonitrile (50OmL). Methyl acrylate (HB, 47Og, 5460mmol, Sigma-Aldrich) was added, followed by the addition of bismuth triflate (15g, Sigma-Aldrich), and the mixture heated under reflux for 18h. The mixture was concentrated under reduced pressure and was chromatographed by flash silica eluted with hexanes, followed by eluting with 10:1 hexanes:EtOAc to provide 36Og of a compound of formula HC as a colorless oil (yield >99%).The identity of the compound of formula HC, dimethyl 3,3'-(cyclooctylazanediyl)dipropanoate, was confirmed using 1H NMR. Compound HC: 1H NMR: δ (400 MHz, CDCl3): 3.68 (3H, s), 2.70 (2H, t, J=IOHz),2.65 (IH, m), 2.40 (2H, t, J= 10Hz), 1.75-1.35 (14H, m).
  • 20
  • (1R,5S)-8-benzyl-8-methyl-3-oxo-8-azoniabicyclo[3.2.1]octane bromide [ No CAS ]
  • [ 5452-37-9 ]
  • (1R,5S)-8-cyclooctyl-8-azabicyclo[3.2.1]octan-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% With potassium carbonate In ethanol; water at 70℃; for 3.5h; 5.19.19 The compound of formula IC, (li?,55)-8-benzyl-8-methyl-3-oxo-8-azoniabicyclo[3.2.1]octane bromide (5g, lβ.lmmol), was mixed with 4OmL ethanol and 2OmL of water. This mixture was added to a mixture at 7O0C of the compound of formula HA (2.Og, lβmmol), and K2CO3 (0.2g, 1.4mmol) in ethanol (15OmL) over 30min. After 3h at 7O0C, the reaction mixture was cooled to a temperature of about 250C and concentrated. The residue was treated with water (5OmL), and extracted three times with chloroform (10OmL for each extraction). The combined organic layers were washed with brine (5OmL), and concentrated to provide 3.5g of the compound of formula ID (yield 92%).
92% With potassium carbonate In ethanol; water at 70℃; for 3.5h; 5.14.14 The compound of formula EC, 8-benzyl-8-methyl-3-oxo-8-azoniabicyclo[3 2 l]octane bromide (5g, 16 lmmol), was mixed with 4OmL of ethanol and 2OmL of water Over 30min, this mixture was added to a mixture of the compound of formula ED (cyclooctanamine, 2 Og, lmmol, Sigma-Aldϖch) and K2CO, (0 2g, 1 4mmol) in ethanol (15OmL) at 7O0C After 3h at 7O0C, the reaction mixture was cooled to a temperature of about 250C and concentrated under reduced pressure The residue was treated with water (5OmL) and extracted three times with CHCl3 (10OmL for each extraction) The combined organic portions were washed with brine (5OmL) and concentrated under reduced pressure to provide 3 5g of the compound of formula EE (yield 92%)
  • 21
  • [ 5452-37-9 ]
  • [ 807638-71-7 ]
  • [ 162515-68-6 ]
  • [ 947370-34-5 ]
  • (R-(E))-1-(((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-methylethenyl)phenyl)propyl)thio)methyl)-cyclopropaneacetic acid cyclooctylammonium salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 1-(sulfanylmethyl)cyclopropaneacetic acid With sodium hydroxide In 1-methyl-pyrrolidin-2-one; water at 20℃; Stage #2: 2-[2-[3(S)-[3-[(1E)-2-(7-chloroquinoline-2-yl)ethenyl]phenyl]-3-methanesulfonyloxypropyl]phenyl]-2-propanol In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; water at 20℃; for 3h; Stage #3: cyclooctylamine In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; water; toluene for 1.5h; 3 Compound (VII) (480 g, 3.29 mol) was added to a clean and dry reactor at room temperature, followed by NMP (6.48 L) to form a solution. Next, NaOH (a 46% solution, 370 mL, 6.3 mol) was added in one portion at room temperature. Then, the solution of compound (III), prepared above, was added drop-wise at room temperature. Then, the reaction mixture was stirred at room temperature for 3 hours and monitored for completion via HPLC. Toluene (12.1 L) and 5% NaCl solution (17.4 L) were added to the reaction mixture and the resulting mixture was stirred for 20 minutes. The layers were separated and the organic layer was washed with water (5.7 L). Cyclooctylamine (420 mL) was added to the organic layer. Water was distilled out of the organic layer by azeotropic distillation over about 1.5 hours. The reactor was then cooled to about 40° C., and the solution seeded with crystalline montelukast cycloocyl ammonium salt. The solution was then cooled to room temperature, whereupon a suspension was formed. The suspension was filtered to obtain a cake. The cake was washed with toluene (550 mL) and dried to afford montelukast cycloocyl ammonium salt (1.13 g, 70% yield). The HPLC purity of the montelukast cycloocyl ammonium salt was 97.7%, and contained 0.25% compound (VI) and 0.46% compound (VIII). The montelukast cycloocyl ammonium salt then was crystallized from toluene having about 2% methanol to obtain montelukast cycloocyl ammonium salt in 85% yield having 99.5% purity and having 0.17% compound (VI) and 0.03% compound (VIII). The product was re-crystallized to obtain 99.7% purity and 0.17% compound (VI) and no detectable compound (VIII).
  • 22
  • [ 37689-86-4 ]
  • [ 5452-37-9 ]
  • [ 1168117-08-5 ]
YieldReaction ConditionsOperation in experiment
78% With 4-methyl-morpholine In dichloromethane at 0 - 20℃; 8 Synthesis of 4-Nitrophenyl cyclooctylcarbamate (8-5):[0337] To a stirred solution of cyclooctylamine (0.20 g, 1.5 mmol) in DCM (15 rnL) was added 4-nitrophenyl carbamate (0.38 g, 1.8 mmol) at 0-50C followed by addition of N- methyl morpholine (0.23 gm,2.25 mmol) under an inert atmosphere, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (100 mL), washed with brine and dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford carbamate 8-5 (0.35g, 78%) as a yellow solid.
  • 23
  • [ 5452-37-9 ]
  • [ 501-53-1 ]
  • benzyl cyclooctylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% With triethylamine In tetrahydrofuran at 20℃; Cooling with ice; 1 To a mixture of 3.7 mL (0.02594 mol) of benzyloxycarbonyl chloride (ZCl) and 15 mL of tetrahydrofuran were added 3g (0.02358 mol) of cyclooctylamine (Compound 1) and 3.6 mL (0.02594 mol) of triethylamine under ice cooling, and the reaction solution was stirred for 24 hours at room temperature. After extraction by adding water and ethyl acetate to the reaction solution, the organic layer was washed with saturated saline, and dried with sodium sulfate. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to obtain 4.54 g (74%) (Compound 2) of a colorless liquid.
  • 24
  • 1-fluoro-2-isocyanato-6-trifluoromethylbenzene [ No CAS ]
  • [ 5452-37-9 ]
  • [ 1338781-01-3 ]
YieldReaction ConditionsOperation in experiment
96% With triethylamine In dichloromethane at 20℃; 4.2. Synthesis of urea compounds. General method General procedure: In a round bottom flask equipped with a stir bar, 1.2 mmol of the appropriate amine was added to 10 mL of anhydrous dichloromethane. To this solution, 1.0 mmol of the appropriate isocyanate followed by 3.6 mmol of triethylamine was added. The reaction was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The resulting residue was purified by flash chromatography using a petroleum ether to ethyl acetate gradient to elute the final compound.
  • 25
  • [ 696-71-9 ]
  • [ 502-49-8 ]
  • [ 5452-37-9 ]
YieldReaction ConditionsOperation in experiment
1: 77 %Chromat. 2: 12 %Chromat. With ammonia In 5,5-dimethyl-1,3-cyclohexadiene at 20 - 140℃; for 29h; Sealed tube; Autoclave;
1: 71 %Chromat. 2: 18 %Chromat. With ammonia In o-xylene at 140℃; for 20h; Sealed tube; Autoclave; General procedure: Ni/CaSiO3 pre-reduced at 600°C was used as a standard catalyst. For the reaction of alcohols with NH3, the pre-reduced catalyst in the closed glass tube sealed with a septum inlet was cooled to room temperature under H2 atmosphere. The mixture of o-xylene (4.0 g), alcohol (3.0 mmol), and n-dodecane (0.5 mmol) was injected to the pre-reduced catalyst inside the glass tube through the septum inlet. Then, the septum was removed under air, and a magnetic stirrer was put in the tube, followed by inserting the tube inside stainless autoclave with a dead space of 33 cm3. Soon after being sealed, the reactor was flushed with NH3 from a high pressure gas cylinder and charged with 0.4 MPa NH3 at room temperature. The amount of NH3 present in the reactor before heating was 6.7 mmol (2.2 equiv. with respect to the alcohol). Then, the reactor was heated typically at 160°C under stirring (150 rpm).
  • 26
  • [ 24509-62-4 ]
  • [ 5452-37-9 ]
YieldReaction ConditionsOperation in experiment
83% With hydrazine In ethanol at 60℃; for 48h; Inert atmosphere; Sealed tube; chemoselective reaction; 2.1 General procedure of nitro compounds reduction by hydrazine catalyzed by Au/TiO2 General procedure: To a sealed tube containing the nitro compound (0.6 mmol) and 2 mL ethanol were added 2.6-6.0 mmol of NH2NH2 (see Table 2) and Au/TiO2 (100 mg, 1 wt.% in [Au], 0.8 mol%). The reaction was heated at 60 °C for an appropriate time (see Table 2) under an inert atmosphere. The reaction was monitored by TLC, and after completion, the slurry was filtered under pressure through a short pad of celite and silica gel to withhold the supported catalyst with the aid of ethanol or methanol (~ 5 mL). The filtrate was evaporated under vacuum to afford the corresponding amines in pure form. The spectroscopic data (1H NMR, 13C NMR) of amines 1a-20a are in agreement with those previously reported [28,30,31], while the majority of them are commercially available substances. The screened catalysts Au/TiO2, Au/Al2O3, and Au/ZnO (~ 1 wt.% in Au) are commercially available (Strem Chemicals), and have an average gold crystallite size of ~ 2-3 nm.
  • 29
  • [ 383132-27-2 ]
  • [ 5452-37-9 ]
  • [ 1432641-71-8 ]
YieldReaction ConditionsOperation in experiment
83% Stage #1: 4,6-dimethyl-1H-indole-2-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.166667h; Inert atmosphere; Stage #2: cyclooctylamine With triethylamine In dichloromethane at 20℃;
69% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; for 3h;
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;
  • 30
  • [ 5452-37-9 ]
  • [ 153034-80-1 ]
  • [ 1430849-04-9 ]
YieldReaction ConditionsOperation in experiment
at 130℃; Example 61A N-cyclooctyl-4-iodo-3-methylpyridin-2-amine <strong>[153034-80-1]2-Fluoro-4-iodo-3-methylpyridine</strong> (700 mg) in cyclooctanamine (3.8 g) was heated at 130 C. overnight, cooled and diluted with dichloromethane. The resulting mixture was loaded onto a silica gel cartridge, eluting with 0-100% dichloromethane in hexanes to provide the title compound.
  • 31
  • [ 5452-37-9 ]
  • [ 153034-80-1 ]
  • [ 1430846-87-9 ]
  • 32
  • [ 1450606-82-2 ]
  • [ 5452-37-9 ]
  • [ 1450607-16-5 ]
YieldReaction ConditionsOperation in experiment
43% Stage #1: 5-(2-pentyloxyphenyl)isoxazole-3-carboxylic acid With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In chloroform at 20℃; for 0.75h; Stage #2: cyclooctylamine In chloroform at 20℃; for 24h; 22 4.1.5. General procedure for the preparation of 5-arylisoxazole-3-carboxamides (44-70) General procedure: To a solution of carboxylic acid 33-43 in dry chloroform (20 mL) were added N,N-diisopropylethylamine (DIEA) (2 equiv) and 1-hydroxybenzotriazole (HOBt) (0.5 equiv), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (1.5 equiv). The resulting mixture was stirred at room temperaturefor 45 min. The appropriate amine (1.2 equiv) was then added, and the solution was stirred at room temperature for additional 24 h. The solution was filtered and washed with 0.5 N aqueous NaOH (20 mL), with 1 N aqueous HCl (20 mL), and water (20 mL). The organic layer was dried over MgSO4 and evaporated under reduce pressure to give a brown oil. The crude material was purified by TLC using the appropriate eluent (cyclohexane/EtOAc 7:3, v/v) and recrystallized in heptane to afford the desired compounds.
  • 33
  • [ 5452-37-9 ]
  • [ 6258-06-6 ]
  • [ 1579267-83-6 ]
YieldReaction ConditionsOperation in experiment
57% With sodium carbonate; copper(II) sulfate In water at 105℃; 2 5.1.2. General procedure B: preparation of 7 and 8 General procedure: To a solution of bromaminic acid sodium salt (0.2 g, 0.495 mmol) in water (5 mL) was added copper sulphate (0.1 mmol) and sodium carbonate (0.4 mmol), followed by cycloheptylamine or cyclooctylamine (0.99 mmol). The reaction mixture was stirred for 6-8 h at 105 °C. The reaction mixture was then cooled to room temperature, filtered and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the crude residue. The residue was purified by silica gel column chromatography(eluted with methanol/ethyl acetate, 1:49 (v/v)) to furnish the compounds 7 and 8 as blue solids.
  • 34
  • [ 1428673-22-6 ]
  • [ 5452-37-9 ]
  • [ 1604042-97-8 ]
YieldReaction ConditionsOperation in experiment
59% With triethylamine In dimethyl sulfoxide at 60℃; for 12h; 15 Example 15. Preparation of 2-(cyclooctylamino)-3,5,6-trifluoro-4- (propylthio)benzenesulfonamide (compound 5). The mixture of 2,3,5,6-tetrafluoro-4-(propylthio)benzenesulfonamide (2f) (0.2g, 0.66mmol), Et3N (0.095mL, 0.68mmol), DMSO (ImL) and cyclooctylamine (O. lmL, 0.72mmol) was stirred at 60°C for 12h. The mixture was then diluted with H20 (20mL) and extracted with EtAc (3>< 10mL). The combined organic phase was dried over MgS04 and evaporated in vacuum. The compound 5. The product was purified by chromatography on a column of silica gel (0.04-0.063mm) with EtAc(5%):CHCl3, Rf= 0.64. Yield: 0.16g, 59%. NMR (300 MHz, CDC13): 1.03(3H, t, J= 7.2Hz, CH3), 1.4-1.75(14H, m, CH2CH3, cyclooctane), 1.8-1.95(2H, m, cyclooctane), 2.98(2H, t, J= 7.2Hz, SCH2), 3.7-3.85(1 H, m, CH of cyclooctane), 5.62(3H, br s, NH, S02NH2). 13C NMR (75 MHz, CDC13): 13.3(CH3), 23.5(cyclooctane), 23.7(cyclooctane), 25.8(cyclooctane), 27.5(cyclooctane), 33(CH2), 36.3(SCH2, t, J(19F-13C)= 3.6Hz), 56.5(CH of cyclooctane, d, J(I9F-13C)= l lHz), 117.3(C1, dd, 'j(19F-13C)= 12Hz, 2J(19F-13C)= 6Hz), 120(C4, t, J(19F-13C)= 21Hz), 132.4(C2, d, J(19F-13C)= 13Hz), 142.2(C5 or C6, ddd, FontWeight="Bold" FontSize="10" J(19F- 13C)= 239Hz, 2J(19F-13C)= 16Hz, 3J(19F-13C)= 5Hz), 145(C5 or C6, ddd, 1J(19F-13C)= 249Hz, 2J(19F-13C)= 17Hz, 3J(19F-13C)= 4Hz), 148.9(C3, d, J(19F-I 3C)= 243Hz). I9F NMR (282 MHz, CDC13): -124.8(C3-F, d, J= l lHz), -143.5(C5-F, dd, FontWeight="Bold" FontSize="10" J= 27Hz, 2J= 12Hz), -149(C6-F, d, J= 26Hz). HRMS calcd. for Ci7H25F3N202S2 [(M+H)+] : 41 1.1382, found: 41 1.1388.
59% With triethylamine In dimethyl sulfoxide at 60℃; for 12h;
  • 35
  • [ 1428673-31-7 ]
  • [ 5452-37-9 ]
  • [ 1604042-98-9 ]
YieldReaction ConditionsOperation in experiment
50% With triethylamine In dimethyl sulfoxide at 70℃; for 28h; 16 Example 16. Preparation of 2-(cyclooctylamino)-3,5,6-trifluoro-4- [2-(4- hydroxyphenyl)ethyl] amino jbenzenesulfonamide (compound 6). The mixture of 2,3,5,6-tetrafluoro-4- [2-(4- hydroxyphenyl)ethyl] amino jbenzenesulfonamide (2o) (0.2g, 0.55mmol), Et3N (0.085mL, 0.61mmol), DMSO (lmL) and cyclooctylamine (0.085mL, 0.61mmol) was stirred at 70°C for 28h. The mixture was then diluted with H20 (20mL) and extracted with EtAc (3 < 10mL). The combined organic phase was dried over MgS04 and evaporated in vacuum. The compound 6. The product was purified by chromatography on a column of silica gel (0.04-0.063mm) with EtAc:CHCl3(l :3), Rf= 0.6. Yield: 0.13g, 50%. NMR (300 MHz, CDC13): 1.4-2(14H, m, cyclooctane), 2.82(2H, t, J= 7Hz, NHCH2CH2), 3.6-3.75(3 H, m, CH of cyclooctane, NHCHZCHA 5.59(2H, s, S02NH2), 6.1 (2H, br s, 2NH), 6.79(2H, d, J= 8.4Hz, ArH), 7.04(2H, d, J= 8.4Hz, ArH). 13C NMR (75 MHz, CDC13): 23.8(cyclooctane), 25.8(cyclooctane), 27.5(cyclooctane), 32.7(cyclooctane), 36.6(NHCH?CH ), 46.9(ΝΗΟ^Η2), 56.4(CH of cyclooctane, d, J(19F- l 3C)= 10Hz), 106.3(C1 , dd, ]J(19F-13C)= 12Hz, 2J(19F-13C)= 5Hz), 1 15.8(C4, signal overlaps with Ar signal), 1 15.83(Ar), 130.2(Ar), 130.28(Ar), 132(C2, d, J(19F-13C)= 13Hz, signal overlaps with C5 or C6 signal), 133.8(C5 or C6, ddd, 1J(I9F-13C)= 239Hz, 2J(19F-13C)= 18Hz, 3J(19F-13C)= 6Hz), 138.5(C3, d, J(19F-13C)= 233Hz), 146.5(C5 or C6, ddd, 'j(19F-13C)= 243Hz, 2J(I9F-13C)= 14Hz, 3J(19F-13C)= 3Hz), 154.8(Ar). 19F NMR (282 MHz, CDC13): -144.8(C5-F, dd, lJ= 23Hz, 2J= 9Hz), -154.1 (C3-F, s), - 171.4(C6-F, d, J= 23Hz). HRMS calcd. for C22H28F3N303S [(M+H)+]: 472.1876, found: 472.1877.
50% With triethylamine In dimethyl sulfoxide at 70℃; for 28h;
  • 36
  • [ 1428673-33-9 ]
  • [ 5452-37-9 ]
  • [ 1604043-28-8 ]
YieldReaction ConditionsOperation in experiment
48% With triethylamine In dimethyl sulfoxide at 60℃; for 32h; 26 Example 26. Preparation of 3,5-bis(cyclooctylamino)-2,6-difluoro-4-[(2- phenylethyl)sulfonyl]benzenesulfonamide (compound 11). The mixture of 2,3,5,6-tetrafluoro-4-[(2-phenylethyl)sulfonyl]benzenesulfonamide (compound 2q) (0.2g, 0.5mmol), Et N (0.142mL, 1.02mmol), DMSO (lmL) cyclooctylamine (0.142mL, 1.02mmol) was stirred at 60°C for 32h. The mixture was then diluted with H20 (20mL) and extracted with EtAc (3>< 10mL). The combined organic phase was dried over MgS04 and evaporated in vacuum. The product was purified by chromatography on a column of silica gel (0.04-0.063mm) with EtAc (10%):CHC13, Rf= 0.72. Yield: 0.15g, 48%. 1H NMR (300 MHz, CDC13): 1.4-2(28H, m, cyclooctane), 3.05-3.15(2H, m, SO?CH?CHz), 3.5-3.6(2H, m, S02CH2CH2), 3.88(2H, br s, 2xCH of cyclooctane), 5.58(2H, s, S02NH2), 6.43(2H, br s, 2NH), 7.1-7.4(5H, m, ArH). 13C NMR (75 MHz,CDCl3): 23.8(cyclooctane), 25.8(cyclooctane), 27.4(cyclooctane), 28.5(S02CH2CH2), 33.5(cyclooctane), 55.9(SO?CH2CH?), 56.2(CH of cyclooctane, t, J= 6Hz), 1 1 1.1 (C4, t, J(19F-,3C)= 5Hz), 126.3(C1 , t, J(19F-13C)= 16Hz), 127.4(Ar), 128.6(Ar), 129.2(Ar), 135.3(C3, dd, 1J(I9F-13C)= 10Hz, 2J(19F-13C)= 6Hz), 137.3(Ar), 139.4(C2, dd, 'j(l9F-13C)= 244Hz, J(19F-3C)= 4.5Hz). 19F NMR (282 MHz, CDC13): -144.1(2F, s). HRMS calcd. for C30H43F2N3O4S2 [(M+H)+]: 612.2736, found: 612.2729.
48% With triethylamine In dimethyl sulfoxide at 60℃; for 32h;
  • 37
  • [ 5452-37-9 ]
  • [ 651-81-0 ]
  • [ 1604042-99-0 ]
YieldReaction ConditionsOperation in experiment
52% With triethylamine In dimethyl sulfoxide at 60℃; for 8h; 17 Example 17. Preparation of 2-(cyclooctylamino)-3,5,6-trifluorobenzenesulfonamide (compound 8a) General procedure: The mixture of 2,3,5,6-tetrafluorobenzenesulfonamide (7) (0.2g, 0.87mmol), Et3N (0.124mL, 0.89mmol), DMSO (ImL) and appropriate nucleophile (0.93mmol) was stirred at 60°C for 8h, compound 8d was obtained after 16h , compound 8f was obtained after stirring at 70°C for 16h. The mixture was then diluted with H20 (20mL) and extracted with EtAc (3X lOmL). The combined organic phase was dried over MgS04 and evaporated in vacuum. The compound 8a. The product was purified by chromatography on a column of silica gel (0.04-0.063mm) with EtAc:CHCl3(l :20), Rf= 0.32. Yield: 0.15g, 52%, mp 1 17-1 18°C. lH NMR (300 MHz, DMSO-D6): 1.4-1.9(14H, m, cyclooctane), 3.72(1H, br s, CH of cyclooctane), 6.35(1H, br s, NH), 7.65-7.8(lH, m, ArH), 8.1(2H, s, S02NH2). 13C NMR (75 MHz, DMSO-D6): 23.6(cyclooctane), 25.7(cyclooctane), 27.6(cyclooctane), 32.8(cyclooctane), 55.7(CH of cyclooctane, d, J(19F-13C)= 10Hz), 1 10.2(C4, t, J(19F-13C)= 25Hz), 120.6(C1, dd, 1J(19F-13C)= 12Hz, 2J(19F-13C)= 5Hz), 132.9(C2, dd, 'J(19F-13C)= 13Hz, 2J(19F-13C)= 3Hz), 141.1(C5 or C6, dt, 'j(l9F-13C)= 240Hz, 2J(19F-13C)= 14Hz), 145(C5 or C6, ddd, 'j(,9F-13C)= 248Hz, 2J(19F-,3C)= 14Hz, 3J(I9F-,3C)= 5Hz), 148.3(C3, dd, 'j(19F-13C)= 236Hz, 2J(19F-13C)= 6Hz). 19F NMR (282 MHz, DMSO-D6): -120.6(C3-F, t, J=13Hz), -133.35:- 133.56(C5-F or C6-F, m), -145.2(C5-F or C6-F, dd, 'j= 25Hz, 2J= 1 lHz). HRMS calcd. for C14H19F3N202S [(M+H)+]: 337.1 192, found: 337.1195.
52% With triethylamine In dimethyl sulfoxide at 60℃; for 8h;
  • 38
  • [ 1428673-20-4 ]
  • [ 5452-37-9 ]
  • [ 1604042-90-1 ]
YieldReaction ConditionsOperation in experiment
56% With triethylamine In dimethyl sulfoxide at 60℃; for 16h; 14 Example 14. Preparation of 2-(cyclooctylamino)-3,5,6-trifluoro-4-[(2- hydroxyethyl)thio]benzenesulfonamide (compound 4a) General procedure: The mixture of 2,3,5,6-tetrafluoro-4[(2-hydroxyethyl)thio]benzenesulfonamide (compound 2c) (0.2g, 0.66mmol), Et3N (0.095mL, 0.68mmol), DMSO (ImL) and appropriate nucleophile (0.68mmol) was stirred at 60°C for 16h. The mixture was then diluted with H20 (20mL) and extracted with EtAc (3>< 10mL). The combined organic phase was dried over MgS04 and evaporated in vacuum. The compound 4a. The product was purified by chromatography on a column of silica gel (0.04-0.063mm) with EtAc:CHCl3(l : 1), Rf= 0.59. Yield: 0.15g, 56%, mp 68-69°C. NMR (300 MHz, CDC13): 1.4-1.75(12H, m, cyclooctane), 1.8-1.95(2H, m, cyclooctane), 2.54(1H, br s, OH), 3.14(2H, t, J= 6Hz, 6Hz, SCH2CH2), 3.75-3.85(lH, m, CH of cyclooctane, signal overlaps with signal of SCH?C1 5.77(2H, s, S02NH2), 6.16(1H, br s, NH). 13C NMR (75 MHz, CDC13): 23.7(cyclooctane), 25.8(cyclooctane), 27.5 (cyclooctane), 33(cyclooctane), 37.5iSCH2CH7, br t), 56.4(CH of cyclooctane, d, J(19F-13C)= l lHz), 61.2(SCH2CH2), 1 17.9(C1 , dd, 1J(19F-13C)= 12Hz, 2J(19F-13C)= 5Hz), 118.3(C4, t, J(19F-13C)= 21Hz), 132.7(C2, d, J(19F-l3C)= 15Hz), 142.1(C5 or C6, ddd, lJ(19F-13C)= 240Hz, 2J(19F- 13C)= 16Hz, 3J(19F-13C)= 5Hz), 145.1 (C5 or C6, ddd, 1J(19F-1 C)= 247Hz, 2J(19F-13C)= 16Hz, 3J(19F-13C)= 4Hz), 149.1(C3, d, J(19F-,3C)= 243Hz). 19F NMR (282 MHz, CDC13): -124.5(C3-F, d, J= l lHz), -143(C5-F, dd, *J= 27Hz, 2J= 12Hz), -149(C6-F, d, J= 26Hz). HRMS calcd. for Ci6H23F3N203S2 [(M+H)+]: 413.1175, found: 413.1175.
56% With triethylamine In dimethyl sulfoxide at 60℃; for 16h;
  • 39
  • [ 5452-37-9 ]
  • [ 82437-64-7 ]
  • [ 122-51-0 ]
  • [ 1621968-03-3 ]
YieldReaction ConditionsOperation in experiment
57% With acetic acid; at 160℃;Inert atmosphere; Autoclave; General procedure: To a pressure bottle containing <strong>[82437-64-7]methyl 3-amino-4-phenylthiophene-2-carboxylate</strong> (100 mg, 0.43 mmol), CH(OEt)3 (1 mL) was added, followed by allylamine hydrochloride (93 mg, 0.99 mmol) and AcOH (0.1 mL). The reaction mixture was stirred and refluxed at 160 C overnight. After the reaction, the mixture was evaporated then solidified with ether. The produced white crystals were filtered and dried in vacuo to give the title compound 4-1 (66 mg, 0.25 mmol, 58 % yield): 1HNMR (300 MHz, CDCl3) delta 8.11 (s, 1H), 7.84-7.79 (m, 3H), 7.50-7.44 (m, 2H), 7.41-7.36 (m, 1H), 6.08-5.95 (m, 1H), 5.34-5.24 (m, 2H), 4.72-4.67 (m, 2H); 13C NMR (100 MHz, CDCl3) delta 157.3, 154.3, 147.3, 138.1, 133.7, 131.9, 130.5,128.7, 128.3, 128.0, 124.9, 119.1, 48.0; LC/MS (ESI+): m/z: calcd for C15H12N2OS: 268.34, [M + H]+; found: 269.05
  • 40
  • [ 5452-37-9 ]
  • sodium 1-(N-cyclooctylamino)diazen-1-ium-1,2-diolate [ No CAS ]
YieldReaction ConditionsOperation in experiment
17% Stage #1: cyclooctylamine With nitrogen(II) oxide In diethyl ether at -78℃; Inert atmosphere; Stage #2: With sodium methylate In methanol; diethyl ether 2.2. Synthesis of alicyclic amine diazeniumdiolates General procedure: Sodium 1-(N-cyclohexylamino)diazen-1-ium-1,2-diolate (CHA/NO; 2) was synthesized according to a previously published procedure [45]. For synthesis of other diazeniumdiolates, in general, a solution of the appropriate alicyclic amine in diethyl ether was placed in a 250 mL Parr bottle. The solution was deaerated with argon, cooled in dry ice, charged with 40 psi of NO, and allowed to stir for 24-48 h. The resulting solid precipitate was collected by filtration and washed with diethyl ether. The ammonium salt was converted to the sodium salt by dissolution in methanol and addition of one equivalent of 25% methanolic sodium methoxide. After several minutes of stirring, the sodium salt was precipitated by addition of diethylether and was collected as a white solid upon vacuum filtration. Note that as hygroscopic sodium salts, ionicdiazenium diolates are not amenable to characterization by high resolution mass spectrometry or elemental analysis. Caution: Preparations of primary amine diazeniumdiolates can be unstable in the solid state, sometimes decomposing suddenly without warning. Minimize the storage amount (typically <250 mg) and storein containers with large head space. Additionally, using exactly 1 eq of base is a crucial step to avoid generation of highly reactive species. See reference 46 for additional details.
  • 41
  • [ 5452-37-9 ]
  • 4-((1-carboxypentyl)oxy)-2-hydroxy-5-(thiophen-3-ylethynyl)benzoic acid [ No CAS ]
  • 4-((1-(cyclooctylamino)-1-oxohexan-2-yl)oxy)-2-hydroxy-5-(thiophen-3-ylethynyl)benzoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
81.6% Stage #1: 4-((1-carboxypentyl)oxy)-2-hydroxy-5-(thiophen-3-ylethynyl)benzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide for 0.0833333h; Stage #2: cyclooctylamine With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; 1 4.5. General procedure for the preparation of compounds 6-13 General procedure: For resynthesis of hits in large scale, the 4-carboxymethoxy in4-(carboxymethoxy)-2-hydroxybenzoic acid (0.1 mmol, 1.0 equiv)was activated by 1-O-benzotriazole-N,N,N0 ,N0-tetramethyluroniumhexafluoro-phosphate (HBTU) (0.1 mmol, 1.0 equiv) in DMF for5 min, then 1-hydroxybenzotriazole (HOBt) (0.1 mmol, 1.0 equiv)and N,N-diisopropylethylamine (0.4 mmol, 4.0 equiv) and amine(0.12 mmol, 1.2 equiv) was added. After stirring at room temperaturefor 2 h, the reaction liquids were directly sent to HPLC purification.Protocol for the Prep-HPLC purification method: reversephase HPLC was carried out on Sunfire Prep C18 OBD column(30 150 mm, 5 lm). Solvent A: water with 0.1% trifluoroaceticacid: Solvent B: Methanol with 0.1% trifluoroacetic acid.Gradient: After 5 min at the initial condition of 90% A and 10% B,solvent B was increased to 100% within 45 min, then maintainedat 100% B for 10 min. Flow rate was 50 mL/min, UV detector at 254 nm.
  • 42
  • [ 5452-37-9 ]
  • 4-((1-carboxypentyl)oxy)-5-(cyclopentylethynyl)-2-hydroxybenzoic acid [ No CAS ]
  • 4-((1-(cyclooctylamino)-1-oxohexan-2-yl)oxy)-5-(cyclopentylethynyl)-2-hydroxybenzoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
75.1% Stage #1: 4-((1-carboxypentyl)oxy)-5-(cyclopentylethynyl)-2-hydroxybenzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide for 0.0833333h; Stage #2: cyclooctylamine With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; 3 4.5. General procedure for the preparation of compounds 6-13 General procedure: For resynthesis of hits in large scale, the 4-carboxymethoxy in4-(carboxymethoxy)-2-hydroxybenzoic acid (0.1 mmol, 1.0 equiv)was activated by 1-O-benzotriazole-N,N,N0 ,N0-tetramethyluroniumhexafluoro-phosphate (HBTU) (0.1 mmol, 1.0 equiv) in DMF for5 min, then 1-hydroxybenzotriazole (HOBt) (0.1 mmol, 1.0 equiv)and N,N-diisopropylethylamine (0.4 mmol, 4.0 equiv) and amine(0.12 mmol, 1.2 equiv) was added. After stirring at room temperaturefor 2 h, the reaction liquids were directly sent to HPLC purification.Protocol for the Prep-HPLC purification method: reversephase HPLC was carried out on Sunfire Prep C18 OBD column(30 150 mm, 5 lm). Solvent A: water with 0.1% trifluoroaceticacid: Solvent B: Methanol with 0.1% trifluoroacetic acid.Gradient: After 5 min at the initial condition of 90% A and 10% B,solvent B was increased to 100% within 45 min, then maintainedat 100% B for 10 min. Flow rate was 50 mL/min, UV detector at 254 nm.
  • 43
  • [ 5452-37-9 ]
  • 4-((1-carboxypentyl)oxy)-2-hydroxy-5-(phenylethynyl)benzoic acid [ No CAS ]
  • 4-((1-(cyclooctylamino)-1-oxohexan-2-yl)oxy)-2-hydroxy-5-(phenylethynyl)benzoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
86.3% Stage #1: 4-((1-carboxypentyl)oxy)-2-hydroxy-5-(phenylethynyl)benzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide for 0.0833333h; Stage #2: cyclooctylamine With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; 4 4.5. General procedure for the preparation of compounds 6-13 General procedure: For resynthesis of hits in large scale, the 4-carboxymethoxy in4-(carboxymethoxy)-2-hydroxybenzoic acid (0.1 mmol, 1.0 equiv)was activated by 1-O-benzotriazole-N,N,N0 ,N0-tetramethyluroniumhexafluoro-phosphate (HBTU) (0.1 mmol, 1.0 equiv) in DMF for5 min, then 1-hydroxybenzotriazole (HOBt) (0.1 mmol, 1.0 equiv)and N,N-diisopropylethylamine (0.4 mmol, 4.0 equiv) and amine(0.12 mmol, 1.2 equiv) was added. After stirring at room temperaturefor 2 h, the reaction liquids were directly sent to HPLC purification.Protocol for the Prep-HPLC purification method: reversephase HPLC was carried out on Sunfire Prep C18 OBD column(30 150 mm, 5 lm). Solvent A: water with 0.1% trifluoroaceticacid: Solvent B: Methanol with 0.1% trifluoroacetic acid.Gradient: After 5 min at the initial condition of 90% A and 10% B,solvent B was increased to 100% within 45 min, then maintainedat 100% B for 10 min. Flow rate was 50 mL/min, UV detector at 254 nm.
  • 44
  • [ 5452-37-9 ]
  • 4-((1-carboxypentyl)oxy)-2-hydroxy-5-((2-methoxyphenyl)ethynyl)benzoic acid [ No CAS ]
  • 4-((1-(cyclooctylamino)-1-oxohexan-2-yl)oxy)-2-hydroxy-5-((2-methoxyphenyl)ethynyl)benzoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
73.1% Stage #1: 4-((1-carboxypentyl)oxy)-2-hydroxy-5-((2-methoxyphenyl)ethynyl)benzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide for 0.0833333h; Stage #2: cyclooctylamine With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; 7 4.5. General procedure for the preparation of compounds 6-13 General procedure: For resynthesis of hits in large scale, the 4-carboxymethoxy in4-(carboxymethoxy)-2-hydroxybenzoic acid (0.1 mmol, 1.0 equiv)was activated by 1-O-benzotriazole-N,N,N0 ,N0-tetramethyluroniumhexafluoro-phosphate (HBTU) (0.1 mmol, 1.0 equiv) in DMF for5 min, then 1-hydroxybenzotriazole (HOBt) (0.1 mmol, 1.0 equiv)and N,N-diisopropylethylamine (0.4 mmol, 4.0 equiv) and amine(0.12 mmol, 1.2 equiv) was added. After stirring at room temperaturefor 2 h, the reaction liquids were directly sent to HPLC purification.Protocol for the Prep-HPLC purification method: reversephase HPLC was carried out on Sunfire Prep C18 OBD column(30 150 mm, 5 lm). Solvent A: water with 0.1% trifluoroaceticacid: Solvent B: Methanol with 0.1% trifluoroacetic acid.Gradient: After 5 min at the initial condition of 90% A and 10% B,solvent B was increased to 100% within 45 min, then maintainedat 100% B for 10 min. Flow rate was 50 mL/min, UV detector at 254 nm.
  • 45
  • [ 1376771-60-6 ]
  • [ 5452-37-9 ]
  • 3-cyclooctyl-1,5,3-dithiazepane [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% With samarium(III) chloride hexahydrate In ethanol; chloroform at 20℃; for 3.5h; Inert atmosphere; Reaction of 1-oxa-3,6-dithiacycloheptane (1) with cycloalkanamines General procedure: A mixture of 0.136 or 0.272 g (1 or 2 mmol) of 1-oxa-3,6-dithiacycloheptane (1) [3] in 5 mL of chloroform and 0.018 g (0.05 mmol) of SmCl3 · 6 H2O was stirred for 30 min at room temperature under argon, and a solution of 1 mmol of the corresponding amine in 5 mL of ethanol was added dropwise. The mixture was stirred for 3 h at room temperature, treated with 2 mL of water, stirred for 30 min more, and extracted with chloroform (20 mL). The extract was evaporated, and the product (compound 2-17) was isolated from the residue by column chromatography on silica gel.
  • 46
  • [ 5452-37-9 ]
  • [ 34404-30-3 ]
  • benzyl (2R)-2-[(tert-butoxy)carbonyl]amino}-4-(cyclooctylcarbamoyl)butanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0℃; for 24h; General procedure: To a solution of 11 or 12 (1.0 eq) and HOBt (1.2 eq) in DMF (8mL) were added S10-14 (1.0 eq) andEDCI (1.2 eq) at 0 C. The mixture was stirred for 24 h and then diluted inCHCl3. The organic phase was washed with water (3),saturated NaHCO3 (3), and brine, dried over Na2SO4,and filtered. The filtrate was concentrated invacuo, and the residue was purified by silica gel flash columnchromatography (CHCl3 /MeOH = 50/1) to afford S1a-c and S2a-d.
  • 47
  • [ 92828-64-3 ]
  • [ 5452-37-9 ]
  • benzyl (2R)-2-[(tert-butoxy)carbonyl]amino}-3-(cyclooctylcarbamoyl)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0℃; for 24h; General procedure: To a solution of 11 or 12 (1.0 eq) and HOBt (1.2 eq) in DMF (8mL) were added S10-14 (1.0 eq) andEDCI (1.2 eq) at 0 C. The mixture was stirred for 24 h and then diluted inCHCl3. The organic phase was washed with water (3),saturated NaHCO3 (3), and brine, dried over Na2SO4,and filtered. The filtrate was concentrated invacuo, and the residue was purified by silica gel flash columnchromatography (CHCl3 /MeOH = 50/1) to afford S1a-c and S2a-d.
  • 48
  • [ 28697-53-2 ]
  • [ 5452-37-9 ]
  • 5-cyclooctylamino-5-deoxy-D-arabinitol [ No CAS ]
YieldReaction ConditionsOperation in experiment
43% With sodium cyanoborohydride; acetic acid In ethanol; water at 20℃; for 4h; 17 5-Cyclooctylamino-5-deoxy-D-arabinitol To a solution of D-arabinose (100 mg, 0.67 mmol) in EtOH(13.3 mL), was added cyclooctylamine (77 mg, 0.60 mmol),NaCNBH3 (126 mg, 2 mmol), and water (0.4 mL). The mixturewas stirred at room temperature for 4 h. The solvent was thenremoved under reduced pressure, and the residue purified byDowex-H+ cation exchange chromatography eluting with 5-35%NH3 in EtOH/H2O to give 5-cyclooctylamino-5-deoxy-D-arabinitol(9d) as a white solid (70 mg, 0.27 mmol, 45%). Rf = 0.18 (DCM/EtOH/MeOH/30% NH3 (aq), 15/2/2/1, v/v/v/v); [a]D25 = +4.9 (c 1.0,EtOH); IR (film) 3348, 2925, 2857, 1642, 1469, 1446, 1054,879 cm1. 1H NMR (500 MHz, CD3OD) d 3.97 (td, J3,4 = 2.1,J4,5 = 6.2 Hz, 1H, H-4), 3.79 (dd, J1a,2 = 3.2, J1a,1b = 10.9 Hz, 1H, H-1a), 3.66 (ddd, J1a,2 = 3.2, J1b,2 = 5.8, J2,3 = 8.0 Hz, 1H, H-2), 3.62(dd, J1b,2 = 5.8, J1a,1b = 10.9 Hz, 1H, H-1b), 3.42 (dd, J3,4 = 2.1,J2,3 = 8.0 Hz, 1H, H-3), 2.83 (d, J4,5 = 6.2 Hz, 2H, H-5), 2.83-2.79(m, 1H, H-10), 1.87-1.73 (m, 4H, H-20-50), 1.61-1.59 (m, 4H, H-20-50), 1.59-1.46 (m, 6H, H-20-50); 13C NMR (125 MHz, CD3OD) d74.3 (C3), 73.0 (C2), 69.7 (C4), 64.9 (C1), 59.2 (C10), 51.0 (C5),33.0, 28.1, 26.9, 25.3 (C20-50); HRMS(ESI) m/z calcd for[C13H27O4N+H]+: 262.2013, obsd: 262.2016.
  • 49
  • [ 5452-37-9 ]
  • [ 79-08-3 ]
  • cylcooctylaminodiacetic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With sodium hydroxide In ethanol; water at 94℃; for 24h; Cylcooctyliminodiacetic acid (CO-IDA: To the reaction flask was added in order: 24 mL ethanol, 6 mL water, 4.0094g cyclooctylamine (31.513 mmols), and 8.8729g bromoacetic acid (63.856 mmols). 12M NaOH was added until pH reached 1 1-12. The pH was monitored until it did not change for an hour. The mixture was refluxed at 94°C for 24 hours. The solution was cooled to room temperature. An ivory precipitate formed and was collected and rinsed with ethanol 3 times, then dried under vacuum for 24 hours. Mass: 1.9326 g. The remaining solution was filtered 3 times and extracted with diethylether (3 X 20 ml). A solid formed in the ether layer and was collected and stirred in acetone for 30 minutes, filtered, rinsed 3 times with ethanol, and dried under vacuum for 24 hours. Mass: 2.5156 g. The remaining water ethanol solution was dripped into spinning acetone. A white solid formed and was collected, stirred in ethanol for 20 minutes, filtered, and dried under vacuum for 24 hours. Mass: 3.6547 g. The total yield was 8.1029 g (85%, as the disodium diwater salt). XH NMR (D20, 300 MHz) δ ppm: 3.218-3.002 (s, 4, CH2), 2.99-2.752 (b, 1, CH), 1.705- 1.165 (m, 14, CH2). M/Z (ESI-MS): exact 243.1471; found 244.1548(M+H). Decomposed at 264 °C.
  • 50
  • [ 683-57-8 ]
  • [ 5452-37-9 ]
  • cyclooctylamidodiacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
66.25% With potassium carbonate In acetonitrile at 60℃; for 16h; Cyclooctylimidodiacetamide(CO-IDAm): Cyclooctylamine (0.7715 g, 6 mmol) and 1.6896 g (12.2 mmol) bromoacetamide were dissolved in 20 ml of acetonitrile. Anhydrous K2CO3 1.8455 g (13.3 mmol) was added. The mixture was stirred and heated at 60 °C for 16 hours and allowed to cool. The flask was sonicated to remove any solid adhered to the glass and the precipitate was filtered off; the filtrate was set aside and the precipitate was washed with water. The solid and the filtrate were combined and heated to reflux; the solution became transparent. This solution was allowed to cool and the resulting crystals were collected by vacuum filtration. The product weighed 0.9702 g (66.25 % yield). 1H NMR (DMSO, 300 MHz) δ= 1.23-1.80(b, 14H), 2.58(m, 1H), 2.92(s, 4H), 7.17(s, 2H), 7.72(s, 2H). ESI-MS m/z: 242.1870(M+H). Melting point 152-154°C.
  • 51
  • [ 683-57-8 ]
  • [ 5452-37-9 ]
  • C11H22N2O [ No CAS ]
YieldReaction ConditionsOperation in experiment
68.9% With potassium carbonate In acetonitrile at 60℃; for 16h; Cvclooctylamineethylamine (CO-EA) : [00181] Cyclooctylamine (0.2500 g, 1.96 mmol) and 0.2710 g (1.96 mmol) bromoacetamide were dissolved in 15 ml of acetonitrile. Anhydrous K2CO3 (0.2717 g, 1.96 mmol ) was added. The reaction was stirred and heated at 60 °C for 16 hours. The remaining solid was removed by filtration, and the filtrate was evaporated under vacuum to yield 0.2500 g of the intermediate amide (68.9 % yield). The intermediate amide (0.2500 g, 1 mmol) was dissolved in 10 ml dry tetrahydrofuran. L1AIH4 (0.3276 g, 8.6 mmol) was dissolved in 5 ml tetrahydrofuran. While in an ice bath, the L1AIH4 solution was slowly added to the monamide solution. The reaction was allowed to stir at 0 °C until the effervescence subsided. The reaction was then heated to 60 °C for 16 hours. The solution was carefully quenched by slow addition of 10 ml of water. The resulting precipitate was filtered and the filtrate was evaporated under vacuum to yield 0.1006 g of a yellow oil. (30% yield). NMR (D20, 500 MHz) δ= 1.22-1.60 (b, 14H), 2.44 (t, J=6.2 Hz, 2H), 2.52 (t, J=6.1 Hz, 2H). H-H COSY shows the cyclooctyl ring methine proton under the triplet at 2.52. ESI-MS m/z: 171.1860(M+H).
  • 52
  • [ 5452-37-9 ]
  • [ 6287-38-3 ]
  • cyclooctyl(3,4-dichlorobenzyl)amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
73.5% Stage #1: cyclooctylamine; 3,4-dichlorobenzaldehyde In methanol at 20℃; for 1h; Stage #2: With sodium tetrahydroborate In methanol at 20℃;
73.5% Stage #1: cyclooctylamine; 3,4-dichlorobenzaldehyde In methanol at 20℃; for 1h; Stage #2: With methanol; sodium tetrahydroborate for 1h; 47 Synthesis of Compound 47 (Cyclooctyl-(3,4-dichloro-benzyl)-amine) After 1 g (5.714 mmol) of 3,4-dichlorobenzaldehyde was dissolved in 10 mL of methanol, 0.727 g (5.714 mmol) of cyclooctylamine was added thereto and reacted at room temperature for 1 hour. 0.32 g (8.45 mmol) of sodium borohydride was slowly added thereto and stirred for 1 hour. The degree of progress of reaction was confirmed by TLC. When the reaction did not proceed further, 40 mL of water was added to the mixture, and the mixture was extracted twice with 30 mL of methylene chloride. The extracts were combined, dried with anhydrous magnesium sulfate to remove water, and then distilled under reduced pressure. The resulting reaction product was separated using a silica gel-filled column with a mixed solvent of ethyl acetate and n-hexane as a mobile phase, to thereby obtain a colorless liquid of cyclooctyl-(3,4-dichloro-benzyl)-amine. Yield: 73.5%. 1H NMR (300 MHz, CDCl3) δ 7.43 (d, J=1.8 Hz, 1H), δ 7.38 (d, J=8.0 Hz, 1H), δ 7.17 (dd, J=8.0 and 1.8 Hz, 1H), δ 3.72 (s, 2H), δ 2.70 (m, 1H), δ 1.80 (m, 14H) .
  • 53
  • [ 5452-37-9 ]
  • 5-phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid [ No CAS ]
  • N-cyclooctyl-5-phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 14h; 40 N-Cyclooctyl-5-phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide N-Cyclooctyl-5-phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide Cyclooctylamine (24 mg, 0.19 mmol) was added to a suspension of compound 1 (0.05 g, 0.16 mmol), WSC (37 mg, 0.19 mmol), HOBt (29 mg, 0.19 mmol) and DMAP (23 mg, 0.19 mmol) in DMF (1.5 mL). The reaction mixture was stirred at room temperature for 14 h, diluted with DCM (0.5 mL) and saturated NaHCO3 solution (0.5 mL), and then separated using PHASE-SEP filtration syringe. The organic layer was concentrated and loaded onto preparative HPLC (Gilson 215 system). The purest fractions were combined to give 64.6 mg (96% yield) of the title compound as a white solid. Reverse Phase LC/MS: CAPCELLPAKCC18UG120, S-3 μm, 2.0*50 mm, UV detection at 220, 8 min. gradient 10-100% Solvent B/A (Solvent A: CH3CN with 0.1% TFA, Solvent B: H2O with 0.1% TFA), 0.5 mL/min. Rt=1.90 min, (96% pure). MS (M+H: 421).
  • 54
  • [ 383132-27-2 ]
  • [ 5452-37-9 ]
  • N-[(4,6-dimethyl-1H-indol-2-yl)methyl]cyclooctylamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane / 20 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / Reflux
  • 55
  • [ 18474-57-2 ]
  • [ 5452-37-9 ]
  • N-cyclooctyl-4-methyl-1H-indole-2-carboxamide [ No CAS ]
  • 56
  • [ 10241-97-1 ]
  • [ 5452-37-9 ]
  • N-cyclooctyl-5-methyl-1H-indole-2-carboxamide [ No CAS ]
  • 57
  • [ 18474-60-7 ]
  • [ 5452-37-9 ]
  • N-cyclooctyl-7-methyl-1H-indole-2-carboxamide [ No CAS ]
  • 58
  • [ 16732-65-3 ]
  • [ 5452-37-9 ]
  • 6-bromo-N-cyclooctyl-1H-indole-2-carboxamide [ No CAS ]
  • 59
  • [ 101861-63-6 ]
  • [ 5452-37-9 ]
  • N-cyclooctyl-4,6-dichloro-1H-indole-2-carboxamide [ No CAS ]
  • 60
  • [ 5452-37-9 ]
  • [ 90-02-8 ]
  • [ 1609159-82-1 ]
YieldReaction ConditionsOperation in experiment
90% In methanol at 20℃; for 16h; Inert atmosphere; Schlenk technique; 2.3 General procedure for the preparation of Schiff-Base Ligands (1a-d) General procedure: To prepare the Schiff base ligands 1a-d, a solution of salicylaldehyde in methanol was slowly added over a solution of the respective cycloalkylamine in methanol. The mixture was stirred at room temperature for 16h and the product was obtained as a yellowish orange oil. Any modifications are described below for each reaction.
  • 61
  • [ 5452-37-9 ]
  • 1-oxa-3,6,9-trithiacyclodecane [ No CAS ]
  • 3-cyclooctyl-1,5,8-trithia-3-azacyclodecane [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% With samarium(III) chloride hexahydrate In ethanol; chloroform at 20℃; for 3h; Recyclization of 1-oxa-3,6,9-trithiacyclodecane (1) with cycloalkylamines (general procedure) General procedure: A mixture of 0.196 g (1 mmol) of compound 1 [3], 5 mL of chloroform, and 0.018 g (0.05 mmol) of SmCl3 · 6 H2O was stirred for 30 min at room temperature, 1 mmol of the corresponding amine in 5 mL of ethanol was added dropwise, and the mixture was stirred for 3 h at room temperature. The mixture was then treated with 2 mL of water, stirred for 30 min, and extracted with chloroform (20 mL). The extract was evaporated, and the residue was purified by silica gel chromatography. Compounds 2-7 were isolated as colorless oils
  • 62
  • [ 5452-37-9 ]
  • 1,6,9-trioxa-3,12-dithiacyclotridecane [ No CAS ]
  • 6-cyclooctyl-1,11-dioxa-4,8-dithia-6-azacyclotridecane [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% With samarium(III) chloride hexahydrate In ethanol; chloroform at 20℃; for 3h; Recyclization of 1,6,9-trioxa-3,12-dithiacyclotridecane (8) with cycloalkylamines (general procedure) General procedure: A mixture of 0.224 g (1 mmol) of compound 8 [3], 5 mL of chloroform, and 0.018 g (0.05 mmol) of SmCl3 · 6 H2O was stirred for 30 min at room temperature, a solution of 1 mmol of the corresponding amine in 5 mL of ethanol was added dropwise, and the mixture was stirred for 3 h at room temperature. The mixture was then treated with 2 mL of water, stirred for 30 min, and extracted with chloroform (20 mL). The extract was evaporated, and the residue was purified by silica gel chromatography. Compounds 9-15 were isolated as colorless oils.
  • 63
  • [ 5452-37-9 ]
  • 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole [ No CAS ]
  • C19H26F2N4O [ No CAS ]
YieldReaction ConditionsOperation in experiment
57% With triethylamine In ethanol at 80℃; for 2h; Inert atmosphere; Synthesis of compound 15 To a solution of compound 4 (50 mg, 0.21 mmol) in EtOH (3 mL), cyclooctylamine (0.04 mL, 0.32 mmol) and Et3N (0.04 mL,0.32 mmol) were added. The reaction mixture was stirred at 80 °C for 2 h and progress of the reaction was monitored by TLC (1:20/MeOH:CH2Cl2, Rf0.52). The organic layer was removed under reduced pressure and the residue was purified by column chromatography (SiO2, 1:20/MeOH:CH2Cl2) to afford compound 15 (43 mg, 57%) as a colorless liquid
  • 64
  • [ 5452-37-9 ]
  • [ 616-38-6 ]
  • [ 17630-21-6 ]
YieldReaction ConditionsOperation in experiment
95% With binder-free NaY zeolite at 150℃; for 1h; General procedure for the methylation of cycloalkanamines with dimethyl carbonate. General procedure: A 17-mL stainless steel high-pressure reactor or a 20-mL glass ampule (the results of parallel runs almost did not differ from each other) was charged with BF-NaY (5 wt %), 100 mmol of cycloalkanamine 1a-8a, and 400 mmol of dimethyl carbonate. The reactor was hermetically closed (the ampule was sealed) and heated for 1 h at 150°C. When the reaction was complete, the reactor (ampule) was cooled to room temperature and opened, the mixture was filtered through a layer of Al2O3, excess dimethyl carbonate was distilled off, and the residue was distilled under atmospheric or reduced pressure or recrystallized from ethanol.
  • 65
  • [ 41014-43-1 ]
  • [ 5452-37-9 ]
  • C16H22N2O [ No CAS ]
  • 66
  • [ 13726-16-4 ]
  • [ 5452-37-9 ]
  • (4-Chloro-3-methoxy-benzyl)-cyclooctyl-methyl-amine [ No CAS ]
  • 67
  • [ 51-80-9 ]
  • [ 14970-87-7 ]
  • [ 5452-37-9 ]
  • 6-cyclooctyl-1,11-dioxa-4,8-dithia-6-azacyclotridecane [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% Stage #1: bis-(dimethylamino)methane; 3,6-dioxa-1,8-octandithiol With samarium(III) chloride hexahydrate In chloroform at 20℃; for 0.5h; Stage #2: cyclooctylamine In ethanol; chloroform at 20℃; for 3h; General procedure for heterocyclization of carbocyclicamines. General procedure: A mixture of N,N,N1,N1-tetramethylmethanediamine(0.27 mL, 2 mmol), 3,6-dioxa-1,8-octanedithiol (0.16 mL, 1 mmol) in 5 mL of CHCl3 and SmCl3.6H2O (0.018 g, 0.05 mmol) was stirred at room temperature for 30 min, then the corresponding cycloalkylamine (1 mmol) in 5 mL of EtOH was added dropwise.The reaction mixture was stirred for 3 h at ~20°C and then evaporated. The residue was chromatographed on a SiO2column obtaining pure heterocycles 4-8.
  • 68
  • [ 5452-37-9 ]
  • [ 85909-02-0 ]
  • [ 13364-13-1 ]
YieldReaction ConditionsOperation in experiment
50% With air In toluene at 100℃; for 24h; Molecular sieve; 25 Under air conditions, add magnetons to a dry, clean 25mL round bottom flask in sequence.N-Boc amide (155.5 mg, 0.5 mmol) represented by the formula IIa,An amine represented by the formula IIIk (45.0 mg, 0.75 mmol),Then, 2.5 mL of toluene dried by molecular sieve was added, and the reaction was performed at 100 ° C for 24 hours.10 mL of water was added to quench the reaction, and extracted with dichloromethane (25 mL x 3 times),The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.The filtrate was evaporated by rotary evaporation to remove the solvent. After concentration, 200-300 mesh silica gel column chromatography was performed.A mixed solvent of ethyl acetate and petroleum ether (1: 3) was rinsed.58 mg of the compound represented by the formula Iaa was isolated with a yield of 50%.
  • 69
  • [ 320-72-9 ]
  • [ 5452-37-9 ]
  • 3,5-dichloro-N-cyclooctyl-2-hydroxybenzamide [ No CAS ]
  • 70
  • [ 5452-37-9 ]
  • 2-(4-sulfamoylbenzamido) thiazole-4-carboxylic acid [ No CAS ]
  • N-cyclooctyl-2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% Stage #1: 2-(4-sulfamoylbenzamido) thiazole-4-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 25℃; for 0.5h; Stage #2: cyclooctylamine With dmap In N,N-dimethyl-formamide at 45℃; for 24h; 4.1.4 Synthesis of 5a-5f and 8a-8e General procedure: Intermediate 4 (1.53mmol), EDCI (1.84mmol), HOBt (1.84mmol) were added into 3mL DMF and stirred at room temperature for 30min. Then, 2-amino-4-ethoxycarbonyl thiazole (1.53mmol) and DMAP (0.46mmol) were added. The reaction was carried out at 45°C for 24h and then cooled to room temperature. Upon completion, the mixture was added to water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol, 60:1-50:1) to obtain compound 5a. The methods for synthesising 5b-5f and 8a-8e were the same as for 5a.
  • 71
  • [ 138642-96-3 ]
  • [ 5452-37-9 ]
  • 6-chloro-N-cyclooctyl-2-methylimidazo[1,2-a]pyridine-3-carboxamide [ No CAS ]
  • 72
  • [ 5452-37-9 ]
  • [ 616-38-6 ]
  • [ 2191-69-7 ]
YieldReaction ConditionsOperation in experiment
91% With binder-free FeHY-mmm zeolite In neat (no solvent) at 120℃; for 1h; Sealed tube; General procedure for the methoxycarbonylation of alkyl-, cycloalkyl-, and arylamines with dimethyl carbonate. General procedure: The reactions were carried out in a 17-mL stainless steel high-pressure micro reactor or a 20-mL glass ampule. The results of parallel runs were almost the same. The reactor (ampule) was charged with 3-5 wt % of FeHY-mmm, 10 mmol of the corresponding amine, and 40 mmol of dimethyl carbonate. The reactor was hermetically closed (the ampule was sealed) and heated at 120°C for 0.5-2 h. When the reaction was complete, the reactor (ampule) was cooled to room temperature and opened, the mixture was filtered through a layer of alumina, excess dimethyl carbonate was distilled off, and the residue was distilled under atmospheric or reduced pressure or crystallized from ethanol.
  • 73
  • [ 5452-37-9 ]
  • [ 616-38-6 ]
  • [ 2191-69-7 ]
  • methyl N-cyclooctyl-N-methylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% With binder-free FeHY-mmm zeolite In neat (no solvent) at 120℃; for 2h; Sealed tube; General procedure for the methoxycarbonylation of alkyl-, cycloalkyl-, and arylamines with dimethyl carbonate. General procedure: The reactions were carried out in a 17-mL stainless steel high-pressure micro reactor or a 20-mL glass ampule. The results of parallel runs were almost the same. The reactor (ampule) was charged with 3-5 wt % of FeHY-mmm, 10 mmol of the corresponding amine, and 40 mmol of dimethyl carbonate. The reactor was hermetically closed (the ampule was sealed) and heated at 120°C for 0.5-2 h. When the reaction was complete, the reactor (ampule) was cooled to room temperature and opened, the mixture was filtered through a layer of alumina, excess dimethyl carbonate was distilled off, and the residue was distilled under atmospheric or reduced pressure or crystallized from ethanol.
  • 74
  • [ 5452-37-9 ]
  • [ 67-64-1 ]
  • [ 100534-98-3 ]
YieldReaction ConditionsOperation in experiment
45% With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; for 15h; Molecular sieve; Inert atmosphere; Preparation of amines 21 General procedure: Sodium triacetoxyborohydride (1.4 eq) and AcOH (1.0 eq) were added to a stirred solution of the ketone (1.0 eq) and the amine (1.0 eq) in DCM (0.33 M) . Upon reaction completion (24-48 h), aqueous NaOH (1 N) was added and the mixture was extracted with Et2O.The combined organic layers were dried upon Na2SO4 and concentrated in vacuo.
  • 75
  • [ 131543-46-9 ]
  • [ 5452-37-9 ]
  • C18H32N2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% In propan-1-ol at 25℃; for 2h; Inert atmosphere; Schlenk technique; 2.2. Synthesis of ligands R-DAB General procedure: Adapting the procedure described by Delaude et al. [39], a mixture of glyoxal (0,25 mol), propanol (100 mL) and water (50 mL) was added dropwise to a solution of the respective cycloalkylamine (0,5 mol, cyclopentylamine-1a, cyclohexylamine-1b, cycloheptylamine-1c and cyclooctylamine-1d) in propanol (300 mL).The reaction mixture was stirred for 2 h at 25 °C, then the orange-colored resulting suspension was filtered with suction and the compound was rinsed with cold propanol (2 100 mL). Further purification was performed by recrystallization from acetonitrile, yielding 1a-d as white crystalline solids.
  • 76
  • [ 5452-37-9 ]
  • [ 19075-58-2 ]
  • 6-bromo-N-cyclooctylbenzo[b]thiophene-2-carboxamide [ No CAS ]
  • 77
  • [ 7254-19-5 ]
  • [ 5452-37-9 ]
  • 5-bromo-N-cyclooctyl-1H-indole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 12h;
  • 78
  • [ 5452-37-9 ]
  • 2-methyl-4H-pyrrolo[3,2-d]thiazole-5-carboxylic acid [ No CAS ]
  • N-cyclooctyl-2-methyl-4H-pyrrolo[3,2-d]thiazole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
62.52% Stage #1: 2-methyl-4H-pyrrolo[3,2-d]thiazole-5-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 30℃; for 1h; Stage #2: cyclooctylamine In N,N-dimethyl-formamide at 30℃; for 12h; Inert atmosphere; 7.1 Step 1. Synthesis of N-cyclooctyl-2-methyl-4H-pyrrolo[3,2-d]thiazole-5-carboxamide To the solution of 2-methyl-4H-pyrrolo[3,2-d]thiazole-5-carboxylic acid (60 mg, 329.31 miho, 1 eq ) in DMF (1 mL) was added CDI (80.10 mg, 493.96 miho, 1.5 eq ) and the mixture was stirred at 30°C for 1 hr. Then cyclooctanamine (62.85 mg, 493.96 miho, 1.5 eq) was added, the mixture was stirred at 30°C for 12 hours under N2. LCMS showed the completion of the reaction. The mixture was filtered and the solid was washed by DMF (2 mL), followed by water (5 mL). Then it was concentrated under reduced pressure to afford N-cyclooctyl-2-methyl-4H-pyrrolo[3,2- d]thiazole-5- carboxamide (60 mg, 205.89 pmol, 62.52% yield, 100% purity) was obtained as a white solid. (0122) LCMS (ESI), m/z 292.1 [M+H] +; NMR (500MHz, DMSO-de) d = 11.81 (br s, 1H), 7.94 (br d, J= 7.9 Hz, 1H), 7.16 (s, 1H), 4.06 - 3.94 (m, 1H), 2.67 (s, 3H), 1.84 - 1.44 (m, 14H).
  • 79
  • [ 5452-37-9 ]
  • [ 105-36-2 ]
  • [ 127413-63-2 ]
YieldReaction ConditionsOperation in experiment
58.4% With triethylamine In dichloromethane at 20℃; for 12h; Synthesis of N-(cyclooctyl)-glycine ethyl ester The product was synthesized by following a reported procedure with modifications.[1] Cyclooctylamine (12.0 g, 94.3 mmol) was dissolved in 200 mL dichloromethane (CH2Cl2), then the solution of ethyl 2-bromoacetate (15.8 g, 94.3 mmol) and triethylamine (14.3 g, 141.5 mmol) was added into the reaction flask. The reaction mixture was stirred at room temperature for 12 h. The mixture was cooled to room temperature, followed by washing with deionization water three times (3 x 200 mL) and brine once (200 mL), and the residue was dried over anhydrous MgSO4. After removing CH2Cl2 under vacuum, a crude product was obtained and further purified through silica gel column chromatography to give the product N-(cyclooctyl)-glycine ethyl ester as a yellow oil (11.8 g, 58.4% yield).
  • 80
  • [ 5452-37-9 ]
  • 4-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carbonyl chloride [ No CAS ]
  • N-cyclooctyl-4-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
52.2% With triethylamine In dichloromethane at 25℃; for 2h; 52 Synthesis of N-cyclooctyl-4-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxamide To a solution of 4-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carbonyl chloride (200 mg, 949.59 umol, 1 eq) in DCM (6 mL) was added TEA (288.27 mg, 2.85 mmol, 396.52 uL, 3 eq) and cyclooctanamine (241.63 mg, 1.90 mmol, 2 eq). The mixture was stirred at 25 °C for 2 hrs. LCMS showed the starting material 2 was consumed and desire product formed. The mixture was directly concentrated under reduce pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM : MeOH = 100 : 1 to 20 : 1). Compound N-cyclooctyl-4-methoxy -1H-pyrrolo[2,3-b]pyridine- 2-carboxamide (150 mg, 495.72 umol, 52.20% yield, 99.6% purity) was obtained as a white solid. LCMS (ESI) m/z 302.2 [M+H] +
  • 81
  • [ 5452-37-9 ]
  • 5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid [ No CAS ]
  • N-cyclooctyl-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
40.91% Stage #1: 5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 30℃; for 0.5h; Stage #2: cyclooctylamine In N,N-dimethyl-formamide at 30℃; for 12h; 65 Example 65. MPL-071 Synthesis of N-cyclooctyl-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide To a solution of 5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (100 mg, 525.77 umol, 1 eq) in DMF (1 mL) was added CDI (110.83 mg, 683.50 umol, 1.3 eq). The mixture was stirred at 30 °C for 0.5 h. cyclooctanamine (86.96 mg, 683.50 umol, 1.3 eq) was added and the reaction mixture was stirred at 30 °C for 12 h. LCMS showed there were no starting material and main desired compound. The reaction was added dropwise to H2O (20 mL). There was much precipitation which was collected by filter. The cake was diluted in CH3CN (5 mL) and H2O (20 mL), then lyophilized. The crude product was purified by silica column chromatography (eluent of 20~80% EtOAc/Petroleum ether gradient, 4 g silica column). All fractions found to contain product by TLC (Petroleum ether:EtOAc = 1:1, Rf = 0.3) were combined and evaporated. Compound N-cyclooctyl-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (65 mg, 215.10 umol, 40.91% yield, 99.08% purity) was obtained as a white solid which was confirmed by LCMS and 1H NMR. LCMS (ESI) m/z 300.2 [M+H]+; 1H NMR (400MHz, DMSO-d6) d =11.71 (s, 1H), 8.12 (br d, J=7.9 Hz, 1H), 7.76 (s, 1H), 7.01 (d, J=1.7 Hz, 1H), 4.07 - 3.98 (m, 1H), 2.48 (s, 3H), 2.31 (s,3H), 1.82 - 1.65 (m, 6H), 1.63 - 1.45 (m, 8H).
  • 82
  • [ 5452-37-9 ]
  • 4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid [ No CAS ]
  • N-cyclooctyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
71.58% Stage #1: 4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 25℃; for 0.25h; Stage #2: cyclooctylamine In N,N-dimethyl-formamide at 25℃; for 12h; 12 Example 12. MPL-037 Synthesis of N-cyclooctyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide To a solution of 4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (200 mg, 869.02 umol, 1 eq) in DMF (4.5 mL) was added CDI (183.18 mg, 1.13 mmol, 1.3 eq) and stirred at 25 °C for 15 min. Then, cyclooctanamine (176.90 mg, 1.39 mmol, 1.6 eq) was added above solution and stirred at 25 °C for 12 h. LCMS showed one main peak with desired MS was detected. The mixture was added water (10 mL) and extracted with EtOAc (15 mL x 3) and the organic phase was washed with water (10 mL x 3) and brine (10 mL x 3) and dried over Na2SO4 and filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH = 1/0 to 160:1). Compound N-cyclooctyl-4- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (212.3 mg, 622.08 umol, 71.58% yield, 99.437% purity) was obtained as a white solid. LCMS (ESI) m/z: 340.1 [M+H] + ; 1H NMR (500MHz, DMSO-d6) d = 12.73 (br s, 1H), 8.62 - 8.44 (m, 2H), 7.47 (d, J = 4.7 Hz, 1H), 7.37 (s, 1H), 4.06 (br dd, J = 3.8, 8.1Hz, 1H), 1.85 - 1.64 (m, 6H), 1.63 - 1.46 (m, 8H).
  • 83
  • [ 5452-37-9 ]
  • 4-fluoro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [ No CAS ]
  • C16H20FN3O [ No CAS ]
YieldReaction ConditionsOperation in experiment
42.91% Stage #1: 4-fluoro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 30℃; for 0.5h; Stage #2: cyclooctylamine In N,N-dimethyl-formamide at 30℃; for 12h; 67 Example 67. MPL-093 Synthesis of N-(4,4-dimethylcyclohexyl)-4-fluoro-1H-pyrrolo[2,3-c]pyridine- 2-carboxamide To a solution of 4-fluoro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (100 mg, 555.14 umol, 1 eq) in DMF (2 mL) was added CDI (117.02 mg, 721.68 umol, 1.3 eq). The mixture was stirred at 30 °C for 0.5 h. Then cyclooctanamine (91.82 mg, 721.68 umol, 1.3 eq) was added. The mixture was stirred at 30 °C for 12 h. LCMS showed there were no starting material and main desired compound. The reaction was added dropwise to H2O (20 mL). There was much precipitation which was collected by filter. The cake was diluted in CH3CN (5 mL) and H2O (20 mL), then lyophilized. The residue was delivered without further purification. Compound N-cyclooctyl-4-fluoro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (70 mg, 238.22 umol, 42.91% yield, 98.47% purity) was obtained as a white solid. LCMS (ESI) m/z 290.1 [M+H]+; 1H NMR (400MHz, DMSO-d6) d =12.40 (br s, 1H), 8.62 (br s, 1H), 8.52 (br d, J=7.8 Hz, 1H), 8.05 (s, 1H), 7.34 (s, 1H), 7.38 - 7.28 (m, 1H), 7.38 - 7.28 (m, 1H), 7.38 - 7.28 (m, 1H), 7.38 - 7.28 (m, 1H), 7.38 - 7.28 (m, 1H), 4.03 (br s, 1H), 1.81 - 1.63 (m, 6H), 1.59 - 1.45 (m, 1H), 1.59 - 1.45 (m, 7H).
  • 84
  • [ 5452-37-9 ]
  • 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid [ No CAS ]
  • 4-bromo-N-cyclooctyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
50.47% Stage #1: 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 25℃; for 0.5h; Inert atmosphere; Stage #2: cyclooctylamine In N,N-dimethyl-formamide at 25℃; for 12h; 51 Example 51. MPL-035 Synthesis of 4-bromo-N-cyclooctyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (100 mg, 414.87 umol, 1 eq) and CDI (100.91 mg, 622.30 umol, 1.5 eq) in DMF (3 mL) the mixture was stirred at 25 °C for 30 min, then cyclooctanamine (79.17 mg, 622.30 umol, 1.5 eq) was added, the mixture was stirred at 25 °C for 12 h under N2. TLC and LC-MS showed the starting material 1 was consumed completely and one main peak with desired mass was detected. The mixture was diluted with DCM (20 mL) and washed with water (20 mL x 5) and HCl (1 M, 20mL). The organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM : MeOH = 1:0 to 200:1). The product 4-bromo-N-cyclooctyl-1H-pyrrolo [2,3-b]pyridine-2-carboxamide (74.4 mg, 209.36 umol, 50.47% yield, 98.562% purity) was obtained as white solid. LCMS (ESI) m/z 350.1 [M+H] +; 1H NMR (400MHz, DMSO-d6) d = 12.47 (br s, 1H), 8.43 (br d, J = 7.5 Hz, 1H), 8.18 (br d, J = 4.9 Hz, 1H), 7.40 (br d, J = 4.6 Hz, 1H), 7.21 (br s, 1H), 4.04 (br s, 1H), 1.81 - 1.66 (m, 6H), 1.52 (br d, J = 9.9 Hz, 8H).
  • 85
  • [ 5452-37-9 ]
  • difluoroacetaldehyde N-tosylhydrazone [ No CAS ]
  • C10H17N3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% With sodium hydride In ethyl acetate at 40℃; General procedure a for the synthesis of hydrazones and 1-substituted 1,2,3-triazoles General procedure: To a dried Schlenk flask, amines (0.4 mmol, 2.0 eq), difluoroacetaldehyde N-tosylhydrazone (0.2 mmol, 49.6 mg, 1.0 eq), base (3 eq or 6.0 eq), and MeOH (4 mL) were added. Then the resultant solution was stirred at room temperature for 5 h, then diluted with 5 mL of CH2Cl2 and filtered through a plug of celite, followed by washing with 20 mL of CH2Cl2. The combined residue was concentrated under reduced pressure, and then the resulting crude product was purified by silica gel column chromatography.
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Cyclopentadecanamine

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Chemical Structure| 3114-70-3

[ 3114-70-3 ]

Cyclohexane-1,4-diamine

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Chemical Structure| 15827-56-2

[ 15827-56-2 ]

cis-Cyclohexane-1,4-diamine

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Amines

Chemical Structure| 5452-35-7

[ 5452-35-7 ]

Cycloheptylamine

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Chemical Structure| 1502-03-0

[ 1502-03-0 ]

Cyclododecanamine

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Chemical Structure| 18618-64-9

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Cyclopentadecanamine

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