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[ CAS No. 3413-28-3 ] {[proInfo.proName]}

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Chemical Structure| 3413-28-3
Chemical Structure| 3413-28-3
Structure of 3413-28-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 3413-28-3 ]

CAS No. :3413-28-3 MDL No. :MFCD04115015
Formula : C11H14FNO Boiling Point : -
Linear Structure Formula :- InChI Key :QUPXFCLFBNUVGX-UHFFFAOYSA-N
M.W : 195.23 Pubchem ID :3734896
Synonyms :

Calculated chemistry of [ 3413-28-3 ]

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.45
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 56.72
TPSA : 21.26 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.99 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.48
Log Po/w (XLOGP3) : 2.12
Log Po/w (WLOGP) : 2.0
Log Po/w (MLOGP) : 2.14
Log Po/w (SILICOS-IT) : 2.65
Consensus Log Po/w : 2.28

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.57
Solubility : 0.524 mg/ml ; 0.00268 mol/l
Class : Soluble
Log S (Ali) : -2.2
Solubility : 1.24 mg/ml ; 0.00634 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.63
Solubility : 0.0458 mg/ml ; 0.000234 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.51

Safety of [ 3413-28-3 ]

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

Application In Synthesis of [ 3413-28-3 ]

* 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 [ 3413-28-3 ]

[ 3413-28-3 ] Synthesis Path-Downstream   1~85

YieldReaction ConditionsOperation in experiment
Starting from (IV-5) (cf. 5.5) and 4-(4-fluorophenoxy)-piperidine Example 1.22 can be prepared and purified analogously to Example 1.16 (cf. 16.). Analytical HPLC-MS (method A): RT=1.15 min.
  • 2
  • [ 3413-28-3 ]
  • [ 446020-63-9 ]
  • 6-(2-{2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-pyrrolidine-1-sulfonyl)-1<i>H</i>-indole [ No CAS ]
  • 3
  • [ 3413-28-3 ]
  • [ 477787-95-4 ]
  • 2-(2-(4-(4-fluorophenoxy)piperidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one [ No CAS ]
  • 4
  • [ 420137-33-3 ]
  • [ 3413-28-3 ]
  • [4-(4-fluoro-phenoxy)-piperidin-1-yl]-(6-hydroxy-1H-benzimidazol-2-yl)-methanone [ No CAS ]
  • 5
  • [ 3413-28-3 ]
  • [ 36603-49-3 ]
  • [ 1026504-07-3 ]
  • 6
  • [ 420137-33-3 ]
  • [ 3413-28-3 ]
  • [4-(4-fluoro-phenoxy)-piperidin-1-yl]-(6-hydroxy-1H-benzimidazol-2-yl)-methanone [ No CAS ]
  • 7
  • [ 3413-28-3 ]
  • [ 681509-02-4 ]
  • 8
  • [ 3413-28-3 ]
  • 2-{4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-phenoxymethyl}-2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-<i>b</i>]oxazole [ No CAS ]
  • 9
  • [ 3413-28-3 ]
  • [ 79-04-9 ]
  • [ 651301-41-6 ]
YieldReaction ConditionsOperation in experiment
71% With triethylamine; In dichloromethane; at 20℃; for 0.5h; To a solution of 4-(4-fluoro-phenoxy)-piperidine (1.24 grams, 6.36 mmol) in dichloromethane was added triethyl amine (1.2 ml, 8.6 mmol) and chloroacetyl chloride (0.54 ml, 7.0 mmol). The reaction was stirred at ambient temperature for 30 minutes. The reaction was concentrated in vacuo and purified by silica gel chromatography to give the title compound (1.22 grams, 71 % yield).
  • 10
  • [ 630407-23-7 ]
  • [ 3413-28-3 ]
  • 7-{4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-benzenesulfonyl}-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine [ No CAS ]
YieldReaction ConditionsOperation in experiment
53% In dimethyl sulfoxide; at 20 - 130℃; for 18h; Example 1 7- 4- [4- (4-FLUORO-PHENOXY)-PIPERIDIN-1-YL]-BENZENESULFONYL}-8-METHOXY-3-METHYL- 2,3, 4, 5-TETRAHYDRO-1 H-3-BENZAZEPINE (E1) 7- (4-FLUORO-BENZENESULFONYL)-8-METHOXY-3-METHYL-2, 3,4, 5-tetrahydro-1 H-3-benzazepine D2 (0.100 g, 0. 287 MMOL) was dissolved in dry DMSO (1 mL) and 4- (4-FLUORO-PHENOXY)- piperidine (3.2 eq. , 0.92 MMOL, 0.180 g), was added at room temperature and the reaction mixture was stirred at 130 C for 18 hours; the reaction was cooled to room temperature and it was purified by SCX ion exchange cartridges first; the crude mixture obtained was subsequently purified by chromatography (MeOH-NH3/DCM) on silica to afford the title compound E1, a white solid, 80 mg, 53 %.
  • 11
  • [ 333954-85-1 ]
  • [ 3413-28-3 ]
YieldReaction ConditionsOperation in experiment
92% With trifluoroacetic acid; In dichloromethane; at 20℃; for 2.5h; To a solution of 4-(4-fluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (2.04 grams, 6.91 mmol) in dichloromethane was added trifluoroacetic acid (3 ml). The reaction was stirred at ambient temperature for 2.5 hours. The reaction was concentrated, diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to give the title compound (1.24 grams, 92 % yield).
85% 1.2 4-(4-Fluoro-phenoxy)-piperidine 2 g (7 mmol) of 4-(4-fluoro-phenoxy)-piperidine 1-carboxylic acid tert-butyl ester was solvated in dichloromethane (12 mL) and trifluoroacetic acid was added at 0 C. (6.17 mL, 54 mmol). The mixture was stirred at room temperature overnight. NaHCO3 was slowly added until pH 9 and the mixture extracted 3 times with dichloromethane and ethyl acetate. The solvent was evaporated to yield 1.81 g (58.5 mmol, 85%) of a white solid that was used without purification on the next steps. MS (m/e): 196.3 (M+H+).
With hydrogenchloride; In methanol; water; at 30℃; for 13h;pH 8.0; Water / MeOH (5 mL / 20 mL) A1 (890 mg, 3.01 mmol) and con.HCl (2 mL) in the mixture was stirred for 12 hours at 30 . Then, after addition of con.HCl (2 mL) and stirred 1 hour or more. After adjusting the mixture to pH = 8 by addition of a saturated NaHCO3, and extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give crude residueTo generate A2, it was used directly in the next step without further stagnation.
9 g With hydrogenchloride; In tetrahydrofuran; at 20℃; for 1h; B. To a solution of tert-butyl 4-(4-fluorophenoxy)piperidine-1-carboxylate (17 g, 57.56 mmol) in THF (100 mL) was added HCl (21.01 g, 575.6 mmol). The reaction was stirred at ambient temperature for 1 h. Water (20 mL) was added to the reaction vessel and was extracted with DCM (6 x 20 ml). The layers were separated and the aqueous phase was added NaHCO3 (20 mL). Then the reaction was extracted with DCM (3 x 20 ml). The layers were separated and the organic phase was washed with saturated aqueous NaCl (2 x 30 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. After concentrated, the residue was purified to give the desired product 4-(4-fluorophenoxy) piperidine (9 g, 46.1 mmol) as a yellow oil.

  • 12
  • [ 3413-28-3 ]
  • [ 31795-93-4 ]
  • [ 354563-94-3 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 29 ((2S)-1-Benzylpyrrolidin-2-yl)-[4-(4-fluorophenoxy)-piperidin-1-yl]-methanone Hydrochloride (Compound 48). Compound 48 was prepared from (2S)-1-benzylpyrrolidin-2-yl carboxylic acid and 4-(4-fluorophenoxy)piperidine as described in Example 1 to yield 516 mg (65%) as the hydrochloride salt. 1H NMR (CDCl3, 500 MHz) delta 7.36 (m, 5H), 6.98 (m, 2H), 6.87 (m, 2H), 4.4 (m, 1H), 3.98 (m, 1H), 3.80 (m, 2H), 3.52 (m, 4H), 3.10 (m, 1H), 2.32 (m, 1H), 2.15 (m, 1H), 1.84 (m, 4H), 1.75 (m, 3H) ppm. MS: m/z 383.5 (M+1)
  • 13
  • [ 3413-28-3 ]
  • [ 22980-10-5 ]
  • [ 63843-66-3 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In chloroform; water; a. 9.8 g of 2-methyl-indole-3-glyoxyloyl chloride are added portionwise to a stirred mixture of 9.0 g of 4-(p-fluorophenoxy)piperidine [Example 9(b)], 11.2 g of potassium carbonate, 45 ml. of chloroform and 45 ml. of water. The mixture is stirred for 16 hours and the resultant buff solid is collected, washed with ether and dried. The solid is recrystallized twice from an ethanol and water mixture to give 1-(2-methylindol-3-ylglyoxyloyl)-4-(p-fluorophenoxy)piperidine, m.p. 213-214.5 C.
  • 14
  • [ 330670-87-6 ]
  • [ 3413-28-3 ]
  • [ 330669-31-3 ]
YieldReaction ConditionsOperation in experiment
In N-methyl-acetamide; ethanol; Scheme III, Step O: The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-(4-fluoro-phenoxy)-piperidine (Table No.1, SM 5) in ethanol essentially as described above in Example 21. Purity by LC/MS=88%, [M+H]+=481.
  • 15
  • [ 330670-95-6 ]
  • [ 3413-28-3 ]
  • [ 330669-16-4 ]
YieldReaction ConditionsOperation in experiment
In N-methyl-acetamide; ethanol; Scheme III, Step O: The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-(4-fluoro-phenoxy)-piperidine (Table No.1, SM 5) in ethanol essentially as described above in Example 21. Purity by LC/MS=86%, [M+H]+=481 and 8%, [M+H]+=573.
  • 16
  • [ 3413-28-3 ]
  • [ 1975-52-6 ]
  • C19H19FN2O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 29h; DIEA 225 μL (1.29 mmol) was added to a solution of 4-(p- fluorophenoxy)-piperidine 250 mg (1.280 mmol), HOBWH2O 250 mg (1.63 mmol), 2-methyl-5-nitrobenzoic acid 255 mg (1.40 mmol) and EDOHCI 268 mg (1.40 mmol) in anhydrous DMF (1.5 ml_) and the mixture was stirred for 29 hours. The mixture was diluted with ethyl acetate (100 ml_), washed twice with saturated NaHCθ3 (2 x 100 ml_) and the aqueous phases were re-extracted with ethyl acetate (100 mL). The combined organic extracts were dried (MgSO4) and evaporated. The residue was purified on a column of silica (40 g) in a hexane-ethyl acetate gradient (0-60% EtOAc). The obtained purified nitro-intermediate was dissolved in a mixture of ethanol (99%, 20 mL) and acetic acid (2 mL). SnCl2*2H2O 1.58 g (6.00 mmol) was added and the mixture was refluxed under Ar for 1 h on oil bath (95 0C). The mixture was cooled, diluted with dichloromethane 50 mL, 1M aq. NaOH 200 mL was added and the mixture was stirred vigorously for Vz hour. The mixture was extracted twice with dichloromethane (2 x 200 mL), and the organic extracts were washed with saturated NaCI (200 mL), combined, dried (MgSO4) and evaporated. Y = 335 mg of amino-substituted intermediate (79.5%) as a pale- yellow amorphous glassy solid.
  • 17
  • [ 3413-28-3 ]
  • [ 120890-66-6 ]
  • [ 944390-30-1 ]
YieldReaction ConditionsOperation in experiment
59.5% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 3.5h; Solid 4-(p-fluorophenoxy)-piperidine 554 mg (2.837 mmol) was added to a solution of 2-chloro-4-fluoro-5-nitrobenzoyl chloride 743 mg (3.121 mmol) in anhydrous dichloromethane (30 mL) at 0 0C, followed by additional dichloromethane (anhydrous, 5 mL) and DIEA (0.54 mL, 3.1 mmol). The mixture was stirred at 0-5 0C for 1 hour, at 5 to 20 0C for 2 h 30 min and then at room temperature for an additional hour. The reaction mixture was quenched with saturated NaHCO3 (20 mL) and stirred for 1 hour, then extracted twice with EtOAc (2 x 100 mL). The organic extracts were washed with additional NaHCO3 (20 mL), dried (MgSO-O and evaporated. The residue was purified on a column of silica (80 g) in hexane-EtOAc gradient, 0 to 70% EtOAc. Y = 670 mg of the nitro intermediate as a pale-yellow foamy amorphous solid (59.5%th) LC/MS(+ESI): 397, 399 (M+1).
  • 18
  • [ 3413-28-3 ]
  • [ 944390-08-3 ]
  • N-{5-chloro-4-[4-(4-fluorophenoxy)-piperidine-1-carbonyl]-pyridin-2-yl}-acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 24h; EDOHCI (100 mg, 0.52 mmol) was added to a solution of 4-(p- fluorophenoxy)-piperidine 100 mg (0.512 mmol), HOBt-H2O 100 mg (0.653 mmol), 2-acetamido-5-chloropyridine-4-carboxylic acid 100 mg (0.4659 mmol) and DIEA 70 μL (0.4 mmol) in anhydrous DMF (1 ml_). The mixture was stirred for 1 day, partitioned between EtOAc (60 ml_) and saturated NaHCO3 solution (60 ml_). The aqueous phase was re-extracted with EtOAc (60 ml_) and the combined organic extracts were washed with another portion of NaHCθ3 (saturated 60 ml_). Combined organic extracts were dried (MgSO4) and evaporated. The residue was purified on a column of silica (40 g) using EtOAc gradient in hexane, 0 to 100% EtOAc. Y = 101mg of a white amorphous glassy solid (55% th). Physical Data: LC/MS (+ESI): 394, 394 (M+1). 1H NMR (cfe-DMSO, 400MHz): δ 10.859 (s, 1H), 8.462 (s, 1 H), 8.065 (S1 1H), 7.117 (m, 2H), 7.025 (m, 2H), 4.611 (br m, 1 H), 4.001 (br m, 1 H), 3.503 (br m, 1H), 3.170 (br m, 1 H), 2.113 (s, 3H), 2.020 (br m, 1 H), 1.881 (br m, 1H), 1.611 (br m, 2H).
  • 19
  • [ 3413-28-3 ]
  • [ 156237-49-9 ]
  • [ 944072-57-5 ]
YieldReaction ConditionsOperation in experiment
63% With caesium carbonate; potassium iodide; In acetonitrile; at 120℃; for 0.333333h;Microwave reactor; l-ϖ-(3-r4-(4-fluorophenoxy)-l-piperidinyl1propyl)-lH-indol-3-yl)ethanone C656b10402] l-[l-(3-chloropropyl)-lH-indol-3-yl]-ethanone (1 17 mg, 0.5 mmol), cesium carbonate (325 mg, 1 mmol), potassium iodide (83 mg, 0.5 mmol) and 4-(4- fluorophenoxy)piperidine (104 mg, 0.45 mmol) were weighed into a MW vial and dry MeCN (2 mL) was added. The vial was capped and heated in the MW at 120 0C for 20 min. The reaction mixture was diluted with EtOAc and washed with water and brine, dried over sodium sulphate, filtered and concentrated onto celite. The product was purified by flash chromatography 0-5 % MeOH in DCM. Yield: 1 1 1 mg (63%). LC/MS purity: UV/MS 98/82.[0403] 1H NMR (400 MHz, CDCl3) δ: 8.25-8.22 (m, 2H), 7.55-7.53 (m, IH), 7.35-7.21 (m, 2H), 7.00-6.91 (m, 4H), 4.40-4.34 (m, 3H), 2.99-2.95 (m, 2H)5 2.70-2.66 (m, 4H), 2.52 (s, 3H), 2.22-2.18 (m, 2H), 2.04-2.00 (m, 2H), 1.88-1.82 (m, 2H).
  • 20
  • [ 3413-28-3 ]
  • [ 944086-30-0 ]
  • N-(3-chlorobenzyl)-1-(1-{3-[4-(4-fluorophenoxy)-1-piperidinyl]propyl}-1H-indol-3-yl)carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
34% With caesium carbonate; potassium iodide; In acetonitrile; at 120℃; for 0.333333h;Microwave reactor; N-(3-chlorobenzyl)-l-(3-f'4-r4-fluorophenoxyVl-piperidinyl]propyϖ-lH-indole-3- carboxamide C292b[0404] l-(3-chloropropyl)-N-(3-chlorobenzyl)-lH-indole-3-carboxamide (180 mg, 0.5 mmol), cesium carbonate (325 mg, 1 mmol), potassium iodide (83 mg, 0.5 mmol) and <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (104 mg, 0.45 mmol) were weighed into a MW vial and dry MeCN (2 mL) was added. The vial was capped and heated in the MW at 120 0C for 20 min. The reaction mixture was diluted with EtOAc and washed with water and brine, dried over sodium sulphate, filtered and concentrated onto celite. The product was purified by flash chromatography 0-5 % MeOH in DCM. Yield: 80 mg (34%). LC/MS purity: UV/MS 99/84.[0405] 1H NMR (400 MHz, CDCl3) δ: 8.14 (dt, J = 8.0 and 0.6 Hz3 IH), 7.88 (s, IH), 7.43 (dt, J = 8.4 and 1.0 Hz, IH), 7.37-7.35 (m, 1H),7.26-7.16 (m, 5H), 6.96-6.92 (m, 2H), 6.85-6.82 (m, 2H), 4.53 (s, 2H), 4.21-4.18 (m, 3H), 2.63-2.59 (m, 2H), 2.25 (t, J = 7.4 Hz, 2H), 2.21-2.13 (m, 2H), 1.98 (pentet, J= 7.4 Hz, 2H), 1.91-1.86 (m, 2H), 1.71-1.63 (m, 2H).
  • 21
  • [ 288-32-4 ]
  • (R)-3-.tert.-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester [ No CAS ]
  • (3R)-benzyl 4-iodo-3-N-(tert-butoxycarbonyl)butanoate [ No CAS ]
  • [ 3413-28-3 ]
  • [ 412015-66-8 ]
YieldReaction ConditionsOperation in experiment
With iodine; triethylamine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; N,N-dimethyl-formamide; Example 14 (R)-3-tert-Butoxycarbonylamino-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid benzyl ester Triphenylphosphine bound to cross-linked polystyrene resin (2.16 g, mol/g, 6.47 mmol) is suspended in dry DCM (50 ml) at ambient temperature under a nitrogen atmosphere. Iodine (1.64 g, 6.47 mmol) is added and the reaction mixture stirred for 15 minutes. Imidazole (0.50 g, 7.35 mmol) is then added and the reaction mixture is stirred for a further 15 minutes. A solution of (R)-3-.tert.-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (prepared as described by D. Gani et al J. Chem. Soc. Perkin Trans. 1, 2513-2525, 1997 (0.909 g, 2.94 mmol) in dry DCM (10 ml) is added and the reaction mixture is stirred at reflux for 1 hour. The polymer is removed by filtration, and the filtrate is first washed with aqueous 5% sodium thiosulphate solution and then water. The organic phase is dried over MgSO4 and evaporated to yield (R)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester as a crude oil. A solution of (R)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester (1.017 g, 2.43 mmol) and 4-(4-fluoro-phenoxy)-piperidine (0.569 g, 2.916 mmol) in DMF (25 ml) is treated with triethylamine (0.406 ml, 2.916 mmol). The reaction mixture is stirred at ambient temperature for 60 hours, and then partitioned between ethylacetate and water. The ethylacetate phase is dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 2:1 hexane/ethylacetate) to afford (R)-3-tert-butoxycarbonylamino-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid benzyl ester. [MH]+ 487.1.
  • 22
  • [ 371-41-5 ]
  • [ 109384-19-2 ]
  • [ 1972-28-7 ]
  • [ 3413-28-3 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; triphenylphosphine; In tetrahydrofuran; methanol; ethyl acetate; Preparation 40 4-(4-Fluorophenoxy)piperidine To a solution of tert-butyl 4-hydroxy-1-piperidinecarboxylate (2.0 g), 4-fluorophenol (1.1 g) and triphenylphosphine (3.9 g) in tetrahydrofuran was slowly added diethyl azodicarboxylate (2.6 g) at 8 C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the crude product. To a solution of the crude product in ethyl acetate (5 ml) and methanol (5 ml) was added 4N hydrogen chloride in ethyl acetate (25 ml) at 8 C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (1.08 g).
  • 23
  • [ 412015-70-4 ]
  • [ 3413-28-3 ]
  • afford{(R)-1-(tert-butoxycarbonylamino-methyl)-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-carbamic acid benzyl ester [MH]+ [ No CAS ]
  • [ 412015-71-5 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In dichloromethane; {(R)-1-(tert-Butoxycarbonylamino-methyl)-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-carbamic acid benzyl ester A solution of [(R)-1-(tert-butoxycarbonylamino-methyl)-2-iodo-ethyl]-carbamic acid benzyl ester (0.61 g, 1.2 mmol) and 4-(4-fluoro-phenoxy)-piperidine (0.24 g, 1.23 mmol) in dichloromethane (5 ml) is treated with triethylamine (0.335 ml, 2.46 mmol). The reaction mixture is stirred at ambient temperature for 5 days, the solvent evaporated and the residue partitioned between ethylacetate and saturated aqueous NaHCO3. The ethylacetate phase is washed with brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 4:1 hexane/ethylacetate) to afford{(R)-1-(tert-butoxycarbonylamino-methyl)-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-carbamic acid benzyl ester [MH]+ 502.2.
  • 24
  • [ 337530-31-1 ]
  • [ 3413-28-3 ]
  • [ 442198-89-2 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 63 (2E)-3-(4-Chlorophenyl)-N-[(1S)-2-({2-[4-(4-fluorophenoxy)-1-piperidinyl]-2-oxoethyl}amino)-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide The title compound was obtained from <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> and [(2S)-2-[(2E)-3-(4-chlorophenyl)-2-propenoyl]amino}-3-(2-pyridyl)propanoyl]amino}-acetic acid in the same manner as in Example 59. ESI-MS: m/z 565(M+1) 1H-NMR (300 MHz, CDCl3) δ 8.60-8.53(m, 1H), 8.07-7.85(2H, m), 7.68-7.56(m, 2H), 7.45(d, J=8 Hz, 2H), 7.35(d, J=8 Hz, 2H), 7.31-7.15(m, 2H), 7.04-6.93(m, 2H), 6.90-6.80(m, 2H), 6.50(dd, J=15,2 Hz, 1H), 5.06-4.97(m, 1H), 4.50-4.40(m, 1H), 4.11-3.95(m, 2H), 3.79-3.20(m, 6H), 1.94-1.75(m, 4H).
  • 25
  • [ 337530-33-3 ]
  • [ 3413-28-3 ]
  • [ 442198-90-5 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 64 5-Chloro-N-[(1S)-2-({2-[4-(4-fluorophenoxy)-1-piperidinyl]-2-oxoethyl}amino)-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide The title compound was obtained from <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> and [(2S)-2-[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanoyl]amino}acetic acid in the same manner as in Example 59. ESI-MS: m[z 579(M+1) 1H-NMR (300 MHz, CDCl3) δ 8.85-8.70(m, 1H), 8.67-8.60(m, 1H), 8.22-8.09(m, 1H), 7.70-7.60(m, 2H), 7.49(d, J=8 Hz, 1H), 7.42(s, 1H), 7.39(dd, J=2,8 Hz, 1H), 7.32-7.16(m, 2H), 7.04-6.92(m, 2H), 6.90-6.80(m, 2H), 5.16-5.06(m, 1H), 4.51-4.40(m, 1H), 4.15-3.96(m, 2H), 3.75-3.44(m, 4H), 3.40-3.26(m, 2H), 1.95-1.73(m, 4H).
  • 26
  • [ 215790-29-7 ]
  • [ 3413-28-3 ]
  • trans-(4-{2-[4-(4-fluorophenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
92.5% trans-(4-{2-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester A mixture of <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (0.150 g, 0.485 mmol), trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (0.117 g, 0.48 mmol), in 1, 2 dichloroethane (3 mL) and methanol (0.500 mL) was stirred for 4 hours at room temperature. Sodium triacetoxyborohydride (0.175 g, 0.829 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2-CH2Cl2/CH3OH (1-9:1). The product fractions were concentrated to give 0.176 g (0.45 mmol, 92.5% yield) of a light yellow solid. MS (m/e): 393.4 (M+H+).
  • 27
  • [ 3413-28-3 ]
  • quinoline-4-carboxylic acid trans-[4-(2-oxo-ethyl)-cyclohexyl]-amide [ No CAS ]
  • quinoline-4-carboxylic acid trans-(4-{2-[4-(4-fluorophenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% Quinoline-4-carboxylic acid trans(4-{2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide The title compound was prepared as follows. 4-(4-Fluoro-phenoxy)-piperidine (intermediate D, example 1) (0.015 g, 0.076 mmol) was solvated in 1,2-dichloromethane (0.300 mL) and quinoline-4-carboxylic acid trans-[4-(2-oxo-ethyl)-cyclohexyl]-amide (0.025 g, 0.084 mmol) was added. Methanol (0.100 mL) was added to improve solubility and the mixture was stirred overnight. Sodium triacetoxyborohydride (0.029, 0.137 mmol) was added to the clear solution that was stirred 10 hours at room temperature. The mixture was concentrated to dryness and the residue was taken up on methanol and purified with preparative HPLC on reversed phase eluding with acetonitrile/water. The combined product fractions were evaporated under reduced pressure to yield 0.034 g of a white solid (0.07 mmol, 93%). MS (m/e): 476.2 (M+H+)
  • 28
  • [ 3413-28-3 ]
  • [ 1094173-12-2 ]
  • [ 1094173-06-4 ]
  • 29
  • [ 3413-28-3 ]
  • [ 1175690-01-3 ]
  • [ 1175690-03-5 ]
YieldReaction ConditionsOperation in experiment
62.8% With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; acid tert-butyl ester A mixture of 6-(1-tert-butoxycarbonyl-azetidin-3-yl)-pyridine-2-carboxylic acid (0.35 g, 1.26 mmol), 4-(4-fluoro-phenoxy)-piperidine (0.32 g, 1.38 mmol) in 5 mL of DMF and diisopropylethylamine (0.358 g, 2.77 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (0.52 g, 1.38 mmol) was stirred at room temperature overnight, extracted with ethyl acetate, washed with saturated NaHCO3, water, brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (50-75% EtOH/Hexane) to furnish 3-{6-[4-(4-fluoro-phenoxy)-piperidine-1-carbonyl]-pyridin-2-yl}-azetidine-1-carboxylic acid tert-butyl ester as a white foam (0.36 g, 62.8%). 1H NMR 400 MHz (CDCl3) δ 7.75 (t, 1H), 7.58 (d 1H), 7.22 (d, 1H), 6.98 (t, 2H), 6.90-6.85 (m, 2H), 4.50 (m, 1H), 4.30 (t, 2H), 4.15 (t. 2H), 3.90-3.75 (m, 4H), 3.60-3.52 (m, 1H), 2.10-1.82 (m, 4H), 1.45 (s, 9H).
  • 30
  • [ 3413-28-3 ]
  • [ 1229828-61-8 ]
  • [ 1229830-32-3 ]
YieldReaction ConditionsOperation in experiment
14.2% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 5 - 20℃; for 15h; Step-1: 7-Benzyloxy-6-chloro-2-[4-(4-fluoro-phenoxy)-piperidine-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tent-butyl ester ; To a solution of 7-Benzyloxy-6-chloro-2,3-dihydro-benzo[1,4]oxazine-2,4-dicarboxylic acid 4-tert-butyl ester (250 mg, 0.59 mmol) in DMF was added 4-(4-Floro-phenoxy)-piperidine (115.2 mg, 0.59 mmol), EDCI (147.6 mg, 0.77 mmol), HOBt (39.2 mg, 0.3 mmol) and DIPEA (0.5 ml, 2.95 mmol) at 5-10 C. The reaction mixture was stirred at room temperature for 15 hours then diluted with water and extracted with ethyl acetate. The ethyl acetate layer was concentrated in vacuo and subjected to column chromatography (Si-gel, 15% EtOAc-hexane) to afford 50 mg (14.2%) of 7-Benzyloxy-6-chloro-2-[4-(4-fluoro-phenoxy)-piperidine-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester. LC/MS [M+H]+: 597.4.
  • 31
  • [ 1233227-60-5 ]
  • [ 3413-28-3 ]
  • (5-chloro-2-{2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethoxy}-phenyl)-urea [ No CAS ]
YieldReaction ConditionsOperation in experiment
47.9% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 5 - 20℃; Step-5: (5-Chloro-2-{2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethoxy}-phenyl)-urea To a solution of (4-Chloro-2-ureido-phenoxy)-acetic acid (100 mg, 0.41 mmol) in DMF was added 4-(4-Fluoro-phenoxy)-piperidine (80 mg, 0.41 mmol), EDCI (102 mg, 0.53 mmol), HOBT (28 mg, 0.21 mmol) and DIPEA (0.2 ml, 1.23 mmol) at 5-10 C. and the mixture was stirred at room temperature for 14-16 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography (silica-gel, 35% ethylacetate-hexane) to afford 83 mg (47.9%) of 5-Chloro-2-{2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethoxy}-phenyl)-urea. LC/MS [M+H]+: 422.1. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.19 (s, 1H), 8.14 (s, 1H), 7.11 (t, 2H, J=8.64), 7.01 (m, 2H), 6.86 (s, 2H), 6.35 (s, 2H), 4.96 (s, 2H), 4.56 (s, H), 4.07 (q, H, J=5.28), 3.81 (m, H), 3.67 (m, H), 3.31 (m, H), 3.17 (d, 2H, J=5.08), 1.90 (m, 2H). HPLC: 99.4%.
  • 32
  • [ 3413-28-3 ]
  • [ 1233228-15-3 ]
  • [ 1233228-16-4 ]
YieldReaction ConditionsOperation in experiment
47.2% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 5 - 20℃; To a solution of (2-tert-butoxycarbonylamino-4-chloro-5-methoxy-phenoxy)-acetic acid (185 mg, 0.5 mmol) in DMF was added 4-(4-Fluoro-phenoxy)-piperidine (109 mg, 0.5 mmol), EDCI (139 mg, 0.73 mmol), HOBT (38 mg, 0.27 mmol) and DIPEA (216 g, 1.67 mmol) at 5-10 C. and the mixture was stirred at room temperature for 14-16 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography (silica-gel, 35% ethyl acetate-hexane) to afford 120 mg (47.2%) of 6,7-Dichloro-2-[4-cyano-4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester. LC/MS [M+H]+: 509.2. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.08 (bs, H), 7.50 (m, H), 6.96 (m, 2H), 6.84 (m, 2H), 6.61 (s, H), 4.76 (s, 2H), 4.46 (m, H), 3.83 (s, 3H), 3.74 (m, H), 3.65 (m, 2H), 3.44 (m, H), 2.08 (s, H), 1.52 (s, 9H), 0.90 (m, H), 0.86 (m, H).
  • 33
  • [ 3413-28-3 ]
  • [ 7304-32-7 ]
  • [ 944390-57-2 ]
YieldReaction ConditionsOperation in experiment
83% 2-Fluoro-5-nitrobenzoic acid 194.5 mg (1.05 mmol) and TFFH 264 mg (1.00 mmol) were dissolved in anhydrous acetonitrile (4 ml_) and DIEA (0.40 mL, 2.28 mmol) was then added. The mixture was stirred for 20 minutes and 4-(p-fluorophenoxy)-piperidine 137 mg (0.70 mmol) was added (as a solid). After stirring for 3 hours 15 minutes 0.5 M sodium carbonate solution (10 mL) was added and stirring continued for Vt hour. The mixture was diluted with water (50 mL) and extracted twice with ether (2 x 70 mL). The combined organic extracts were washed with saturated NaHCU3 (60 mL), combined, dried (MgSO4) and evaporated. The residue was purified on a column of silica (40 g) in hexane-ethyl acetate gradient 0-50% EtOAc. The nitro-substituted intermediate 210 mg (83%Y) was obtained as a pale yellow glassy solid. This intermediate 210 mg (0.579 mmol) was dissolved in a mixture of ethanol (99%, 15 mL) and acetic acid (1 mL), SnCI2«2H2O 0.80 g (3.5 mmol) was added and the mixture was refluxed under Ar in an oil bath (900C) for 1 hour. The mixture was cooled, 1M NaOH (150 mL) and dichloromethane (20 mL) were added and the mixture was stirred vigorously for 45 minutes. The mixture was extracted twice with dichloromethane (2 x 150 mL). The organic <n="34"/>extracts were washed with 1M NaOH (150 ml_) and saturated NaCI (150 mL). The combined organic extracts were dried (MgSO4) and evaporated. The obtained crude amino-substituted intermediate 200 mg (104%Y from the nitro- derivative) was used without purification for the next step.
  • 34
  • [ 3413-28-3 ]
  • [ 135270-13-2 ]
  • [ 1325210-74-9 ]
YieldReaction ConditionsOperation in experiment
42% With lithium perchlorate; In acetonitrile; at 160℃; for 0.5h;Microwave irradiation; EXAMPLE 1: Preparation of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-(4-fluorophenoxy)piperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol To a suspension of acetonitrile (4 mL) in <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (180.5 mg, 0.92 mmol) in a microwave reaction vessel were added lithium perchlorate (133.4 mg, 1.25 mmol) and 1-(((2R,3R)-2-(2,4-difluorophenyl)-3-methyloxyran-2-yl)methyl)-1H-1,2,4-triazole (126.0 mg, 0.48 mmol), followed by exposure to microwaves at 160C for 30 min. After the termination of the reaction, the reaction mixture was concentrated in a vacuum, diluted in ethyl acetate and washed with distilled water and saline to separate an organic solvent layer. The organic solvent layer was dried over anhydrous magnesium sulfate and evaporated at reduced pressure. Isolation and purification of the residue through silica gel chromatography afforded the title compound as a white solid (yield 42 %).1H-NMR(CDCl3, 300 MHz) δ 8.00(s, 1H), 7.78(s, 1H), 7.53-7.44(m, 1H), 6.98-6.91(m, 2H), 6.86-6.69(m, 4H), 5.34(bs, 1H), 4.87(d, 1H, J=14.4Hz), 4.80(d, 1H, J=15.2Hz), 4.25-4.11(m, 1H), 3.02-2.89(m, 2H), 2.62-2.59(m, 2H), 2.28-2.20(m, 1H), 1.98-1.93(m, 2H), 1.85-1.72(m, 2H), 1.00-0.96(d, 3H).
42% With lithium perchlorate; In acetonitrile; at 160℃; for 0.5h;microwave irradiation; To a suspension of acetonitrile (4 mL) in <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (180.5 mg, 0.92 mmol) in a microwave reaction vessel were added lithium perchlorate (133.4 mg, 1.25 mmol) and 1-(((2R,3R)-2-(2,4-difluorophenyl)-3-methyloxyran-2-yl)methyl)-1H-1,2,4-triazole (126.0 mg, 0.48 mmol), followed by exposure to microwaves at 160 C. for 30 min. After the termination of the reaction, the reaction mixture was concentrated in a vacuum, diluted in ethyl acetate and washed with distilled water and saline to separate an organic solvent layer. The organic solvent layer was dried over anhydrous magnesium sulfate and evaporated at reduced pressure. Isolation and purification of the residue through silica gel chromatography afforded the title compound as a white solid (yield 42%).1H-NMR (CDCl3, 300 MHz) δ 8.00 (s, 1H), 7.78 (s, 1H), 7.53-7.44 (m, 1H), 6.98-6.91 (m, 2H), 6.86-6.69 (m, 4H), 5.34 (bs, 1H), 4.87 (d, 1H, J=14.4 Hz), 4.80 (d, 1H, J=15.2 Hz), 4.25-4.11 (m, 1H), 3.02-2.89 (m, 2H), 2.62-2.59 (m, 2H), 2.28-2.20 (m, 1H), 1.98-1.93 (m, 2H), 1.85-1.72 (m, 2H), 1.00-0.96 (d, 3H).
  • 35
  • [ 3413-28-3 ]
  • [ 115029-23-7 ]
  • 2-(4-(4-fluorophenoxy)piperidin-1-yl)-5-(trifluoromethyl)benzoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
10% With 4-methyl-morpholine; at 110℃; for 18h; General procedure: To a solution of <strong>[115029-23-7]2-fluoro-5-(trifluoromethyl)benzoic acid</strong> (6.26 g, 30.0 mmol) and (S)-3-(4-fluorophenoxy)pyrrolidine (7.0 g, 38.62 mmol) in 1,4-dioxane (100 mL) was added 4-methylmorpholine (10.0 mL, 91.04 mmol). The resulting mixture was heated at 110 C for 18 h, concentrated in vacuo, and the residue cooled in an ice bath and acidified with 5% hydrochloric acid solution to pH?3; extracted with EtOAc (100 mL x 3) and washed with water and brine. The organic solution was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, the residue was subjected to column chromatography eluting with a gradient of 20-50% ethyl acetate in hexanes to give 4 as a colorless solid (6.84 g, 61%). mp 98-99 C (EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) delta 8.36-8.21 (m, 1H), 7.72-7.65 (m, 1H), 7.25-7.20 (m, 1H), 6.99-6.92 (m, 2H), 6.85-6.77 (m, 2H), 4.98 (br s, 1H), 3.82-3.73 (m, 1H), 3.66-3.54 (m, 1H), 3.44-3.28 (m, 2H), 2.37-2.24 (m, 2H); 13C NMR (75 MHz, CDCl3) delta 170.0, 157.6 (d, JCF = 238.0 Hz), 152.8, 150.8, 130.0, 129.7, 123.8 (q, JCF = 269.9 Hz), 123.4 (q, JCF = 31.1 Hz), 120.1, 118.9, 116.9, 116.8, 116.3, 116.0, 76.6, 58.7, 51.3, 31.4; MS (ES+) m/z 370.0 (M+1). Anal. Calcd for C18H15F4NO3: C, 58.54; H, 4.09; N, 3.79. Found: C, 58.52; H, 4.06; N, 3.89.
  • 36
  • [ 475111-38-7 ]
  • [ 3413-28-3 ]
  • 4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(4-fluorophenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h; General procedure: Example 2: General procedure for the preparation of compounds (IB 1-20): Cynuric chloride (1) (lOg, 54.2 mmol, 1.0 eq) was substituted by morpholine (7) (4.72 ml, 5.42 mmol, 1.0 eq) in methylene chloride (60 ml), at -50 C for 20 min to obtain intermediate (3). The intermediate (3) (5 g, 1.0 eq) on further treatment with di-substitued benzimidazole (7) (1.4 eq) in presence of K2C03 (1.44 eq) in DMF (20 ml) , at -5 C for 30 min and then at room temperature for 4 h led to intermediate (8) . To the solution of intermediate (8) (100 mg, 1.0 eq) in DMF (3 ml) are added K2C03 (1.4 eq) and substituted aryloxy piperidines (6) (1.44 eq).This resulting reaction mixture was stirred at room temperature for 24 h. The thus-obtained mixture was poured into water (30 ml) and extracted with ethyl acetate twice washed with 2N HC1 solution and dried under vacuo. This crude product was purified by silica gel column chromatography using an ethyl acetate and hexane mixture as solvent to obtained the compounds formula (1B1-20).
  • 37
  • [ 3413-28-3 ]
  • [ 189078-47-5 ]
  • 4-(4-(4-fluorophenoxy)piperidin-1-yl)-N-methyl-6-morpholino-N-phenyl-1,3,5-triazin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h; General procedure: Example 1: General procedure for the preparation of compounds (IA1-20): Cynuric chloride (1) (lOg, 54.2 mmol, 1.0 eq) was substituted by morpholine (7) (4.72 ml, 5.42 mmol, 1.0 eq) in methylene chloride (60 ml), at -50 C for 20 min to obtain intermediate (3). The intermediate (3) (5 g, 1.0 eq) on further treatment with di-substitued amine (4) (1.4 eq) in presence of K2C03 (1.44 eq) in DMF (20 ml) , at -5 C for 30 min and then at room temperature for 4 h led to intermediate (5) . To the solution of intermediate (5) (100 mg, 1.0 eq) in DMF (3 ml) were added K2C03 (1.4 eq) and substituted aryloxy piperidines (6) (1.44 eq).This resulting reaction mixture was stirred at room temperature for 24 h. The thus-obtained mixture was poured into water (30 ml) and extracted with ethyl acetate twice washed with 2N HC1 solution and dried under vacuo. This crude product was purified by silica gel column chromatography using a ethyl acetate and hexane mixture as solvent to obtained the compound of formula 1Α(1-20).
  • 38
  • [ 22280-60-0 ]
  • [ 3413-28-3 ]
  • C17H18FN3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 16h; B1 in DMF (15 mL)(1.50 g, 7.68 mmol), 2-chloro-5-nitropyridine (1.33 g, 7.68 mmol), K2CO3 (3.18 g, 23.0 mmol) in a mixture of 40 16 hours It was stirred. After diluting the mixture with water (20 mL) and extracted with EtOAc (30 mL x2). The combined extracts are washed with brine (60 mL x 2), dried over anhydrous Na2SO4 and concentrated under reduced pressure, after creating the crude residue, the crude residue was silica gel column (PE / EtOAc = 10 / purification by 1) produced by the compound B2.
  • 41
  • [ 3413-28-3 ]
  • C17H20FN3O [ No CAS ]
  • 42
  • [ 3413-28-3 ]
  • C22H25FN4O [ No CAS ]
  • 43
  • [ 3413-28-3 ]
  • C25H27F2N3O2 [ No CAS ]
  • 44
  • [ 3413-28-3 ]
  • C21H27FN4O2 [ No CAS ]
  • 45
  • [ 3413-28-3 ]
  • C17H19FN2O [ No CAS ]
  • 46
  • [ 3413-28-3 ]
  • [ 350-46-9 ]
  • C17H17FN2O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In acetonitrile; for 16h;Reflux; CH3CN (10 mL) in the A2 (280 mg, 1.15 mmol), 4 - fluoro-nitrobenzene (162 mg, 1.15 mmol) and Et3N (232 mg, 2.30 mmol) the mixture to reflux16 hoursIt was heated. CH3CN was removed by concentration under reduced pressure. The residue was silica gel column: to give the (eluent PE / EtOAc = 20/1) produced the compound A3.
  • 47
  • [ 3413-28-3 ]
  • [ 1263188-46-0 ]
  • 4-(2-chloro-4-nitro-1H-imidazol-1-yl)-1-[4-(4-fluorophenoxy)piperidin-1-yl]-2-methylbutan-2-ol [ No CAS ]
  • 48
  • [ 3413-28-3 ]
  • [ 1263188-34-6 ]
  • 4-(2-chloro-4-nitro-1H-imidazol-1-yl)-1-[4-(4-fluorophenoxy)piperidin-1-yl]butan-2-ol [ No CAS ]
  • 49
  • [ 3413-28-3 ]
  • [ 1449698-48-9 ]
  • 2-(4-(4-fluorophenoxy)piperidin-1-yl)-8-nitro-6-(trifluoromethyl)-4H-benzo[e][1,3]thiazine-4-one [ No CAS ]
  • 50
  • [ 3413-28-3 ]
  • 2-(8-chloro-1-oxo-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)acetaldehyde [ No CAS ]
  • 8-chloro-2-(2-(4-(4-fluorophenoxy)piperidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
180 mg C. To a solution of <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (200 mg, 1.024 mmol) in DCM (5 mL) was added 2-(8-chloro-1-oxo-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)acetaldehyde (0.254 g, 1.07 mmol) and acetic acid (0.061 g, 1.019 mmol).The solution was stirred at room temperature for 20 min. Then NaBH(AcO)3 (0.54 g, 2.547 mmol) was added. The reaction was stirred at ambient temperature for 2 h. Water (10 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM (3 x 20 mL). The combined organics were dried over anhydrousNa2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with DCM: MeOH= 100: 1 to 60:1 to give 200 mg of crude product. The crude product was dissolved in HCl- Et2O (20 mL) and stirred at room temperature for 10 min. The mixture solution was concentrated. The residue was washed with Et2O (15 mL). The HCl solid was dissolved in DCM and basified with sat. Na2CO3. The mixture solution was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM (2 x 5 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated to give 180 mg of product.
  • 51
  • [ 3413-28-3 ]
  • 1-((4-(4-fluorophenoxy)piperidin-1-yl)methyl)-2,3-dihydro-1H-indene-5-carbonitrile [ No CAS ]
  • 52
  • [ 3413-28-3 ]
  • 1-((7-fluoro-2,3-dihydro-1H-inden-1-yl)methyl)-4-(4-fluorophenoxy)piperidine hydrochloride [ No CAS ]
  • 53
  • [ 3413-28-3 ]
  • 1-((4-(4-fluorophenoxy)piperidin-1-yl)methyl)-2,3-dihydro-1H-indene-4-carbonitrile [ No CAS ]
  • 54
  • [ 3413-28-3 ]
  • 6-((4-(4-fluorophenoxy)piperidin-1-yl)methyl)-6,7-dihydro-5H-cyclopenta[b]pyridine dihydrochloride [ No CAS ]
  • 55
  • [ 3413-28-3 ]
  • 1-(chroman-4-ylmethyl)-4-(4-fluorophenoxy)piperidine hydrochloride [ No CAS ]
  • 56
  • [ 3413-28-3 ]
  • 1-(2-(2,3-dihydro-1H-inden-1-yl)ethyl)-4-(4-fluorophenoxy)piperidine hydrochloride [ No CAS ]
  • 57
  • [ 3413-28-3 ]
  • 1-(2-(2,3-dihydro-1H-inden-2-yl)ethyl)-4-(4-fluorophenoxy)piperidine hydrochloride [ No CAS ]
  • 58
  • [ 3413-28-3 ]
  • 1-((5-bromo-2,3-dihydro-1H-inden-1-yl)methyl)-4-(4-fluorophenoxy)piperidine [ No CAS ]
  • 59
  • [ 3413-28-3 ]
  • 1-((7-fluoro-2,3-dihydro-1H-inden-1-yl)methyl)-4-(4-fluorophenoxy)piperidine [ No CAS ]
  • 60
  • [ 3413-28-3 ]
  • 1-((4-bromo-2,3-dihydro-1H-inden-1-yl)methyl)-4-(4-fluorophenoxy)piperidine [ No CAS ]
  • 61
  • [ 3413-28-3 ]
  • 6-((4-(4-fluorophenoxy)piperidin-1-yl)methyl)-6,7-dihydro-5H-cyclopenta[b]pyridine [ No CAS ]
  • 62
  • [ 3413-28-3 ]
  • 1-(chroman-4-ylmethyl)-4-(4-fluorophenoxy)piperidine [ No CAS ]
  • 63
  • [ 3413-28-3 ]
  • 1-(2-(2,3-dihydro-1H-inden-1-yl)ethyl)-4-(4-fluorophenoxy)piperidine [ No CAS ]
  • 64
  • [ 3413-28-3 ]
  • 7-(2-(4-(4-fluorophenoxy)piperidin-1-yl)ethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine [ No CAS ]
  • 65
  • [ 3413-28-3 ]
  • 7-(2-(4-(4-fluorophenoxy)piperidin-1-yl)ethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride [ No CAS ]
  • 66
  • [ 3413-28-3 ]
  • 1-(2-(2,3-dihydro-1H-inden-2-yl)ethyl)-4-(4-fluorophenoxy)piperidine [ No CAS ]
  • 67
  • [ 3413-28-3 ]
  • 7-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid [ No CAS ]
  • (7-fluoro-2,3-dihydro-1H-inden-1-yl)(4-(4-fluorophenoxy)piperidin-1-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
130 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; A. To a solution of <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (160 mg, 0.82 mmol) in DCM (15 mL) was added 7-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid (150 mg, 0.83 mmol, synthesized according to Example T-34), triethyl amine (0.21 g, 2.05 mmol) and hydroxybenzotriazole (0.17 g, 1.23 mmol).1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.31 g, 1.64 mmol). Water (20 mL) was added to the reaction vessel and was extracted with EtOAc (3 x 20 ml). The layers were separated and the organic phase was washed with saturated aqueous NaCl (2 x 20 mL). The combined organics were dried over anhhdrous Na2SO4, filtered and concentrated in vacuo. After concentrated, the residue was purified by silica column chromatography (Hexane: EtOAc= 1: 1) to give the desired product (130 mg) as a yellow oil.
  • 68
  • [ 3413-28-3 ]
  • [ 1132943-94-2 ]
  • (5-bromo-2,3-dihydro-1H-inden-1-yl)(4-(4-fluorophenoxy)piperidin-1-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.25 g With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h; A. To a solution of 5-bromo-2,3-dihydro-1H-indene-1-carboxylic acid (180 mg, 0.747 mmol, synthesized according to Example T-34) in DCM (3 mL) was added <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (0.146 g, 0.747 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.101 g, 0.747 mmol), triethylamine (0.227 g, 2.241 mmol) and EDCI (0.287 g, 1.494 mmol). The reaction was stirred at ambient temperature for 16 h. Water (5 mL) and DCM (5 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM (2 x 5 mL). The organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of petroleum ether (85%) and EtOAc (15%) to petroleum ether (80%) and EtOAc (20%) to provide (5-bromo-2,3-dihydro- 1H-inden-1-yl)(4-(4-fluorophenoxy)piperidin-1-yl)methanone (0.25 g, 0.598 mmol) as a yellow oil.
  • 69
  • [ 3413-28-3 ]
  • [ 66041-35-8 ]
  • (4-bromo-2,3-dihydro-1H-inden-1-yl)(4-(4-fluorophenoxy)piperidin-1-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.08 g With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 5h; A. To a solution of 4-bromo-2,3-dihydro-1H-indene-1-carboxylic acid (1 g, 4.148 mmol, synthesized according to Example T-34) in DCM (30 mL) was added <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (0.8098 g, 4.148 mmol), triethylamine (1.0493 g, 10.37 mmol) and HATU (2.3658 g, 6.222 mmol). The reaction was stirred at ambient temperature for 5 h. Water (30 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of hexanes (90%) and EtOAc (10%) to hexanes (70%) and EtOAc (30%) to provide (4-bromo-2,3-dihydro-1H-inden-1-yl)(4-(4- fluorophenoxy)piperidin-1-yl)methanone (1.08 g, 2.5819 mmol) as a colorless oil.
  • 70
  • 6,7‑dihydro‑5H‑cyclopenta[b]pyridine‑6‑carboxylic acid hydrochloride [ No CAS ]
  • [ 3413-28-3 ]
  • (6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)(4-(4-fluorophenoxy)piperidin-1-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; C. To a solution of crude 6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylic acid hydrochloride (300 mg, 1.5027 mmol) in DMF (20 mL) was added <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (0.2934 g, 1.5027 mmol), HBTU (0.57 g, 2.2541 mmol) and Et3N (0.5312 g, 5.2595 mmol). The reaction was stirred at ambient temperature for 12 h. Water (50 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 25 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product (300 mg) was used for the next step without purification.
  • 71
  • [ 20426-80-6 ]
  • [ 3413-28-3 ]
  • 1-chroman-4-yl(4-(4-fluorophenoxy)pipendin-1-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 2h; C. To a solution of chroman-4-carboxylic acid (100 mg, 0.56 mmol) and 4-(4- fluorophenoxy)piperidine (110 mg, 0.56 mmol) in DCM (10.0 mL) was added 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g, 0.56 mmol), N- Hydroxybenzotrizole (0.08 g, 0.56 mmol) and triethylamine (0.11 g, 1.12 mmol). The reaction was stirred at ambient temperature for 2 h. Water (20 mL) was added and then extracted with DCM (3 X 30 mL). The combined organics were washed with brine, dried over Na2SO4. After filtered and concentrated, the residue was purified by silica column chromatography (EtOAc: hexanes = 1.5: 1) to give the desired product (100 mg, 0.28 mmol) as colorless oil.
  • 72
  • [ 3413-28-3 ]
  • [ 38425-65-9 ]
  • 2-(2,3-dihydro-1H-inden-1-yl)-1-(4-(4-fluorophenoxy)piperidin-1-yl)ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.7 g With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 2h; D. To a solution of 2-(2,3-dihydro-1H-inden-1-yl)acetic acid (500 mg, 2.84 mmol) in DCM (30 mL) was added <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (0.4 g, 2.03 mmol), triethylamine (0.62 g, 6.09 mmol) and HOBT (0.38 g 2.84 mmol) and EDCl (0.54 g 2.84 mmol). The reaction was stirred at ambient temperature for 2 h. Water (25 mL) and DCM (100 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was washed with saturated aqueous NaCl (2 x 30 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide 2-(2,3-dihydro-1H- inden-1-yl)-1-(4-(4-fluorophenoxy)piperidin-1-yl)ethanone (0.7 g, 1.98 mmol) as a yellow oil.
  • 73
  • [ 3413-28-3 ]
  • 2-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)acetic acid [ No CAS ]
  • 2-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-1-(4-(4-fluorophenoxy)piperidin-1-yl)ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.45 g With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 2h; D. To a solution of 2-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)acetic acid (360 mg, 2.03 mmol) in DCM (30 mL) was added <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (0.4 g, 2.03 mmol), triethylamine (0.62 g, 6.09 mmol) and HATU (1.54 g, 4.06 mmol). The reaction was stirred at ambient temperature for 2 h. Water (25 mL) and DCM (100 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was washed with saturated aqueous NaCl (2 x 30 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide 2-(6,7-dihydro-5H- cyclopenta[b]pyridin-7-yl)-1-(4-(4-fluorophenoxy)piperidin-1-yl)ethanone (0.45 g, 1.27 mmol) as a yellow oil.
  • 74
  • [ 3413-28-3 ]
  • [ 37868-26-1 ]
  • 2-(2,3-dihydro-1H-inden-2-yl)-1-(4-(4-fluorophenoxy)piperidin-1-yl)ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
120 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h; A. To a solution of <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (100 mg, 0.512 mmol) in DCM (3 mL) was added 2-(2,3-dihydro-1H-inden-2-yl)acetic acid (0.09 g, 0.512 mmol), 1H-benzo[d][1,2,3]triazol- 1-ol (0.069 g, 0.512 mmol), EDCI (0.197 g, 1.024 mmol) and triethylamine (0.155 g, 1.536 mmol). The reaction was stirred at ambient temperature for 16 h. Saturated aqueous NaCl (4 mL) and DCM (5 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was washed with saturated aqueous NaCl (1 x 3 mL). The DCM was dried over anhydrous Na2SO4, filtered and concentrated in vacuo.The resulting oil was purified by flash column chromatography with a gradient elution of hexanes (90%) and EtOAc (10%) to hexanes (75%) and EtOAc (25%) to provide 2-(2,3-dihydro-1H- inden-2-yl)-1-(4-(4-fluorophenoxy)piperidin-1-yl)ethanone (120 mg, 0.34 mmol) as a colorless oil.
  • 75
  • [ 3413-28-3 ]
  • 2-(7-bromo-1-oxo-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)acetaldehyde [ No CAS ]
  • 7-bromo-2-(2-(4-(4-fluorophenoxy)piperidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
150 mg With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 1h; C. To a solution of 2-(7-bromo-1-oxo-4,5-dihydro-1H-benzo[c]azepin-2(3H)- yl)acetaldehyde (140 mg, 0.5 mmol) in DCM (10 mL) was added <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (0.12 g, 0.6 mmol), acetic acid (0.03 g, 0.5 mmol) and sodium triacetoxyborohydride (0.21 g, 1 mmol). The reaction was stirred at ambient temperature for 1 h. Water (20 mL) was added to the reaction vessel and was extracted with DCM (3 x 15 ml). The layers were separated and the organic phase was washed with saturated aqueous NaCl (2 x 15 mL). The combined organics were dried over anhhdrous Na2SO4, filtered and concentrated in vacuo. After concentration, the residue was purified by silica column chromatography (Hexane: EtOAc= 1: 3) to give the desired product (150 mg) as a yellow oil.
  • 76
  • [ 3413-28-3 ]
  • 2-(7-bromo-1-oxo-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)acetaldehyde [ No CAS ]
  • 7-bromo-2-(2-(4-(4-fluorophenoxy)piperidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one hydrochloride [ No CAS ]
  • 77
  • [ 3413-28-3 ]
  • C12H13NO2 [ No CAS ]
  • 2-(2-(4-(4-fluorophenoxy)piperidin-1-yl)propyl)-3,4-dihydroisoquinolin-1(2H)-one [ No CAS ]
  • 78
  • [ 3413-28-3 ]
  • spiro[isochroman-4,2’-oxirane] [ No CAS ]
  • 4-((4-(4-fluorophenoxy)piperidin-1-yl)methyl)isochroman-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
50 mg In methanol; at 60℃; for 8h; To a solution of spiro[isochroman-4,2'-oxirane] (50 mg, 0.3083 mmol) in MeOH (10 mL) was added <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (0.0602 g, 0.3083 mmol). The reaction was stirred at 60 C for 8 h. The reaction mixture was concentrated in vacuo. The resulting oil was purified by reverse phase HPLC with a gradient elution of MeOH (30%) and water(70%) to MeOH (70%) and water (30%) to provide 4-((4-(4-fluorophenoxy)piperidin-1-yl)methyl)isochroman-4-ol (50 mg, 0.1357 mmol) as an oil.
  • 79
  • [ 3413-28-3 ]
  • [ 62956-62-1 ]
  • 4-(4-fluorophenoxy)-1-((6-methoxy-2,3-dihydro-1H-inden-1-yl)methyl)piperidine hydrochloride [ No CAS ]
  • 80
  • [ 3413-28-3 ]
  • [ 62956-62-1 ]
  • (4-(4-fluorophenoxy)piperidin-1-yl)(6-methoxy-2,3-dihydro-1H-inden-1-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
550 mg With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 1h; C. To a solution of 6-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (500 mg, 2.6 mmol) in DCM (30 mL) was added <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (0.51 g, 2.6 mmol), triethylamine (0.53 g, 5.2 mmol) and HBTU (1.31 g, 5.2 mmol). The reaction was stirred at ambient temperature for 1 h. Water (10 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was washed with saturated aqueous NaCl (1 x 5 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of hexanes (100%) to hexanes (70%) and EtOAc (30%) to provide (4-(4- fluorophenoxy)piperidin-1-yl)(6-methoxy-2,3-dihydro-1H-inden-1-yl)methanone (550 mg, 1.49 mmol) as a yellow oil.
  • 81
  • [ 3413-28-3 ]
  • C11H13Br [ No CAS ]
  • 1-(1-(2,3-dihydro-1H-inden-1-yl)ethyl)-4-(4-fluorophenoxy)piperidine [ No CAS ]
  • 82
  • [ 3413-28-3 ]
  • 1-(6-methoxy-2,3-dihydro-1H-1-indenyl)-1-ethanone [ No CAS ]
  • 4-(4-fluorophenoxy)-1-(1-(6-methoxy-2,3-dihydro-1H-inden-1-yl)ethyl)piperidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a solution of 1-(6-methoxy-2,3-dihydro-1H-inden-1-yl)ethanone (90 mg, 0.47 mmol) in THF (1 mL) was added <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (0.09 g, 0.47 mmol) and TTIP (0.4 g, 1.41 mmol). The reaction mixture was heated to 50 C and stirred at that temperature for 2 h. NaBH3CN (0.12 g, 1.88 mmol) was added to the solution. The reaction was stirred at ambient temperature for 30 min.1M aqueous HCl (20 mL) and DCM (100 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was washed with saturated aqueous NaHCO3 (2 x 20 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting oil was purified by reverse phase HPLC with a gradient elution of MeOH (5%) and water (95%) to MeOH (40%) and water (60%) to provide 4-(4-fluorophenoxy)-1-(1-(6-methoxy-2,3-dihydro-1H-inden-1-yl)ethyl)piperidine (5 mg of the early eluting peak and 10 mg of the late eluting peak) as a colorless oil.
  • 83
  • [ 87033-30-5 ]
  • [ 3413-28-3 ]
  • [ 1147550-11-5 ]
  • 2-(4-(4-fluorophenoxy)piperidin-1-yl)-8-nitro-6-(trifluoromethyl)-4H-benzo[e][1,3]thiazine-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
To 2-chloro-3-nitro-5-trifluoromethylbenzoic acid (12 mmol) was added 20 mL of dichloromethane.Oxalyl chloride (30.5 mmol) and 0.05 mL of DMF were slowly added dropwise under stirring at room temperature for two hours.After the reaction was completed, the reaction solution was spoked, dissolved in 15 mL of dichloromethane, and slowly added dropwise with ammonium thiocyanate (36 mmol).Add PEG-400 (0.2g), stir at room temperature for 1.5 hours; filter,The filtrate was added to a solution of <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> in dichloromethane.Stir at room temperature for 40 minutes. After the reaction is completed, the reaction solution is spun dry, column chromatography,A yellow solid 1b was obtained with a yield of 47%.
  • 84
  • [ 3413-28-3 ]
  • [ 22980-10-5 ]
  • [ 63843-67-4 ]
  • 85
  • [ 3413-28-3 ]
  • 4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzaldehyde [ No CAS ]
  • 3-(6-(4-((4-(4-fluorophenoxy)piperidin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
6.02% With phenylsilane; dibutyltin chloride; In tetrahydrofuran; at 90℃; for 16h;Sealed tube; To the stirred solution of 4-[[1-(2,6-dioxo-3- piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]benzaldehyde (250 mg, 627.49 umol) in THF (6 mL) was added <strong>[3413-28-3]4-(4-fluorophenoxy)piperidine</strong> (122.51 mg, 627.49 umol) followed by the addition of dibutyltin(2+);dichloride (228.79 mg, 752.99 umol, 168.23 uL) and phenylsilane (67.90 mg, 627.49 umol,77.43 uL).The reaction mixture was then stirred at 90C for 16 hours in a sealed tube.TLC showed formation of new spot.The reaction mixture was diluted with ethyl acetate, washed with water and brine solution.The organic fraction was separated.It was dried over anhydrous sodium sulphate, evaporated under reduced pressure to obtain the crude compound which was purified by flash chromatography using 0-5% MeOH-DCM to afford 3-[6-[[4-[[4-(4- fluorophenoxy)-1-piperidyl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6- dione Compound 258 (22 mg, 37.78 umol, 6.02% yield, 99.2% purity) as yellow solid.1H NMR (400 MHz, DMSO-d6): d 11.09 (s, 1H), 8.31 (d, J=8Hz, 1H), 8.05 (d, J=8Hz, 1H),7.80 (t, J=8Hz, 1H),7.39 (d, J=8Hz, 1H), 7.21-7.15 (m, 4H), 7.08-7.02 (m, 3H),6.90 (bs,2H) 5.42- 5.39 (m, 1H), 4.34 (s, 2H), 4.24 (s, 1H), 3.37 (s, 2H) 2.95-2.88 (m, 1H), 2.77-2.70 (m, 1H), 2.67- 2.59 (m, 3H), 2.12-2.06 (m, 3H), 2.04 (m, 2H), 1.54 (m, 2H), LCMS (ES+) = 578.2 [M+H]+.
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