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[ CAS No. 5382-16-1 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 5382-16-1
Chemical Structure| 5382-16-1
Chemical Structure| 5382-16-1
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Product Details of [ 5382-16-1 ]

CAS No. :5382-16-1 MDL No. :MFCD00005999
Formula : C5H11NO Boiling Point : -
Linear Structure Formula :- InChI Key :HDOWRFHMPULYOA-UHFFFAOYSA-N
M.W : 101.15 Pubchem ID :79341
Synonyms :
Chemical Name :4-Piperidinol

Calculated chemistry of [ 5382-16-1 ]

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 2.0
Molar Refractivity : 31.91
TPSA : 32.26 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.15 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.33
Log Po/w (XLOGP3) : -0.33
Log Po/w (WLOGP) : -0.65
Log Po/w (MLOGP) : -0.16
Log Po/w (SILICOS-IT) : 0.73
Consensus Log Po/w : 0.18

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.26
Solubility : 55.7 mg/ml ; 0.551 mol/l
Class : Very soluble
Log S (Ali) : 0.11
Solubility : 131.0 mg/ml ; 1.3 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -0.44
Solubility : 37.0 mg/ml ; 0.366 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 5382-16-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P264-P280-P302+P352-P305+P351+P338-P332+P313-P337+P313-P362+P364 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 5382-16-1 ]

* 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 [ 5382-16-1 ]

[ 5382-16-1 ] Synthesis Path-Downstream   1~93

  • 1
  • [ 5382-16-1 ]
  • [ 445-28-3 ]
  • [ 131269-81-3 ]
  • 2
  • [ 5382-16-1 ]
  • [ 58656-98-7 ]
  • [ 95017-91-7 ]
  • 3
  • [ 5382-16-1 ]
  • [ 68077-26-9 ]
  • [ 75001-74-0 ]
  • 4
  • [ 5382-16-1 ]
  • [ 82419-35-0 ]
  • [ 82419-37-2 ]
YieldReaction ConditionsOperation in experiment
In water; dimethyl sulfoxide; EXAMPLE 4 140 mg of <strong>[82419-35-0]9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid</strong> and 404 mg of 4-hydroxypiperidine were added to 2 ml of dimethylsulfoxide. The mixture was stirred at a temperature of from about 100 to 110 C. (bath temperature) for 5.5 hours and the reaction mixture was concentrated to dryness in vacuo. Water was added to the residue and the mixture was neutralized with diluted hydrochloric acid to yield precipitate. The precipitate was collected by filtration, washed with water, and then recrystallized from ethanol to provide 66 mg of 9-fluoro-10-(4-hydroxy-1-piperidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid with m.p. 220-240 C. (with decomposition). Analysis for C18 H19 FN2 O5; Calculated: C 59.66, H 5.29, N 7.73; Found: C 59.24, H 5.26, N 7.65.
  • 5
  • [ 5382-16-1 ]
  • [ 350-46-9 ]
  • [ 79421-45-7 ]
YieldReaction ConditionsOperation in experiment
93% With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 1.0h; Reference Example 5 Synthesis of Compound 12 [Show Image] Compound 11 (2.12 g, 15.0 mmol) and Compound 8 (1.82 g, 18.0 mmol) were dissolved in DMF (15 ml), potassium carbonate (2.52 g, 18.0 mmol) was added, and the mixture was stirred at 85C for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, followed by extraction with chloroform. After dried with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-acetonitrile) to obtain Compound 12 (3.10 g, yield 93%). mp 115.6-117C 1H-NMR (CDCl3 / TMS) deltappm: 1.62-1.74 (m, 2H), 1.99-2.02 (m, 2H), 2.87-2.95 (m, 2H), 3.47-3.54 (m, 2H), 3.82-3.88 (m, 1H), 6.85 (d, J = 8.7Hz, 2H), 7.19 (d, J = 8.7Hz, 2H).
92% With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; Step: 3A-1Synthesis of l-(4-Nitro-phen -piperidin-4-ol.Procedure:K2C03 (2.44g, 0.0177mol) followed by l-Fluoro-4-nitro-benzene (lg, 0.00708mol) was added to a stirred solution of Piperidin-4-ol (0.86g, 0.00850mol) in DMF (5ml) and stirred at RT. The resulting reaction mixture was heated at 60C. The reaction was monitored by the TLC (50% EtOAc: hexane). The reaction mixture was cooled to RT, and ice was added into it to precipitate a solid which was collected to afford 1.45g (92% yield) of l-(4- Nitro-phenyl)-piperidin-4-ol.
86.14% With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 5.0h; Weigh the compound 18 (10.00 g, 70.87 mmol) in a reaction flask,Piperidinol 26 (7.87 g, 77.96 mmol) was added sequentially,Potassium carbonate (11.74 g, 85.04 mmol),85 mL of DMF,70 heating and stirring,5h, stop reaction; filter,Filter insoluble solids,And rinsed with a small amount of DMF,The filtrate was poured into 650 mL of water,Static precipitation, solidification,The filter cake was dried at 60 C under vacuum for 14.56 gOrange solid 33, the yield was 86.14%.
84.74% With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 1.0h; To a stirred solution of 135 1-fluoro-4-nitrobenzene (3 g, 21.27 mmol, 1 eq) and 452 piperidin-4-ol (3.2 g, 31.91 mmol, 1.5 eq) in 47 DMF (20 mL) was added 64 K2CO3 (3.8 g, 27.65 mmol, 1.3 eq). Reaction mixture was stirred at 85 C. for 1 hr. Progress of reaction was monitored by LCMS. After consumption of starting material, reaction mixture was poured on ice cold water and precipitated 453 compound was filtered off and dried under vacuum. Solid was washed with diethyl ether and pentane to obtain 4 g (84.74%) of 1-(4-nitrophenyl)piperidin-4-ol. (0515) LCMS: 223 [M+1]+
78% With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 1.0h; To a solution of 14.1g (0.10mol) of 4-fluoronitrobenzene in 200mL of N, N-dimethylformamide were added 20.73 (0.15mol) of potassium carbonate and 10.1g (0.10mol) of 4-hydroxypiperidine and the mixture was stirred for 1 hour at 140C. The reaction mixture was cooled to room temperature and the mixture was treated with chloroform, then insoluble substances were removed off by filtration. The filtrate was condensed and the residue was recrystallized from ethanol to give 17. 27g (78%) of the title compound.
71% With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 105℃; for 48.0h; The 1-(4-Amino-phenyl)-piperidin-4-ol is prepared from p-fluoronitrobenzene by using the following multiple step procedure: Step 1: 1-(4-Nitro-phenyl)-piperidin-4-ol.; A 100 mL round bottom flask was dried in an oven overnight and cooled to room temperature under Ar(g). The flask was charged with fluoronitrobenzene (0.500 mL, 4.71 mmol), Piperidin-4-ol (0.619 g, 2.30 mmol) and dioxane (9.0 mL). To the resulting solution, diisopropyl ethyl amine (0.463 mL, 6.12 mmol) was added dropwise, and the reaction was allowed to stir at 105 C. for 48 h. The mixture was extracted with EtOAc (3×50 mL), and brine (2×50 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified over silica (10% MeOH/90% CHCl3) affording a yellow solid (0.742 g, 3.34 mmol, 71% yield).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; Example 7 1-(4-(4-(1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperidin-4-ol A mixture of 1-fluoro-4-nitrobenzene (0.588 mL, 5.55 mmol), 4-hydroxypiperidine (0.560 g, 5.54 mmol) and K2CO3 (1.50 g, 10.9 mmol) in dimethylformamide (DMF) (10 mL) was stirred at room temperature overnight. Water was then added to induce precipitation. The yellowish solid was collected by filtration (0.90 g).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; A mixture of l-fluoro-4-nitrobenzene (0.588 mL, 5.55 mmol), 4-hydroxypiperidine (0.560 g, 5.54 mmol) and K2CO3 (1.50 g, 10.9 mmol) in DMF (10 mL) was stirred at room temperature overnight. Water was added to induce precipitation. The yellowish solid was collected by filtration (0.90 g).
With potassium carbonate; In water; dimethyl sulfoxide; at 100℃; for 4.0h; To a mixture of 1-fluoro-4-nitrobenzene (2.82 g, 20 mmol) and K2CO3 (6.92 g, 50 mmol) in dimethyl sulfoxide (20 mL) was added piperidin-4-ol (2.22 g, 22 mmol) and the reaction was heated to 100 C. for 4 hours. This solution was poured into 200 ml of water and extracted with ethyl acetate (30 mL*3). The organic phase was combined and washed with saturated brine and dried over anhydrous sodium sulfate.
1.025 g With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 8.0h;Reflux; A solution of 1-fluoro-4-nitrobenzene (0.658 g, 4.66 mmol), 4-hydroxypiperidine (0.590 g, 5.81 mmol) and DIEA (1.24 mL, 7.12 mmol) in anhyd CH3CN (7 mL) was refluxed for 8 hours. The volatiles were removed in vacuo and the residue was suspended in water (15 mL) to give a bright yellow suspension. The solid was collected by vacuum filtration, washed with water and dried in vacuo to give 1.025 g 1-(4-nitro-phenyl)-piperidin-4-ol. MS (MH+): 223
With piperidine; potassium carbonate; In dimethyl sulfoxide; at 120℃; for 4.0h; Piperidine in dimethyl sulfoxide (3 mL) -4-ol (1.4 mmol), 1- fluoro-4-nitrobenzene (1.6 mmol) and potassium carbonate (2.8 mmol) the mixture was heated for 4 hours at 120 . After cooling, then the mixture is poured in water, which is generatedThe solid was filtered and was washed with water and dried to produce a B1.
With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; General procedure: Substituted amine (1.2 equiv) was added to a mixture of 4-fluoronitrobenzene (1 equiv) and K2CO3 (2.0 equiv) in DMF (7mL/g). The reaction mixture was stirred at 40C and followed by TLC. After completion of the reaction, the mixture was poured into stirring ice-water. The resulting precipitate was filtered and dried to obtain compounds 11 as a yellow solid.

  • 6
  • [ 5382-16-1 ]
  • [ 4701-17-1 ]
  • [ 207290-72-0 ]
YieldReaction ConditionsOperation in experiment
71% In water;Reflux; 5-Bromothiophene-2-carboxaldehyde was placed in a reactor, and water was added thereto. 4-Hydroxypiperidine (3 eq) was added to the reactor, and the mixture was stirred for tens of minutes or overnight under reflux. Immediately after completion of reaction, the reaction mixture was filtered through filter paper, and the filtrate was cooled for tens of minutes with a flow of water and then for several hours with ice. The precipitated crystals were recovered through filtration under suction and washed with cold water. The crystals were dried and dissolved in chloroform. The chloroform solution was dried over sodium sulfate anhydrate, and the dried solution was filtered through a silica gel pad. The filtrate was washed with chloroform until the color thereof became faint. The filtrate was concentrated under reduced pressure until the start of crystallization. n-Hexane was added to the mixture, and stirring was performed overnight at room temperature. The formed crystals were recovered through filtration, washed with n-hexane, and dried under reduced pressure, to thereby yield 5-(4-hydroxypiperidin-1-yl)-thiophene-2-carboxaldehyde. By use of 5-bromothiophene-2-carboxaldehyde (42.30 g) and 4-hydroxypiperidine (67.30 g), amine incorporation was performed according to Production Step 1, to thereby yield 5-(4-hydroxy-piperidin-1-yl)-thiophene-2-carboxaldehyde (yield: 33.00 g, 71%). The thus-produced 5-(4-hydroxy-piperidin-1-yl)-thiophene-2-carboxaldehyde (10.56 g) and 3,4-dimethoxybenzyl cyanide (8.86 g) were subjected to condensation according to Production Step 2, to thereby yield (Z)-2-(3,4-dimethoxy-phenyl)-3-[5-(4-hydroxy-piperidin-1-yl)-thiophen-2-yl]-acrylonitrile (yield: 13.50 g, 73%). The thus-produced (Z)-2-(3,4-dimethoxy-phenyl)-3-[5-(4-hydroxy-piperidin-1-yl)-thiophen-2-yl]-acrylonitrile (20.00 g) was dissolved in chloroform (650 mL), and the solution was reacted with pyridine (6.41 g) and bromoacetyl bromide (14.13 g) according to Production Step 3 (Method A), to thereby yield bromo-acetic acid 1-[5-[(Z)-2-cyano-2-(3,4-dimethoxy-phenyl)-vinyl]-thiophen-2-yl]-piperidin-4-yl ester (yield: 23.00 g, 87%). The thus-produced bromo-acetic acid 1-[5-[(Z)-2-cyano-2-(3,4-dimethoxy-phenyl)-vinyl]-thiophen-2-yl]-piperidin-4-yl ester (2.30 g) was dissolved in chloroform (100 mL), and the solution was reacted with piperidine (533 mg) and triethylamine (658 mg) according to Production Step 4, to thereby yield the title compound (yield: 1.40 g, 60%).
  • 7
  • [ 5382-16-1 ]
  • [ 2785-89-9 ]
  • paraformaldehyde [ No CAS ]
  • [ 81490-74-6 ]
  • 8
  • [ 5382-16-1 ]
  • [ 26032-72-4 ]
  • [ 881194-69-0 ]
  • [ 881194-89-4 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In butan-1-ol; at 120℃; for 12h;Product distribution / selectivity; A mixture of compound, <strong>[26032-72-4]2,4-dichloro-6-phenyl-pyrimidine</strong> (13 g, 57.77 mmol), piperidin-4-ol (2.9 g, 28.88 mmol) and triethylamine (32.14 mL, 231.11 mmol) in butanol (110 mL) was stirred at 1200C for 12 hours under nitrogen atmosphere. The reaction mixture was then poured into water (250 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were collected, combined, washed with water (50 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum. The residue thus obtained was purified by column chromatography using ethyl acetate-petroleum ether to give the two compounds, l-(4-chloro-6-phenyl- pyrimidin-2-yl)-piperidin-4-ol and 1 -(2-chloro-6-phenyl-pyrimidin-4-yl)-piperidin-4- ol in ratio 1:4 (overall yield: 51%). Spectral data for l-(4-chloro-6-phenyl-pyrimidin-2-yl)-piperidin-4-ol: M.P.: 105-1100C.1HNMR(400MHz,OmegaMUSDO-d6):delta8.03-8.0(m,2H),7.56-7.43 (m,3H),6.92(s, IH), 4.67(brs, IH),4.52-4.0(m,2H),4.02-3.98(m, IH),3.48-3.41 (m,2H),2.16-1.96(m, 2H), 1.59-1.50(m,2H). IR(KBr,cm"1):3327, 1564. MS:m/z(CI)290(M+, 100).Spectral data for l-(2~Chloro-6-phenyl-pyrimidin-4-yl)-piperidin-4-ol: M.P.: 120-1250C. EPO <DP n="222"/>1H NMR (400 MHz, DMSO-J6): delta 7.96-7.92 (m, 2H), 7.48-7.42 (m, 3H), 6.78 (s, IH), 4.21-4.10 (m, 2H), 4.08-4.0 (m, IH), 3.49-3.41 (m, 2H), 1.99-1.94 (m, 2H),1.66-1.57 (m, 2H). I IRR ((KKBBrr,, c cmm""11)):: 3333'77, 1591. MS: m/z (CI) 290 (M", 100).
Product distribution / selectivity; The following compounds presented in Examples 40-47 were prepared in accordance with Scheme 5, by a procedure analogous to that disclosed in Example 39, using starting materials with the appropriate substitution.
  • 9
  • [ 5382-16-1 ]
  • [ 55676-22-7 ]
  • [ 265108-19-8 ]
  • 10
  • [ 5382-16-1 ]
  • [ 380844-49-5 ]
  • 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[3-(4-hydroxy-piperidin-1-yl)-propoxy]-6-methoxy-quinoline-3-carbonitrile [ No CAS ]
  • 11
  • [ 5382-16-1 ]
  • [ 369-25-5 ]
  • [ 247035-19-4 ]
YieldReaction ConditionsOperation in experiment
With dimethyl sulfoxide; In water; ethyl acetate; Intermediate 34: Methyl 3-fluoro-4-(4-hydroxypiperidin-1-yl)benzoate Dimethyl sulfoxide (100 ml) was added to 24.5 g of 4-hydroxypiperidine to prepare a solution. <strong>[369-25-5]Methyl 3,4-difluorobenzoate</strong> (33.2 g) was added to the solution. The mixture was stirred at 120 C. for 8 hr. The reaction solution was then cooled to room temperature, and poured into 1,000 ml of water, followed by extraction twice with 750 ml of ethyl acetate. The combined organic layer was washed twice with 500 ml of saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under the reduced pressure to prepare 42.3 g of the title compound. Physicochemical Properties of Intermediate 34
  • 12
  • [ 5382-16-1 ]
  • [ 334792-52-8 ]
  • [ 334792-54-0 ]
  • 13
  • [ 5382-16-1 ]
  • [ 82702-31-6 ]
  • [ 334792-21-1 ]
  • 14
  • [ 5382-16-1 ]
  • [ 1722-12-9 ]
  • [ 893755-98-1 ]
YieldReaction ConditionsOperation in experiment
81% With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 18h; Step 1 : 1-(2-Pyrimidinyl)-4-piperidinol (180) <n="157"/>4-Hydroxypiperidine (1.5 g, 14.7 mmol) was combined with 2-chloropyrimidine (1.5 g, 13.4 mmol) and diisopropylethylamine (6 ml_, 33.5 mmol) into 50 ml. acetonitrile. The mixture was heated at 80 0C for 18 hours. The reaction mixture was then concentrated to dryness and the crude residue was then purified on via flash column chromatography using a gradient of 0-60% ethylacetate/hexane to give 2.1 g (81%) of the desired compound 180 as a white solid. 1H NMR (400 MHz, CDCI3): delta 8.28 (d, J = 4.6 Hz 2 H), 6.49 (t, J = 4.8 Hz, 1 H), 4.49 - 4.33 (m, 2 H), 4.01 - 3.88 (m, 1 H), 3.37 - 3.21 (m, 2 H), 2.02 - 1.90 (m, 2 H), 1.60 - 1.45 (m, 2 H); LCMS (ESI): m/z 180 (M + H)+.
  • 16
  • [ 5382-16-1 ]
  • XCH2COOH [ No CAS ]
  • [ 3518-83-0 ]
  • 17
  • [ 5382-16-1 ]
  • [ 23499-01-6 ]
  • 18
  • [ 5382-16-1 ]
  • [ 62965-10-0 ]
  • [ 325796-51-8 ]
YieldReaction ConditionsOperation in experiment
64% With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 12h; Step A [1S-(4-Hydroxy-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid benzyl ester To a cold solution (0 C.) of the Z-tert-leucine (3.48 g, 13.1 mmol) and 4-hydroxy piperidine (1.4 g, 13.7 mmol) in CH2Cl2 (40 ml) were added WSC (2.75 g, 14.4 g) followed by HOAt (18 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 12 hours and then washed with water and brine. The combined organic layer was dried over MgSO4 and the solvent removed under reduced pressure to furnish a yellow oil which was purified through flash chromatography. The desired compound was obtained in 64% yield. 1H NMR; delta (CDCl3), 7.34 (5H, s), 5.58 (1H, m), 5.08 (2H, m), 4.60 (1H, m), 3.91 (3H, m), 3.49-3.05 (2H, m), 1.91 (4H, m), 0.98 (9H, d, J=3.57); ESMS; +ve ion 371 [M+Na]; HPLC: RT=5.44 min.
  • 19
  • [ 5382-16-1 ]
  • [ 52147-97-4 ]
  • [ 61348-47-8 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In tetrahydrofuran; at 20℃; Triethylamine (8. 0g, 0. [079MOL)] was added to a stirred solution of [E- (3-] styrenesulphonyl chloride [(12.] 0g, 0. [059MOL)] and 4-hydroxypiperidine (8. 0g, 0. [079MOL)] in THF (100ml) at RT. Stirring was continued overnight before the reaction mixture was reduced to low volume and partitioned between EtOAc followed by aqueous 1M [HC1,] saturated [NAHCO3] and brine. The organic fraction was then dried [(NA2SO4)] and evaporated to give a solid product. (12.75g ; 0. 046mol) ; NMR (CDC13) : 1.5-1. 8 (m, 4H), 1.9-2. 1 (m, 2H), 3.0-3. 2 (m, 2H), 3.4-3. 6 (m, 2H), 3.85 (s, 1H), 6.65 (s, 1H), 7.3-7. 6 (m, 6H); MS: 268.
  • 20
  • [ 5382-16-1 ]
  • [ 96606-37-0 ]
  • 2,6-difluoro-4-(4-hydroxy-piperidin-1-yl)-benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
21% With N-ethyl-N,N-diisopropylamine; In methanol; at 65℃; for 4h; Example 7: Synthesis OF 3-AMINO-4-ETHOXY-6- (4-HYDROXY-PIPERIDIN-1-YL)- benzo [B] THIOPHENE-2-CARBOXYLIC acid amide To a solution of 1.0 g (6.4 mmol) of 2, 4,6-trifluorobenzonitrile in MEOH (35 mL) was added 0.65 g (6.4 mmol) of 4-hydroxypiperidine and 1.2 mL (6.7 mmol) OFF, N diiisopropylethylamine. The mixture was heated to 65 C FOR 4 h then cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.325 g (21 %) OF 2, 6-DIFLUORO-4- (4-HYDROXY- PIPERIDIN-L-YL)-BENZONITRILE as a white solid.
  • 21
  • [ 5382-16-1 ]
  • [ 1435-49-0 ]
  • [ 245057-73-2 ]
YieldReaction ConditionsOperation in experiment
With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 1.5h;Heating / reflux; 4-Hydroxypiperidine (50 g) was added portionwise to a stirred suspension ofpotassium fert-butoxide (1 10.9 g) in THF (900 mL) at room temperature and undernitrogen. The mixture was heated at reflux and l,2-dichloro-4-fluorobenzene (98 g) addeddropwise over 30 min. The mixture was stirred at reflux for another 1 h then cooled downs10 to room temperature, diluted with ethyl acetate (500 mL) and washed with water (500 mL).The organic phase was diluted further with ethyl acetate (500 mL) and extracted with 1Mhydrochloric acid (200 mL). The aqueous extract was adjusted to over pH 10 by additionof a solution of sodium hydroxide and extracted twice with tert-butylmethyl ether (750mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated1 5 under vacuum to yield the sub-title compound as a dark oil which was used as such in thenext step.MS (ESI+ve) 246/248 [M+H]+.H NMR 5 (CDC13) 1.60-1.70 (2H, m), 1.97-2.03 (2H, m), 2.75 (2H, td), 3.15 (2H,dt), 4.29-4.37 (1H, m), 6.78 (1H, dd), 7.00 (1H, d), 7.31 (1H, d).
  • 22
  • [ 5382-16-1 ]
  • [ 84946-20-3 ]
  • 1-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-hydroxypiperidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
In isoamylic alcohol; for 12h;Heating / reflux; EXAMPLE 2 1-[1-(4-Fluorobenzyl)-1H-benzimidazol-2-yl]-4-hydroxypiperidine (3) A mixture of 3.9 g of 4-hydroxypiperidine, 5 g of 2-chloro-1-(4-fluorobenzyl)-benzimidazol in 30 mL of isoamylic alcohol is taken to reflux for 12 hours. Once the reaction has finished, the product is isolated by removal of the solvent under reduced pressure and redissolving the residue in 15 mL of ethyl acetate and 15 mL of water. The organic phase is decanted, and the aqueous phase is extracted again with 7 mL of ethyl acetate. The organic phases are brought together and the solvent is removed. The obtained residue is crystallized in toluene, obtaining 3.7 g of 1-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-hydroxypiperidine (3). 13C-NMR (CDCl3, delta in ppm): 34.17 (CH2), 47.05 (CH2), 48.64 (CH2), 67.04 (CH), 109.27 (CH), 143.40 (C), 163.37 (C).
  • 23
  • [ 5382-16-1 ]
  • [ 67-64-1 ]
  • [ 5570-78-5 ]
YieldReaction ConditionsOperation in experiment
100% A mixture of 4-hydroxypiperidine (10g, 0.10mol), acetone (21.8mL, 0.30mol), acetic acid (5.7mL, 0.10mol) and tetrahydrofuran (150mL) was stirred in an ice bath for 15 minutes. Sodium triacetoxyborohydride (31.3g, 0.15mol) was then added portionwise and the mixture was stirred for a further 10 minutes. The reaction mixture was then warmed and stirred at room temperature for 10 minutes and at 40C for 2.5 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in water (50mL). The aqueous solution was basified to pH9 with 0.88 ammonia and the solution was stirred for 30 minutes. The reaction mixture was then extracted with diethyl ether (2x200mL) and the combined extracts were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography on silica gel, eluding with dichloromethane:methanol:0.88 ammonia, 96:4:1 to 90:10:1, to afford the title product as a yellow oil in quantitative yield, 14.6g. 1H-NMR(CDCl3, 400MHz) delta: 0.92-1.02(m, 6H), 1.41-1.57(m, 2H), 1.77-1.89(m, 2H), 2.07-2.23(m, 2H), 2.57-2.78(m, 3H), 3.43-3.85(brm, 2H) MS ES+ m/z 144 [MH]+
100% Preparation 3 1 -lsopropyl-piperidin-4-olA mixture of 4-hydroxypiperidine (1Og, O.IOmol), acetone (21.8ml, 0.30mol), acetic acid (5.7ml, O.IOmol) and tetrahydrofuran (150ml) was stirred in an ice bath for 15 minutes. Sodium triacetoxyborohydride (31.3g, 0.15mol) was then added portion wise and the mixture was stirred for a further 10 minutes. The reaction mixture was then warmed and stirred at room temperature for 10 minutes and at 400C for 2.5 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in water (50ml). The aqueous solution was basified to pH9 with 0.88 ammonia and the solution was stirred for 30 minutes. The reaction mixture was then extracted with diethyl ether (2x200ml) and the combined extracts were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 96:4:1 to 90:10:1 , to afford the title product as a yellow oil in quantitative yield, 14.6g.1HNMR(CDCI3, 400MHz) delta: 0.92-1.02(m, 6H), 1.41-1.57(m, 2H), 1.77-1.89(m, 2H), 2.07-2.23(m, 2H), 2.57-2.78(m, 3H), 3.43-3.85(brm, 2H) MS ES+ m/z 144 [MH]+
29% To a stirred solution of piperidin-4-ol (1 g, 9.87 mmol) in DCE (100 ml) under an atmosphere of nitrogen was added acetic acid (1.78 g, 29.7 mmol) and acetone (5.72 g, 98.7 mmol). The reaction mixture was stirred for 12 h at RT before addition of STAB (6.29 g, 29.7 mmol).After stirring for 12 h at RT the reaction mixture was concentrated at reduced pressure to give a white solid. Purification by FCC [SiO2, eluting on a gradient from 98:2 EtOAc/MeOH to90:10:1 EtOAc/MeOH/NH3] to give the title compound (412 mg, 29 %) as a colourless oil.1H NMR (250 MHz, CHLOROFORM-J) delta ppm 4.97 (1 H, br. s.), 3.39 (1 H, m, J=8.6, 4.0Hz), 2.23 - 2.77 (3 H, m), 1.88 - 2.16 (2 H, m), 1.49 - 1.75 (2 H, m), 1.35 (2 H, m, J=12.6,9.3, 9.3, 3.6 Hz), 0.63 - 0.97 (6 H, m).
To a suspension of 4-hydroxypiperidine (30 g) and Na2SO4 (20 g) in 600 ml of chloroform, is added 24 ml of acetone and stirred for 24 h at AT, then 120 g of sodium triacetoxyborohydride are gradually added, and stirred for a further 24 h at AT. 400 ml MeOH are added dropwise, stirring continued for 2 h at AT and the solvent evaporated in vacuo. The residue is redissolved in 40 ml water, basified, extracted with DCM and the organic layer is evaporated in vacuo. 24.1 g of the desired product are obtained.

  • 24
  • [ 5382-16-1 ]
  • [ 75-26-3 ]
  • [ 5570-78-5 ]
YieldReaction ConditionsOperation in experiment
80% With potassium carbonate; In methanol;Heating / reflux; Intermediate 21: Methanesulfonic acid 1-isopropyl-piperidin-4-yl ester [] Step 1:; 4-Hydroxypiperidine (2.13g, 21.1mmol), K2CO3 (5.83g, 2eq.), 2-bromopropane (11.2g, 91 mmol, 4.3eq.) and MeOH (21.3ml) were refluxed together overnight. The reaction was allowed to cool to room temperature and quenched with 2M HCl solution (40ml) and extracted with TBME (40ml). The aqueous phase was basified to pH 14 with 2M NaOH solution and extracted with DCM (9 x 50ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo to give 1-isopropyl-4-hydroxypiperidine (2.41g, 80%th) as a pale yellow oil.1H NMR (400MHz, CDCl3) delta3.67 (m, 1H), 2.85-2.66 (m, 3H), 2.33-2.20 (m, 2H), 1.99-1.38 (m, 5H), 1.04 (d, 6H).
35% With potassium carbonate; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 12h; In a similar fashion (Rl, GP A) 2-bromopropane (1.46 g, 11.86 mmol), gave the title compound (0.5 g, 35% yield) as oil after purification by FCC [SiO2, eluting with 85:15:2 DCM / MeOH / NH3].1H NMR (250 MHz, CHLOROFORM-J) delta ppm 4.97 (1 H, br. s.), 3.39 (1 H, m, J=8.6, 4.0 Hz), 2.23 - 2.77 (3 H, m), 1.88 - 2.16 (2 H, m), 1.49 - 1.75 (2 H, m), 1.35 (2 H, m, J=12.6, 9.3, 9.3, 3.6 Hz), 0.63 - 0.97 (6 H, m).
With potassium carbonate; In methanol; for 12h;Reflux; <Preparation of Intermediate 7> l-isopropyl-piperidin-4-oI 4-piperidinol (2.13 g, 21.1mmol) was added to methanol (21 mL), and potassium carbonate (5.83 g, 42.2 mmol) and 2-bromopropane (11.2 g, 90.7 mmol) were further added thereto, followed by refluxing for 12 hours while stirring. Then, the reaction mixture was mixed with 2M HCl (40 mL) and extracted three times with dichloromethane (50 mL). The organic layer thus obtained was dried over anhydrous magnesium sulfate, and filtered and distilled under reduced pressure to obtain the title compound (2.2g) as oil. 1H NMR (300 MHz, CDC13): delta 3.65(m, 1H), 2.76(m, 2H), 2.26(m, 3H), 1.92(m, 2H), 1.56(m, 2H), 1.02(d , 6H).
2.2 g With potassium carbonate; In methanol; for 12h;Reflux; 4-piperidinol (2.13 g, 21.1 mmol) was added to methanol (21 mL), and potassium carbonate (5.83 g, 42.2 mmol) and 2-bromopropane (11.2 g, 90.7 mmol) were further added thereto, followed by refluxing for 12 hours while stirring. Then, the reaction mixture was mixed with 2M HCl (40 mL) and extracted three times with dichloromethane (50 mL). The organic layer thus obtained was dried over anhydrous magnesium sulfate, and filtered and distilled under reduced pressure to obtain the title compound (2.2 g) as oil. [0331] 1H NMR (300 MHz, CDCl3): delta 3.65 (m, 1H), 2.76 (m, 2H), 2.26 (m, 3H), 1.92 (m, 2H), 1.56 (m, 2H), 1.02 (d, 6H).

YieldReaction ConditionsOperation in experiment
Example 103 By an analogous procedure to that described in example 101 starting with 2,6-dichloro-9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)purine and 4-hydroxypiperidine was prepared 2-chloro-6-(4-hydroxy-1-piperidinyl) -9-(beta-D-ribofuranosyl)purine (W. Kampe et al, Patent No. DE 2157036); mass spectrum (ESI) m/z 386 [M+H]+.
  • 26
  • [ 5382-16-1 ]
  • [ 23806-24-8 ]
  • 1-[3-(dmethylamino)propyl]-3-ethylcarbodiimide hydrochloride [ No CAS ]
  • (4-Hydroxy-1-piperidinyl)(3-methyl-thien-2-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; benzotriazol-1-ol; In N,N-dimethyl-formamide; Step A. (4-Hydroxy-1-piperidinyl)(3-methyl-2-thienyl)methanone To a solution of <strong>[23806-24-8]3-methyl-2-thiophenecarboxylic acid</strong> (1.76 g, 12.39 mmol), 1-[3-(dmethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.85 g, 14.87 mmol), 1-hydroxybenzotriazole (2.18 g, 16.10 mmol), N-methylmorpholine (1.88 g, 18.58 mmol) and 4-hydroxypiperidine (1.25 g, 12.39 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 72 hours. The reaction mixture was poured into water (100 mL) and extracted with chloroform. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel Merck-60 (eluant: ethyl acetate) to afford the title compound (1.78 g, 7.9 mmol). MS ((+)ESI, m/z): 226 [M+H]+ 1H NMR (DMSO-d6, 300 MHz) d 7.35 (d, J=5.0 Hz, 2H), 6.90 (d, J=5.0 Hz, 2H), 4.74 (d, J=4.4 Hz, 1H), 3.82 (m, 2H), 3.65 (m, 1H), 3.01 (m, 2H), 2.22 (s, 3H), 1.77 (m, 2H) and 1.34 (m, 2H).
  • 27
  • [ 383865-57-4 ]
  • [ 5382-16-1 ]
  • 4-Hydroxy-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% 4-Hydroxy-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide Using <strong>[383865-57-4]4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine</strong> and piperidin-4-ol the title compound was obtained as yellow solid (50%). MS: m/e=393 (M+H+).
  • 28
  • [ 5382-16-1 ]
  • [ 6940-78-9 ]
  • [ 6665-86-7 ]
  • [ 140439-26-5 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 68 7-[4-(4-hydroxypiperidinyl)butoxy]-2-phenyl-4H-1-benzopyran-4-one hydrochloride The compound was prepared by the method of Example 1 from <strong>[6665-86-7]7-hydroxyflavone</strong>, 1-bromo-4-chlorobutane, and 4-hydroxypiperidine: mp 207-209 C.
  • 29
  • [ 5382-16-1 ]
  • [ 54512-75-3 ]
  • [ 6665-86-7 ]
  • [ 140439-06-1 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 36 7-[5-(4-Hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one The compound was prepared by a method similar to Example 3 from <strong>[6665-86-7]7-hydroxyflavone</strong>, 1-bromo-5-chloropentane, and 4-hydroxypiperidine: mp 94-95 C.
  • 30
  • [ 5382-16-1 ]
  • [ 6294-17-3 ]
  • [ 6665-86-7 ]
  • [ 139652-60-1 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 37 7-[6-(4-Hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one The compound was prepared by a method similar to Example 3 from <strong>[6665-86-7]7-hydroxyflavone</strong>, 1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp 130-131 C.
  • 31
  • [ 5382-16-1 ]
  • [ 4549-31-9 ]
  • [ 6665-86-7 ]
  • [ 139653-09-1 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 69 7-[7-(4-hydroxypiperidinyl)heptoxy]-2-phenyl-4H-1-benzopyran-4-one hydrochloride The compound was prepared by the method of Example 2 from <strong>[6665-86-7]7-hydroxyflavone</strong>, 1,7-dibromoheptane, and 4-hydroxypiperidine: mp 143-144 C.
  • 32
  • [ 5382-16-1 ]
  • [ 4549-32-0 ]
  • [ 6665-86-7 ]
  • [ 139653-08-0 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 67 7-[8-(4-Hydroxypiperidinyl)octoxy]-2-phenyl-4H-1-benzopyran-4-one hydrochloride The compound was prepared by the method of Example 2 from <strong>[6665-86-7]7-hydroxyflavone</strong>, 1,8-dibromooctane, and 4-hydroxypiperidine.
  • 33
  • [ 5382-16-1 ]
  • [ 79414-82-7 ]
YieldReaction ConditionsOperation in experiment
34% With HI; potassium carbonate; hydroxylamine-O-sulfonic acid; In ethanol; water; Petroleum ether; REFERENCE EXAMPLE 6 Synthesis of 1-amino-4-hydroxypiperidine In 10 ml of water was dissolved 0.6 g(6 mmol) of hydroxylamine-O-sulfonic acid and 1.82 g(1.8 mmol) of 4-hydroxypiperidine was added thereto. After refluxing for 1 hour, the reaction mixture was cooled to 5 C. and 0.84 g(6.1 mmol) of potassium carbonate was added thereto. The reaction mixture was stirred for 10 min and the precipitate was filtered off. The filtrate was concentrated under the reduced pressure and 15 ml of dry ethanol was added to give precipitate, which was filtered off. While cooling the filtrate to 5~10 C., 0.85 ml of 57% HI was slowly added and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added 50 ml of petroleum ether. The filtrate was washed with acetone to give 1.41 g of the desired compound(34%). m.p.=117-119 C. NMR (DMSO-d6, delta) 1.12~1.98 (m, 4H), 2.41~2.86 (m, 2H) 2.86~3.24 (m, 2H), 3.40~3.79 (m, 1H) 5.23 (br, 2H, NH2)
  • 34
  • [ 5382-16-1 ]
  • [ 126728-20-9 ]
  • C16H21N5O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
The appropriate 2,4-dichloro-pyridopyrimidine (3)(1 equivalent) was suspended in CH2Cl2 (4 ml of solvent per mmol of material) and to this mixture was added triethylamine (1 equivalent). The resultant orange solution was then cooled to 0 C. and the appropriate amine (R2H) (1 equivalent) added dropwise as a 0.1 M solution in CH2Cl2 over 5 minutes. The mixture was stirred for a further 45 minutes before it was diluted with water and extracted with CH2Cl2 (×2). The organic extracts were dried using MgSO4, filtered and concentrated in vacuo to give a crude solid that was purified by flash chromatography (SiO2) using Hexanes:EtOAc (2:3) as eluent to give the desired product (1 equivalent) which was diluted in dimethylacetamide (0.7 M) and the appropriate amine (R1H) (2.5 equivalents) added. The reaction mixture was heated to 60 C. for 16 hours. Upon completion the reaction mixture was submitted for preparative HPLC purification to give the desired pyridopyrimidine-2,4-diamines, as detailed below:
  • 35
  • [ 5382-16-1 ]
  • [ 3740-92-9 ]
  • [ 881195-05-7 ]
YieldReaction ConditionsOperation in experiment
91% With triethylamine; In butan-1-ol; at 20 - 40℃; for 16h;Heating / reflux; To a solution of 4,6-dichloro-2-phenyl pyrimidine (Ig, 4.42 mmol) and triethyl amine (1.78 g, 17.6 mmol) in n-butanol (10 mL) was added 4-hydroxy piperidine (0.44 g, 4.4 mmol) to temperature in the range of 20-400C with stirring. The mixture was then stirred under reflux for 16 hours under nitrogen. The mixture was cooled to room temperature, poured into water (25 mL) and extracted with EtOAc (2 x 15 mL). Organic layers were collected, combined dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography using EtO Ac-pet ether to give the desired compound (1.15 g, 91percent yield).
  • 36
  • [ 5382-16-1 ]
  • [ 26032-72-4 ]
  • [ 881194-69-0 ]
YieldReaction ConditionsOperation in experiment
The following compounds presented in Examples 52-92 w^ere prepared in accordance with Scheme 6, by a procedure analogous to that disclosed in Examples 39 and 48, using starting materials with the appropriate substitution.
  • 37
  • [ 5382-16-1 ]
  • [ 2528-00-9 ]
  • [ 135017-70-8 ]
YieldReaction ConditionsOperation in experiment
7.84 g (97.4%) In N-methyl-acetamide; chloroform; EXAMPLE 47 [1-[1-[(5-Piperidinomethyl-2-furanyl)methyl]-piperidinyl-4-amino](methylamino)methylene]propanedinitrile (Compound 46) In 45 ml of dimethylformamide was dissolved 6.0 g (31.8 mmol) of <strong>[2528-00-9]ethyl 5-chloromethyl-2-furancarboxylate</strong> followed by addition of 9.64 g (95.5 mmol) of 4-hydroxypiperidine and the mixture was stirred at room temperature for 20 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with 100 ml of chloroform and washed with saturated aqueous sodium chloride solution twice. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to give 7.84 g (97.4%) of ethyl 5-(4-hydroxypiperidinomethyl)-2-furancarboxylate (Compound s) as light brown oil. NMR (CDCl3) delta (ppm): 7.08 & 6.27 (each 1H, each d, J=3.1 Hz), 4.32 (2H, q), 3.65 (1H, m), 3.59 (2H, s), 2.80 (2H, m), 2.24 (2H, m), 1.4-2.06 (4H, m), 1.36 (3H, t)
  • 38
  • [ 5382-16-1 ]
  • [ 66575-29-9 ]
  • [ 598-21-0 ]
  • [ 122517-87-7 ]
YieldReaction ConditionsOperation in experiment
0.109 g (76.4%) With 2,3-Dimethylaniline; In hexane; dichloromethane; ethyl acetate; EXAMPLE 7 7beta-Acetoxy-8,13-epoxy-1alpha-[(4-hydroxypiperidin-1-yl)acetoxy]-6beta,9alpha-dihydroxylabd-14-en-11-one hydrochloride To a stirred solution of 106 mg of 7beta-acetoxy-8,13-epoxy-1alpha,6beta,9alpha-trihydroxylabd-14-en-11-one in 1 ml of dry dichloromethane containing 0.038 ml of dimethylaniline, in an ice bath, was added dropwise a solution of 0.027 ml of bromoacetyl bromide in 1 ml of dry dichloromethane. The mixture was stirred at 0 for 1 hr, allowed to warm to room temperature, poured onto ice sodium bicarbonate ethyl acetate, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Filteration followed by evaporation of solvent provided an oil which was dissolved in 1 ml of dichloromethane and added to a stirred solution of 0.10 g of 4-hydroxypiperidine in 1 ml of ethyl acetate. The mixture was stirred 1 hr at room temperature, poured onto ice/water ethyl acetate, extracted with ethyl acetate, washed with water, saturated sodium chloride solution and dried over anhydrous sodium sulfate. Filteration followed by evaporation of the solvent provided an oil. The oil was dissolved in a minimum volume of 30% ethyl acetate/hexane and flash chromatographed on 25 g of silica gel (230-400 mesh). Concentration of the appropriate fractions gave an oil. Treatment of the oil with ethereal hydrogen chloride gave 0.109 g (76.4%) of product as the hydrochloride, mp 166-189.
  • 39
  • [ 5382-16-1 ]
  • [ 17973-86-3 ]
  • [ 1020658-69-8 ]
YieldReaction ConditionsOperation in experiment
In isopropyl alcohol; at 150℃; for 0.333333h;Microwave; A suspension of <strong>[17973-86-3]3,6-dibromopyridazine</strong> and 4-hydroxypiperidine (1.5 equiv.) in isopropanol (2 M) was heated in microwave at 150 0C. After a period of 20 min., the crude residue was partitioned between ethyl acetate and water. The organic phase was separated, dried over MgSO4, filtered and evaporated under reduced pressure. The title compound was purified by flash chromatography eluting with 50% acetone in dichloromethane
  • 40
  • [ 5382-16-1 ]
  • [ 19745-07-4 ]
  • [ 1020658-72-3 ]
YieldReaction ConditionsOperation in experiment
In isopropyl alcohol; at 160℃; for 0.166667h;Microwave; To a mixture of <strong>[19745-07-4]2,5-dichloropyrazine</strong> in 2-propanol (0.2 M) was added 4- hydroxypiperidine (2.2 equiv.). The reaction was heated in the microwave at 160 0C for 10 min.The solvent was evaporated under reduced pressure and the title compound was purified by flash chromatography eluting with ethyl acetate
  • 41
  • [ 5382-16-1 ]
  • [ 14891-10-2 ]
  • [ 5804-85-3 ]
  • [ 1131451-62-1 ]
YieldReaction ConditionsOperation in experiment
To a stirred solution of 4-hydroxypiperidine (464 mg, 4.58 mmol) and ethyl 3-oxopyrrolidine-1-carboxylate (610 mg, 3.82 mmol) in 1,2-dichloroethane (25 mL) was added titanium isopropoxide (1.09 g, 3.82 mmol), and the mixture was stirred at room temperature overnight. Then a 1.0 M solution of diethylaluminum cyanide (1.02 g, 9.17 mmol) was added at room temperature and the mixture was stirred for 24 h. Diluted with dichloromethane (25 mL) and quenched with saturated ammonium chloride solution (10 mL) at 0 C. Then mixture was filtered through a small pad of celite, and the resulting filtrate was concentrated in vacuo to afford the title compound as a yellow gum (1.0 g). 1H NMR (CDCl3, 400 MHz): delta 4.22 (q, 2H), 4.21-4.1 (dd, 1H), 3.79-3.62 (m, 3H), 3.38 (dd, 1H), 2.9 (brs, 1H), 2.7 (brs, 1H), 2.54-2.35 (m, 3H), 2.18-1.85 (brm, 3H), 1.68-1.45 (m, 3H), 1.25 (t, 3H). MS (M+1): 268.14.
Step A. The preparation of ethyl 3-cyano-3-(4-hydroxy-1-piperidyl)pyrrolidine-1-carboxylate A stirred solution of 4-hydroxypiperidine (464 mg, 4.58 mmol) and ethyl 3-oxopyrrolidine-1-carboxylate (610 mg, 3.82 mmol) in 1,2-dichloroethane (25 mL) was added with titanium isopropoxide (1.09 g, 3.82 mmol), and the mixture was stirred at room temperature overnight. Then a 1.0 M solution of diethylaluminum cyanide (1.02 g, 9.17 mmol) was added at room temperature and the mixture was stirred for 24 hours. The reaction mixture was diluted with dichloromethane (25 mL) and quenched with saturated ammonium chloride solution (10 mL) at 0 C. Then mixture was filtered through a small pad of celite, and the filtrate was concentrated in vacuo to afford the title compound as a yellow gum (1.0 g). 1H NMR (CDCl3, 400 MHz): delta 4.22 (q, 2H), 4.21-4.1 (dd, 1H), 3.79-3.62 (m, 3H), 3.38 (dd, 1H), 2.9 (brs, 1H), 2.7 (brs, 1H), 2.54-2.35 (m, 3H), 2.18-1.85 (brm, 3H), 1.68-1.45 (m, 3H), 1.25 (t, 3H). MS (M+1): 268.14.
  • 42
  • [ 5382-16-1 ]
  • [ 147754-12-9 ]
  • [ 1164178-52-2 ]
YieldReaction ConditionsOperation in experiment
94% 4-Hydroxy-piperidine (1.05 g) was dissolved in 7 ml_ MTBE and 5 ml_ THF. Potassium tert-butylate (1.43 g) was added and the mixture was heated to 50 0C for 30 min. After cooling to rt, 4-Fluoro-2-methyl-benzonitrile (1.32 g) was added in portions. After stirring at rt for 2 h the reaction was quenched with water. The phases were separated and the aqueous layer was extracted with ethyl acetate (3x 10 ml_). The combined organic layers were washed with brine (10 mL), dried with MgSpsi4 and concentrated to yield 1.92 g (94percent) 2-Methyl-4-(piperidin-4-yloxy)-benzonitrile. Mass (ESI) (C13Hi6N2O): calcd. 216, found 217 [M+H]+.
  • 43
  • [ 5382-16-1 ]
  • [ 60702-69-4 ]
  • [ 796600-10-7 ]
YieldReaction ConditionsOperation in experiment
4-Piperidinol (6.5 g) was added to a solution of potassium tert-butoxide (7.2 g) in N-methyl-2-pyrrolidinone (25 mL) and stirred at room temperature for 30 min. The reaction mixture was cooled to 0 C and <strong>[60702-69-4]2-chloro-4-fluoro-benzonitrile</strong> (10 g) was added portionwise. The reaction mixture was allowed to reach room temperature and was stirred overnight. LC/MS showed a major peak with the required product mass. The reaction was quenched by addition of ammonium chloride solution and the mixture was partitioned partitioned between ethyl acetate and water. The ethyl acetate was washed with water then brine, dried (MgSO4), filtered and concentrated in vacuo. Crude material was purified by flash chromatography, eluting with 2-5% methanol, 0. 1% triethylamine in dichloromethane to give the title compound (6.6 g). MS (APCI+ve) 236/238; 1H NMR delta (CD3OD) 2.00-2. 29 (4H, m), 3.22-3. 47 (4H, m), 4.85-4. 92 (1H, M), 7.14 (1H, dd), 7.33 (1H, d), 7.76 (1H, d)
  • 44
  • [ 5382-16-1 ]
  • [ 90729-43-4 ]
  • 45
  • [ 5382-16-1 ]
  • [ 874676-81-0 ]
  • [ 1108164-37-9 ]
YieldReaction ConditionsOperation in experiment
87% With triethylamine; In tetrahydrofuran; at 20℃; for 16h; 1-(5-Chloropyrimidin-2-yl)piperidin-4-ol To a one dram vial was added piperidin-4-ol (101 mg, 1 mmol), <strong>[874676-81-0]5-chloro-2-iodopyrimidine</strong> (240 mg, 1.000 mmol), and THF (1 mL) to produce a suspension. To this mixture was added TEA (0.153 mL, 1.100 mmol). The reaction was stirred at room temperature for 16 hours. Ethyl acetate (7 mL) was added at that point and the mixture was washed with water (4*2 mL). The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-40% ethyl acetate/hexane) to give Intermediate 4 (185 mg, 87% yield) as white powder. 1H NMR (CDCl3, 500 MHz) delta 8.22 (2H, s), 4.24-4.44 (2H, m), 3.83-4.04 (1H, m), 3.15-3.50 (2H, m), 1.83-2.02 (2H, m), 1.40-1.60 (2H, m); MS (ESI) 214.2 (M+H).
  • 46
  • [ 5382-16-1 ]
  • [ 16681-59-7 ]
  • [ 1247891-65-1 ]
YieldReaction ConditionsOperation in experiment
1-(1-Methyl-1H-imidazol-2-yl)piperidin-4-ol A mixture of N-methyl-2-bromoimidazole (7.3 g, 45.3 mmol) and 4-hydroxypiperidine (11.4 g, 113 mmol, 2.5 eq) was stirred at 140 C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with 10% aq. NaOH solution to pH 12. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2*25 mL). The combined organic layers were washed with water (20 mL) followed by brine (20 mL), dried over sodium sulfate, filtered, and evaporated under vacuum. The solid residue was purified by column chromatography by eluting with 5% to 20% methanol in dichloromethane to yield the title compound as yellow solid. 1H NMR (CDCl3, 300 MHz): delta=6.64 (d, J=0.9 Hz, 1H), 6.75 (d, J=0.9 Hz, 1H), 3.85-3.84 (m, 1H), 3.47 (s, 3H), 3.24-3.22 (m, 2H), 2.94-2.92 (m, 2H), 2.01-1.98 (m, 2H), 1.71-1.69 (m, 2H). MS (ES+): m/z=182.28 (100) [MH+]. HPLC: tR=0.74 & 1.13 min (verypolar-5 min, ZQ3).
  • 47
  • [ 5382-16-1 ]
  • [ 287953-54-2 ]
  • 48
  • [ 5382-16-1 ]
  • [ 100-00-5 ]
  • [ 79421-45-7 ]
YieldReaction ConditionsOperation in experiment
93% With potassium carbonate; In N,N-dimethyl acetamide; at 130℃; for 3.0h; 4-chloronitrobenzene (31.5 g, 200 mmol) was dissolved in N,N-dimethylacetamide (80 ml), and potassium carbonate (35.9 g, 260 mmol) and 4-hydroxypiperidine (22.3 g, 220 mmol) were added thereto, followed by stirring under heat at 130 C. for 3 hours. After cooling to room temperature, water was added to the mixture, and the precipitate was collected by filtration. The obtained solid was dried under reduced pressure, thereby obtaining 4-hydroxy-N-(4-nitrophenyl)piperidine (41.3 g, 93%) as a yellow solid.1H-NMR (CDCl3): delta (ppm) 1.52-1.74 (m, 2H), 1.92-2.04 (m, 2H), 3.14-3.35 (m, 2H), 3.73-4.08 (m, 3H), 6.82 (d, J=9.6 Hz, 2H), 8.11 (d, J=9.6 Hz, 2H)
  • 50
  • [ 5382-16-1 ]
  • [ 75-05-8 ]
  • [ 3518-83-0 ]
  • 51
  • [ 5382-16-1 ]
  • [ 22536-67-0 ]
  • [ 1108164-37-9 ]
  • 52
  • [ 5382-16-1 ]
  • [ 450-83-9 ]
  • [ 1374859-10-5 ]
  • 53
  • [ 5382-16-1 ]
  • [ 450-83-9 ]
  • [ 1374858-29-3 ]
  • 54
  • [ 5382-16-1 ]
  • [ 350-46-9 ]
  • [ 142752-12-3 ]
  • 55
  • [ 5382-16-1 ]
  • [ 21943-17-9 ]
  • [ 1410166-29-8 ]
YieldReaction ConditionsOperation in experiment
50% With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 140℃; for 1.0h;Inert atmosphere; Microwave irradiation; General procedure: A solution of 56 (1.50 g, 7.16 mmol), the appropriate secondary amine (8.59 mmol, 1.20 equiv) and diisopropylethylamine (1.50 mL, 8.59 mmol) in n-butanol (15 mL)was heated in a microwave reactor using variable wattage to 140 C for 1 h. The mixture was concentrated and purified by flash column chromatography on silica, eluting with 9:1 dichloromethane/methanol, to give gave 58-63.
  • 56
  • [ 5382-16-1 ]
  • [ 50-00-0 ]
  • [ 159326-68-8 ]
  • [ 1417736-67-4 ]
YieldReaction ConditionsOperation in experiment
15% Intermediate 44 A 1 - [(4-Aminopyrrolo [2, 1 -fj [ 1 ,2,4]triazin-7-yl)methyi]piperidin-4-ol 4-Hydroxypiperidine (3.62 g, 35.8 mmol) and 37% formalin solution (2.9 g, 35.8 mmol) were dis- solved in acetic acid (150 mL) and stirred at room temperature for 1 h. To this solution was added a solution of pyrrolo [2, 1 -fj [ 1 ,2,4]triazin-4-amine (2.0 g, 14.9 mmol; prepared according to the procedure described in WO 2007/056170-A2, Intermediate A) in acetic acid (150 mL), and the mixture was stirred at 60C for 2 h. The solvent was then evaporated, and the residue was taken up in 200 mL of half-concentrated aqueous potassium bicarbonate solution and extracted with 200 mL dichloromethane. The organic layer was washed with water (2 x 50 mL) and discarded. The combined aqueous layers were evaporated to dryness, and the residue was treated with a 10: 1 mixture of dichloromethane and methanol (2 x 100 mL). The organic extracts were evaporated, and the residue was purified by preparative 1 1 PLC (method 4) to give 1.16 g (15% of th.) of the title compound. LC -MS (method 7): t = 0.18 min; MS (ESIpos): m/z (%) = 248.3 (30) [M+H]+, MS (ESIneg): m/z (%) = 246.5 (100) [M-H]~.H NMR (400 MHz, ds-OMSO): delta (ppm) = 1.35 (br. m, 2H), 1.67 (br. m, 2H), 2.07 (t, 2H), 2.70 (br. m, 2H), 3.38 (br. m, 1H), 3.75 (s, 21 1 ). 4.5 . (br, 1H), 6.52 (d, 1H), 6.84 (d, 1 1 1 ). 7.62 (br, 2H), 7.82 (s, 1H).
  • 57
  • [ 5382-16-1 ]
  • [ 159326-68-8 ]
  • [ 1417736-68-5 ]
  • 58
  • [ 5382-16-1 ]
  • [ 6271-78-9 ]
  • [ 1429414-74-3 ]
YieldReaction ConditionsOperation in experiment
75% With N-ethyl-N,N-diisopropylamine; at 110℃; for 8h; a) 6-(4-hvdroxypiperidin-1 -vhnicotinamide To the solution of <strong>[6271-78-9]6-chloronicotinamide</strong> (5.0g, 32 mmol) in DtPEA (50 mL), piperidin-4-ol (3.2 mg, 32 mmol) was added and the mixture was stirred at 110 C for 8h. The reaction mixture was concentrated under reduced pressure to afford the crude product. The residue was further purified by silica gel chromatography (DCM: MeOH=20:1) to afford the title compound (5.3 g, 75%) as a yellowish solid. [LCMS RtB = 1.39 min, [M+H]+ = 222.1 ].
75% With N-ethyl-N,N-diisopropylamine; at 110℃; for 8h; a) 6-(4-hydroxypiperidin-1-yl)nicotinamide To the solution of <strong>[6271-78-9]6-chloronicotinamide</strong> (5.0 g, 32 mmol) in DIPEA (50 mL), piperidin-4-ol (3.2 mg, 32 mmol) was added and the mixture was stirred at 110 C. for 8 h. The reaction mixture was concentrated under reduced pressure to afford the crude product. The residue was further purified by silica gel chromatography (DCM: MeOH=20:1) to afford the title compound (5.3 g, 75%) as a yellowish solid. [LCMS RtB=1.39 min, [M+H]=222.1].
  • 59
  • [ 5382-16-1 ]
  • [ 877399-50-3 ]
  • 60
  • [ 5382-16-1 ]
  • [ 19064-67-6 ]
  • [ 1542135-82-9 ]
YieldReaction ConditionsOperation in experiment
100% With N-ethyl-N,N-diisopropylamine; at 120℃; for 8h; To a solution of 6-chloropyridazin-3(2H)-one (2.6 g, 20 mmol) in DIPEA (30 mL) was added piperidin-4-ol (2.4 g, 20 mmol) and the mixture was stirred at 120 t for 8h. The reaction mixture was concentrated under reduced pressure to afford the crude product, which wasfurther purified by silica gel chromatography (DCM/MeOH2O/1) to afford the title compound (3.9 g, 100%) as a yellow solid. [LCMS: Rt = 0.77 mm, m/z 196.2 (M-fHfl.
100% With N-ethyl-N,N-diisopropylamine; at 120℃; for 8h; To a solution of 6-chloropyridazin-3(2H)-one (2.6 g, 20 mmol) in DIPEA (30 mL) was added piperidin-4-ol (2.4 g, 20 mmol) and the mixture was stirred at 120 C. for 8 h. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was further purified by silica gel chromatography (DCM/MeOH=20/1) to afford the title compound (3.9 g, 100%) as a yellow solid. [LCMS: Rt=0.77 min, m/z 196.2 (M+H)+].
  • 61
  • [ 5382-16-1 ]
  • [ 122368-54-1 ]
  • 62
  • [ 5382-16-1 ]
  • [ 633328-95-7 ]
  • [ 1578253-31-2 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In ethanol; at 75℃; for 18h; PREPARATION xl5: 1-(5-Bromo-4-methylpyrimidin-2-yl)piperidin-4-ol [0194] 5-Bromo-2-chloro-4-methylpyrimidine (100 mg, 0.482 mmol), piperidin-4-ol (48.8 mg, 0.482 mmol), Et3N (0.202 mL, 1.446 mmol) and EtOH (2 mL) were mixed in a 4 mL vial equipped with a magnetic stir bar to give an orange solution. The reaction mixture was stirred for 18 hours at 75C and was subsequently partitioned between water (20 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was back-extracted with EtOAc (20 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated to give crude title compound as a white solid (150 mg).
  • 63
  • [ 5382-16-1 ]
  • [ 1211534-25-6 ]
  • [ 1610036-07-1 ]
YieldReaction ConditionsOperation in experiment
88% With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 14h; [00443j 1 12A. 1-(5-Chloro-2-methoxypyridin-4-yl)piperidin-4-ol: To a round bottom flask was added 27B (2.8 g, 13 mmol), piperidin-4-ol (1.40 g, 13.8 mmol), K2C03 (8.70g, 62.9 mmol) and DMSO (30 mL). The reaction mixture was stirred at 110 °C for 14 h. The reaction mixture was partitioned between water (150 mL) and EtOAc (150 mL). The organic layer was separated, washed with water (2 x 100 mL) and brine (100 mL), dried over Mg504, filtered, and concentrated. The residue was purified by silica chromatography to give 1 12A (2.7 g, 11 mmol, 88percent yield) as a colorless oil. LC-MSAnal. Calc?d for C11H15C1N202: 242.70, found [M+H] 243.1, 245.0. ?HNMR(400 MHz, CDC13) oe 7.97 (s, 1H), 6.27 (s, 1H), 3.94 - 3.84 (m, 4H), 3.51 - 3.37 (m, 2H), 2.90 (ddd,J=12.3, 9.2, 3.0 Hz, 2H), 2.07- 1.95 (m, 2H), 1.84- 1.66 (m, 2H).
88% With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 14h; solution of 1 J (2.80 g, 12.6 mmol), piperidin-4-ol (1.40 g, 13.8 mmol), and K2C03 (8.70 g, 62.9 mmol) in DMSO (30 mL) was stirred at 110 °C for 14 h. The reaction mixture was partitioned between water (150 mL) and EtOAc (150 mL). The organic layer was separated, washed with water (2 x 100 mL) and brine (100 mL), dried over MgS04, filtered, and concentrated. The residue was purified by silica chromatography to give 4A (2.70 g, 11.1 mmol, 88percent yield) as a colorless oil. LC-MS Anal. Calc'd for CnHi5CiN202: 242.70 found [M+H] 243.0. 1H NMR (400 MHz, CDC13) delta 7.97 (s, IH), 6.27 (s, IH), 3.94 - 3.84 (m, 4H), 3.51 - 3.37 (m, 2H), 2.90 (ddd, J=12.3, 9.2, 3.0 Hz, 2H), 2.07 - 1.95 (m, 2H), 1.84 - 1.66 (m, 2H).
  • 64
  • [ 5382-16-1 ]
  • [ 65202-50-8 ]
  • [ 1307469-49-3 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 100℃; for 20h; A solution of 6-chloropyridazine-3-carboxylic acid (0.50 g, 3.2 mmol) in 11 mL of SOCl2 was heated at 75° C. for 2 h and was then concentrated and redissolved in 5 mL of MeOH. To the solution was added a 25percent solution of sodium methoxide (0.75 mL, 3.5 mmol, 1.1 eq) in MeOH. The reaction mixture was stirred at room temperature for 20 h and was then quenched with H2O and extracted with dichloromethane. Silica gel flash chromatography (EtOAc/MeOH 90:10) of the residue afford a 2:1 mixture of the 6-chloropyridazine-3-carboxylic acid and 6-methoxypyridazine-3-carboxylic acid (0.160 g). To a solution of the mixture of ester and chloride in 1.9 mL of p-dioxane was added 4-hydroxy piperidine (0.094 g, 93 mmol) followed by diisopropylethylamine (0.49 mL, 2.8 mmol). The mixture was heated at 100° C. for 20 h then concentrated. Purification with silica gel flash chromatography afforded methyl 6-(4-hydroxypiperidin-1-yl)pyridazine-3-carboxylate (0.15 g, 63 mmol).
  • 65
  • [ 5382-16-1 ]
  • [ 25055-86-1 ]
  • [ 1620483-15-9 ]
  • 66
  • [ 5382-16-1 ]
  • [ 5382-17-2 ]
  • 67
  • [ 5382-16-1 ]
  • [ 50-00-0 ]
  • [ 529-84-0 ]
  • 6,7-dihydroxy-8-((4-hydroxypiperidin-1-yl)methyl)-4-methyl-2H-chromen-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
650 mg In ethanol; at 80℃; for 10h; 1 g of 4-methyl-6,7-dihydroxycoumarin was weighed and dissolved in 50 ml of ethanol, Adding 37percent formaldehyde aqueous solution 0.9ml, 4-hydroxypiperidine 0.4ml, heated to 80 °C reaction 10hThe TLC test reaction was completed and the solvent was evaporated to dryness under reduced pressureSilica gel column chromatography (eluent: dichloromethane: methanol = 10: 1 to 3: 1) to give 650 mg of Compound Iad, brown solid.
  • 68
  • [ 5382-16-1 ]
  • [ 52092-47-4 ]
  • 1-(6-nitropyridin-3-yl)piperidin-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With potassium carbonate; In dimethyl sulfoxide; at 90℃; General procedure: Desired aromatic halide (19 or 32 or 33) (1 equiv), 4-hydroxypiperidine(1 equiv) an aprotic base such as Et3N or K2CO3(2?3 equiv) in DMSO or EtOH was heated in a sealed vessel untilconsumption of the starting material was observed. Work-up consistedof either partial mixture evaporation, addition of water andfiltration of the resulting solid to afford the product (as in case of37) or partition of the partially evaporated mixture between EtOAcand water, extraction of the aqueous layer with portions of EtOAcuntil no UV absorption in the organic extract and then evaporationof the combined organic layer to the crude product that was purifiedvia column chromatography
65% With potassium carbonate; In dimethyl sulfoxide; at 90℃;Sealed tube; A mixture of <strong>[52092-47-4]2-nitro-5-chloropyridine</strong> (500 mg, 3.16 mmol), 4-hydroxypiperidine (320 mg, 3.16 mmol) and K2C03 (870 mg, 6.31 mmol) in DMSO (10 mL) in a sealed vessel was stirred at 90 °C overnight, then cooled, concentrated to a small volume (approx. 3 mL) and partitioned between EtOAc and water. The EtOAc layer was collected, evaporated and the residue waschromato graphed on a silica gel column with 30-100percent EtOAc in hexanes gradient to afford the product, l-(6-nitropyridin-3-yl)piperidin-4-ol, as a yellow solid (460 mg, 65percent yield). ). 1HNMR (600 MHz, DMSO- 6) delta 1.42 (m, 2H), 1.81 (m, 2H), 3.24 (ddd, J= 13.2, 9.6, 3.0 Hz, 2H), 3.75 (m, 1H), 3.83 (m, 2H), 4.78 (d, J=4.2 Hz, 1H), 7.45 (dd, J=9.0, 3.0 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 8.23 (d, J=3.0 Hz, 1H). ATR IR (cm"1) 3393, 3321, 3107, 3088, 2947, 2930, 2855, 1569, 1507, 1490, 1420, 1382, 1324, 1270, 1260, 1219, 1173, 1101, 1072, 1016, 1003, 962, 901, 824, 745, 692, 664, 629, 615. LC-MS (ESI) m/z for C10H13N3O3 calculated: 223.10, observedM+H]:224.
  • 69
  • [ 5382-16-1 ]
  • [ 23132-21-0 ]
  • 1-(3-methyl-5-nitropyridin-2-yl)piperidine-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.1 g With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 3h; (1) <strong>[23132-21-0]2-bromo-3-methyl-5-nitropyridine</strong> (10g), 4- hydroxypiperidine piperidine (5.6g) and potassium carbonate (6.4g) and N, N- dimethylformamide (30) was added and after stirring for 3 hours at 70 on, then process the reaction mixture with water, the organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and removing the solvent under reduced pressure distilled 1- (3-methyl-5 -nitro-pyridin-2-yl) piperidine-4-ol (1.10g).
  • 70
  • [ 5382-16-1 ]
  • [ 5470-17-7 ]
  • C10H12BrN3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
2.83 g In N,N-dimethyl-formamide; at 60℃; for 0.5h; (1) <strong>[5470-17-7]3-Bromo-2-chloro-5-nitropyridine</strong> (2.38g) in N, N- dimethylformamide (10) 4- piperidinol (2.23g) was added and the solution at 60 0.5 hour to it stirred. Water was added to the reaction solution, the precipitated solid was filtered and collected to give a yellow solid (2.83g).
  • 71
  • [ 5382-16-1 ]
  • [ 5470-17-7 ]
  • C17H16BrN3O4 [ No CAS ]
  • 72
  • [ 5382-16-1 ]
  • [ 1003845-06-4 ]
  • 2'-bromo-2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine] [ No CAS ]
  • 1-(5-(1,2',3,3'-tetrahydrospiro[benzo[4,5]imidazo[2,1-c][1,4]oxazine-4,1'-inden]-7-yl)pyrimidin-2-yl)piperidin-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
66% To a vial was added <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (0.200 g, 1.263 mmol), EtOH (3 mL), and piperidin-4-ol (128 mg, 1.263 mmol) followed by the addition of TEA (196 mu, 1.404 mmol). The contents were heated at about 80 C for about 0.5 h. The mixture was then added to 2-5 mL microwave vial preloaded with 2'-bromo-2,3,6',8'-tetrahydrospiro[indene-l,9'-pyrido[3',2':4,5]imidazo[2, l- c][l,4]oxazine] (0.100 g, 0.281 mmol, Preparation 92) and SiliaCirf DPP-Pd (0.112 g, 0.028 mmol, 0.25 mmol/g load, SiliCycle Cat R390-100). The final volume of EtOH was brought to 4 mL and 1M Cs2C03 (0.101 mL, 0.201 mmol) was added. The vial was capped and the contents were heated via microwave irradiation (Biotage Initiator) at 130 C for 20 min. The contents were cooled and concentrated directly onto silica gel and purified by flash chromatography (1-10% DCM/MeOH, 40 g Redisep Gold). Fractions were concentrated to yield title compound (0.085 g, 66%) as a white solid; LC/MS (Table 1, Method f) R, = 0.87 min; MS m/z: 455 (M+H)+ . (TNF IC50=A).
  • 73
  • [ 5382-16-1 ]
  • [ 1003845-06-4 ]
  • 2-bromo-8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine [ No CAS ]
  • 1-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% To a vial was added <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (48.2 mg, 0.305 mmol) , EtOH (1 mL) and piperidin-4-ol (30.8 mg, 0.305 mmol) followed by the addition of TEA (0.042 mL, 0.305 mmol). The mixture was heated at about 95 C for about 2 h. The reaction was cooled to rt and to the solution was added 2-bromo-8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2', l':2,3]imidazo[4,5-6]pyridine (50 mg, 0.152 mmol, Preparation 16), Cs2C03 (99 mg, 0.305 mmol), and Siliacat Pd-DPP (60.9 mg, 0.015 mmol). The mixture was heated to about 95 C for about 2. The reaction was cooled to rt, filtered, the filter cake wash with MeOH, and the filtate concentrated under reduced pressure. The crude product was purified by preparative HPLC (Table 1, Method ap) to afford the title compound (56 mg, 86 %); LC/MS (Table 1, method e) Rt = 0.75 min; MS m/z: 427 (M+H)+. (TNF IC50= A).
  • 75
  • [ 5382-16-1 ]
  • [ 610-36-6 ]
  • C12H15N3O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 8h; General procedure: To a mixture of <strong>[610-36-6]4-amino-2-nitrobenzoic acid</strong> (1.0 g, 5.49 mmol)in DMF (100 mL) was added morpholine (2.39 mL, 27.5 mmol),HATU (3.13 g, 8.23 mmol) and DIPEA (1.36 mL, 8.23 mmol). Thereaction mixture was stirred at room temperature overnight, thenconcentrated to remove the DMF. The residue was diluted withwater (100 mL) and extracted with DCM (3 x 80 mL). The organicphase was concentrated and purified by flash column chromatography(0-5% MeOH in DCM) to afford S3b (1.25 g, 91%) as a solid.
  • 76
  • [ 5382-16-1 ]
  • [ 446-59-3 ]
  • C12H16FNO2 [ No CAS ]
  • 77
  • [ 5382-16-1 ]
  • [ 59907-13-0 ]
  • C12H16FNO [ No CAS ]
  • 78
  • [ 5382-16-1 ]
  • [ 452-62-0 ]
  • C12H16FNO [ No CAS ]
  • 79
  • [ 5382-16-1 ]
  • [ 40273-45-8 ]
  • C10H13FN2O [ No CAS ]
  • 80
  • [ 5382-16-1 ]
  • [ 884495-00-5 ]
  • C11H15FN2O2 [ No CAS ]
  • 81
  • [ 5382-16-1 ]
  • [ 138274-14-3 ]
  • 1-(5-benzyloxypyrimidin-2-yl)piperidin-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
63.7% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 17h;Inert atmosphere; Stir a mixture of <strong>[138274-14-3]5-benzyloxy-2-chloro-pyrimidine</strong> (2.30 g, 9.90 mmol) , piperidin-4-ol (1.23 g, 11.9 mmol) and DIPEA (3.88 mL, 29.7 mmol) in DMF (30 mL, 388 mmol) at 100 under a N2atmosphere for 17 hrs. Dilute the mixture with water (200 mL) and extract with EtOAc (3×50 mL) . Combine the organic extracts wash with brine (3×50 mL) , dry over Na2SO4, filter, and concentrate the filtrate. Subject the residue to silica gel flash column chromatography eluting with a mixture of 60EtOAc and 40PE to give the title compound (2.00 g, 6.31 mmol, 63.7%) as a white solid.1H NMR (400 MHz, CDCl3) delta 1.40-1.60 (m, 2H) , 1.90-1.99 (m, 2H) , 3.17-3.29 (m, 2H) , 3.85-3.95 (m, 1H) , 4.25-4.39 (m, 2H) , 5.09 (s, 2H) , 7.38-7.52 (m, 5H) , 8.14 (s, 2H) .
  • 82
  • [ 5382-16-1 ]
  • [ 50461-59-1 ]
  • 83
  • [ 5382-16-1 ]
  • [ 302964-08-5 ]
  • N-(2-chloro-6-methylphenyl)-2-[[2-methyl-6-(4-hydroxypiperidin-1-yl)pyrimidin-4-yl]amino]thiazole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
130 mg With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 90 - 92℃; for 10h;Inert atmosphere; To a mixture of the starting material 7H (150 mg, 0.38 mmol) and dioxane (8 mL) were added 4-hydroxypiperidine (115 mg, 1.14 mmol, 3 eq) and DIEA (147 mg, 1.14 mmol, 3 eq) at room temperature. The mixture was then stirred at 90-92 C. under nitrogen for 10 h. LC-MS analysis showed the product peak. The mixture was not a clear solution. The mixture was concentrated to dryness and suspended in 50 mL acetonitrile containing 20% HPLC grade water. The mixture was then centrifuged at 4000 rpm for 15 min. The pellet was re-suspended in acetonitrile and centrifuged again at 4000 rpm for 15 min. The final pellet was dried under nitrogen to afford the target compound IX (H-21) (130 mg) as an off-white solid. LC-MS: 459.14 (M+H); 1H NMR (DMSO-d6): 11.42 (s, 1H. NH), 9.83 (s, 1H, NH), 8.19 (s, 1H), 7.40 (m, 1H), 7.24 (m, 2H), 6.05 (s, 1H), 4.78 (s, 1H), 3.95 (m, 2H), 3.75 (m, 1H), 3.22 (s, 3H), 3.18 (m, 2H), 2.43 (s, 3H), 1.85 (m, 2H), 1.35 (m, 2H).
  • 84
  • [ 5382-16-1 ]
  • [ 1780-33-2 ]
  • 1-(6-chloro-2.5-dimethylpyrimidin-4-yl)piperidin-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 110℃; for 8h; A mixture of <strong>[1780-33-2]4,6-dichloro-2,5-dimethylpyrimidine</strong> (5 g, 28.2 mmol), piperidin-4- ol (3.5 g, 34.6 mmol) and DIPEA (10 mL, 57.3 mmol) in dioxane (100 mL) was stirred for 8 h at 110 °C. The solvent was concentrated in vacuo and the residue was taken up in DCM (200 mL) and water (100 mL). The organic phase was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was suspended in petroleum ether (100 mL) and after stirring for 15, the title compound was isolated by filtration. MS: 242 (M+1).
  • 85
  • [ 5382-16-1 ]
  • [ 89763-93-9 ]
  • C13H14F3NO2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
3.57 g With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 15h; A suspension of the Compound 1(3.84 g), 4-hydroxypi- peridine (2.53 g), and potassium carbonate (4.13 g) in N,N-dimethylformamide (15 mE) was stirred at 130 C. for 15 hours. The reaction mixture was allowed to cool to room temperature, and ethyl acetate was added thereto, and then the resulting mixture was washed with an aqueous solution of sodium hydrogen carbonate and saturated brine, dried, and concentrated under reduced pressure. The resulting residues were purified by silica gel column chromatography (hexane:ethyl acetate=71 :29 to 15:85) to give the Compound 2 (3.57 g) as a yellow powdet MS (APCI): mlz 274 [M+H]
  • 86
  • [ 5382-16-1 ]
  • [ 63897-12-1 ]
  • 1-(2-chloro-6-methyl-3-nitropyridin-4-yl)piperidin-4-ol [ No CAS ]
  • 1-(4-chloro-6-methyl-3-nitropyridin-2-yl)piperidin-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
54.6% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h; [0209] To a solution of <strong>[63897-12-1]2,4-dichloro-6-methyl-3-nitropyridine</strong> (1.6 g, 7.73 mmol) and DIPEA (2.025 mL, 1 1,59 mmol) in DCM (18.62 mL) was added dropwise a solution of piperidm-4-ol (0.938 g, 9.27 mmol) in DCM (4.66 mL). The reaction mixture was stirred at 20C for 3 hours, then concentrated on Celite, and purified by column chromatography (80 g silica gel column) eluting with a gradient of 0-100% EtOAc in heptane to give the title compound as a yellow solid (1.146 g, 54.6%). .H NMR (500 MHz, DMSO- e) delta ppm 1.37 - 1.45 (m, 2 H), 1.78 (ddt,./ 12.69. 6.10, 3.30, 3.30 Hz, 2 H), 2.37 (s, 3 H), 3.04 (ddd, J=13.06, 9.40, 3.42 Hz, 2 H), 3.34 - 3.40 (m, 2 H), 3,70 (tq, J=8.15, 4.01Hz, 1H), 4.79 (d,.7=4.39 Hz, 1 1 1). 7.08 (s, 1H); ESI-MS m/z [M+H] 273.1, Byproduct I-(4-chloro-6-methyl-3-nitropyridin-2-yl)piperidin-4-ol, was obtained as a yellow oil. NMR (500 MHz, DMSO-cfe) delta ppm 1,35 - 1.42 (m, 2 H), 1.75 - 1.80 (m, 2 H), 2.38 (s, 3 1 1). 3.09 (ddd,/ 1 3.06. 9.64, 3.17 Hz, 2 H), 3.57 (ddd,./ 9.52. 8.30, 4.15 Hz, 2 H), 3.67 - 3,73 (m, 1H), 4,76 (d, J=4.39 Hz, 1H), 6,99 (s, 1H); ESI-MS m/z [M+H]
  • 87
  • [ 5382-16-1 ]
  • [ 67848-71-9 ]
  • 88
  • [ 5382-16-1 ]
  • [ 119-61-9 ]
  • [ 43076-61-5 ]
  • [ 90729-43-4 ]
YieldReaction ConditionsOperation in experiment
31 g The preparation method of ebastine provided in this embodiment specifically includes the following steps: (1) Add benzophenone (30 g, 0.165 mol) to 300 mL of toluene solution, stir and dissolve, aluminum trichloride (2.2 g, 0.017 mol) was added in sequence,trifluoromethanesulfonic acid (2.5 g, 0.018 mol),the mixture was heated to 50 C for 20 min, cooled to room temperature, p-toluenesulfonic acid (31.2 g, 0.18 mol) was added, 4-hydroxypiperidine (17.2 g, 0.17 mol) was added, and the mixture was heated to reflux, and refluxed with water for 5 h. After the reaction was completed, the reaction solution was cooled to room temperature, and 230 mL of 1N NaOH solution was slowly added thereto under ice cooling, and the mixture was stirred for 30 minutes, left to stand for 30 minutes, and the aqueous layer was separated. The organic layer was further added with sodium hydrogencarbonate (35 g, 0.41 mol). ,4-chloro-1-(4-tert-butylphenyl)-1-butanone (37.5 g, 0.157 mol), warmed to reflux, and refluxed with water for 12 h. After the reaction was completed, the temperature was lowered to room temperature and washed three times. , 200mL each time, wash to neutral.(2) The obtained organic solution was evaporated to the remaining 10% volume, 100 mL of 95% ethanol was added, the temperature was dissolved, the temperature was lowered to -10 C, and the crystal was frozen for 12 hours. The next day, the crystal was filtered off and dried to obtain ebastine (31g) 0.067mol), mp 84.2-86.3C, total yield 40%
  • 89
  • [ 5382-16-1 ]
  • [ 1206640-82-5 ]
  • C19H17Br2ClFN3O2S [ No CAS ]
  • C23H22ClF3N6O3S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
45.5% To a stirred mixture of Intermediate 1 (500 mg, 0.88 mmol, 1.0 eq.) in EtOH (2 mL) was added a solution of Na2SO3 (112 mg, 0.88 mmol, 1.0 eq.) in water (2 mL) at room temperature. The resulting mixture was stirred for 6 h at 50 C. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (5/1) to afford the desired product (413 mg, 82.5%) as a light yellow solid. ESI MS m/z=567.90, 569.90[M+H]+. Step 146b. To a solution of the compound from Step 146a (200 mg, 0.34 mmol, 1.0 eq.) and <strong>[1206640-82-5]1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (125 mg, 0.51 mmol, 1.5 equiv) in THF (2 mL) and H2O (0.5 mL) were added K3PO4 (144.20 mg, 0.679 mmol, 2 equiv) and [1,1?-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (22 mg, 0.03 mmol, 0.1 eq.). After stirring for 6 h at 50 C., the resulting organic layer was concentrated under reduced pressure. The residue was purified by Prep-TLC with MeOH/DCM (1/10) to afford the desired product (135 mg, 65.8%) as a yellow solid. ESI MS m/z=604.05, 606.05 [M+H]+. Step 146c. To a stirred mixture of the compound from Step 146b (100 mg, 0.17 mmol, 1.0 eq.) in DCM (1 mL) were added oxalic dichloride (63 mg, 0.50 mmol, 3.0 eq.) and DMF (1 drop) at 0 C. The resulting mixture was stirred for 5 h at 0 C. The resulting mixture was concentrated under vacuum to give the desired product (100 mg) as a crude product, which was used directly in next step without further purification. Step 146d. To a stirred solution of the compound from Step 146c (100 mg, crude) in DCM (1 mL) was added piperidin-4-ol (50 mg, 0.50 mmol) at room temperature. The resulting mixture was stirred for 3h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc/hexanes=1/1) to afford the desired product (70 mg) as a yellow solid. ESI MS m/z=687.05, 689.05 [M+H]+. Step 146e. To a solution of the compound from Step 146d (60 mg, 0.09 mmol, 1.0 eq.) in DCM (1 mL) was added TFA (0.5 mL) at room temperature. The resulting mixture was stirred for 2h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC to afford the title compound (23.3 mg, 45.5%) as a yellow solid. ESI MS m/z=587.20, 589.20 [M+H]+.
  • 90
  • [ 5382-16-1 ]
  • [ 468075-00-5 ]
  • C12H13ClF3NO2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; ruphos; In tetrahydrofuran; at 120℃; for 2h;Microwave irradiation; General procedure: To a solution of Compound 6A (138 mg, 0.32 mmol) in tolunen (4 mL) was added N-methylpiperazine (160 mg, 1.6 mmol), t-BuONa (61 mg, 0.64 mmol), Pd2(dba)3 (29 mg, 0.032 mmol), and Xantphos (37 mg, 0.064 mmol) and heated in a microwave oven at 120 C for 2 hours. The mixture was concentrated and purified by reverse phase column chromatography to afford Compound 6B. LC-MS (ESI) m/z: 440 [M+H]+.
  • 91
  • [ 5382-16-1 ]
  • [ 25118-59-6 ]
  • (4-bromo-3-chlorophenyl)(4-hydroxypiperidin-1-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
41% [0480] Step 1: Synthesis of (4-bromo-3-chlorophenyl)(4-hydroxypiperidin-1-yl)methanone. To a stirred solution of 3-chloro-4-bromo benzoic acid (4-hydroxypiperidine (1.71 g, 16.98 mmol) was added, and the mixture stirred at rt for 16 h. The progress of the reaction was monitored by TLC, and when complete it was cooled to 0 C, water (300 mL) was added, and the whole was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography, eluting with 0-80% ethyl acetate in petroleum ether to give (4-bromo- 3-chlorophenyl)(4-hydroxypiperidin-1-yl)methanone (l.lg, 41%).
  • 92
  • [ 5382-16-1 ]
  • [ 1435-48-9 ]
  • 1-(2,4-dichlorophenyl)piperidin-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
4% With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 80℃; for 16h; A solution of piperidin-4-ol (1.01 g, 9.99 mmol), 2,4-dichloro-l-fluorobenzene (1.65 g, 10.00 mmol), and DIEA (2.58 g) in dry DMSO (20 mL) was stirred for 16 h at 80 C, then cooled and extracted with 2x50 mL of EtOAc. The combined organic layers were concentrated under vacuum and purified with silica gel chromatography using EtOAc / hexane (2: 1) to afford 110 mg (4%) of the title compound as an off-white solid. LC-MS: (ES, m/z): 246 NMR (300 MHz, DMSO- e) d 7.50 (d, J = 2.5 Hz, 1H), 7.32 (dd, J = 8.6, 2.5 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 4.70 (d, J = 4.2 Hz, 1H), 3.61 (tt, J = 8.6, 4.3 Hz, 1H), 3.13 (dt, J = 10.2, 4.2 Hz, 2H), 2.70 (ddd, J = 12.1, 9.7, 2.9 Hz, 2H), 1.91 - 1.72 (m, 2H), 1.54 (dtd, J = 12.7, 9.2, 3.6 Hz, 2H).
  • 93
  • [ 5382-16-1 ]
  • [ 641569-94-0 ]
  • (4-hydroxypiperidin-1-yl)(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% Compound 7 (0.37 g, 1.2 mmol) was taken in a round bottom flask, dissolved in 5 ml of anhydrous DMF, and the solution was stirred at 0 C, and HOBt (0.21 g, 1.5 mmol) and EDCi (0.38 g) were added to the system. , 2 mmol), DIPEA (0.3 ml, 3 mmol) and a catalytic amount of DMAP. After 1 h of activation, the compound 4-hydroxypiperidine (0.10 g, 1 mmol) was added thereto and allowed to react at room temperature for 12 h. After completion of the reaction, washed with water and extracted 3 times with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product pressurization,As a pale yellow solid was purified by column chromatography to give compound D1 (0.15g, 37% yield).
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