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Product Details of [ 147804-30-6 ]

CAS No. :147804-30-6 MDL No. :MFCD07779385
Formula : C11H19NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :ULSBMKGFFFMGOI-UHFFFAOYSA-N
M.W : 213.27 Pubchem ID :22135564
Synonyms :

Calculated chemistry of [ 147804-30-6 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.91
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 60.41
TPSA : 42.07 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.81 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.85
Log Po/w (XLOGP3) : 1.11
Log Po/w (WLOGP) : 1.41
Log Po/w (MLOGP) : 1.15
Log Po/w (SILICOS-IT) : 1.62
Consensus Log Po/w : 1.63

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.66
Solubility : 4.63 mg/ml ; 0.0217 mol/l
Class : Very soluble
Log S (Ali) : -1.59
Solubility : 5.53 mg/ml ; 0.0259 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.51
Solubility : 6.56 mg/ml ; 0.0308 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.62

Safety of [ 147804-30-6 ]

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

Application In Synthesis of [ 147804-30-6 ]

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

  • Downstream synthetic route of [ 147804-30-6 ]

[ 147804-30-6 ] Synthesis Path-Downstream   1~37

  • 1
  • [ 2181-42-2 ]
  • [ 79099-07-3 ]
  • [ 147804-30-6 ]
YieldReaction ConditionsOperation in experiment
98% To a solution of NaH (1.68 g, 42.0 mmol) in dry DMF (70 mL) at 0 C., (CH3)3SI (8.56 g, 42.0 mmol) was added and allowed to stirred at room temperature for 30 minutes. tert-Butyl 4-oxopiperidine-1-carboxylate (7.00 g, 35.0 mmol) was added at 0 C. and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50.0 mL) and extracted with EtOAc (2*100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give the product (7.40 g, 98%) as colorless oil. MS: m/z=214 (M+H+).
82% A 60% suspension of NaH in oil (230 mg; 5.5 mmol) in DMSO (6 ml) under argon was treated with <strong>[2181-42-2]trimethylsulphonium iodide</strong> (1.26 g; 5.75 mmol) at 5C. The mixture was stirred for 30 minutes and C7 (l. Og; 5 mmol) was added. The mixture was stirred for 1 hour at room temperature. The mixture was partitioned between water and diethyl ether. The diethyl ether was evaporated and the residue purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH2C12 (0-30% EtOAc) to give D7 (870 mg). Yield: 82%
70% Step 1. Synthesis of Intermediate 7-2. To a solution of <strong>[2181-42-2]trimethylsulfoxonium iodide</strong> (26.5 g, 130 mmol) in 50 mL of DMSO at 10 C under N2, NaH (5.18 g, 60% in miniral oil, 130 mmol) was added portionwise and the mixture was stirred at 10 C for 30 mins. Intermediate 7-1 (20 g, 100 mmol) in DMSO (50 mL) was added dropwise maintaining the temperature below 15 C and stirring was continued at 15 C for 20 hrs. The reaction was quenched at 10 C with water (200 mL) and extracted with MTBE (2 x 300 mL). The combined organic phases were washed with water (2 x 400 mL), brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (PE:EtOAc = 6:1) to give Intermediate 7-2 (15 g, 70%) as an off-white solid. (0337) 1H NMR (400 MHz, CDCl3) delta 3.77-3.66 (m, 2H), 3.43 (m, 2H), 2.69 (s, 2H), 1.86-1.72 (m, 2H), 1.52-1.39 (m, 11H).
65% NaH in mineral oil (10 g, 0.25 mol, 50 %) was added in portions with stirring under an atmosphere of Ar to DMSO (150 mL) over a period of 20 min. Then the mixture was heated on a water-bath to 75 0C and stirred about 20 min at room temperature until evolution of hydrogen ceased. The mixture was cooled to 25 0C, diluted by adding THF (15O mL), cooled to 5 0C and treated with a solution of trimethylsulfonium iodide (51 g, 0.25 mol) in DMSO (200 mL). Then compound 1 (40 g, 0.2 mol) was added to the mixture. The reaction was heated to 25 0C and stirred at this temperature for ~2 h. Then pH was adjusted to 8 with glacial acetic acid and the mixture was diluted by adding water (500 mL), ethylacetate (400 mL), hexane (20O mL) and dichloromethane (10O mL). The organic layer was separated, washed with water (2 x 200 mL), diluted by adding dichloromethane (100 mL) and washed with brine. Combined aqueous layer was extracted with ethylacetate (300 mL) and hexane (150 mL). The organic layer was washed similarly. Then organic layers were filtered sequentially through SiO2 (50 g). The combined filtrate was evaporated and the residue (45 g) was crystallized from hexane (60 ml_) at -18 0C to give the title compound as white crystals (bp 56-590C) in 65% (28 g, 0.13 mol) yield.

  • 2
  • [ 147804-30-6 ]
  • [ 614730-97-1 ]
YieldReaction ConditionsOperation in experiment
66% With pyridine hydrofluoride; In dichloromethane; at -10 - 20℃; A solution of the commercially available epoxide (2 g, 9.38 mmol) in 10 mL dichloromethane was added dropwise to a cooled mixture (-10 C.) of 0.6 mL of HF Py hydrogen fluoride in pyridine (70%) and 10 mL of dichloromethane cooled at -10 C. Then the mixture was stirred at room temperature for 4 hours, was then diluted with dichloromethane and was washed with a saturated aqueous solution of sodium carbonate. The organic phase was separated, dried over Na2SO4, filtered and the solvents were removed to give a residue. The residue was purified by chromatography on silica using ethyl acetate/heptanes (20 to 50%) to afford the title compound as a yellowish oil (1.44 g, 66%).1H-NMR (400 MHz, CDCl3): =1.44 (s, 9H), 1.47-1.63 (m, 2H), 1.85 (m, 2H), 3.08 (m, 2H), 3.56 (s, 1H), 3.61 (s, 1H), 3.92 (brs, 2H).MS ESI: m/z=233.98 (M+).
66% With pyridine hydrofluoride; In pyridine; dichloromethane; at -10 - 20℃; for 4h; Step A A solution of the commercially available epoxide (2 g, 9.38 mmol) in 10 mL dichloromethane was added dropwise to a cooled mixture (-10 C) of 0.6 mL of HF Py hydrogen fluoride in pyridine (-70%) and 10 mL of dichloromethane cooled at -10C. Then the mixture was stirred at room temperature for 4 hours, was then diluted with dichloromethane and was washed with a saturated aqueous solution of sodium carbonate. The organic phase was separated, dried over Na2SO4, filtered and the solvents were removed to give a residue. The residue was purified by chromatography on silica using ethyl acetate/heptanes (20 to 50 %) to afford the title compound as a yellowish oil (1.44 g, 66 %). 1H-NMR (400 MHz, CDCl3): delta = 1.44 (s, 9H), 1.47-1.63 (m, 2H), 1.85 (m, 2H), 3.08 (m, 2H), 3.56 (s, 1H), 3.61 (s, 1H), 3.92 (brs, 2H). MS ESI: m/z = 233.98 (M+)
39% [Reference Example 2] Synthesis of 4-fluoro-4-(hydroxymethyl)piperidinecarboxylic acid tert-butyl ester A mixed solution of 6-aza-1-oxaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (10.0 g, 46.9 mmol) in benzene-ether (2:1) (750 mL) was cooled to 0C, and after adding BF3·OEt2 (29.6 mL, 234 mmol) to the solution, it was stirred 1 hour. The reaction mixture was poured into ice-cooled 1N NaOH (500 ml) and stirred. After extraction with AcOEt (500 ml x 3 times), the extract was washed with water and then with saturated brine, and finally dried over anhydrous MgSO4. The solvent was distilled off, and the crude product was purified by silica gel column chromatography (30% AcOEt/hexane) to obtain 4-fluoro-4-(hydroxymethyl)piperidinecarboxylic acid tert-butyl ester. The compound was identified by 1H-NMR. The yield was 4.26 g (39%). 1H-NMR (270 MHz, CDCl3): 1.45-1.70(m,2H), 1.46(s,9H), 1.83-1.93(m,2H), 3.10(brt,2H,J=11.3Hz), 3.60(d,2H,J=20.3Hz), 3.94(brd,2H,J=11.3Hz)
A 70% solution of hydrofluoric acid in pyridine (12 mL) was added drop-wise to a solution of intermediate 16 (10 [G)] in anhydrous DCM (200 mL) previously cooled to-40C under a Nitrogen atmosphere. After 1.5 hours, further hydrofluoric acid in pyridine (6 mL) was added. After stirring for further 15 minutes, a saturated sodium hydrogen carbonate solution was added. The layers were separated and the aqueous phase was extracted three times with further DCM. The combined organic extracts were washed with brine, dried and concentrated [IN VACUO] to a residue which was purified by flash chromatography (CH/AcOEt 6: 4) to give the pure title compound (990 mg) and a fraction of title compound (6.01 [G)] impure of pyridine. Thus, this material was diluted with AcOEt and washed three times with a pH3 buffer solution and brine. The organic layer was dried and concentrated in vacuo to give a further amount of title compound (5.12 g). T. [I.] c.: CH/AcOEt 1: 1, [RF=0.] 35. NMR [(D6-DMSO)] : [8] (ppm) 4.99 (t, [1H)] ; 3.79 (m, 2H); 3.43 (dd, 2H); 3.01 (bt, 2H); 1.8-1. 4 (m, 4H); 1.43 (s, 9H).
In dichloromethane; at 0℃; for 2h;Inert atmosphere; ferf-Butyl 4-fluoro-4-(hydroxymethyl)piperidine-1 -carboxylate:In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of ferf-butyl 1-oxa-6-azaspiro[2.5]octane-6- carboxylate (2.50 g, 1 1.72 mmol) in dry CH2CI2 (20 mL) was added HF. Pyridine (1.00 mL, 8.20 mmol). The mixture was stirred at 0 C for 1 h, then more HF. Pyridine (0.50 mL, 4.10 mmol) was added and the mixture further stirred at 0 C for 1 h. Ice-water (100 mL) was then added followed by 2N aq. NaOH to reach neutral pH. The layers were separated and the aq. layer extracted with CH2CI2 (3x). The combined org. extracts were dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by FC (hept-EA, 1 :0 -> 1 :1 ) to afford the title compound as a colorless oil. LC-MS-conditions 08: tR = 0.66 min.
With pyridine hydrofluoride; In dichloromethane; at 0℃; for 2h;Inert atmosphere; tert-Butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2.50 g, 11.72 mmol) in dry CH2Cl2 (20 mL) was added HF.Pyridine (1.00 mL, 8.20 mmol). The mixture was stirred at 0 C. for 1 h, then more HF.Pyridine (0.50 mL, 4.10 mmol) was added and the mixture further stirred at 0 C. for 1 h. Ice-water (100 mL) was then added followed by 2N aq. NaOH to reach neutral pH. The layers were separated and the aq. layer extracted with CH2Cl2 (3*). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (hept-EA, 1:0->1:1) to afford the title compound as a colorless oil. LC-MS-conditions 08: tR=0.66 min.
21 g With pyridine; hydrogen fluoride; In dichloromethane; for 12h; [0055] 28 g of 1-oxa-6-azaspiro[2.5]octane-6-carboxylate was dissolved in 100 mL of dichloromethane (DCM) andcooled. 120 mL of 70% hydrogen fluoride solution in pyridine was added and reacted for another 12 hours. When thereaction was completed, 100 mL of water was added. The reaction mixture was extracted with 100 mL of DCM for threetimes and purified by chromatography on silica gel (petroleum ether (PE): ethyl acetate (EA) = 4: 1) and dried by arotatory evaporator to obtain 21 g of 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate as basically colorless liquid product.
21 g With pyridine hydrogenfluoride; In dichloromethane; for 12h; Dissolve 28 g of 6-tert-butoxycarbonyl-1-oxa-6-azaspiro [2.5] octane in 100 mL of dichloromethane (DCM),Cool, add 120 mL of 70% hydrogen fluoride pyridine solution,Reaction for another 12 hours, the reaction is over,Add 100mL of water and extract three times with 100mL of DCM.Petroleum ether (PE): ethyl acetate (EA) = 4: 1 through the column,Spin-dried to give 21 g of a substantially colorless liquid product,(4-fluoro-1-Boc substituted piperidin-4-yl) methanol.

  • 3
  • [ 147804-30-6 ]
  • [ 392331-66-7 ]
YieldReaction ConditionsOperation in experiment
95% With ammonium hydroxide; In methanol; at 80℃; for 16h;Sealed tube; A 100-mL sealed tube fitted with a magnetic stir bar was charged with tert-Butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (300 mg, 1.28 mmol) and a solution of ammonium hydroxide in methanol (20 mL, 7M). The solution was stirred for 16 h at 80 C. in an oil bath and cooled to room temperature. The mixture was concentrated under vacuum to afford tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (350 mg, >95%) used without further purification. LCMS (ESI) m/z 231 [M+H].
86% With ammonia; In methanol; at 20℃; for 12h; To a stirred solution of tert-butyl 1-oxa-6-aza-spiro[2.5]octane-6-carboxylate (0.64 grams, 3.0 mmol, obtained in the above step) in methanol (4 mL) at room temperature, a solution of ammonia (NH3) in methanol (7M, 8 mL) was added and the reaction was stirred for12 hours. The volatiles were removed under reduced pressure to obtain the crude mass which was triturated with hexanes and ether which yielded the above titled compound (0.6 gram). Yield: 86 %.?H - NMR CDCI3 (6 ppm): 1.45 (9H, s), 1.35 - 1.60 (4H, m), 2.63 (2H, s), 3.10 - 3.25 (2H, m), 3.80 - 3.95 (2H, m).Mass (m/z): 231.5 (M+H)4.
86% With ammonia; In methanol; at 20℃; for 12h; To a stirred solution of N-tert butyloxycarbonyl1-oxa-6-aza-spiro[2.5]octane 21 (0.64 g, 3.0 mmols) in methanol(4.0 mL) at r.t., a solution of ammonia (NH3)in methanol (7M, 8.0 mL) was added and the reaction was stirred for 12 hours.The volatiles were removed under reduced pressure to obtain the crude masswhich was triturated with hexanes and ether which yielded the above titledcompound 22c (0.6 g) in 86% yield.1H - NMR CDCl3 (CDCl3): d 3.95 - 3.80 (m, 2H), 3.25 -3.10 (m, 2H), 2.63 (s, 2H), 1.35 - 1.60 (m, 4H), 1.45 (s, 9H). Mass (m/z): 231.5 (M+H)+. Anal. (C11H22N2O3) C, H, N
76% With ammonia; In methanol; at 25 - 40℃; for 40h; tert-Butyl l-Oxa-6-aza-spiro[2.5]octane-6-carboxylate (0.5 grams, 2.34 mmole) was added to methanolic ammonia solution (20 mL, 14.83 % w/v) at room temperature. Then reaction mass was stirred for 40 hours at room temperature in a closed vessel. The progress of the reaction was monitored by TLC. After completion of the reaction (TLC), the reaction mass was concentrated on rotavacuum to obtain the title compound. Yield: 0.41 gram (76%). 'H-NMR(8 ppm): 1.35 - 1.69 (16H, m), 2.61 (2H, s), 3.10 - 3.20 (2H, m), 3.81 -3.90(2H, m); Mass (m/z): 231.3 (M+H)+.
76% With ammonia; In methanol; at 20℃; for 40h; tert-Butyl l-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.5 grams, 2.34 mmole, obtained in the step (i) of preparation 5) was added to methanolic ammonia solution (20 mL, 14.83 % w/v) at RT. Then reaction mass was stirred for 40 hours at RT in a closed vessel. The reaction mass was concentrated under vacuum to obtain the title compound. Weight: 0.41 gram (Yield: 76 %). (0385) - NMR (delta ppm): 1.35 - 1.69 (16H, m), 2.61 - 2.69 (2H, m), 3.10 - 3.20 (2H, m), 3.81 - 3.90 (2H, m); (0386) Mass (m/z): 231.3 (M+H)+ .
69% With ammonia; In methanol; at 20℃; Intermediate 2M: tert-butyl 4-(amiriomethyl)-4-hydroxypiperidine-1 -carboxylate A mixture of intermediate 1A (10.0 g, 46.9 mmol) and ammonia solution (201 mL, 7 M solution in methanol, 1.4 mol) was stirred at r.t. overnight. The solvent was removedunder vacuum and the residue was purified by flash chromatography, silica gel, gradient dichioromethane to methanol:dichloromethane (1:4) to give the title compound (7.4 g, 69% yield) as a white solid. HPLC retention time: 2.15 mm; MS:131 (M+H-100).
69% With ammonia; In methanol; at 20℃; A solution of intermediate 1A (10.0 g, 46.9 mmol) in ammonia (201 ml_, 7 M solution in methanol, 1.4 mol) was stirred at r.t. overnight. The solvent was removed under vacuum and the residue was purified by flash chromatography, silica gel, gradient dichloromethane to methanokdichloromethane (1 :4) to give the title compound (7.4 g, 69% yield) as a white solid. HPLC retention time: 2.15 min; MS: 131 (M+H-100).
69% With ammonia; In methanol; at 20℃; Intermediate 2A: fert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate A mixture of intermediate 1A (10.0 g, 46.9 mmol) and ammonia solution (201 mL, 7 M solution in methanol, 1.4 mol) was stirred at r.t. overnight. The solvent was removed under vacuum and the residue was purified by flash chromatography, silica gel, gradient dichloromethane to methanokdichloromethane (1 :4) to give the title compound (7.4 g, 69% yield) as a white solid. HPLC retention time: 2.15 min; MS: 131 (M+H-100).
60.5% With ammonia; In ethanol; water;Inert atmosphere; A stirred solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (9.0 g, 42.2 mmol) in ethanol (60 ml) was added with ammonia (100 ml). The resulting mixture was stirred under a nitrogen atmosphere overnight. The mixture was concentrated under reduced pressure. The residue was added with water (50 ml) and extracted with ethyl acetate (150 ml*3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane:methanol (20:1) as eluents to give 4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.87 g, 60.5%) as a white solid. MS m/z (ESI): 231 [M+1]
60.5% With ammonia; In ethanol; A stirred solution of l-oxa-6-aza-spiro [2.5] octane-6-carboxylic acid tert-butyl ester (9.0 g, 42.2 mmol) in ethanol(60 ml) was added with ammonia (100 ml). The resulting mixture was stirred under a nitrogen atmosphere overnight. The mixture was concentrated under reduced pressure. The residue was added with water (50 ml) and extracted with ethyl acetate (150 ml><3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane: methanol (20:1) as eluents to give 4-aminomethyl-4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (5.87 g, 60.5%) as a white solid. MS m/z (ESI): 231[M+1] ,
With ammonia; In methanol; water; at 0 - 20℃; for 7h; 4-Aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester is prepared from 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (Bourrain et al Bioorg. Med. Chem. Lett. 9(23):3369-3374 (1999)). Concentrated aqueous NH4OH (6 mL) is added to a solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (0.50 g, 2.3 mmol) in MeOH (4 mL) at 0 C. The reaction mixture is removed from the cooling and allowed to warm to room temperature. After 7 hours, the reaction mixture is concentrated under reduced pressure to afford desired product as a white solid.
With ammonium hydroxide; In methanol; at 0 - 20℃; for 16h; aqueous ammonia (6mL)was added to a solution of tert-butyl 1-oxa-6-azaspiro[2.5]octan-6-carboxylate (500mg, 2mmol) in methanol (4mL) at0C. The reaction solution warmed to room temperature and was stirred for 16 hours, then concentrated under reduced pressure to give a colorless oil (530mg, 2.3mmol) with a yield of 100%, which was used directly in the next step withoutpurification.

  • 4
  • [ 6302-65-4 ]
  • [ 147804-30-6 ]
  • [ 700834-36-2 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In 4-methyl-2-pentanone; for 9h;Heating / reflux; Dimethylformamide (ten drops) was added to a suspension of 4-mercaptobenzoic acid (5.0 g) in methanol (32 mL), followed by dropwise addition of thionyl chloride (3.5 mL) under cooling with ice-water. The mixture was stirred at room temperature for five minutes and was heated under reflux for two hours. Insoluble matter was collected by filtration, washed with methanol, and dried to yield crystals (4.50 g). Anhydrous potassium carbonate (4.34 g) was added to a solution of the crystals (2.00 g) and 1-(tert-butoxycarbonyl)piperidine-4-spiro-2'-oxirane (2.23 g) in 4-methyl-2-pentanone (26 mL), followed by heating under reflux under nitrogen atmosphere for nine hours. The reaction mixture was mixed with an ice water (50 mL) and was extracted with ethyl acetate. The organic layer was sequentially washed with water and brine and was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography [Chromatorex NHTM] (eluent; hexane:ethyl acetate = 19:1 to 1:1), and crystallized from a 5:1 mixture of hexane and ether to yield the titled compound (2.55 g) as crystals.
  • 5
  • [ 147804-30-6 ]
  • [ 188132-02-7 ]
  • [ 644968-01-4 ]
YieldReaction ConditionsOperation in experiment
With copper(I) bromide dimethyl sulphide complex In tetrahydrofuran at 30℃; for 3h; A solution of iso-propylmagnesium chloride in tetrahydrofuran (2M, 130 mL) was added dropwise over 30 minutes to a stirred solution of 2-bromo-4-fluoroanisole (34.2 mL) in anhydrous tetrahydrofuran (400 mL) at 30 °C under nitrogen. After a further 16 hours at 30 °C, copper (I) bromide dimethyl sulphide complex (0.4 g) was added followed by solution of tert-butyl 1-oxa-6-azaspiro [2.5] octane-6-carboxylate (56.2 g) in anhydrous tetrahydrofuran (110 mL). After a further 3 hours at 30 °C, the solution was cooled to 20 °C, diluted with water (600 mL) and extracted with tert.-butyl methyl ether (600 mL) then ethyl acetate (600 mL). Combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give crude sub-title compound (86 g) as a solid. APCI-MS : m/z 240 [M+H- (CH3) 2CCH2-C02
  • 6
  • [ 6192-52-5 ]
  • [ 147804-30-6 ]
  • [ 239073-94-0 ]
  • [ 239073-93-9 ]
YieldReaction ConditionsOperation in experiment
In methanol; ethyl acetate R.56 1-(Tert-butoxycarbonyl)-4-methoxy-4-piperidinecarbaldehyde Reference Example 56 1-(Tert-butoxycarbonyl)-4-methoxy-4-piperidinecarbaldehyde To a solution of 6-(tert-butoxycarbonyl)-1-oxa-6-azaspiro[2,5]octane (17.5 g) in methanol (250 ml) was added p-toluene sulfonic acid hydrate (285 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with sodium bicarbonate solution and saturated brine, dried and concentrated, and the residue was crystallized from ice-cooled hexane to give colorless solid of 1-(tert-butoxycarbonyl)-4-methoxy-4-piperidinemethanol (9.32 g). 1H-NMR (CDCl3) δ: 1.46 (9H, s), 1.30-1.87 (4H, m), 3.05-3.23 (2H, m), 3.24 (3H, s), 3.51 (2H, d, J=6.0 Hz), 3.68-3.83 (2H, m).
  • 7
  • [ 452-08-4 ]
  • [ 147804-30-6 ]
  • [ 644968-01-4 ]
YieldReaction ConditionsOperation in experiment
A solution of iso-propylmagnesium chloride in tetrahydrofuran (2M, 130ml) was added dropwise over 30 minutes to a stirred solution of <strong>[452-08-4]2-bromo-4-fluoroanisole</strong> (34.2ml) in anhydrous tetrahydrofuran (400ml) at 30C under nitrogen. After a further 16 hours at 30C, copper(I)bromide dimethyl sulphide complex (0.4g) was added followed by a solution of 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid, 1,1-dimethylethyl ester (56.2g) in anhydrous tetrahydrofuran (110ml). After a further 3 hours at 30C, the solution was cooled to 20C, diluted with water (600ml) and extracted with tert.-butyl methyl ether (600ml) then ethyl acetate (600ml). Combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give crude sub-title compound (86 g) as a solid. APCI-MS: m/z 240 [M+H-(CH3)2CCH2-CO2]+
  • 8
  • [ 1996-30-1 ]
  • [ 147804-30-6 ]
  • [ 644967-79-3 ]
YieldReaction ConditionsOperation in experiment
67% A solution of iso-propylmagnesium chloride in tetrahydrofuran (2M, 106.6ml) was added dropwise over 15 minutes to a stirred solution of <strong>[1996-30-1]2-bromo-4-chloro-1-fluorobenzene</strong> (42.5g) in anhydrous tetrahydrofuran (250ml) at 0C under nitrogen. After a further 15 minutes, a solution of 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid, 1,1-dimethylethyl ester (43.2g) in anhydrous tetrahydrofuran (50ml) was added followed by copper(I)bromide dimethyl sulphide complex (0.4g). The mixture was stirred at 40C for 18 hours, cooled to 20C, diluted with water (300ml) and extracted with with tert.-butyl methyl ether (2 x 300ml). Organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residual oil was dissolved in 1,2-dimethoxypropane (200ml). Potassium tert.-butoxide (22.8g) was added and the mixture stirred at 40C for 16 hours then at 50C for 24 hours. Further potassium tert.-butoxide (5.7g) was added and stirring continued at 50C for 2 hours then at 55C for 4 hours. Water (500ml) was added and the mixture extracted with tert.-butyl methyl ether (2 x 300ml). Organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give the sub-title compound (47.45g, 67 %) as an oil. 1H-NMR (400 MHz, CDCIl3) : delta 1.47 (9h, s), 1.67 (2H, td), 1.85-1.93 (2H, m), 2.94 (2H, s), 3.39 (2H, td), 3.65-3.80 (2H, m), 6.67 (1H, d), 7.06 (1H, d), 7.10 (1H, s).
  • 9
  • [ 60633-25-2 ]
  • [ 147804-30-6 ]
  • [ 1003567-08-5 ]
YieldReaction ConditionsOperation in experiment
82% Step 2: 4-(5-Chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester. 2-Bromo-4-chloroanisole is treated with isopropylmagnesium chloride dissolved in THF to produce the Grignard reagent in situ. A catalytic amount of copper (I) bromide dimethyl sulphide complex (CuBr1SMe2) and a solution of l-oxa-6-aza-spiro[2.5]octane-6- carboxylic acid tert-butyl ester in THF are added to produce the desired piperidinol.A solution of isopropylmagnesium chloride in THF (2 M, 2.96 kg, 3036 ml, 6.07 mol) was added to a stirred solution of 2-bromo-4-chloro-l-methoxybenzene (1.26 kg, 5.69 mol) in THF (5.5 kg) at a temperature of between 15 and 25 0C and stirring continued at this temperature for 6 - 8 h. Copper(I) bromide dimethylsulphide complex (8.8 g, 42.8 mmol) was added to the reaction mixture and stirring continued at between 17 and 20 0C for 10 min. A solution of l-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester in THF (3.1 kg, 39% w/w, 1.21 kg contained weight, 5.67 mol) was added to the reaction over a period of 20 min, maintaining the temperature between 15 and 20 0C, followed by further THF (2.3 kg). After stirring at between 20 and 25 0C for 10 - 12 h, the reaction mixture was cooled to between 5 and 10 0C and a mixture of water (97 ml) and THF (220 g) added over 20 min followed by ethyl acetate (8 kg) and a solution of ammonium chloride (1.72 kg) in water (9.68 kg). The reaction mixture was warmed to between 25 and 30 0C and stirred at this temperature for around 20 min. The layers were separated, the aqueous layer was extracted with ethyl acetate (8 kg) and the combined organic layers were washed with water 2 x 6 kg). The organic phase was concentrated under vacuum at 40 - 45 0C to 2-3 L total volume then heptane (8 kg) added to the solution over a period of 30 min. After cooling to ambient temperature then further cooling to 0-5 0C and holding at this temperature, the solid was collected by filtration, washed with a mixture of ethyl acetate and heptane (1:5, 1.4 kg) followed by heptane (1.5 kg) then dried to afford 4-(5-chloro-2- methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester as a solid, 1.65 kg (82%).1H NMR (399.824 MHz, CDCl3) delta 7.19 (dd, J= 8.7, 2.8 Hz, IH), 7.09 (d, J= 2.8 Hz, IH), 6.82 (d, J= 8.7 Hz, IH), 3.92 - 3.71 (m, 5H), 3.11 (t, J= 11.7 Hz, 2H), 2.80 (br s, 2H), 2.46 (s, exch D2O, IH), 1.60 - 1.42 (m, HH) APCI-MS: m/z 256/258 (MH+ - (CH3)3OCO).
82% Step 2: 4-(5-Chloro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl esterBromobenzene _.._ _ .CMP Grignard 2-Bromo-4-chloroanisole is treated with isopropylmagnesium chloride dissolved in THF to produce the Grignard reagent in situ. A catalytic amount of copper (I) bromide dimethyl sulphide complex (CuBr1SMe2) and a solution of l-oxa-6-aza-spiro[2.5]octane-6- carboxylic acid tert-butyl ester in THF are added to produce the desired piperidinol.A solution of isopropylmagnesium chloride in THF (2 M, 2.96 kg, 3036 ml, 6.07 mol) was added to a stirred solution of 2-bromo-4-chloro-l-methoxybenzene (1.26 kg, 5.69 mol) in THF (5.5 kg) at a temperature of between 15 and 25 0C and stirring continued at this temperature for 6 - 8 h. Copper(I) bromide dimethylsulphide complex (8.8 g, 42.8 mmol) was added to the reaction mixture and stirring continued at between 17 and 20 0C for 10 min. A solution of l-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester in THF (3.1 kg, 39% w/w, 1.21 kg contained weight, 5.67 mol) was added to the reaction over a period of 20 min, maintaining the temperature between 15 and 20 0C, followed by further THF (2.3 kg). After stirring at between 20 and 25 0C for 10 - 12 h, the reaction mixture was cooled to between 5 and 10 0C and a mixture of water (97 ml) and THF (220 g) added over 20 min followed by ethyl acetate (8 kg) and a solution of ammonium chloride (1.72 kg) in water (9.68 kg). The reaction mixture was warmed to between 25 and 30 0C and stirred at this temperature for around 20 min. The layers were separated, the aqueous layer was extracted with ethyl acetate (8 kg) and the combined organic layers were washed with water 2 x 6 kg). The organic phase was concentrated under vacuum at 40 - 45 0C to 2-3 L <n="21"/>total volume then heptane (8 kg) added to the solution over a period of 30 min. After cooling to ambient temperature then further cooling to 0-5 0C and holding at this temperature, the solid was collected by filtration, washed with a mixture of ethyl acetate and heptane (1:5, 1.4 kg) followed by heptane (1.5 kg) then dried to afford 4-(5-chloro-2- methoxybenzyl)-4-hydroxypiperidine-l-carboxylic acid tert-butyl ester as a solid, 1.65 kg (82%).1H NMR (399.824 MHz, CDCl3) delta 7.19 (dd, J= 8.7, 2.8 Hz, IH), 7.09 (d, J= 2.8 Hz, IH), 6.82 (d, J= 8.7 Hz, IH), 3.92 - 3.71 (m, 5H), 3.11 (t, J= 11.7 Hz, 2H), 2.80 (br s, 2H), 2.46 (s, exch D2O, IH), 1.60 - 1.42 (m, HH) APCI-MS: m/z 256/258 (MH+ - (CH3)3OCO).
  • 10
  • [ 374063-92-0 ]
  • [ 147804-30-6 ]
  • [ 1134111-42-4 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; Example Kl: 1-Methylcyclopropyl 4-methoxy-4-((5-(4- (methylsulfonyl)piperazin-l-yl)pyrazin-2-yloxy)methyl)piperidine-l-carboxylate. <n="95"/>[00211] Step A: A solution of KIa (2.22 g, 10.4 mmol) and 2-bromo-5- hydroxypyrazine (2 g, 11.4 mmol) in N-methylpyrrolidinone (10 mL) is treated with K2CO3 (2.37 g, 17.1 mmol) and heated to 80 C overnight. After cooling to room temperature, the reaction is diluted with ethyl acetate and extracted with water twice. The organics are dried over MgSO4, filtered evaporated and purified by silica gel using a linear gradient of 0-100% ethyl acetate in hexane to afford KIb; ESIMS m/z for (M+H+) Ci5H23BrN3O4 calcd.: 388.1, found: 388.2.
  • 11
  • [ 93224-85-2 ]
  • [ 147804-30-6 ]
  • [ 1241953-16-1 ]
YieldReaction ConditionsOperation in experiment
8-Chlorospiro[isochromene-3,4'-piperidinl- 1 (4H)-one To a solution of 2-bromo-6-chloro- benzoic acid (1.50 g, 6.37 mmol) in THF (25 mL) at -78 C was added «-butyl lithium (2.5 M in hexanes, 5.35 mL, 13.38 mmol) dropwise. The solution was stirred for Ih before l-oxa-6-aza- spiro[2.5]octane-6-carboxylic acid ester (1.63 g, 7.64 mmol; prepared as described in literature procedure Sabbani, S. et al, Bioorg. Med. Chem. Lett. 2008, 18, 5804-5808) in THF (8.5 mL) was added to the mixture. The stirring was continued for 5 h at -78 C, then left overnight and warmed to room temperature. The reaction mixture was quenched with NaOH (1 N, 30 mL). The volatiles were removed under reduced pressure. The resulting aqueous layer was washed with MTBE (15 mL) and acidified with 6N HCl (30 mL). The lactonization and deprotection were achieved by heating to 60 0C for 3 h. The resulting mixture was cooled in an ice bath to keep the temperature below 20 0C as it was basified with IO N NaOH to pH 10-12. The aqueous layer was extracted with IPA (2x 60 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by Combiflash chromatography (amine column, elution with 0-10%MeOH/DCM) to afford the title compound as solid. 1H NMR (CDCl3, 400 MHz) 7.45-7.40 (2H, m), 7.19-7.14 (IH, m), 4.36 (IH, br), 3.17-3.09 (2H, m), 3.05 (2H, s), 2.94 (2H, ddd), 1.96-1.88 (2H, m), 1.74 (2H, ddd). MS (ESI, Q+) m/z 252.0, 254.0 (M + 1, 35Cl, 37Cl).
  • 13
  • [ 26621-44-3 ]
  • [ 147804-30-6 ]
  • [ 1354693-40-5 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h; A mixture of <strong>[26621-44-3]3-nitro-1H-pyrazole</strong> (226 mg, 2.0 mmol), 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (500 mg, 2.34 mmol), potassium carbonate (345 mg, 2.5 mmol) in DMF (3 mL) was stirred at 80 C. for 1 h. The mixture was then diluted with water and ethyl acetate. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated to afford 4-hydroxy-4-(3-nitro-pyrazol-1-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.83 g), which was taken directly to the hydrogenation conditions.
  • 14
  • [ 1996-30-1 ]
  • [ 147804-30-6 ]
  • [ 1055710-50-3 ]
  • 15
  • [ 31374-18-2 ]
  • [ 147804-30-6 ]
  • [ 1426340-66-0 ]
YieldReaction ConditionsOperation in experiment
85% With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; Into the solution of Si (2. 13g, 11 .8mmol) in 5OmL DMF was added S3 (2.78g, 13.Ommol) and C52CO3 (11.54g, 35.4mmol). The mixture was heated at 80C overnight. Then the reaction was cooled to room temperature, and diluted with EtOAc. The solution was washed with saturated NH4C1 (5OmLx2) Aqueous phase was extracted with more EtOAc. Combined organic phase was washed with brine, dried over MgSO4, followed by filtration and evaporation under reduced pressure. The crude material was purified by flash column chromatography (40% to 100% EtOAc in hexanes) to afford 3.94g product in 85% yield.
68% With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; Step 1: Preparation of tert-butyl 4-[(7-chloro-4-oxo-3,4-dihydroquinazolin-3-yl)methyl]-4- hydroxypiperidine- 1 -carboxylate To a solution of <strong>[31374-18-2]7-chloro-3,4-dihydroquinazolin-4-one</strong> (0.40g, 2.2mmol, 1 eq) in DMF (5ml_) was added compound from step 1 of example 1 (0.47g, 1 eq) and cesium carbonate (2.17g, 3eq). The reaction mixture was heated at 80 C overnight, and then allowed to reach room temperature. The mixture was washed with a saturated NH4CI solution, and then extracted with AcOEt. The combined organic extracts were dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3/7). A second purification by flash chromatography on silica gel was performed (eluent: cyclohexane/ethyl acetate 6/4 to 0/10) to give tert-butyl 4-[(7-chloro-4-oxo-3,4- dihydroquinazolin-3-yl)methyl]-4-hydroxypiperidine- 1 -carboxylate (0.6g, 68%) as a colourless oil.
  • 16
  • [ 88887-87-0 ]
  • [ 147804-30-6 ]
  • 1,1-dimethylethyl 4-hydroxy-4-[(1-methylcyclopropyl)amino]methyl}-1-piperidine carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
61% In ethanol; at 86℃; for 20h;Sealed tube; Inert atmosphere; In a sealed reaction vessel purged with nitrogen, a mixture of 1 , 1 -dimethylethyl 1 - oxa-6-azaspiro[2.5]octane-6-carboxylate (1.05 g, 4.92 mmol), ethanol (8 mL) andl- methylcyclopropanamine hydrochloride (0.7 g, 9.84 mmol) was heated at 85 °C affording a clear yellow solution. After 20 h, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure to afford the title compound (1.7 g, 61percent), which was used in next step without further purification. MS(ES)+ m/e 285 [M+H]+.
  • 17
  • [ 147804-30-6 ]
  • [ 50675-14-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sodium hydride / 1.5 h / 0 °C 1.2: 1 h / 50 °C 2.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C
Multi-step reaction with 2 steps 1: sodium hydride / 0 - 50 °C 2: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C
  • 18
  • [ 4175-76-2 ]
  • [ 147804-30-6 ]
  • C13H19ClN2O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
General procedure: To a solution of the corresponding 4-chloroaryl reagent (0.9 mmol) in THF (10 mL) was added dropwise n-BuLi (0.392 mL, 0.98 mmol) at -78C under N2. After 1 h stirring at -78C, a solution of tert-butyl l-oxa-6-azaspiro[2.5]octane-6- carboxylate (200 mg, 0.98 mmol) in 1 mL of THF was added dropwise to the reaction mixture, followed by BF3.OEt2 (299.3 mg, 0.98 mmol) at -78C under N2. The reaction mixture was stirred at -78C for 3 h, and then the reaction mixture was allowed to warm to r.t. and stirred at r.t. overnight. The reaction mixture was cooled to -30C and quenched by Sat. NH4C1. The resulting mixture was extracted with EtOAc (50 mL, twice). The combined organic phase was washed with brine, dried over anhy. Na2S04 and concentrated in vacuo. The residue was purified by standard methods to afford 52B.
  • 19
  • [ 147804-30-6 ]
  • [ 930785-40-3 ]
  • 20
  • [ 147804-30-6 ]
  • [ 1352926-03-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: ammonia / methanol / 20 °C 2.1: potassium carbonate / water; ethyl acetate / 0.5 h / 0 °C 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran; <i>tert</i>-butyl alcohol / 20 °C / Reflux 4.1: dimethylsulfide borane complex / tetrahydrofuran / 2 h / 55 °C 4.2: Reflux 5.1: acetic acid / tetrahydrofuran / 0.25 h / 20 °C 5.2: 20 °C
  • 21
  • [ 159326-71-3 ]
  • [ 147804-30-6 ]
  • tert-butyl 4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere; To a 100-mL round-bottom flask fitted with a nitrogen inlet, magnetic stir bar and condenser was charged cesium carbonate (21.7 g, 66.6 mmol), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (6.16 g, 28.9 mmol), <strong>[159326-71-3]pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one</strong> (3.00 g, 22.2 mmol), and DMF (50 ml). The reaction was heated at 80 C. for 2 h and then diluted with water (50 mL) and ethyl acetate (100 mL). The organic phase was removed and the aqueous phase was further extracted with ethyl acetate (100 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography using 1:1 ethyl acetate/hexane as mobile phase to provide tert-butyl 4-hydroxy-4-((4-oxopyrrolo[2,1-f][1,2,4]triazin-3 (4H)-yl)methyl)piperidine-1-carboxylate (Intermediate 2-1, 4.62 g, 60%). LCMS (ESI) m/z 349.02 [M+H].
  • 22
  • [ 19178-25-7 ]
  • [ 147804-30-6 ]
  • tert-butyl 4-hydroxy-4-((4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)methyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; To a solution of <strong>[19178-25-7]pyrido[3,4-d]pyrimidin-4(3H)-one</strong> (12 mg, 0.080 mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (21 mg, 0.10 mmol) in DMF (0.400 mL) was added cesium carbonate (78 mg, 0.240 mmol). The reaction mixture was stirred at 80 C. for 16 h, then cooled to room temperature, diluted with ethyl acetate (0.5 mL) and washed with water (0.5 mL). The organic layer was concentrated under reduced pressure to afford tert-butyl 4-hydroxy-4-((4-oxopyrido[3,4-d]pyrimidin-3 (4H)-yl)methyl)piperidine-1-carboxylate, which was used without further purification. LCMS: (ESI) m/z 361.19 [M+H].
  • 23
  • [ 19181-54-5 ]
  • [ 147804-30-6 ]
  • tert-butyl 4-hydroxy-4-((8-methyl-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; To a solution of <strong>[19181-54-5]8-methylquinazolin-4(3H)-one</strong> (20 mg, 0.125 mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (33 mg, 0.156 mmol) in DMF (0.625 mL) was added cesium carbonate (122 mg, 0.375 mmol). The reaction mixture was stirred at 80 C. for 16 h, then cooled to room temperature, diluted with ethyl acetate (0.5 mL) and washed with water (0.5 mL). The organic layer was concentrated under reduced pressure to afford tert-butyl 4-hydroxy-4-((8-methyl-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate, which was used without further purification. LCMS: (ESI) m/z 396.29 [M+Na].
  • 24
  • [ 439692-81-6 ]
  • [ 147804-30-6 ]
  • tert-butyl 4-hydroxy-4-((4-oxo-6-propylthieno[2,3-d]pyrimidin-3(4H)-yl)methyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 16h; C.4.1 tert-butyl 4-hydroxy-4-((4-oxo-6-propylthieno[2,3-d]pyrimidin-3(4H)-yl)methyl)piperidine-1-carboxylate To a solution of 6-propylthieno[2,3-d]pyrimidin-4(3H)-one (12 mg, 0.06 mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (16 mg, 0.075 mmol) in DMF (0.3 mL) was added cesium carbonate (59 mg, 0.18 mmol). The reaction mixture was stirred at 80° C. for 16 h, then cooled to room temperature, diluted with ethyl acetate (0.5 mL) and washed with water (0.5 mL). The organic layer was concentrated under reduced pressure to afford tert-butyl 4-hydroxy-4-((4-oxo-6-propylthieno[2,3-d]pyrimidin-3(4H)-yl)methyl)piperidine-1-carboxylate, which was used without further purification. LCMS: (ESI) m/z 430.31 [M+Na].
  • 25
  • [ 4765-77-9 ]
  • [ 147804-30-6 ]
  • tert-butyl 4-((4-chloro-6-oxopyrimidin-1(6H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 16.0h; A solution of 6-chloropyrimidin-4(3/-/)-one (3.72 g, 28.5 mmol), Epoxide 1 (6.08 g, 28.5 mmol) and DIPEA (7.47 mL, 42.7 mmol) in DMF (35 mL) was heated at 80 C for 16 h. The reaction mixture was allowed to cool to RT before it was quenched by the addition of saturated NH4CI(aq) (20 mL) and the resulting mixture was extracted with EtOAc. The combined organic extracts were dried over MgS04, concentrated and the residue was purified by chromatography (Grace 120 g Resolv, 0-100% EtOAc in cyclohexane) to give tert-butyl 4-((4-chloro-6-oxopyrimidin-1 (6/-/)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (5.87 g, 60%) as an off-white solid. LCMS (Method B): RT = 0.99 min, m/z = 342 [M+H]+.
44% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; General procedure: The appropriate nucleophile (1 equiv.), the epoxide (1-3 equiv.) and a base, either Cs2C03 (1-3 equiv.) or DIPEA (1.5 equiv.), were suspended in DMF and the mixture was heated at 80 C for 10-24 h or as indicated. The reaction was cooled to RT. Saturated aqueous ammonium chloride solution or water was added and the mixture was extracted with DCM or EtOAc (*3). The combined organic extracts were dried (Biotage phase separator or MgS04), concentrated and the residue was purified by flash chromatography (Biotage KP-Sil and/or KP-NH, 0-100% EtOAc in cyclohexane; then 0-30% MeOH in EtOAc) to give the product.
44% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; General procedure: The appropriate nucleophile (1 equiv.), the epoxide (1-3 equiv.) and a base (1-5 equiv.) were suspended in a solvent and the reaction mixture was heated under the stated conditions. (0735) The reaction was allowed to cool to rt, saturated NH4CI(aq) or water was added and the resulting mixture was extracted using DCM or EtOAc (x 3). The combined organic extracts were dried (phase separator or MgS04), concentrated under reduced pressure and the remaining residue was purified by flash chromatography to give the product.
  • 26
  • [ 16234-10-9 ]
  • [ 147804-30-6 ]
  • tert-butyl 4-hydroxy-4-((4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)methyl)piperidine-1-carboxylate [ No CAS ]
  • 27
  • [ 147804-30-6 ]
  • [ 112204-58-7 ]
  • C17H22BrNO4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
15.8% With sodium hydride; In N,N-dimethyl-formamide; at 150℃;Inert atmosphere; Dissolve <strong>[112204-58-7]5-bromo-2-fluorophenol</strong> (950 mg, 5.0 mmol) in dry DMF (10 mL) and slowly add sodium hydrogen (200 mg, 5.0 mmol) at 0 C under a nitrogen atmosphere.After stirring for 5 minutes, Compound C-1 (1.1 g, 5.0 mmol) was added, and the temperature was raised to 150 C. to react overnight.After quenching with water (30 mL), the aqueous phase was extracted with ethyl acetate (15 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated by flash column chromatography (petroleum ether/ethyl acetate=20 : 1) Compound 51-b (0.3 g, 15.8%) was obtained.
  • 28
  • [ 286946-77-8 ]
  • [ 147804-30-6 ]
  • C16H22BrClN2O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% With potassium carbonate; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; To a 100 mL round-bottom flask, 52-d (495 mg, 2.4 mmol), compound C-1 (511 mg, 2.4 mmol), K2CO3 (816 mg, 6 mmol), DMF (10 mL) were successively added. The mixture was stirred overnight at 90C under a nitrogen atmosphere. After the solvent was distilled off under reduced pressure, the crude product was subjected to flash column chromatography (petroleum ether/ethyl acetate = 5:1) to give compound 52-c (0.42 g, 42%).
  • 29
  • [ 147804-30-6 ]
  • [ 863561-70-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sodium azide; ammonium chloride / methanol; water / 15 h / Heating / reflux 2: 15-crown-5; sodium hydride / tetrahydrofuran 3: hydrogen / palladium 10% on activated carbon / ethanol; ethyl acetate / 2.5 h / 912.06 Torr
  • 30
  • [ 403-01-0 ]
  • [ 147804-30-6 ]
  • C19H26FNO6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% With lithium perchlorate; In acetonitrile; at 80℃; (2)Compound j (8 g, 1.0 eq), compound k (1.5 eq), lithium perchlorate (1.7 eq) and acetonitrile (50 ml) were added to a three-necked flask, and the mixture was heated to 80 ° C to stir the reaction for 12-18 h.Cool down to room temperature,Diluted with 200 ml of ethyl acetate.Wash with saturated brine and dry over anhydrous sodium sulfate.Concentrate the organic phase to dryness, over the fast column,Obtaining 9.06 g of compound l,Yield: 63percent.
  • 31
  • [ 20872-93-9 ]
  • [ 147804-30-6 ]
  • C19H24N4O6 [ No CAS ]
  • 32
  • [ 403-01-0 ]
  • [ 147804-30-6 ]
  • C19H25NO6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
6.37 g (2) Compound j (8 g, 1.0 eq), compound k (1.5 eq), lithium perchlorate (1.7 eq) and acetonitrile (50 ml) were added to a three-necked flask, heated to 80 ° C and stirred for 12-18 h. After completion, the mixture was cooled to room temperature, diluted with 200 ml of ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfateObtaining 9.06 g of compound l,Yield: 63percent. (3) Compound l (8g, 1.0 eq), cesium carbonate (1.5 eq) and acetonitrile (50 ml) were added to a three-necked flask, heated to 60 ° C and stirred for 6-8 h. After the reaction was completed, the temperature was lowered to room temperature, and 200 ml was added. Diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate6.37 g of compound m was obtained in a yield: 84percent.
  • 33
  • [ 171178-33-9 ]
  • [ 147804-30-6 ]
  • C18H23ClN4O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 48h; 6-Chloro-3/7-pyrido[3,2-i/]pyrimidin-4-onc (1.242 g, 6.67 mmol), tert- butyl l-oxa-6- azaspiro[2.5]octane-6-carboxylate (2.34 g, 11 mmol) and K2CO3 (2.76 g, 19.9 mmol) were stirred in DMF (20 ml) at 70 C for 48 hours. The reaction mixture was filtered, and the resulted filtrate was purified by preparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HC03-MeCN, gradient), to give tert- butyl 4-[(6-chloro-4-oxo-quinazolin-3- yl)methyl]-4-hydroxy-piperidine- 1 -carboxylate.
  • 34
  • [ 171178-33-9 ]
  • [ 147804-30-6 ]
  • C26H33N5O5 [ No CAS ]
  • 35
  • [ 1060813-07-1 ]
  • [ 147804-30-6 ]
  • tert-butyl 4-(3-chloro-4,5-difluorobenzyl)-4-hydroxypiperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% Stage #1: 5-bromo-1-chloro-2,3-difluorobenzene With n-butyllithium In tetrahydrofuran at -78℃; for 1.5h; Inert atmosphere; Stage #2: With boron trifluoride diethyl etherate In tetrahydrofuran for 0.25h; Stage #3: 1-oxa-6-aza-spiro-[2.5]octane-6-caboxylic acid tert-butyl ester In tetrahydrofuran at -78 - 25℃; for 20h; 100.1 Step 1: Preparation of tert-butyl 4-(3-chloro-4,5-difluorobenzyl)-4-hydroxypiperidine-1-carboxylate To a solution of 5-bromo-1-chloro-2,3-difluorobenzene (4.5 g, 19.9 mmol) in dry tetrahydrofuran (60 mL) at -78 °C was added n-butyllithium (2.5 M, 8.7 mL, 21.9 mmol) drop-wise under argon. The reaction mixture was stirred at - 78 C for 1.5 h, then boron trifluoride etherate (47% wt, 5.6 mL, 20.6 mmol) was added slowly. The reaction solution was stirred for 15 min before a solution of tert-butyl 1-oxa- 6-azaspiro[2.5]octane-6-carboxylate (4.2 g, 19.9 mmol) in dry tetrahydrofuran (20 mL) was added drop- wise. The reaction mixture was stirred at -78 °C for 2 h and then at 25 °C for 18 h. The reaction solution was quenched with saturated ammonium chloride aqueous solution and basified to pH = 9 with 2 N sodium hydroxide aqueous solution. The aqueous layer was extracted with ethyl acetate (60 mL x 2). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by Combi-Flash (Biotage, 80 g silica gel, eluted with ethyl acetate in petroleum ether from 20 to 30%) to give tert-butyl 4-(3-chloro-4,5-difluorobenzyl)-4- hydroxypiperidine-1-carboxylate (4 g, 11.08 mmol, 55%) as a colorless oil. LCMS (ESI) m/z: 306.2 [M- 56+H]+.
  • 36
  • [ 147804-30-6 ]
  • [ 4983-28-2 ]
  • C15H22ClN3O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 70 - 80℃; for 12h; Inert atmosphere; 34 Under the protection of nitrogen, potassium carbonate (6.36 g, 46.01 mmol) was added to a solution of 2-chloro-5-hydroxypyrimidine (3 g, 22.98 mmol) and 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (8.82 g, 41.37mmol) in DMF(50mL). The mixture was stirred at 70-80 °C for 12 hours, the reaction mixture was cooled to 25°C, ethyl acetate (80 mL) was added thereto at 25 °C, and then the mixture was filtered, the filtrate was washed with saturated ammonium chloride aqueous solution (50 mL × 1 time), the aqueous phase was extracted with ethyl acetate (50 mL × 2 times). The combined organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain the compound 34A. 1H NMR (400MHz, DMSO-d6) δ = 8.56 (s, 2H), 3.99 (s, 2H), 3.78 - 3.66 (m, 2H), 3.18 - 3.00 (m, 2H), 1.59 - 1.50 (m, 4H), 1.41 (s, 9H). LCMS (ESI) m/z: 344.2 [M+1].
With potassium carbonate In N,N-dimethyl-formamide at 70 - 80℃; for 12h; Inert atmosphere; 34 Under the protection of nitrogen, potassium carbonate (6.36 g, 46.01 mmol) was added to a solution of 2-chloro-5-hydroxypyrimidine (3 g, 22.98 mmol) and 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (8.82 g, 41.37mmol) in DMF(50mL). The mixture was stirred at 70-80 °C for 12 hours, the reaction mixture was cooled to 25°C, ethyl acetate (80 mL) was added thereto at 25 °C, and then the mixture was filtered, the filtrate was washed with saturated ammonium chloride aqueous solution (50 mL × 1 time), the aqueous phase was extracted with ethyl acetate (50 mL × 2 times). The combined organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain the compound 34A. 1H NMR (400MHz, DMSO-d6) δ = 8.56 (s, 2H), 3.99 (s, 2H), 3.78 - 3.66 (m, 2H), 3.18 - 3.00 (m, 2H), 1.59 - 1.50 (m, 4H), 1.41 (s, 9H). LCMS (ESI) m/z: 344.2 [M+1].
  • 37
  • [ 827599-22-4 ]
  • [ 147804-30-6 ]
  • tert-butyl 4-hydroxy-4-(((1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 120℃; 47.1 Step 1: tert-butyl 4-hydroxy-4-(((lR,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3- yl)methyl)piperidine-l -carboxylate To ((lR,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (150 mg, 0.70 mmol) and tert- butyl l-oxa-6-azaspiro[2.5]octane-6-carboxylate (96 mg, 0.84 mmol) in DMSO (5 mL) was added N,N-diisopropylethylamine (0.17 mL, 0.99 mmol). The reaction was stirred at 120 °C for ~20 h then allowed to cool to room temperature. The reaction was diluted with MeOH and purified via prep-HPLCMS (Waters SunFire C18, 5 μm particle size, 30x100 mm; mobile phase: Aq(0.1% TFA)/MeCN 60 mL/min; gradient: 10 - 30% MeCN over 5 min). The combined fractions were basified to pH>10 with saturated aq Na2CO3 then extracted with DCM (3 x 40 mL). The combined DCM layers were washed with brine (1 x 30 mL), dried with MgSO4, filtered and concentrated to afford tert-butyl 4-hydroxy-4-(((lR,5S,6r)-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)methyl)piperidine-l-carboxylate (159 mg, 0.49 mmol, 69%). LCMS calcd. for C17H31N2O4+ [M+H]+ m/z = 327.2; found: 327.1.
69% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 120℃; 47.1 Step 1: tert-butyl 4-hydroxy-4-(((lR,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3- yl)methyl)piperidine-l -carboxylate To ((lR,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (150 mg, 0.70 mmol) and tert- butyl l-oxa-6-azaspiro[2.5]octane-6-carboxylate (96 mg, 0.84 mmol) in DMSO (5 mL) was added N,N-diisopropylethylamine (0.17 mL, 0.99 mmol). The reaction was stirred at 120 °C for ~20 h then allowed to cool to room temperature. The reaction was diluted with MeOH and purified via prep-HPLCMS (Waters SunFire C18, 5 μm particle size, 30x100 mm; mobile phase: Aq(0.1% TFA)/MeCN 60 mL/min; gradient: 10 - 30% MeCN over 5 min). The combined fractions were basified to pH>10 with saturated aq Na2CO3 then extracted with DCM (3 x 40 mL). The combined DCM layers were washed with brine (1 x 30 mL), dried with MgSO4, filtered and concentrated to afford tert-butyl 4-hydroxy-4-(((lR,5S,6r)-6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)methyl)piperidine-l-carboxylate (159 mg, 0.49 mmol, 69%). LCMS calcd. for C17H31N2O4+ [M+H]+ m/z = 327.2; found: 327.1.
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