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Product Details of [ 89151-44-0 ]

CAS No. :89151-44-0 MDL No. :MFCD03427086
Formula : C12H23NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :YBNJZIDYXCGAPX-UHFFFAOYSA-N
M.W : 229.32 Pubchem ID :854140
Synonyms :

Calculated chemistry of [ 89151-44-0 ]

Physicochemical Properties

Num. heavy atoms : 16
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.92
Num. rotatable bonds : 5
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 67.37
TPSA : 49.77 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.61 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.84
Log Po/w (XLOGP3) : 1.53
Log Po/w (WLOGP) : 1.64
Log Po/w (MLOGP) : 1.44
Log Po/w (SILICOS-IT) : 1.31
Consensus Log Po/w : 1.75

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.9
Solubility : 2.92 mg/ml ; 0.0127 mol/l
Class : Very soluble
Log S (Ali) : -2.18
Solubility : 1.5 mg/ml ; 0.00655 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.52
Solubility : 6.99 mg/ml ; 0.0305 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.18

Safety of [ 89151-44-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 89151-44-0 ]

* 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.

  • Upstream synthesis route of [ 89151-44-0 ]
  • Downstream synthetic route of [ 89151-44-0 ]

[ 89151-44-0 ] Synthesis Path-Upstream   1~24

  • 1
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  • [ 169457-73-2 ]
YieldReaction ConditionsOperation in experiment
88% With carbon tetrabromide; triphenylphosphine In dichloromethane EXAMPLE 21.1
Tert-butyl-4-(2-bromoethyl)piperidine-1-carboxylate
To a solution of tert-butyl-4-(2-hydroxyethyl)piperidine-1-carboxylate (1.5 g, 6.54 mmol) and tetrabromide carbon (3.25 g, 9.81 mmol) in DCM (20 ml), the solution of triphenylphosphine (1.72 g, 6.54 mmol) was added slowly.
The reaction was stirred overnight and diluted with hexanes (50 ml), washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
Purification by flash chromatography (silica gel, gradient elution with 10 to 30percent ether/hexanes) provided a yellow oil (1.67 g, 88percent).
1H NMR (300 MHz, CDCL3): 4.07 (br, 2H), 3.35 (br, 2H), 2.60 (br, 2H), 1.69-1.72 (m, 2H), 1.56-1.60(m, 3H), 1.36 (s, 9H), 0.86-1.06 (m, 2H).
87% With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; Example 14; 4-(2-Bromo-ethyl)-piperidine-1-carboxylic Acid tert-butyl Ester; A solution of triphenyl-phosphane (1.716 g, 6.54 mmol) in dichloromethane was added slowly over an hour to the solution of 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester and tetrabromomethane in dichloromethane (20 mL) at room temperature. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was diluted with hexane (50 mL), and then washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and condensed to dryness. The crude residue was purified on silica gel using ether:hexane=10percent:90percent then ether:hexane=30percent:70percent to give the product as colorless oil (1.67 g, 87percent).1HNMR (300 MHz, CDCl3): (ppm) 4 (br, 2H), 3.35 (t, 2H), 2.58 (br, 2H), 1.7 (q, 2H), 1.59 (br, 3H), 1.35 (s, 9H), 1.02 (br, 2H)
87% With carbon tetrabromide; triphenylphosphine; potassium iodide In tetrahydrofuran; [(2)H6]acetone; dichloromethane; ethyl acetate at 0 - 30℃; Inert atmosphere tert-Butyl 4-[2-[4-(Benzyloxy)phenoxy]ethyl]piperidine-1-carboxylate
Into a 100-mL round-bottom flask was placed a solution of 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethanol (1.10 g, 4.80 mmol) and tetrabromomethane (2.40 g, 7.24 mmol, 1.86 equiv.) in tetrahydrofuran (30 mL).
Triphenylphosphine (1.26 g, 4.80 mmol, 1.00 equiv.) in CH2Cl2 was added slowly under N2 at 0° C.
The resulting solution was stirred overnight at 30° C. and then concentrated under vacuum.
The residue was applied onto a silica gel column, which was eluted with EtOAc/petroleum ether 1:10 to 1:5.
This resulted in 1.22 g (87percent) of the bromide as a colorless oil.
A solution/suspension of tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (1.22 g, 4.18 mmol), 4-(benzyloxy)phenol (1.01 g, 5.04 mmol, 1.20 equiv.), K2CO3 (830 mg, 6.01 mmol, 1.40 equiv.) and KI (75 mg, 0.45 mmol, 0.11 equiv.) in acetone was heated to reflux under N2 overnight.
After cooling to room temperature, the mixture was diluted with 100 mL of EtOAc, and the solids were filtered off.
The filtrate was concentrated under vacuum, and the residue was applied onto a silica gel column, which was eluted with ethyl acetate/petroleum ether (1:5) to afford the product (1.25 g, 73percent) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.43-7.29 (m, 5H), 6.90 (d, 2H, J=6.6 Hz), 5.01 (s, 2H), 4.08 (d, 2H, J=7.2 Hz), 3.95 (t, 1H, J=4.2 Hz), 2.70 (t, 2H, J=9.6 Hz), 1.71-1.69 (m, 5H), 1.45 (s, 9H), 1.20-1.15 (m, 2H). LC-MS (ESI) m/z 434 (M+Na+).
86% With carbon tetrabromide; triphenylphosphine In tetrahydrofuran at 20℃; for 20 h; Compound 26; N-Boc-4-(2-bromoethyl)piperidine; N-Boc-4-(2-hydroxyethyl)piperidine (0 95 g, 4.17 mmol) was dissolved in dry THF (20 mL), and carbon tetrabromide (1.34 g, 4.0 mmol) was added. Then a solution of triphenylphosphine (1.15 g, 4.38 mmol) in dry tetrahydrofuran (2 mL) was added dropwise over 2 h. The mixture was stirred at room temperature for 18 h, and then diethyl ether (50 mL) added to the mixture. The reaction mixture was filtered, and filtrate concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (9: 1 hexane: ethyl acetate) to give 26 (1.05 g, 86percent) as an oil.
84% With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; for 20 h; STEP A: A solution of tetrabromomethane (874 mg, 2.6 mmol) in DCM (10 mL) is slowly added dropwise to the solution of N-Boc-piperidm-4-ethanol (550 mg, 0.0023 mmol) and triphenylphosphine (681 mg, 2.6 mol) in DCM (10 mL) at 0°C. The reaction is stirred at RT for 20 h. The organic solvent is removed under reduced pressure and the crude is purified by flash column chromatography (eluent petroleum ether/EtOAc) to give the expected compound (0.59 g, 2 mmol, Yield: 84percent) as colourless oil.
84.5% With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; To a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (15.0 g, 65.5 mmol) and PPh3 (20.6 g, 78.6 mmol) in dry DCM (200 mL) was added a solution of CBr4 (24.9 g, 75.3 mmol) in dry DCM (100 mL) at 0°C. The mixture was stirred at rt overnight. Themixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 100: 1 30: 1) to give the title compound (16.3 g, 84.5percent yield) as a white solid. LC-MS: m/z 239 [M+H-56j.

Reference: [1] RSC Advances, 2016, vol. 6, # 52, p. 46170 - 46185
[2] Patent: US2007/32469, 2007, A1, . Location in patent: Page/Page column 46
[3] Patent: US2009/192169, 2009, A1, . Location in patent: Page/Page column 60
[4] Patent: US2013/184313, 2013, A1, . Location in patent: Paragraph 1666
[5] Patent: WO2008/27521, 2008, A1, . Location in patent: Page/Page column 63
[6] Patent: WO2013/64919, 2013, A1, . Location in patent: Page/Page column 59
[7] Patent: WO2017/27684, 2017, A1, . Location in patent: Paragraph 00243
[8] Journal of Medicinal Chemistry, 1992, vol. 35, # 17, p. 3254 - 3263
[9] Journal of Medicinal Chemistry, 1999, vol. 42, # 22, p. 4584 - 4603
[10] Journal of Medicinal Chemistry, 2004, vol. 47, # 3, p. 711 - 719
[11] Patent: US2011/294754, 2011, A1, . Location in patent: Page/Page column 5
[12] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 6, p. 1318 - 1323
[13] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 96 - 112
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Reference: [1] Patent: US5861414, 1999, A,
  • 3
  • [ 135716-08-4 ]
  • [ 89151-44-0 ]
YieldReaction ConditionsOperation in experiment
86%
Stage #1: With palladium 10% on activated carbon; hydrogen In methanolInert atmosphere
Stage #2: With diisobutylaluminium hydride In diethyl ether at -20℃; for 0.166667 h;
The above resulting product (639mg,2.4mmol) dissolved in 6ml of methanol, Underargon added the argon was replaced with hydrogen three times and reaction was carried out overnightin a hydrogenation apparatus (4 atm H2). The reaction solution was filteredthrough celite and washed with ethyl acetate. The filtrate was concentrated andseparated by column chromatography to give a white solid, 722 mg, 100percent yield. theabove resulting product(506mg,1.9mmol) dissolved in 10ml of ether, reaction was colled down to -20 ° C, added diisobutylaluminum hydride(1.0M,5mL,5mmol), reaction was carried out for 10 minutes until the starting material disappeared. Then Poured into saturated sodium potassium tartrate solution, stirred at room temperature for 3 hours to clarify the reaction mixture,the aqueous phase was extracted three times with ether and the organic phases were combined and washed with saturated NaClsolution and dried over Na2SO4, After Concentration, carriedout column chromatography separation to obtain a White solid, 368mg, yield 86percent.
Reference: [1] Patent: CN102952072, 2016, B, . Location in patent: Paragraph 0110-0111
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 13, p. 2167 - 2172
[3] Patent: US2012/71461, 2012, A1,
[4] Patent: CN107793408, 2018, A,
[5] Patent: WO2018/68297, 2018, A1,
[6] Patent: US6140333, 2000, A,
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YieldReaction ConditionsOperation in experiment
91% With lithium triethylborohydride In tetrahydrofuran at -78 - 1℃; for 1 h; Inert atmosphere To a solution of tert-butyl 4- (2-ethoxy-2-oxoethyl) piperidine-1-carboxylate (22 g, 81 mmol) in dry THF (100 mL) at -78 under N2 atmosphere was added Super-H (200 mL, 200 mmol, 1M in THF) . The resulting mixture was stirred at rt for 1h and then treated with MeOH (10 mL) and saturated aqueous NH4Cl (100 mL) at 0. The mixture was stirred at rt for 1h and extracted with EtOAc (200 mL × 3) . The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (silica gel: 300-400 mesh, PE/EtOAc 5/1 to 2/1) to afford tert-butyl 4- (2-hydroxyethyl) piperidine-1-carboxylate (17 g, 91) . LRMS m/z (M-100) 130.1 found, 130.1 required.
108g for 21 h; Reflux Intermediate 2 (500 mmol), 10percentPd/C, THF (1000 mL) was added to a 1 L hydrogenation reactor. Outside temperature 60°C, Reaction under 2.0MPa pressure for 10h, Stop the reaction, filter, Intermediate 3 in THF was obtained. Lithium borohydride (1000 mmol) is added, 21h reflux reaction, Stop the reaction, Cool down to 5~10°C 30percent aqueous HCl solution (200 mL) was added in sequence. 20percent aqueous HCl solution (200 mL), Stir 1h, Extract with ethyl acetate (200mL×3) Combine the ethyl acetate layers, Followed by water (100mL×2), Saturated brine (100mL × 2) wash, Drying with anhydrous sodium sulfate, filter, Concentrated to give 108 g of a white solid (Intermediate 4), The two-step yield was a total of 94percent.
Reference: [1] European Journal of Organic Chemistry, 2014, vol. 2014, # 33, p. 7413 - 7425
[2] Patent: WO2018/68297, 2018, A1, . Location in patent: Page/Page column 136
[3] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 13, p. 2167 - 2172
[4] Patent: US2003/191316, 2003, A1, . Location in patent: Page/Page column 32-33
[5] Patent: US2012/71461, 2012, A1, . Location in patent: Page/Page column 124; 132
[6] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 332 - 353
[7] Patent: CN107793408, 2018, A, . Location in patent: Paragraph 0168; 0172
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YieldReaction ConditionsOperation in experiment
98% at 20℃; for 16 h; To a stirred solution of 2-piperidin-4-ylethanol (25.5 g, 197 mmol) in tetrahydrofuran (250 mL) was added di-tert-butyl dicarbonate (43.0 g, 197 mmol) at room temperature.
After 16 h the reaction mixture was concentrated under reduced pressure to provide tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (44.3 g, 98percent) as colorless oil.
1H NMR (300 MHz, CDCl3) δ 4.11-4.05 (m, 2H), 3.72-3.66 (m, 2H), 2.73-2.65 (m, 2H), 1.74-1.59 (m, 4H), 1.55-1.43 (m, 2H), 1.38 (s, 9H), 1.19-1.09 (m, 2H).
95% With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 24 h; 3.25 1-tert-Butyloxycarbonyl-4-hydroxyethyl-piperidine (61KS82)
4-Piperidineethanol (1.05 g, 8.13 mmol) was dissolved in dioxane/water (1:1, 50 mL) followed by the addition of Boc2O (2.13 g, 9.76 mmol) and NaHCO3 (8.62 g, 81.3 mmol).
The mixture was stirred at room temperature for 24 h before extraction with DCM was performed.
The combined organic phase was washed consecutively with citric acid (5percent sol.) and aqueous NaHCO3 followed by drying (Na2SO4), filtration and evaporation of the solvent to give the title compound (61KS82) (1.77 g, 95percent).
1H NMR (CDCl3) δ 1.12 (dq, 2H, J=4.6 Hz, 11.8 Hz), 1.35-1.55 (m, 14H), 2.70 (t, 2H, J=12.8 Hz), 3.70 (t, 2H, J=6.3 Hz, -CH2C2OH), 3.95-4.20 (m, 2H); 13C NMR (CDCl3) δ 28.7 (Boc-H3), 32.8, 39.5, 44.2, 60.5, 67.3, 79.4 (-(CH3)3), 155.1 (C=O).
95% at 0 - 25℃; for 4.25 h; Inert atmosphere To a solution of 2-(piperidin-4-yl)ethanol (2.42 g, 18.7 mmol) in dichloromethane (24 mL) was added under nitrogen at 0 °C di-tert-butyl dicarbonate (4.09 g, 4.35 mL, 18.7 mmol). There was a strong gas evolution The solution was stirred at 0 °C for 15 min and at room temperature for 4 h. The reaction mixture was washed with water (50 mL), potassium hydrogen sulfate (10percent aqueous solution, 50 mL) and brine (50 mL). The aqueous layers were back-extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate to yield colorless oil (4.1 g, 95 percent). MS: m/z = 230.5 (M+H)+
95% at 20℃; for 2 h; 2-(N-tert-Butoxycarbonyl-4-piperidinyl)ethanol 2-(4-Piperidinyl)ethanol (1.0 g, 7.7 mmol) was dissolved in methanol (50 ml). To this solution, di-tert-butyl carbonate (2.0 g, 9.3 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was confirmed by TLC to be complete, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:acetone=9:1) to obtain N-tert-butoxycarbonyl-2-(4-piperidinyl)ethanol (1.68 g, yield: 95percent).
91.83% at 15 - 20℃; for 20 h; 2-(Piperidin-4-yl)ethan-1-ol (3.00 g, 23.22 mmol) was dissolved in 30 mL dichloromethane. Di-tert-butyl dicarbonate (5.22 g, 23.92 mmol) was slowly added portionwise at 15 to 20° C. After that, the reaction mixture was stirred for 20 h at room temperature. The reaction mixture was slowly poured into 50 mL water after the reaction was complete as monitored by TLC. Then, the mixture was extracted with dichloromethane (50 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (Height: 250 mm, Diameter, 20 mm, 100-200 slica gel, petroleum/ethyl acetate=3:1, 1:1) to afford 2-(1-tert-butoxycarbonyl-4-piperidyl)ethanol (4.89 g, 91.83percent yield) as a colorless liquid.
91% at 0 - 20℃; To an ice-cold solution of 4-(2-hydroxyethyI) piperidine (4.25 g, 33 mmol) in CH2CI2 (5 ml_) was added a solution of di-te/t-butyl dicarbonate (7.2 g, 33 mmol) in CH2CI2 (30 ml.) over 1 h. The mixture was stirred at r.t. overnight. The solvent was removed. The residue was dissolved in Et2O (5OmL), washed with 1 M aq. NaH2PO4, sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 6.9 g (91percent) of the title compound.13C NMR (CDCI3) δ 154.9, 79.3, 60.1, 44.0, 39.3, 32.5, 32.1, 28.5
88% at 20℃; To A solution of 2- (4-PIPERIDYL) ETHANOL (9. 63 G, 74. 5 MMOL) IN DMF (100 ML) AT 0 C, DI-TERT-BUTYL DICARBONATE (16. 26 g, 5 mol) was added slowly. The mixture was stirred overnight at room temperature. The solvent was concentrated and the residue was dissolved in A mixture of ETOAC and water. The phases were separated. The organic phase was dried over NA2S04 and concentrated to dryness, to afford 15.09 g of the desired product : 88percent).
88% With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 3 h; To a stirred solution of 2-(piperidin-4-yl)ethanol (LXX, lg, 7.72 mmol) in tetrahydrofuran and water mixture (40 mL, 1 : 1) was added sodium bicarbonate (1.62 g, 19.32 mmol) and Boc anhydride (2.6 mL, 11.6 mmol) at room temperature and stirred for 3 h. The reaction mixture was diluted with ethyl acetate and the organic portion was washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure to get the crude product which was purified by flash column chromatography using ethylacetate-hexane gradient to afford the titled product as gummy solid (LXXI, 1.6 g, 88 percent). LC-MS m/z calcd for C12H23NO3, 229.2; found 130.2 [M-Boc]+.
87% at 20℃; A mixture of 4-piperidin ethanol (2. 0 g, 15 mmol, 1.0 eq. ) and t-butyl dicarbonate (3. 87 ML, 18.5 MMOL,). 2 eq. ) in anhydrous THF (80 mL) is kept under stirring at room temperature for one night. The solvent is then removed by evaporation under reduced pressure and the raw product obtained purified by flash chromatography using AcOEt : petroleum ether 60 : 40 as eluent mixture. 4-(2-Hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (37) is obtained as a colourless oil (3.1 G, 13.4 mmol, yield = 87percent) HPLC (method A) : Rt = 7.92 min. H1 NMR (No., CDCL3-D3, 300 MHz) : 1.14 (DQ, 2H, Hf, J=6. 3,13. 5 Hz); 1.47 (S, 9H, C (CH3) 3) : 1. 55 (pt, 2H, Hc, J= 6.3 HZ) ; 1. 50-1.65 (m, 1H, Hc); 1.69 (d, 2H, Hd, J=13. 2 Hz); 1.89 (s, 1H, OH) ; 2.71 (LAD, 2H, Hb, J= 2. 1, 12.9 Hz) ; 3.73 (t, 2H, Hg, J= 6.3 Hz) ; 4.10 (m, 2H, Ha).
85.2% With triethylamine In dichloromethane at 0 - 25℃; (0.01 mol) of 4-piperidineethanol, 2.4 ml (0.02 mol) of triethylamine and 30 ml of dichloromethane were charged into a 150 ml three-necked flask. After cooling to 0 ° C, 2.54 g (0.01 mol) of di-t-butyl dicarbonate was slowly added dropwise. After completion of the reaction, the reaction was carried out at 25 ° C overnight. The reaction was terminated by the disappearance of the starting material by TLC (PE: EA = 2: 1). Dichloromethane was distilled off under reduced pressure, 40 ml of ethyl acetate was added thereto, and the mixture was washed with saturated brine, neutralized and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 2.27 g (85.2percent) of a clear oil.
52 g at 20℃; [00482] To a stuffed solution of 2-(piperidin-4-yl)ethanol (30 g, 0.2322 mmol) in i,2-dichloromethane (200 ml) was added in portions di-tert-butyl dicarbonate (53 g, 0.24 mmol) . The resultant mixture was stuffed at room temperature overnight. After confirming reaction completion by thin-layer chromatography, the reaction mixture was washed with water and concentrated to yield compound INT-1(52g).
52 g at 20℃; To a stirred solution of 2-(piperidin-4-yl)ethanol (30 g, 0.2322 mmol) in 1,2-dichloromethane (200 ml) was added in portions di-tert-butyl dicarbonate (53 g, 0.24 mmol) . The resultant mixture was stirred at room temperature overnight. After confirming reaction completion by thin-layer chromatography, the reaction mixture was washed with water and concentrated to yield compound INT-1 (52g).
52 g at 20℃; Preparation of tert-butyl 4-(2-hydroxyethyl)piperidine- 1 -carboxylate (TNT-1):[00491] To a stirred solution of 2-(piperidin-4-yl)ethanol (30 g, 0.2322 mmol) in i,2-dichloromethane (200 ml) was added in portions di-tert-butyl dicarbonate (53 g, 0.24 mmol) . The resultant mixture was stirred at room temperature overnight. After confirming reaction completion by thin-layer chromatography, the reaction mixture was washed with water and concentrated to yield compound INT-1 (52g).

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[42] Patent: WO2013/158644, 2013, A2, . Location in patent: Paragraph 00479; 00481; 00482
[43] Patent: US2015/31674, 2015, A1, . Location in patent: Paragraph 0277
[44] Patent: WO2015/38649, 2015, A1, . Location in patent: Paragraph 00532
[45] Patent: US2015/232444, 2015, A1, . Location in patent: Paragraph 0420; 0421
[46] Patent: WO2015/134464, 2015, A2, . Location in patent: Paragraph 00488; 00490
[47] Patent: WO2015/188085, 2015, A1, . Location in patent: Paragraph 0372
[48] Patent: WO2007/122410, 2007, A1, . Location in patent: Page/Page column 80-81
  • 6
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Reference: [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 16, p. 2537 - 2551
[2] Tetrahedron Letters, 1995, vol. 36, # 41, p. 7379 - 7382
[3] Patent: US5866685, 1999, A,
[4] Patent: WO2018/106518, 2018, A1, . Location in patent: Page/Page column 79; 80
  • 7
  • [ 622-26-4 ]
  • [ 34619-03-9 ]
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YieldReaction ConditionsOperation in experiment
100% at 20℃; A solution (20 ml) of di-tert-butyl carbonate (8.95 g, 41.0 mmol) in tetrahydrofuran was added dropwise to a solution (80 ml) of 4-piperidineethanol (5.30 g, 41.0 mmol) in tetrahydrofuran at room temperature and stirred overnight.
After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate.
The resulting solution was washed successively with a 1M aqueous hydrochloric acid solution, a saturated aqueous sodium chloride solution, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol = 98/2) to obtain the title compound (9.67 g, quantitative).; 1H-NMR(CDCl3) 4.18 (br,2H), 3.66-3.74 (m,2H), 2.69 (br,2H), 1.68 (br,2H), 1.45-1.57 (m,2H).
52 g at 20℃; To a stirred solution of 2-(piperidin-4-yl)ethanol (30 g, 0.2322 mmol) in1 ,2-dichloromethane (200 ml) was added in portions di-tert-butyl dicarbonate (53 g,0.24 mmol) . The resultant mixture was stirred at room temperature overnight. Afterconfirming reaction completion by thin-layer chromatography, the reaction mixturewas washed with water and concentrated to yield compound INT-l (52g).
Reference: [1] Patent: EP1640369, 2006, A1, . Location in patent: Page/Page column 31
[2] Patent: WO2015/143004, 2015, A1, . Location in patent: Paragraph 00829; 00831; 00832
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  • [ 84358-13-4 ]
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Reference: [1] Patent: WO2015/112441, 2015, A1, . Location in patent: Page/Page column 74
  • 9
  • [ 79099-07-3 ]
  • [ 89151-44-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 13, p. 2167 - 2172
[2] Patent: US2012/71461, 2012, A1,
[3] European Journal of Organic Chemistry, 2014, vol. 2014, # 33, p. 7413 - 7425
[4] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 332 - 353
[5] Patent: CN102952072, 2016, B,
[6] Patent: CN107793408, 2018, A,
[7] Patent: WO2018/68297, 2018, A1,
[8] Patent: US6140333, 2000, A,
  • 10
  • [ 24424-99-5 ]
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YieldReaction ConditionsOperation in experiment
81% With hydrogenchloride; sodium hydrogencarbonate In tetrahydrofuran; water; ethyl acetate Step B
4-(2-Hydroxy-1-ethyl)-1-tert-butoxycarbonyl-piperidine
Dissolved sodium bicarbonate (134 g, 1.6 mol) and 4-(2-hydroxy-1-ethyl)-1-piperidine acetate (38 g, 0.2 mol, from Step A) in 500 mL of 50percent tetrahydrofuran in water.
Added di-tert-butyl dicarbonate (35 g, 0.2 mol) and stirred at r.t. overnight.
Diluted with ethyl acetate and extracted the aq. layer with 2*300 mL of ethyl acetate.
Washed the combined organic layers with 2*300 mL of 1 N HCl and brine.
Dried over MgSO4 and concentrated to afford 37.4 g (81percent) of the title compound. ESI-MS: 230 (M+H); HPLC A: 2.76 min.
Reference: [1] Patent: US6498161, 2002, B1,
  • 11
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Reference: [1] Patent: US6635657, 2003, B1,
  • 12
  • [ 28356-58-3 ]
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Reference: [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 16, p. 2537 - 2551
  • 13
  • [ 51052-78-9 ]
  • [ 89151-44-0 ]
Reference: [1] Tetrahedron Letters, 1995, vol. 36, # 41, p. 7379 - 7382
[2] Journal of Medicinal Chemistry, 1994, vol. 37, # 16, p. 2537 - 2551
[3] Patent: CN103755686, 2016, B,
  • 14
  • [ 622-26-4 ]
  • [ 89151-44-0 ]
Reference: [1] Patent: US6194435, 2001, B1,
  • 15
  • [ 123-91-1 ]
  • [ 622-26-4 ]
  • [ 89151-44-0 ]
Reference: [1] Patent: US5861414, 1999, A,
  • 16
  • [ 622-26-4 ]
  • [ 64-19-7 ]
  • [ 89151-44-0 ]
Reference: [1] Patent: US5281585, 1994, A,
  • 17
  • [ 13292-87-0 ]
  • [ 157688-46-5 ]
  • [ 89151-44-0 ]
Reference: [1] Patent: US6265434, 2001, B1,
  • 18
  • [ 16853-85-3 ]
  • [ 135716-09-5 ]
  • [ 89151-44-0 ]
Reference: [1] Patent: US6140333, 2000, A,
  • 19
  • [ 6622-91-9 ]
  • [ 89151-44-0 ]
Reference: [1] Tetrahedron Letters, 1995, vol. 36, # 41, p. 7379 - 7382
  • 20
  • [ 24424-99-5 ]
  • [ 89151-44-0 ]
Reference: [1] Patent: US2003/187016, 2003, A1,
[2] Patent: US6140333, 2000, A,
  • 21
  • [ 169206-65-9 ]
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Reference: [1] Patent: US2004/2504, 2004, A1, . Location in patent: Page/Page column 23-24; 26-27
  • 22
  • [ 89151-44-0 ]
  • [ 142247-38-9 ]
Reference: [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 16, p. 2537 - 2551
  • 23
  • [ 89151-44-0 ]
  • [ 146093-46-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 13, p. 2167 - 2172
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 12, p. 1779 - 1788
[3] Patent: US2015/336943, 2015, A1,
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  • [ 865-33-8 ]
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  • [ 175213-46-4 ]
Reference: [1] Organic Letters, 2013, vol. 15, # 19, p. 5072 - 5075
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