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Chemical Structure| 6457-49-4
Chemical Structure| 6457-49-4
Structure of 6457-49-4 * Storage: {[proInfo.prStorage]}
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Product Details of [ 6457-49-4 ]

CAS No. :6457-49-4 MDL No. :MFCD00174228
Formula : C6H13NO Boiling Point : -
Linear Structure Formula :- InChI Key :XBXHCBLBYQEYTI-UHFFFAOYSA-N
M.W : 115.17 Pubchem ID :420771
Synonyms :

Calculated chemistry of [ 6457-49-4 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 2.0
Molar Refractivity : 36.72
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) : -7.1 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.62
Log Po/w (XLOGP3) : -0.14
Log Po/w (WLOGP) : -0.4
Log Po/w (MLOGP) : 0.21
Log Po/w (SILICOS-IT) : 0.96
Consensus Log Po/w : 0.45

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.4
Solubility : 45.9 mg/ml ; 0.398 mol/l
Class : Very soluble
Log S (Ali) : -0.08
Solubility : 95.1 mg/ml ; 0.825 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.86
Solubility : 15.8 mg/ml ; 0.137 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 6457-49-4 ]

Signal Word:Danger Class:8
Precautionary Statements:P280-P305+P351+P338-P310 UN#:3263
Hazard Statements:H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 6457-49-4 ]

* 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 [ 6457-49-4 ]
  • Downstream synthetic route of [ 6457-49-4 ]

[ 6457-49-4 ] Synthesis Path-Upstream   1~37

  • 1
  • [ 1126-09-6 ]
  • [ 6457-49-4 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20℃;
Stage #2: With sodium hydroxide; water In tetrahydrofuran at 20℃; for 0.5 h;
To A suspension of LIAIH4 (10. 10 G, 0. 266 MOL) IN THF (150 ML) AT 0 C, A SOLUTION OF ETHYL PIPERIDINE-4-CARBOXYLATE (18. 13 G, 0. 120 MOL) IN THF (300 ML) WAS ADDED slowly. This was stirred at room temperature overnight. It was cooled with an ice bath and A mixture of water (14 ML) and THF (28 ML) was added slowly. Afterwards, A mixture of 15percent aqueous NAOH (14 mL) and water (37 ML) was added followed by stirring at room temperature for 30 min. The precipitate obtained was filtered and the filtrate was concentrated, to afford 17. 88 g of the desired compound (yield : quantitative).
100%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃;
Stage #2: With ethanol; water In tetrahydrofuran at 0℃;
2d) 4-Piperidinemethanol To a suspension of lithium aluminium hydride (8.3 mmol; 310 mg) in anhydrous THF (5 ml) at 00C was added dropwise a solution of ethyl isonipecotate (6.4 mmol; 1.0 g) in anhydrous THF (5 ml). The reaction mixture was stirred at room temperature for 35 minutes. After cooling to 00C, aqueous ethanol (95percent) was added cautiously and the hydroxides thus formed were removed by filtration. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 1.34 g (100percent) of pure product as an oil.1H NMR (DMSO-d6, δ ppm): 1.09-1.18 (m, 2H); 1.50 (m, 1 H); 1.66- 1.69 (m, 2H); 2.53-2.61 (m, 3H); 3.05-3.08 (m, 2H); 3.25 (d, 2H); 4.60 (s, 1 H).
92% With lithium aluminium tetrahydride In diethyl ether for 7 h; Reflux To a solution of ethyl isonipecotate (2 mL, 13.0 mmol, 1.0 eq.) in Et2O (150 mL) was added portion-wise LiAlH4 (1.48 g, 39 mmol, 3.0 eq.) at 0°C and the reaction mixture was refluxed for 7h. The mixture was then cooled to 0°C and the reaction was then slowly quenched with 1.5 mL of water, 1.5 mL of 15percent NaOH solution followed by 4.5 mL of water to afford a granular inorganic precipitate. The white solid was filtered and washed several times with EtOAc. Evaporation of the filtrate under reduced pressure provided compound 21 as a colorless oil (92percent yield); 1H NMR (CDCl3, 400 MHz) δ 3.45 (d, 3J = 5.9 Hz, 2H), 3.08 (m, 2H), 2.59 (dt, 2J = 12.0 Hz, 3J = 3.0 Hz, 2H), 1.96 (br s, 1H), 1.71 (m, 2H), 1.60-1.55 (m, 1H), 1.17-1.07 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 66.9 (CH2), 45.9 (2*CH2), 38.8 (CH), 29.7 (2*CH2); IR (neat, cm-1) ν 3369, 2923, 2855, 1636, 1531, 1425, 1266, 1036. Spectral and analytical data matched with literature.[3]
61%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃;
Stage #2: With sodium hydroxide; water In tetrahydrofuran at 0℃;
To a mixture of LiAIH4 (8.82 g, 0.23 mol) and THF (125 mL), cooled at 0 °C, a solution of ethyl isonipecotate (18 mL, 0.117 mol) in THF (325 mL) was added dropwise under Ar-atmosphere, the mixture was stirred at room temperature overnight. A mixture of H2O (12.03 mL) and THF (25 mL), followed by a mixture of 15 percent NaOH (10.03 mL) and H2O (32.4 mL) were slowly added at 0 °C. The resulting mixture was washed with THF, filtered and concentrated to dryness. The residue was partitioned between H2O and CHCI3, the phases were separated, the aqueous phase was extracted with CHCI3 and the combined organic phases were <n="70"/>dried over Na2SO4 and concentrated to afford 8.2 g of the desired product (61 percent yield).

Reference: [1] Patent: WO2004/76450, 2004, A1, . Location in patent: Page 59
[2] Patent: WO2010/12611, 2010, A1, . Location in patent: Page/Page column 27
[3] RSC Advances, 2016, vol. 6, # 22, p. 17929 - 17940
[4] European Journal of Medicinal Chemistry, 2019, p. 234 - 248
[5] European Journal of Medicinal Chemistry, 2017, vol. 139, p. 773 - 791
[6] Journal of Medicinal Chemistry, 1991, vol. 34, # 3, p. 1073 - 1079
[7] Patent: WO2008/119792, 2008, A1, . Location in patent: Page/Page column 68-69
[8] Journal of the Chemical Society, 1937, p. 1523,1525
[9] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 8, p. 1047 - 1052
[10] Journal of Labelled Compounds and Radiopharmaceuticals, 1999, vol. 42, # SUPPL. 1, p. S782-S784
[11] Patent: US4925850, 1990, A,
[12] Patent: US4931449, 1990, A,
[13] Patent: US4977159, 1990, A,
[14] Patent: US4885302, 1989, A,
[15] Patent: US5821240, 1998, A,
  • 2
  • [ 498-94-2 ]
  • [ 6457-49-4 ]
Reference: [1] Journal of the Chemical Society, 1937, p. 1523,1525
[2] Patent: US2002/13348, 2002, A1,
[3] Patent: US6303593, 2001, B1,
[4] Patent: US6303593, 2001, B1,
[5] Patent: US5854268, 1998, A,
[6] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 6, p. 2607 - 2622
[7] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 661 - 664
  • 3
  • [ 586-95-8 ]
  • [ 6457-49-4 ]
Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1938, vol. &lt;2&gt; 151, p. 65,79
[2] Patent: US2003/55244, 2003, A1,
  • 4
  • [ 622387-50-2 ]
  • [ 4282-40-0 ]
  • [ 6457-49-4 ]
YieldReaction ConditionsOperation in experiment
20%
Stage #1: With sodium hydride In tetrahydrofuran at 20℃; for 0.5 h;
Stage #2: at 50℃; for 26 h;
A 10 mL teflon reaction vessel was charged with the alcohol from Example A5 (0.5 g, 1.4 mmol) and tetrahydrofuran (4 mL) under N2. A 60percent NaH oil dispersion (74 mg, 1.9 mmol) was then added in one portion with much gassing. After stirring at room temperature for 30 min, a solution of 1-iodoheptane (0.39 g, 1.7 mmol) in tetrahydrofuran (1 mL) was added dropwise. The resulting mixture was heated to 50° C. for 26 hr, and then cooled to room temperature. Afterward, the mixture was partitioned between saturated ammonium chloride (5 mL) and ethyl acetate (5 mL). The organic layer was washed with water (5 mL), filtered through Celite, and concentrated in vacuo. Flash column chromatography on silica gel afforded a white crystalline solid product (131 mg, 20percent yield). 1H NMR (CDCl3) ? 0.88 (t, J=6.8 Hz, 3H), 1.22-1.35 (m, 8H), 1.52 (s, 9H), (m, 2H), 1.60-1.75 (m, 2H), 1.80-1.90 (m, 2H), 2.11 (td, J=4.5, 12.6 Hz, 2H), 2.32 (d, J=11.4 Hz, 2H), 3.17 (m, 2H), 3.25 (m, 2H), 3.31 (t, J=12.2 Hz, 2H), 3.40 (t, J=6.6 Hz, 2H), 3.46 (m, 1H), 3.55 (m, 2H), 3.96 (dd, J=4.2, 11.4 Hz, 2H); Electrospray mass spectrometry showed m/z=448 (M+H)+.
Reference: [1] Patent: US2005/9838, 2005, A1, . Location in patent: Page 295
  • 5
  • [ 123855-51-6 ]
  • [ 6457-49-4 ]
Reference: [1] Patent: WO2018/13867, 2018, A1, . Location in patent: Paragraph 525
  • 6
  • [ 2971-79-1 ]
  • [ 6457-49-4 ]
Reference: [1] European Journal of Organic Chemistry, 2008, # 25, p. 4277 - 4295
  • 7
  • [ 5325-94-0 ]
  • [ 6457-49-4 ]
Reference: [1] Patent: US5081128, 1992, A,
  • 8
  • [ 586-95-8 ]
  • [ 63608-14-0 ]
  • [ 6457-49-4 ]
Reference: [1] Patent: US4243807, 1981, A,
  • 9
  • [ 383865-57-4 ]
  • [ 6457-49-4 ]
Reference: [1] Patent: US2002/45615, 2002, A1,
  • 10
  • [ 399580-55-3 ]
  • [ 6457-49-4 ]
Reference: [1] Journal of the American Chemical Society, 1943, vol. 65, p. 2458
  • 11
  • [ 858263-30-6 ]
  • [ 6457-49-4 ]
Reference: [1] Journal of the American Chemical Society, 1943, vol. 65, p. 2458
  • 12
  • [ 99190-03-1 ]
  • [ 6457-49-4 ]
Reference: [1] Journal of the American Chemical Society, 1943, vol. 65, p. 2458
  • 13
  • [ 101990-69-6 ]
  • [ 6457-49-4 ]
Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1938, vol. &lt;2&gt; 151, p. 65,79
  • 14
  • [ 99-11-6 ]
  • [ 6457-49-4 ]
Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1938, vol. &lt;2&gt; 151, p. 65,79
  • 15
  • [ 5398-44-7 ]
  • [ 6457-49-4 ]
Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1938, vol. &lt;2&gt; 151, p. 65,79
  • 16
  • [ 1570-45-2 ]
  • [ 6457-49-4 ]
  • [ 1126-09-6 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1959, vol. 24, p. 212,216
  • 17
  • [ 6457-49-4 ]
  • [ 20691-89-8 ]
Reference: [1] Patent: US2003/125339, 2003, A1,
[2] Patent: US6878714, 2005, B2,
[3] Patent: WO2009/147219, 2009, A1,
  • 18
  • [ 6457-49-4 ]
  • [ 50-00-0 ]
  • [ 20691-89-8 ]
Reference: [1] Patent: US2003/225106, 2003, A1, . Location in patent: Page 52-53; 72; 73; 128
  • 19
  • [ 1570-45-2 ]
  • [ 6457-49-4 ]
  • [ 1126-09-6 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1959, vol. 24, p. 212,216
  • 20
  • [ 6457-49-4 ]
  • [ 91419-52-2 ]
Reference: [1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 7, p. 1157 - 1163
  • 21
  • [ 6457-49-4 ]
  • [ 138163-08-3 ]
Reference: [1] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 661 - 664
  • 22
  • [ 6457-49-4 ]
  • [ 145508-94-7 ]
Reference: [1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 5, p. 783 - 794
[2] European Journal of Medicinal Chemistry, 2019, p. 234 - 248
  • 23
  • [ 6457-49-4 ]
  • [ 166815-96-9 ]
Reference: [1] Journal of Labelled Compounds and Radiopharmaceuticals, 1999, vol. 42, # 13, p. 1289 - 1300
[2] Molecules, 2016, vol. 21, # 12,
[3] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 16, p. 4497 - 4505
[4] Angewandte Chemie - International Edition, 2018, vol. 57, # 10, p. 2712 - 2715[5] Angew. Chem., 2018, vol. 130, p. 2742 - 2745,4
[6] Bioorganic Chemistry, 2018, vol. 81, p. 681 - 688
  • 24
  • [ 6457-49-4 ]
  • [ 24424-99-5 ]
  • [ 98-59-9 ]
  • [ 166815-96-9 ]
Reference: [1] Patent: US5763458, 1998, A,
  • 25
  • [ 6457-49-4 ]
  • [ 340962-93-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 491 - 494
  • 26
  • [ 6457-49-4 ]
  • [ 501-53-1 ]
  • [ 122860-33-7 ]
YieldReaction ConditionsOperation in experiment
89% With triethylamine In dichloromethane at 0 - 20℃; for 2 h; Example 24.; N-Benzyloxycarbonyl-4- (hydroxymethyl) piperidine (E-12);. A stirred solution of 4-hydroxymethylpiperidine (2.0 g, 17.4 mmol) in dry dichloromethane (DCM, 100 mL) was cooled to 0°C, treated with triethylamine (4.8 mL, 34.8 mmol) followed by benzyl chloroformate (3.7 mL, 34.8 mmol), allowed to warm to room temperature and stirred for two hours. The mixture was partitioned between DCM (50 mL) and water (30 mL). The layers were separated and the aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phases were washed with brine (1 x 30 mL), dried over Na2S04 and evaporated to a residue, that was purified by column chromatography using a gradient of 70 to 100 percent EtOAc in hexanes as eluant to give 3.85 g (89 percent) of E-12 as clear oil : 1H NMR (CDC13) S 1. 17 (m, 2H), 1.72 (m, 3H), 2.15 (br s, 1H), 2. 78 (t, 2H, J=12. 24), 3.47 (d, 2H, J=6. 04), 4.20 (d, 2H, J=11. 68), 5.12 (s, 2H), 7.33 (m, 5H).
89% With triethylamine In dichloromethane at 0 - 20℃; To a stirred solution of 4-hydroxymethylpiperidine (1.0 g, 8.7 mmol, 1.0 equiv) in dry CH2Cl2 (50 mL) was added Et3N (2.4 mL, 17.4 mmol, 2.0 equiv) and benzylchoroformate (1.85 niL, 17.4 mmol, 2.0 equiv) at 0 "C. The mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was washed with water (20 mL) and the aqueous phase was extracted with CH2Cl2 (2 x 25 mL). The combined organic phases were washed with brine (15mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel to afford compound 64-a (1.95 g, 89percent) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 5.10 (s, 2H), 4.20 (br d, J= 11.2 Hz, 2H), 3.48 (d, J= 6.4 Hz, 2H), 2.77 (t, J= 12.8 Hz, 2H), 1.62-1.70 (m, 3H), 1.10-1.20 (m, 2H).
42% With triethanolamine In dichloromethane Step B
Preparation of benzyl 4-(hydroxymethyl)-1-piperidinecarboxylate
Dissolved the amine (5.0 g, 45.8 mmol) from Step A in CH2Cl2 (50 ml) with TEA (22.5 ml, 158.6 mmol) and cooled to 0° C., then added benzyl chloroformate (10.4 ml, 73.3 mmol)and stirred at room temperature ca. 24 hr.
Extracted CH2Cl2 versus saturated NaHCO3and combined the organic layers, dried on MgSO4, filtered and evaporated.
Purified by flash chromatography to yield the pure title compound (3.34 g, 42percent).
MS (APCI) (M+H)+=250
Reference: [1] Patent: WO2005/80394, 2005, A1, . Location in patent: Page/Page column 131
[2] European Journal of Organic Chemistry, 2008, # 25, p. 4277 - 4295
[3] Patent: WO2010/46780, 2010, A2, . Location in patent: Page/Page column 63-64
[4] Journal of the American Chemical Society, 2017, vol. 139, # 24, p. 8110 - 8113
[5] Patent: US2003/55244, 2003, A1,
[6] Patent: US5719303, 1998, A,
[7] Patent: US2007/54896, 2007, A1, . Location in patent: Page/Page column 24
[8] Synthesis, 2011, # 22, p. 3669 - 3674
[9] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 661 - 664
[10] Patent: WO2014/70976, 2014, A1, . Location in patent: Page/Page column 20
  • 27
  • [ 6457-49-4 ]
  • [ 13139-17-8 ]
  • [ 122860-33-7 ]
YieldReaction ConditionsOperation in experiment
96% With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 1 h; Piperidin-4-ylmethanol (5.2 g, 45.1 mmol) was dissolved in 60 mE of THF and 60 mE of saturated NaHCO3 aq and then benzyl (2,5-dioxopyrrolidin- 1 -yl) carbonate (11.25 g, 45.1 mmol) added portionwise. The mixture was stirred for 1 h at RT, partitioned between AcOEt and water, washed twice with 1M HClaq and saturated NaClaq. Organic layer was dried over Na2504, evaporated under reduced pressure to afford the title compound (10.77 g, 43.2 mmol, 96percent yield). The product obtained was used in the following steps without thrther purifications. UPLC-MS: 0.80 mm, 250.2 [M+H]+, method 1.
Reference: [1] Patent: US2016/235734, 2016, A1, . Location in patent: Paragraph 0706; 0707; 0708
  • 28
  • [ 6457-49-4 ]
  • [ 1885-14-9 ]
  • [ 122860-33-7 ]
YieldReaction ConditionsOperation in experiment
44% With triethylamine In dichloromethane a)
1-Benzyloxycarbonyl-4-hydroxymethyl-piperidine.
A solution of 4-hydroxymethyl-piperidine (1.0g, 8.7 mmol) in dichloromethane (20ml) was treated triethylamine (1.3ml, 9.6 mmol) then benzylchloroformate (1.4ml, 9.6 mmol).
After 14h the reaction mixture was diluted with dichloromethane and washed with dilute aqueous sodium bicarbonate solution.
The organic extract was dried and evaporated.
Chromatography on silica eluding with 1:1 ethyl acetate:hexane afforded the product as a clear oil (0.97g, 44percent).
Reference: [1] Patent: EP1051413, 2003, B1,
  • 29
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  • [ 31139-36-3 ]
  • [ 122860-33-7 ]
Reference: [1] Patent: US4968704, 1990, A,
  • 30
  • [ 6457-49-4 ]
  • [ 67-64-1 ]
  • [ 280774-03-0 ]
Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 23, p. 8115 - 8117
  • 31
  • [ 6457-49-4 ]
  • [ 107-31-3 ]
  • [ 835633-50-6 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: at 0 - 20℃; for 2 h;
Stage #3: With hydrogenchloride In diethyl ether; dichloromethane
4-Piperidinemethanol (10 g, 87 mmol) was dissolved in methyl formate (7 mL, 113 mmol) 0 °C, and maintained at that temperature for 30 min, then allowed to reach 20 °C and stirred 90 min. Solid sodium hydroxide was added (0.87 g, pellets) and the mixture was left overnight. Dichloromethane was added, the NAOH removed by filtration and the solution treated with 1M HCL in ether (10 mL). The mixture was filtered through Celite and the solvent was removed under reduced pressure to afford the crude title COMPOUND. 1H NMR (400 MHz, CDC13) : 0. 85-1. 1 (2H, m); 1.55-1. 85 (3H, m); 2.5-2. 7 (1H, m); 2.95-3. 1 (1H, m); 3.3 (2H, D, J7 Hz); 3.6-3. 7 (1H, m); 4.1-4. 3 (1H, m); 8 (1H, s)
100%
Stage #1: at 0 - 20℃; for 2 h;
Stage #2: at 20℃;
Stage #3: With hydrogenchloride In diethyl ether; dichloromethane
4-PIPERIDINEMETHANOL (10 g, 87 mmol) was dissolved in methyl formate (7 ML, 113 mmol) 0 °C, and maintained at that temperature for 30 min, then allowed to reach 20 °C and stirred 90 min. Solid sodium hydroxide was added (0.87 g, pellets) and the mixture was left overnight. Dichloromethane was added, the NAOH removed by filtration and the solution treated with 1M HC1 in ether (10 mL). The mixture was filtered through Celite and the solvent was removed under reduced pressure to afford the crude title COMPOUND. 1H NMR (400 MHz, CDC13) : 0.85-1. 1 (2H, M) ; 1.55-1. 85 (3H, m); 2.5-2. 7 (1H, M) ; 2.95-3. 1 (1H, M) ; 3.3 (2H, d, J7 Hz); 3.6-3. 7 (1H, m); 4.1-4. 3 (1H, M) ; 8 (1H, s).
Reference: [1] Patent: WO2005/9443, 2005, A1, . Location in patent: Page/Page column 57
[2] Patent: WO2005/9978, 2005, A1, . Location in patent: Page 63
[3] Helvetica Chimica Acta, 2006, vol. 89, # 5, p. 936 - 946
[4] Patent: WO2005/21551, 2005, A1, . Location in patent: Page/Page column 64
[5] Patent: WO2005/42518, 2005, A2, . Location in patent: Page/Page column 63
[6] Patent: WO2005/70900, 2005, A1, . Location in patent: Page/Page column 70
  • 32
  • [ 6457-49-4 ]
  • [ 256411-39-9 ]
Reference: [1] Patent: US2013/102621, 2013, A1,
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 15, p. 3249 - 3253
  • 33
  • [ 6457-49-4 ]
  • [ 148550-51-0 ]
  • [ 875318-46-0 ]
YieldReaction ConditionsOperation in experiment
99%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide; acetonitrile at 20℃; for 0.166667 h;
Stage #2: for 0.333333 h;
Stage 1 - Coupling; Piperidin-4yl-methanol (2.48g, 21.55mmol) was stirred in 1 :1 DMF/MeCN (2OmL) with K2CO3 (8.9g, 64.65mmol) for 10 minutes at RT under a nitrogen atmosphere. Intermediate F (5g, 21.55mmol) was then added and the reaction allowed to stir for 20 minutes. It was then diluted with H2O (10OmL) and extracted with EtOAc (2 x 10OmL). The combined organic layers were dried (MgSO4) and the solvent removed in vacuo to give the product as an orange solid which was used in the next step without further purification (5.7Og, 99percent). m/z = 266 [M+H]+.
54% With potassium carbonate In acetonitrile at 10 - 20℃; for 4 h; A solution of 2-(methylsulfonyl)- 5-pyrimidinecarboxylic acid, ethyl ester (0.094 mol)in acetonitrile (40ml) was added at 10°C to a suspension of 4-piperidinemethanol(0.086 mol) and potassium carbonate (0.172 mol) in acetonitrile (200ml) under N2flow. The mixture was brought to room temperature, then stirred for 4 hours, pouredout into water and extracted with EtOAc. The organic layer was separated, dried(MgSO4), filtered, and the solvent was evaporated. The residue (23 g) was crystallizedfrom acetonitrile/diethyl ether. The precipitate was filtered off and dried, yielding 7.8g(34percent) of intermediate 8. The mother layer was evaporated. The residue (17g) waspurified by column chromatography over silica gel (20-45um) (eluent:DCM/MeOH/NH4OH 97/3/0.1). The pure fractions were collected and the solvent wasevaporated, yielding 4.6g (20percent) of intermediate 8, melting point 129°C.
20% With potassium carbonate In acetonitrile at 10 - 20℃; for 4 h; a) Preparation of intermediate 3 A solution of 2-(methylsulfonyl)-5-pyrimidinecarboxylic acid ethyl ester (0.094 mol) in acetonitrile (40ml) was added at 1O0C to a suspension of 4-piperidinemethanol (0.086 mol) and K2CO3 (0.172 mol) in acetonitrile (200ml) under N2 flow. The mixture was brought to room temperature, then stirred for 4 hours, poured into H2O and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (23 g) was crystallized from acetonitrile/diethyl ether. The mother layer was evaporated and the obtained residue was purified by column chromatography over silica gel (eluent: CH2C12/CH3OH/NH4OH 97/3/0.1; 20-45μm). The pure fractions were collected and the solvent was evaporated, yielding 4.6g (20percent) (M.P.: 129°C) of intermediate 3.
20% With potassium carbonate In acetonitrile at 10 - 20℃; for 4 h; a) Preparation of intermediate 7 A solution of 2-(methylsulfonyl)-5-pyrimidinecarboxylic acid, ethyl ester (0.094 mol) in acetonitrile (40ml) was added at 100C to a suspension of 4-piperidinemethanol (0.086 mol) and potassium carbonate (0.172 mol) in acetonitrile (200ml) under N2 flow. The mixture was brought to room temperature, then stirred for 4 hours, poured out into water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (23g) was crystallized from CHβCN/diethyl ether. The precipitate was filtered off and dried, yielding 7.8g (34percent) of intermediate 7. The residue was purified by column chromatography over silica gel (20-45 μm) (eluent: DCM/MeOH/NH4OH 97/3/0.1). The pure fractions were collected and the solvent was evaporated, yielding 4.6g (20percent) of intermediate 7, melting point 129°C.

Reference: [1] Patent: WO2008/53131, 2008, A1, . Location in patent: Page/Page column 51; 53
[2] Patent: WO2006/10750, 2006, A1, . Location in patent: Page/Page column 30-31
[3] Patent: WO2007/82878, 2007, A1, . Location in patent: Page/Page column 26
[4] Patent: WO2007/82882, 2007, A1, . Location in patent: Page/Page column 30
  • 34
  • [ 6457-49-4 ]
  • [ 89793-12-4 ]
  • [ 875318-46-0 ]
YieldReaction ConditionsOperation in experiment
95% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2.5 h; Step 18a: Ethyl 2-(4-hydroxypiperidin-l-yl)pyrimidine-5-carboxylate (Compound 0701)A mixture of compound 0605 (900 mg, 4.84 mmol), piperidin-4-ylmethanol (0.56 g, 4.86 mmol) and potassium carbonate (330 mg, 2.39 mmol) in DMF (2 mL) was stirred at ambient temperature for 2.5 h. The DMF was removed under reduced pressure and the residue was poured into brine, filtered to obtain the product 0701 (1.20 g, 95 percent) as a yellow solid: LCMS: 266 [M+ 1]+. 1H NMR (400 MHz, DMSO- dβ) δ 1.10 (m, 2H), 1.29 (t, J= 7.2 Hz, 3H), 1.72 (m, 3H), 2.97 (m, 2H), 3.27 (m, 2H), 4.26 (q, J= 7.2 Hz, 2H), 4.75 (m, 2H), 8.76 (m, 2H).
Reference: [1] Patent: WO2009/36016, 2009, A1, . Location in patent: Page/Page column 70
  • 35
  • [ 6457-49-4 ]
  • [ 79-22-1 ]
  • [ 916078-39-2 ]
YieldReaction ConditionsOperation in experiment
90% With potassium carbonate In water at 0 - 30℃; for 18 h; 4-Hydroxymethylpiperidine (1.0 g, 8.6 mmol) was dissolved in water (15 mL) and cooled to 0° C.
To this solution was added dropwise a solution of potassium carbonate (4.8 g, 34.7 mmol) in water (10 mL), followed by methyl chloroformate (2.68 mL, 34.7 mmol).
The mixture was stirred vigorously and allowed to warm to room temperature over 2 h.
After stirring overnight (16 h), the reaction mixture was acidified with 6M aqueous hydrochloric acid and extracted with dichloromethane (3*60 mL).
The extracts were combined, dried over sodium sulfate and filtered.
The filtrate was evaporated to yield the title intermediate (1.4 g, 8.1 mmol, 93percent) as a colorless oil. (m/z): C8H15NO3 calcd. 173.11; found 156.2 [M-H2O+H]+. 1H NMR (300 MHz, DMSO-d6): δ (ppm) 0.98 (m, 2H), 1.52 (m, 1H), 1.63 (br d, 2H), 2.72 (br m, 2H), 3.23 (d, 2H), 3.56 (s; 3H), 3.95 (br d, 2H), 4.48 (br s, 1H).; 4-Hydroxymethylpiperidine (47.6 g, 1.0 eq) and water (300 mL) were charged to a flask. The resulting mixture was cooled to 0-10° C. Potassium carbonate (85.7 g, 1.5 eq) dissolved in water (150 mL) and methyl chloroformate (38.4 mL, 1.1 eq) were added while maintaining the temperature at below 10° C. When the addition was complete, the reaction mixture was warmed up to 20-30° C. for 1 hour. After the reaction was complete, dichloromethane (500 mL) was added to the reaction mixture. The organic layer was collected and washed with 1 M phosphoric acid solution (200 mL), saturated sodium bicarbonate solution (200 mL) and saturated sodium chloride solution (200 mL). The organic layer was dried over sodium sulfate (50 g, 1 w/w eq) and then distilled under vacuum to produce the title intermediate. (67.0 g, 90percent yield)
Reference: [1] Patent: US2006/270652, 2006, A1, . Location in patent: Page/Page column 25-26
[2] European Journal of Medicinal Chemistry, 2016, vol. 109, p. 75 - 88
  • 36
  • [ 6457-49-4 ]
  • [ 1199-49-1 ]
  • [ 1032823-75-8 ]
Reference: [1] Organic Process Research and Development, 2016, vol. 20, # 8, p. 1469 - 1475
  • 37
  • [ 6457-49-4 ]
  • [ 1401966-69-5 ]
Reference: [1] Patent: US9346840, 2016, B2,
[2] Patent: JP5813855, 2015, B2,
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