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Product Details of [ 40499-83-0 ]

CAS No. :40499-83-0 MDL No. :MFCD00005256
Formula : C4H9NO Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 87.12 Pubchem ID :-
Synonyms :

Calculated chemistry of [ 40499-83-0 ]

Physicochemical Properties

Num. heavy atoms : 6
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 2.0
Molar Refractivity : 27.11
TPSA : 32.26 Ų

Pharmacokinetics

GI absorption : Low
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) : -7.32 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.2
Log Po/w (XLOGP3) : -0.69
Log Po/w (WLOGP) : -1.04
Log Po/w (MLOGP) : -0.57
Log Po/w (SILICOS-IT) : 0.52
Consensus Log Po/w : -0.12

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : 0.05
Solubility : 98.8 mg/ml ; 1.13 mol/l
Class : Highly soluble
Log S (Ali) : 0.49
Solubility : 268.0 mg/ml ; 3.07 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -0.13
Solubility : 64.4 mg/ml ; 0.74 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.25

Safety of [ 40499-83-0 ]

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 [ 40499-83-0 ]

* 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 [ 40499-83-0 ]
  • Downstream synthetic route of [ 40499-83-0 ]

[ 40499-83-0 ] Synthesis Path-Upstream   1~21

  • 1
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  • [ 50-00-0 ]
  • [ 13220-33-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2465 - 2469
  • 2
  • [ 100-39-0 ]
  • [ 40499-83-0 ]
  • [ 775-15-5 ]
Reference: [1] Patent: US2005/54850, 2005, A1,
  • 3
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  • [ 100-52-7 ]
  • [ 775-15-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2465 - 2469
  • 4
  • [ 775-15-5 ]
  • [ 40499-83-0 ]
Reference: [1] Tetrahedron, 2006, vol. 62, # 24, p. 5763 - 5774
[2] Synthetic Communications, 1983, vol. 13, # 13, p. 1117 - 1124
  • 5
  • [ 105-33-9 ]
  • [ 40499-83-0 ]
Reference: [1] Patent: CN105924379, 2016, A, . Location in patent: Paragraph 0021; 0024
  • 6
  • [ 74889-62-6 ]
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Reference: [1] Patent: US5179212, 1993, A,
  • 7
  • [ 135969-16-3 ]
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Reference: [1] Patent: US5179212, 1993, A,
  • 8
  • [ 105-33-9 ]
  • [ 40499-83-0 ]
Reference: [1] Patent: US4910320, 1990, A,
  • 9
  • [ 109-97-7 ]
  • [ 60-29-7 ]
  • [ 107-13-1 ]
  • [ 40499-83-0 ]
  • [ 408309-29-5 ]
Reference: [1] Patent: US5512603, 1996, A,
  • 10
  • [ 70442-87-4 ]
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Reference: [1] Tetrahedron Letters, 1987, vol. 28, # 48, p. 6041 - 6044
  • 11
  • [ 109-97-7 ]
  • [ 60-29-7 ]
  • [ 107-13-1 ]
  • [ 40499-83-0 ]
  • [ 408309-29-5 ]
Reference: [1] Patent: US5512603, 1996, A,
  • 12
  • [ 40499-83-0 ]
  • [ 10387-40-3 ]
  • [ 23123-19-5 ]
Reference: [1] ACS Catalysis, 2016, vol. 6, # 3, p. 1732 - 1736
  • 13
  • [ 101469-91-4 ]
  • [ 40499-83-0 ]
  • [ 100243-39-8 ]
Reference: [1] Synthetic Communications, 1985, vol. 15, # 7, p. 587 - 598
  • 14
  • [ 50-00-0 ]
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  • [ 104641-60-3 ]
YieldReaction ConditionsOperation in experiment
92% With formic acid In tetrahydrofuran for 5 h; Heating / reflux In a 100 ml flask, 2 g (R)-3-Hydroxy pyrrolidine, 25 ml THF, 0.49 g paraformaldehyde and 1.5 g formic acid (90percent) were added. The mixture was stirred under reflux for 5 hours (until all solid disappeared), then cooled at 0° C. and added with 10 ml of NaOH solution (10 N) to adjust the pH to about 10. The organic layer was separated and dried over MgSO4. After filtering the dried solution and removing the solvent (THF), an oily product (1.5 g, 92percent) of (R)3 was obtained. 1H NMR (CDCl3, 300 MHz): 1.50-1.60 (m, 1H), 1.98-2.10 (m, 1H), 2.25 (s, 3H), 2.25-2.40 (m, 2H), 2.50-2.60 (m, 1H), 2.61-2.70(m, 1H), 3.80(brs, 1H), 4.20-4.30(m, 1H).
85.6%
Stage #1: With sodium tetrahydroborate In methanol; water at 10 - 20℃; for 2.33333 h;
Stage #2: With hydrogenchloride In methanol; water for 0.333333 h;
15 g (0.172 mol) of (3R)-pyrrolidin-3-ol (commercially available) were dissolved in 240 ml of MeOH. This solution was cooled to 10-15°C, and formaldehyde (124.5 mi of a 36 percent solution in water, diluted with 125 ml of MeOH) and NaBH4 (16.27 g, 0.43 mol) were added in small portions, alternativately during 1h, maintaining the temperature at 10-15°C. After 20 min the mixture was warmed to room temperature and the reaction continued for 1 hour. The reaction mixture was acidified with HCI 2N, stirred during 20 minutes and neutralised with solid NaHCO3. MeOH and most of the water were evaporated and the residue was diluted with a small quantity of water, basified with solid K2C03 and exhaustively extracted with CHC13. The organic phases were combined and dried over Na2SO4. CHCl3 was evaporated to give an oil which was purified by Kugelrohr distillation at reduced pressure (0.2-0. 3 mbar, 50-60°C oven) to give 14.91 g (85.6 percent) of the title product. 'H-NMR (CDCI3) :. No. 1.60-1. 80 (m, 1H), 2.10-2. 40 (m, 5H), 2.40-2. 70 (m, 2H), 2.75-2. 95 (m, 1H), 4.20-4. 40 (m, 1H), 4.40-4. 50 (bs, 1H, OH).
Reference: [1] Patent: US2007/123557, 2007, A1, . Location in patent: Page/Page column 16
[2] Patent: WO2003/87094, 2003, A2, . Location in patent: Page/Page column 34
  • 15
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YieldReaction ConditionsOperation in experiment
98% With triethylamine In acetonitrile at 0 - 20℃; for 24 h; Inert atmosphere Step 1: In a 500 mL oven-dried round-bottomed flask charged with (R)-3-pyrrolidinol (5.15 g, 58 mmol) was added dry CH3CN (200 mL) to give a light brown solution under N2. Then Et3N (16.2 mL, 0.12 mol) was added dropwise. This was cooled to 0 °C and then CbzCl (48 mL, 83 mmol) was added dropwise. The temperature was allowed to warm up to rt gradually. After stirring for 24 h, solvent was removed in vacuo. The residue was treated with DCM and DI water. Organic layer was separated and the aqueous layer was extracted with DCM once. The combined organic layer was dried ( a2S04) and concentrated in vacuo. The crude material was purified by S1O2 column chromatography eluting with Hexane: EtOAc = 1 : 1 to provide the desired alcohol 1 (12.6 g, 98percent).1H NMR (CDCI3, 400 MHz): δ 7.37 - 7.30 (m, 5H), 5.14 (s, 2H), 4.52 - 4.46 (m, 1H), 3.60 - 3.41 (m, 4H), 2.01 - 1.95 (m, 2H), 1.61 (br s, 1H).
83% With triethylamine In dichloromethane at 0℃; for 2 h; Inert atmosphere To a solution of (R)-pyrrolidin-3-ol (10 g, 114.8 mmol) and NEt3 (18.3 mL, 131.2 mmol) in CH2C12(120 mL) under N2 atmosphere stirred in an ice/water bath, was added Cbz-Cl (15.6mL, 109.31 mmol) dropwise. The reaction was stirred in the ice/water bath for 2 h. The reaction was worked up by the addition of CH2C12 (25 mL), and iN aqueous solution of HC1 (100 mL). The organic phase was separtated, washed with saturated aqueous solution of NaHCO3 (100 mL), and brine (100 mL), dried over Na2504 and the solvent was removed in vacuo. The yellowish residue was dissolved in EtOAc and filtered through a silica gel pad, washing with more EtOAc until no more product was washed out. The solvent was evaporated to afford a light yellowish oil as the title compound (20. 19g, 83percent). LC/MS (Rt = 1.49 mi +ESI m/z: MH+ = 222.3).
Reference: [1] Journal of Organic Chemistry, 2001, vol. 66, # 25, p. 8513 - 8517
[2] Patent: WO2011/160020, 2011, A2, . Location in patent: Page/Page column 57
[3] Patent: US2001/41700, 2001, A1,
[4] Patent: US6313117, 2001, B1,
[5] Patent: WO2017/186148, 2017, A1, . Location in patent: Page/Page column 43; 44
[6] Bioscience, Biotechnology and Biochemistry, 1995, vol. 59, # 7, p. 1287 - 1290
[7] Acta Chemica Scandinavica, 1989, vol. 43, # 3, p. 290 - 295
[8] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 13, p. 1773 - 1778
[9] Bulletin of the Chemical Society of Japan, 1999, vol. 72, # 12, p. 2737 - 2754
[10] Patent: WO2005/44195, 2005, A2, . Location in patent: Page/Page column 36-37
[11] Patent: WO2006/40192, 2006, A1, . Location in patent: Page/Page column 21
[12] Patent: WO2004/43940, 2004, A1, . Location in patent: Page 45-46
[13] Patent: WO2005/116029, 2005, A1, . Location in patent: Page/Page column 49
[14] Patent: WO2005/108382, 2005, A1, . Location in patent: Page/Page column 36-37
[15] Patent: WO2005/44195, 2005, A2, . Location in patent: Page/Page column 36-37
  • 16
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YieldReaction ConditionsOperation in experiment
57% With triethylamine In dichloromethane at 20℃; for 12 h; To a solution of pyrrolidin-3-ol (10.45 g, 120.1 mmol) in dichloromethane (300 mL) was added benzyl chloroformate (24.6 g, 144 mmol) and triethylamine (24.3 g, 240.2 mmol). The resulting solution was stirred at room temperature for 12 hours. After concentrating the reaction, the remaining material was partitioned between ethyl acetate (100 mL) and water (60 mL). The layers were separated. The organic layer was washed with water (60 mL), aqueous saturated sodium chloride solution (60 mL), dried and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 2:1) to give benzyl 3-hydroxypyrrolidinyl-1-carboxylate (15.2 g, 57percent) as a colorless gum. LCMS m/z = 222.1 [M+H]+.
49% for 20 h; Prβparatlon 16; S-Hydroxy-pyrrolldlne-i-carboxyllc acid benzyl ester; 3-Pyrrolidiπol (6.99g, 68.9 mmol), benzyl chloroformata (10.66 mL, 75.8 mmol) and CH2CI2 (200 mL) were stirred for 2Oh then washed with water and brine, dried (MgSO4) and concentrated to give a thick yellow oil. Chromatography, flushing first with 20percent EtOAc/ hexaπes then eluting with 30percent MeOH/EtOAc, afforded 7.4Og (49percent) of the title compound: NMR (CDCI3) δ 7.35-7.26 (m, 5H), 5.11 (s, 2H), 4.46 (br s, 1H), 3.60-3.38 (m, 4H)1 2.00-2.82 (m, 2H).
Reference: [1] Chemical Communications, 2007, # 21, p. 2136 - 2138
[2] Patent: WO2017/216726, 2017, A1, . Location in patent: Page/Page column 581
[3] Patent: WO2007/60526, 2007, A1, . Location in patent: Page/Page column 44; 71
[4] Journal of Medicinal Chemistry, 2007, vol. 50, # 12, p. 2818 - 2841
[5] Bulletin of the Chemical Society of Japan, 1996, vol. 69, # 1, p. 207 - 215
[6] Journal of Medicinal Chemistry, 1998, vol. 41, # 21, p. 4080 - 4100
[7] Journal of Labelled Compounds and Radiopharmaceuticals, 1999, vol. 42, # SUPPL. 1, p. S207-S209
[8] Patent: US5786358, 1998, A,
[9] Patent: EP761668, 1997, A2,
[10] Advanced Synthesis and Catalysis, 2007, vol. 349, # 8-9, p. 1475 - 1480
[11] Synthesis, 2011, # 22, p. 3669 - 3674
  • 17
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YieldReaction ConditionsOperation in experiment
47% With sodium hydroxide In tetrahydrofuran; water at 20℃; for 3 h; To the solution of pyrrolidin-3-ol (1.0 g, 11 mmol) in THF (5 mL) and 1M NaOH (5 mL) was added dibenzyldicarbonate (3.3, 11 mmol) at room temperature. The reaction mixture was stirred for 3 h then the THF removed under reduced pressure. The residue was dissolved in DCM (50 mL) and washed successively with saturated NaHCO3 (2.x.20mL) and saturated NaCl (2.x.20 mL). The solution was dried over Na2SO4, decanted and concentrated. Benzyl 3-hydroxypyrrolidine-1-carboxylate (1.1 g, 47percent) was isolated by prep. HPLC YMC ODSA 30.x.100 mm, 20-100percent MeOH/H2O (0. 1percent TFA) gradient over 10 mins at 20 mL/min flow rate at a retention time of 4.93 min. LCMS: 1.21 min [M+1] 222.06 (2 min gradient, MeOH/H2O 0.1percent TFA).
Reference: [1] Patent: US2007/161685, 2007, A1, . Location in patent: Page/Page column 126
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Reference: [1] Journal of Medicinal Chemistry, 1992, vol. 35, # 8, p. 1393 - 1398
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Reference: [1] Patent: US2002/58809, 2002, A1,
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Reference: [1] Patent: EP1087934, 2004, B1, . Location in patent: Page 25-26
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  • [ 101385-93-7 ]
Reference: [1] Patent: US2006/189643, 2006, A1, . Location in patent: Page/Page column 9
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