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[ CAS No. 73731-37-0 ] {[proInfo.proName]}

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Chemical Structure| 73731-37-0
Chemical Structure| 73731-37-0
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Product Details of [ 73731-37-0 ]

CAS No. :73731-37-0 MDL No. :MFCD00077072
Formula : C19H19NO5 Boiling Point : -
Linear Structure Formula :- InChI Key :OYULCCKKLJPNPU-DIFFPNOSSA-N
M.W : 341.36 Pubchem ID :6992530
Synonyms :

Calculated chemistry of [ 73731-37-0 ]

Physicochemical Properties

Num. heavy atoms : 25
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.26
Num. rotatable bonds : 7
Num. H-bond acceptors : 5.0
Num. H-bond donors : 3.0
Molar Refractivity : 91.14
TPSA : 95.86 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.65 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.05
Log Po/w (XLOGP3) : 2.44
Log Po/w (WLOGP) : 2.36
Log Po/w (MLOGP) : 1.74
Log Po/w (SILICOS-IT) : 2.15
Consensus Log Po/w : 2.15

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -3.39
Solubility : 0.14 mg/ml ; 0.00041 mol/l
Class : Soluble
Log S (Ali) : -4.1
Solubility : 0.0274 mg/ml ; 0.0000801 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -4.35
Solubility : 0.0152 mg/ml ; 0.0000446 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.94

Safety of [ 73731-37-0 ]

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

Application In Synthesis of [ 73731-37-0 ]

* 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 [ 73731-37-0 ]
  • Downstream synthetic route of [ 73731-37-0 ]

[ 73731-37-0 ] Synthesis Path-Upstream   1~21

  • 1
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  • [ 73724-48-8 ]
YieldReaction ConditionsOperation in experiment
91%
Stage #1: With caesium carbonate In methanol for 0.25 h; Inert atmosphere
Stage #2: at 20℃; Inert atmosphere
At r.t. a solution of FmocONSu (3.37 g, 10.0 mmol) in 25 mL of Dioxane12 is added over 1h to a solution of L-threonine (1.19 g, 10.0 mmol) and Na2CO3 (1.06 g, 10.0 mmol) in 10 mL Dioxane and 25 mL water. The resulting suspension is stirred overnight and becomes clear. The solvent is evaporated in vacuo and the product is precipitated with 1M HClaq. at pH 4, filtered, washed with water and dissolved in EtOAc. The organic phase is dried (Na2SO4) and evaporated to yield the product quantitatively as a white solid which does not need any further purification. Under argon atmosphere Fmoc-threonine (2.67 g, 7.80 mmol) is dissolved in 32 mL dry MeOH. Then Cs2CO3 (1.40 g, 4.30 mmol) is added.11 After 15 min the solvent is evaporated and the resulting solid is three times suspended in CH2Cl2 and evaporated to remove all the MeOH. The Cs-salt is then suspended in 36 mL of dry DMF under argon atmosphere and stirred with benzylbromide (1.02 mL, 1.47 g, 8.60 mmol) over night at r.t. After evaporation of the solvent in vacuo, the residue is partitioned between water and CH2Cl2. The water phase is subsequently extracted two times with EtOAc. The combined organic phases are dried (Na2SO4) and evaporated. The crude product is purified either by recrystallisation from EtOAc or by silica column chromatography (cyclohexane/EtOAc 4 : 1) to get Fmoc-threoninebenzylester (3.07 g, 7.10 mmol, 91percent, Rf = 0.17 (cyclohexane/EtOAc 3 : 1)) as a white solid. The Fmoc-threoninebenzylester (2.16 g, 5.00 mmol) is dissolved in 48 mL dry CH2Cl2 under argon atmosphere. The solution is cooled to 0°C and NEt3 (770 μL, 560 mg, 5.50 mmol) and Triisopropylsilyltriflat (1.42 mL, 1.61 g, 5.25 mmol) is added subsequently.12 The mixture is allowed to warm to r.t. and is stirred 1h. Then 30 mL of dilute K2CO3- solution is added. The phases are separated and the water phase is extracted two times with CH2Cl2. The combined organic phases are dried (Na2SO4) and evaporated. The crude product is purified by silica column chromatography (cyclohexane/EtOAc 10 : 1) to get Fmoc(OTIPS)benzylester (2.47 g, 4.20 mmol, 84percent, Rf = 0.61 (cyclohexane/EtOAc 3 : 1)) as a colourless oil. Fmoc(OTIPS)benzylester (0.87 g, 1.48 mmol) is dissolved in 7.4 mL dry CH2Cl2 under argon atmosphere. The solution is cooled to 0°C and 7.4 mL of 40percent (v/v) Piperidine solution in dry CH2Cl2 are added dropwise.13 After 15 min of stirring at 0°C, the mixture is concentrated in vacuo at 25°C to an oil and put immediately onto the silica column (cyclohexane/EtOAc 5 : 1 + 0.5percent NEt3, elution of product with 1 : 1 + 0.5percent NEt3). Yield of the title compound 17d is 0.44 g (1.20 mmol, 81percent) as a colourless oil.
Reference: [1] Tetrahedron, 2012, vol. 68, # 2, p. 697 - 704
[2] Organic and Biomolecular Chemistry, 2007, vol. 5, # 16, p. 2645 - 2657
[3] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 1, p. 145 - 156
[4] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 7, p. 1978 - 1987
[5] ChemBioChem, 2017, vol. 18, # 6, p. 527 - 538
  • 2
  • [ 73731-37-0 ]
  • [ 71989-35-0 ]
Reference: [1] Tetrahedron Letters, 1992, vol. 33, # 49, p. 7605 - 7608
  • 3
  • [ 72-19-5 ]
  • [ 82911-69-1 ]
  • [ 73731-37-0 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With sodium carbonate In 1,4-dioxane; water at 20℃; Inert atmosphere
Stage #2: With hydrogenchloride In water
At r.t. a solution of FmocONSu (3.37 g, 10.0 mmol) in 25 mL of Dioxane12 is added over 1h to a solution of L-threonine (1.19 g, 10.0 mmol) and Na2CO3 (1.06 g, 10.0 mmol) in 10 mL Dioxane and 25 mL water. The resulting suspension is stirred overnight and becomes clear. The solvent is evaporated in vacuo and the product is precipitated with 1M HClaq. at pH 4, filtered, washed with water and dissolved in EtOAc. The organic phase is dried (Na2SO4) and evaporated to yield the product quantitatively as a white solid which does not need any further purification. Under argon atmosphere Fmoc-threonine (2.67 g, 7.80 mmol) is dissolved in 32 mL dry MeOH. Then Cs2CO3 (1.40 g, 4.30 mmol) is added.11 After 15 min the solvent is evaporated and the resulting solid is three times suspended in CH2Cl2 and evaporated to remove all the MeOH. The Cs-salt is then suspended in 36 mL of dry DMF under argon atmosphere and stirred with benzylbromide (1.02 mL, 1.47 g, 8.60 mmol) over night at r.t. After evaporation of the solvent in vacuo, the residue is partitioned between water and CH2Cl2. The water phase is subsequently extracted two times with EtOAc. The combined organic phases are dried (Na2SO4) and evaporated. The crude product is purified either by recrystallisation from EtOAc or by silica column chromatography (cyclohexane/EtOAc 4 : 1) to get Fmoc-threoninebenzylester (3.07 g, 7.10 mmol, 91percent, Rf = 0.17 (cyclohexane/EtOAc 3 : 1)) as a white solid. The Fmoc-threoninebenzylester (2.16 g, 5.00 mmol) is dissolved in 48 mL dry CH2Cl2 under argon atmosphere. The solution is cooled to 0°C and NEt3 (770 μL, 560 mg, 5.50 mmol) and Triisopropylsilyltriflat (1.42 mL, 1.61 g, 5.25 mmol) is added subsequently.12 The mixture is allowed to warm to r.t. and is stirred 1h. Then 30 mL of dilute K2CO3- solution is added. The phases are separated and the water phase is extracted two times with CH2Cl2. The combined organic phases are dried (Na2SO4) and evaporated. The crude product is purified by silica column chromatography (cyclohexane/EtOAc 10 : 1) to get Fmoc(OTIPS)benzylester (2.47 g, 4.20 mmol, 84percent, Rf = 0.61 (cyclohexane/EtOAc 3 : 1)) as a colourless oil. Fmoc(OTIPS)benzylester (0.87 g, 1.48 mmol) is dissolved in 7.4 mL dry CH2Cl2 under argon atmosphere. The solution is cooled to 0°C and 7.4 mL of 40percent (v/v) Piperidine solution in dry CH2Cl2 are added dropwise.13 After 15 min of stirring at 0°C, the mixture is concentrated in vacuo at 25°C to an oil and put immediately onto the silica column (cyclohexane/EtOAc 5 : 1 + 0.5percent NEt3, elution of product with 1 : 1 + 0.5percent NEt3). Yield of the title compound 17d is 0.44 g (1.20 mmol, 81percent) as a colourless oil.
Reference: [1] European Journal of Organic Chemistry, 2011, # 20-21, p. 3685 - 3689
[2] Tetrahedron, 2012, vol. 68, # 2, p. 697 - 704
[3] ChemBioChem, 2018, vol. 19, # 11, p. 1142 - 1146
[4] Tetrahedron Letters, 1993, vol. 34, # 24, p. 3837 - 3840
[5] Australian Journal of Chemistry, 2011, vol. 64, # 6, p. 723 - 731
[6] Synthetic Communications, 2009, vol. 39, # 11, p. 2022 - 2031
[7] Canadian Journal of Chemistry, 1982, vol. 60, p. 976 - 980
  • 4
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YieldReaction ConditionsOperation in experiment
80% With potassium carbonate In acetonitrile at 20℃; for 2 h; General procedure: To a solution of H-Phe-OH (100 mg, 60.5 mmol) in 50 percent MeCN (6.1 mL)were added Fmoc-OPhth (233 mg, 60.5 mmol) and K2CO3 (167 mg, 121 mmol) and stirred at room temperature. After 2 h of stirring saturated sodium bicarbonate solution and H2O were added and the resulting solution was washed with diethyl ether. The aqueous phase is acidified to pH 1 with 1M HCl and extracted with diethyl ether. The organic phase was washed with 1 M HCl, H2O, brine, dried over MgSO4. The filtrate was evaporatedevaporated under reduced pressure to give yellow solid as crude product.
Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 16, p. 1600 - 1603
  • 5
  • [ 176380-53-3 ]
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Reference: [1] Journal of Organic Chemistry, 2001, vol. 66, # 21, p. 7178 - 7183
  • 6
  • [ 72-19-5 ]
  • [ 28920-43-6 ]
  • [ 73731-37-0 ]
Reference: [1] Journal of the Chinese Chemical Society, 2011, vol. 58, # 4, p. 509 - 515
[2] European Journal of Medicinal Chemistry, 2016, vol. 121, p. 592 - 609
  • 7
  • [ 89024-98-6 ]
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Reference: [1] Chemistry - A European Journal, 2015, vol. 21, # 31, p. 11014 - 11016
  • 8
  • [ 72-19-5 ]
  • [ 88744-04-1 ]
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Reference: [1] Synthesis, 1986, # 4, p. 303 - 305
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Reference: [1] Organic Letters, 2012, vol. 14, # 24, p. 6346 - 6349
  • 10
  • [ 377082-52-5 ]
  • [ 73731-37-0 ]
Reference: [1] Journal of Organic Chemistry, 2001, vol. 66, # 21, p. 7178 - 7183
  • 11
  • [ 918531-00-7 ]
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Reference: [1] ChemistryOpen, 2017, vol. 6, # 2, p. 206 - 210
  • 12
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Reference: [1] Organic Preparations and Procedures International, 1998, vol. 30, # 2, p. 183 - 186
  • 13
  • [ 24324-17-2 ]
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Reference: [1] Canadian Journal of Chemistry, 1982, vol. 60, p. 976 - 980
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  • [ 82911-72-6 ]
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Reference: [1] Canadian Journal of Chemistry, 1982, vol. 60, p. 976 - 980
  • 15
  • [ 133180-01-5 ]
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Reference: [1] Tetrahedron Letters, 1991, vol. 32, # 4, p. 471 - 474
  • 16
  • [ 73731-37-0 ]
  • [ 18162-48-6 ]
  • [ 146346-82-9 ]
Reference: [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 18, p. 4858 - 4862[2] Angew. Chem., 2013, vol. 125, # 18, p. 4958 - 4962
[3] Tetrahedron Letters, 2001, vol. 42, # 23, p. 3807 - 3809
  • 17
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  • [ 146346-82-9 ]
Reference: [1] Tetrahedron Letters, 1992, vol. 33, # 49, p. 7605 - 7608
  • 18
  • [ 73731-37-0 ]
  • [ 100-51-6 ]
  • [ 175291-56-2 ]
YieldReaction ConditionsOperation in experiment
67%
Stage #1: With phosphorus trichloride In tetrahydrofuran at -5 - 5℃; for 0.0833333 h; Inert atmosphere
Stage #2: With 2,6-dimethylpyridine In tetrahydrofuran at -5 - 5℃; Inert atmosphere
General Procedure for Amino Acid PhosphorylationIn the following description, a "volume" equivalent is one mL of liquid per gram of the limiting reagent (e.g., the dry amino acid).Amino acid dryingHydrated forms of amino-group-protected amino acids (hydrated specified as >0.5 wtpercent water) are dried prior to use. The amino-group-protected amino acid (1.0 equivalents of dry compound) is charged to a flask. Dry THF (4 volumes, EMD OmniSolv HPLC grade, >99.99percent) is added and the total volume is marked on the outside of the flask. The mixture is heated in a 70°C bath and THF (about 2 volumes) is removed via distillation at 700 mbar. The solution is then diluted to the original, marked volume with dry THF. This distillation and dilution cycle is repeated two additional times. The final water content of the amino acid solution should be <0.20 wtpercent by Karl-Fischer (KF) titration.Step One: Dichlorophosphite preparationTo a flask flushed with nitrogen, THF (8 volumes) is charged. The solvent is cooled to 0°C and PC13 (1.30 equivalents, Aldrich, Reagent Plus grade, 99percent) is charged to the flask at a rate that maintains the solution at 0-5 °C. When the addition is complete and the solution is below 2.5 °C, a suitable base such as pyridine (Aldrich, anhydrous, 99+percent) (1 equivalent) may optionally be added at a rate that keeps the reaction temperature at - 5°C to 5°C. This optional step is especially useful when the dichlorophosphite is prepared from tert-butanol. With the reaction temperature below 2.5°C, a suitable alcohol such as tert-butanol or benzyl alcohol (BnOH; Aldrich, ACS grade, 99+percent) (1.50 equivalents) is added at a rate that keeps the reaction at -5 to 5°C. The solution is then allowed to stir for 5 minutes at 0-5°C and the consumption of PC13 is confirmed by 31P NMR (in CDCI3). A suitable base such as 2,6-lutidine (Aldrich, >99percent) (3.00 equivalents; 2.00 equivalents if a base was added previously) is then added to the flask at a rate that keeps the reaction at -5 to 5 °C. This forms a thick slurry.Step Two: Phosphite ester intermediate preparationA suitable base such as 2,6-lutidine (1.0 equivalents) is added to the dried amino- group-protected amino acid (APG-A.A.) solution. This solution is then added to the mixture from step one at a rate that keeps the reaction at -5 to 5°C. Additional THF (1 volume) is used to rinse the flask containing the APG-A.A. solution into the reaction. HPLC assays (Method 1) are taken at 10 min intervals starting 5 minutes after the addition to confirm reaction completion (no change in the ratio of APG-A.A. to intermediate phosphite ester at 225/210 nm).Step Three: Hydrolysis to phosphite esterAfter three consistent HPLC traces are observed, H20 (3.6 volumes) is added to the flask at a rate that does not allow the reaction to go above 10°C. During the addition, a two-phase solution is formed.Step Four: Oxidation to phosphateA suitable oxidant is then added to the two-phase mixture. When the oxidant isNaBr03/NaBr, solid NaBr (2.32 equivalents, Aldrich, ACS grade, 99+percent) is added to the two-phase mixture in the reactor at 0°C; an aqueous solution (20 wtpercent in water) of NaBr03 (0.48 equivalents, Riedel-de-Haen, puriss grade, 98percent> NaBr03 in DI water) is then added at a rate that keeps the reaction at 0-5°C. After the oxidant addition is complete the cooling is removed to allow the reaction to warm to ambient temperature, being careful not to allow the reaction to exotherm above 30°C. HPLC assays (Method 1) are taken to confirm reaction completion (phosphite ester intermediate <1.5 Apercent at 225/210 nm). When reaction completion is observed an aqueous solution (10 wtpercent> in water) of Na2S205 (1 volume, Sigma- Aldrich, ACS grade, 97+percent> Na2S205 in DI water) is added to the flask in one portion.Example 2. Fmoc (BnO) Phosphothreonine.67percent yield. 1H NMR (400 MHz, DMSO): δ 7.89 (d, 2H), 7.78 (d, 2H), 7.71 (d, 1H), 7.38 (m, 9H), 4.92 (d, 2H), 4.81 (m, 1H), 4.26 (m, 4H), 1.30 (d, 3H); 13C NMR (400 MHz, DMSO): δ 170.95 (s, 1C), 156.51 (s, 1C), 143.74 (d, 2C), 140.65 (d, 2C), 136.96 (d, 1C), 128.29 (s, 2C), 127.89 (s, 1C), 127.61 (s, 2C), 127.50 (s, 2C), 127.03 (s, 2C), 125.40 (d, 2C), 120.04 (s, 2C), 73.10 (d, 1C), 67.35 (d, 1C), 66.05 (s, 1C), 58.59 (d, 1C), 46.59 (s, 1C), 18.17 (d, 1C); 31P NMR (400 MHz, DMSO): δ -2.27; HRMS: [MH+] = 512.14700 (Calc =512.14688); Specific Rotation: +5.99°
Reference: [1] Patent: WO2013/12416, 2013, A1, . Location in patent: Page/Page column 70-71; 75
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  • [ 175291-56-2 ]
Reference: [1] Bulletin of the Chemical Society of Japan, 1996, vol. 69, # 2, p. 465 - 468
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  • [ 176380-53-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 9, p. 1797 - 1803
  • 21
  • [ 334-48-5 ]
  • [ 29022-11-5 ]
  • [ 1429504-34-6 ]
  • [ 35661-38-2 ]
  • [ 73731-37-0 ]
  • [ 73724-45-5 ]
  • [ 109425-55-0 ]
  • [ 88223-98-7 ]
  • [ 144120-53-6 ]
  • [ 144120-52-5 ]
  • [ 333366-23-7 ]
  • [ 103060-53-3 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 3, p. 748 - 751
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