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[ CAS No. 189321-66-2 ] {[proInfo.proName]}

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Chemical Structure| 189321-66-2
Chemical Structure| 189321-66-2
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Product Details of [ 189321-66-2 ]

CAS No. :189321-66-2 MDL No. :MFCD01321006
Formula : C10H17NO5 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 231.25 Pubchem ID :-
Synonyms :

Calculated chemistry of [ 189321-66-2 ]

Physicochemical Properties

Num. heavy atoms : 16
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.8
Num. rotatable bonds : 4
Num. H-bond acceptors : 5.0
Num. H-bond donors : 1.0
Molar Refractivity : 59.45
TPSA : 76.07 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) : -7.45 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.05
Log Po/w (XLOGP3) : 0.37
Log Po/w (WLOGP) : 0.33
Log Po/w (MLOGP) : -0.07
Log Po/w (SILICOS-IT) : -0.1
Consensus Log Po/w : 0.51

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.24
Solubility : 13.2 mg/ml ; 0.0572 mol/l
Class : Very soluble
Log S (Ali) : -1.53
Solubility : 6.78 mg/ml ; 0.0293 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.12
Solubility : 177.0 mg/ml ; 0.764 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.14

Safety of [ 189321-66-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P264-P273-P280-P305+P351+P338-P337+P313-P391-P501 UN#:N/A
Hazard Statements:H319-H413 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 189321-66-2 ]

* 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 [ 189321-66-2 ]
  • Downstream synthetic route of [ 189321-66-2 ]

[ 189321-66-2 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 189321-66-2 ]
  • [ 103003-01-6 ]
YieldReaction ConditionsOperation in experiment
26% With borane In tetrahydrofuran at 0 - 20℃; for 2.5 h; To N-Boc morpholine-2-carboxylic acid (2g) in THF (5ML) at 0°C was added a solution of borane. THF complex (1 N, 10. 38MOI) and the mixture was stirred for 30min at 0°C, and for 2hr at room temperature. Water (200ml) was added to the reaction and the mixture extracted with CH2CI2, dried with NA2SO4, and concentrated in vacuo to give 490mg of product (26percent). The product was then stirred in 4N HCI/DIOXANE to give the amine salt.
Reference: [1] Patent: WO2004/33440, 2004, A1, . Location in patent: Page 173
  • 2
  • [ 189321-66-2 ]
  • [ 135065-69-9 ]
YieldReaction ConditionsOperation in experiment
97%
Stage #1: With borane-THF In tetrahydrofuran at 0 - 20℃; for 0.416667 h;
Stage #2: With methanol; acetic acid In tetrahydrofuran
A solution of 4-[(1 ,1-dimethylethyl)oxy]carbonyl}-2-morpholinecarboxylic acid (2.0 g, 21.6 mmol) in THF (45 mL) was cooled to 0 °C. A solution of borane (39 mL, 39.0 mmol, 1 M in THF) was added over 25 min via addition funnel. After warming to RT, the reaction was quenched by dropwise addition of methanol/acetic acid (18 mL, 9:1 v/v). The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 1 N HCI. The aqueous layer was extracted with ethyl acetate and combined extracts were washed with water, 1 N NaOH, water, brine and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded 1.83 g (97percent) of the desired material. 1H NMR (400 MHz, CDCI3) δ ppm 1.49 (s, 9 H) 2.30 (br d, J=11.37 Hz, 1 H) 2.69 - 2.79 (m, J=9.51 , 6.41 , 3.28, 3.28 Hz, 1 H) 2.84 (ddd, J=13.77, 10.86, 3.16 Hz, 2 H) 3.27 - 3.38 (m, 1 H) 3.47 (br s, 1 H) 3.63 - 3.75 (m, 2 H) 4.10 - 4.19 (m, 1 H) 4.27 (br s, 1 H).
26%
Stage #1: With borane-THF In tetrahydrofuran at 0 - 20℃; for 2.5 h;
Stage #2: With water In tetrahydrofuran
To N-Boc morpholine-2-carboxylic acid (2 g) in THF (5 ml) at 0 C. was added a solution of borane. THF complex (IN, f 0.38 ml) and the mixture was stirred for 30 min at 0 C., and for 2 hr at room temperature. Water (200 ml) was added to the reaction and the mixture extracted with CH2C12, dried with Na2SO4, and concentrated in vacuo to give 490 mg of product (26percent). The product was then stirred in 4N HCl/dioxane to give the amine salt.
Reference: [1] Patent: WO2007/58850, 2007, A2, . Location in patent: Page/Page column 43
[2] Patent: US2004/147559, 2004, A1, . Location in patent: Page 84
[3] Patent: US6335338, 2002, B1, . Location in patent: Page column 6
  • 3
  • [ 189321-66-2 ]
  • [ 74-88-4 ]
  • [ 500789-41-3 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 36 h; To a solution of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (CAS Number 18932 1-66-2; 0.500 g, 2.164 mmol) in dry DMF (3 ml) was added K2C03 (1.190 g, 8.66 mmol) and methyliodide (0.922 g, 6.49 mmol) at rt. The reaction mixture was stirred at rt for 36 h then poured into 1M HC1 (20 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with water (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 4-(tert- butyl) 2-methyl morpholine-2,4-dicarboxylate (0.624 g, quantitative). This material was used for nextstep without further purification. LCMS: Method C, 1.756 mi MS: ES+ 246.48.
95% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24 h; To a solution of 4-(tert-butoxycarbonyl)-2-morpholine dicarboxylic acid (231 mg, 1.00 mmol) in dimethylformamide (2.0 ml), methyl iodide (0.125 ml, 1.33 mmol) and potassium carbonate (152 mg, 1.10 mmol) were added. The resulting mixture was stirred at room temperature for 24 h. To the reaction mixture, a 10percent aqueous citric acid solution was added. The resulting mixture was diluted with ethyl acetate. After the organic layer was dried over Na2SO4, the solvent was distilled off to give the title compound (232 mg, 0.95 mmol, 95percent). MS (ESI) m/z 246 (M+H)+. 1H NMR (CDCl3) δ 1.47 (9H, s), 3.02-3.18 (2H, m), 3.58 (1H, td, J = 11.1, 2.6 Hz), 3.74-3.80 (4H, m), 3.98-4.14 (3H, m).
90% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 15 h; Inert atmosphere 4-(tert-Butoxycarbonyl)morpholine-2-carboxylic acid (500 mg, 2.16 mmol) and potassium carbonate (900 mg, 6.51 mmol) were placed in a round-bottom flask. The flask was flushed with nitrogen and DMF (5 mL) was added. The mixture was cooled to 0°C while stirring and iodomethane (0.54 mL, 8.67 mmol) was added dropwise. The reaction mixture was allowed to warm to r.t. and stirred for 15 h. The reaction mixturewas quenched with saturated aqueous ammonium chloride solution (15 mL), diluted with water (30 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography (0-25percent ethyl acetate in heptane) to afford the title compound (478 mg, 90percent). oH (500 MHz, DMSO-d6) 4.18 (dd,J 8.4, 3.4 Hz, 1H), 3.84 (dt, J 11.6, 4.1 Hz, 2H), 3.67 (s, 3H), 3.54-3.44 (m, 2H), 3.31 (s,1H), 3.09 (ddd, J 13.2, 9.1, 3.4 Hz, 1H), 1.40 (s, 9H).
Reference: [1] Patent: WO2018/60691, 2018, A1, . Location in patent: Page/Page column 47
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 9, p. 3072 - 3093
[3] Patent: WO2014/9295, 2014, A1, . Location in patent: Page/Page column 175
[4] Patent: WO2004/5295, 2004, A1, . Location in patent: Page 155
  • 4
  • [ 189321-66-2 ]
  • [ 75-11-6 ]
  • [ 74-88-4 ]
  • [ 500789-41-3 ]
YieldReaction ConditionsOperation in experiment
96%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 15 h;
Stage #2: at 20℃; for 48 h;
4-Tert-butyl 2-methyl morpholine-2,4-dicarboxylate (5 g, 21.62 mmol) was dissolved in DMF (60 mL), K2C03 (9.10 g, 64.9 mmol) and iodomethane (4.98 mL, 80 mmol) were added and the suspension was stirred for 15 h at 60 °C. The reaction mixture was cooled to room temperature, poured into saturated NH4CI and extracted with EtOAc. The organic layer was washed with saturated NH4C1 and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified through a short column of silica (heptane :EtO Ac 100:0 to 50:50) to yield 4-tert-butyl 2-methyl morpholine-2,4- dicarboxylate (5.09 g, 96 percent) as a white solid. MS (ES) C11H19NO5 requires: 245, found: 268.2 [M+Na]+.
Reference: [1] Patent: WO2011/73119, 2011, A1, . Location in patent: Page/Page column 53-54
  • 5
  • [ 67-56-1 ]
  • [ 189321-66-2 ]
  • [ 500789-41-3 ]
Reference: [1] Patent: WO2011/26917, 2011, A1, . Location in patent: Page/Page column 78
[2] Patent: WO2011/26904, 2011, A1, . Location in patent: Page/Page column 77
[3] Patent: WO2012/101063, 2012, A1, . Location in patent: Page/Page column 153-154
[4] Patent: WO2012/101064, 2012, A1, . Location in patent: Page/Page column 196
[5] Patent: EP3248980, 2017, A1, . Location in patent: Paragraph 0231; 0232; 0233
  • 6
  • [ 189321-66-2 ]
  • [ 18107-18-1 ]
  • [ 500789-41-3 ]
Reference: [1] Patent: WO2007/28654, 2007, A1, . Location in patent: Page/Page column 42-43
  • 7
  • [ 500789-41-3 ]
  • [ 189321-66-2 ]
YieldReaction ConditionsOperation in experiment
93%
Stage #1: With potassium hydroxide In methanol; water at 20℃; for 8 h;
Stage #2: With citric acid In methanol; water
A lmol/L aqueous potassium hydroxide solution (3 mL) was added to methyl 4-(tert-butoxycarbonyl)morpholine-2-carboxylate (251 mg, 1.02 mmol) in methanol (15 mL).
The mixture was stirred at room temperature for 8 hours.
Subsequently, water was added to the mixture, followed by addition of a 5percent aqueous citric acid solution to make themixtureacidic.
The mixture was then extracted with ethyl acetate.
The extract was washed with brine and was dried over magnesium sulfate.
Evaporation of the solvent gave 219 mg (93percent) of the desired compound as a colorless powder.
1H NMR (400 MHz, DMSO-d6) δ 1.40 (9H, s), 2.70 (1H, dd, J = 41.6, 15.3 Hz), 3.03-3.09 (1H, m), 3.43-3.54 (2H, m), 3.78 (1H, m), 3.85 (1H, dt, J = 11.6, 3.7 Hz), 4.04 (1H, dd, J = 8.6, 3.7 Hz), 12.73 (1H, brs).
Reference: [1] Patent: EP1780210, 2007, A1, . Location in patent: Page/Page column 58
  • 8
  • [ 135065-69-9 ]
  • [ 189321-66-2 ]
Reference: [1] Patent: WO2012/120476, 2012, A1, . Location in patent: Page/Page column 58
[2] Patent: US2013/345213, 2013, A1, . Location in patent: Paragraph 0355
  • 9
  • [ 768371-16-0 ]
  • [ 189321-66-2 ]
Reference: [1] Patent: WO2004/74291, 2004, A1, . Location in patent: Page 67
  • 10
  • [ 189321-66-2 ]
  • [ 937063-34-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 9, p. 3072 - 3093
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