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[ CAS No. 135065-69-9 ] {[proInfo.proName]}

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Chemical Structure| 135065-69-9
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Product Details of [ 135065-69-9 ]

CAS No. :135065-69-9 MDL No. :MFCD03426270
Formula : C10H19NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 217.26 Pubchem ID :-
Synonyms :

Calculated chemistry of [ 135065-69-9 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.9
Num. rotatable bonds : 4
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 58.84
TPSA : 59.0 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) : -7.54 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.59
Log Po/w (XLOGP3) : 0.12
Log Po/w (WLOGP) : 0.23
Log Po/w (MLOGP) : 0.03
Log Po/w (SILICOS-IT) : 0.33
Consensus Log Po/w : 0.66

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.0
Solubility : 21.8 mg/ml ; 0.1 mol/l
Class : Very soluble
Log S (Ali) : -0.91
Solubility : 26.4 mg/ml ; 0.122 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.57
Solubility : 58.2 mg/ml ; 0.268 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 135065-69-9 ]

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 [ 135065-69-9 ]

* 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 [ 135065-69-9 ]
  • Downstream synthetic route of [ 135065-69-9 ]

[ 135065-69-9 ] Synthesis Path-Upstream   1~15

  • 1
  • [ 24424-99-5 ]
  • [ 40987-24-4 ]
  • [ 135065-69-9 ]
YieldReaction ConditionsOperation in experiment
87%
Stage #1: With ammonium formate In methanol at 20℃; for 4 h;
Stage #2: With triethylamine In acetonitrile at 0 - 20℃; for 3 h;
Ammonium formate (3.04 g, 48.2 mmol) and 10percent palladium on activated carbon (500 mg) were added to (4-benzylmorpholin-2-yl)methanol (1.00 g, 4.82 mmol) in methanol (50 mL).
The mixture was stirred at room temperature for 4 hours.
Subsequently, the reaction mixture was filtered through Celite and the solvent was evaporated.
The resulting residue was dissolved in acetonitrile (20 mL).
While this solution was chilled in an ice bath, ditert-butyl dicarbonate (1.58 g, 7.23 mmol) and triethylamine (1.35 mL, 9.64 mmol) were added and the mixture was stirred at room temperature for 3 hours.
The solvent was evaporated and water was added to the residue.
The mixture was then extracted with ethyl acetate and the extract was washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent.
Purification of the residue by silica gel column chromatography (hexane: ethyl acetate = 5:1 -> 1:1) gave 907 mg (87percent) of the desired compound as a colorless oil.
1H NMR (400MHz, DMSO-d6) δ 1.40 (9H, s), 2.47-2.66 (1H, m), 2.73-2.92 (1H, m),3.25-3.45 (4H, m), 3.70 (1H, d, J = 13.4 Hz), 3.79 (1H, dd, J = 11.6, 2.4 Hz), 3.85 (1H, d, J = 12.8 Hz), 4.77 (1H, t, J = 5.5 Hz).
Reference: [1] Patent: US2004/192653, 2004, A1,
[2] Patent: EP1780210, 2007, A1, . Location in patent: Page/Page column 55-56
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 17, p. 4080 - 4083
  • 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
  • [ 24424-99-5 ]
  • [ 103003-01-6 ]
  • [ 135065-69-9 ]
YieldReaction ConditionsOperation in experiment
47% With dmap In dichloromethane at 20℃; for 16 h; A mixture of 2-hydroxymethylmorpholine (720 mg; 6.15 mmol; 1 eq.), di-tert-butyl dicarbonate (2.01 g; 9.22 mmol; 1.5 eq.) and 4-(dimethylamino)pyridine (7.5 mg; 0.06 mmol; 0.01 eq.) in DCM (6 mL) was stirred at room temperature for 16 hours then concentrated in vacuo. Purification by column chromatography (0percent to 30percent EA in heptanes) afforded the title compound (633 mg, 47percent) as a colourless oil. 1H NMR (300 MHz, CDCI3) δ 4.09-3.73 (m, 3H), 3.73-3.62 (m, 1H), 3.62-3.38 (m, 3H), 3.06-2.83 (m, 1 H), 2.83-2.57 (m, 1 H), 1.98 (dd, J = 6.9, 5.3 Hz, 1H), 1.46 (s, 9H).
Reference: [1] Patent: WO2013/91773, 2013, A1, . Location in patent: Page/Page column 64
[2] Patent: EP411912, 1991, A2,
[3] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 1, p. 170 - 174
[4] Journal of Organic Chemistry, 2014, vol. 79, # 10, p. 4644 - 4649
[5] Journal of Medicinal Chemistry, 2017, vol. 60, # 6, p. 2227 - 2244
  • 4
  • [ 500789-41-3 ]
  • [ 135065-69-9 ]
Reference: [1] Patent: WO2004/5295, 2004, A1, . Location in patent: Page 155-156
  • 5
  • [ 1152411-05-6 ]
  • [ 135065-69-9 ]
Reference: [1] Patent: WO2007/58850, 2007, A2, . Location in patent: Page/Page column 44
  • 6
  • [ 1542717-38-3 ]
  • [ 135065-69-9 ]
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 10, p. 4644 - 4649
  • 7
  • [ 1607004-67-0 ]
  • [ 135065-69-9 ]
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 10, p. 4644 - 4649
  • 8
  • [ 1607004-58-9 ]
  • [ 135065-69-9 ]
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 10, p. 4644 - 4649
  • 9
  • [ 1607004-68-1 ]
  • [ 135065-69-9 ]
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 10, p. 4644 - 4649
  • 10
  • [ 40987-25-5 ]
  • [ 135065-69-9 ]
Reference: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 6, p. 2227 - 2244
  • 11
  • [ 40987-24-4 ]
  • [ 135065-69-9 ]
Reference: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 6, p. 2227 - 2244
  • 12
  • [ 135065-69-9 ]
  • [ 218594-02-6 ]
Reference: [1] Patent: WO2008/145681, 2008, A2, . Location in patent: Page/Page column 90-91
  • 13
  • [ 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
  • 14
  • [ 135065-69-9 ]
  • [ 765914-78-1 ]
YieldReaction ConditionsOperation in experiment
63% With carbon tetrabromide; triphenylphosphine In dichloromethane at -20 - 20℃; for 19.5 h; To a solution of the compound of Example 2(c) (0.67 g, 3.1 mmol) in dichloromethane (35 mL) at -20 0C was added CBr4 (2.06 g, 6.17 mmol) followed by dropwise addition of a solution of PPh3 (1.70 g, 6.48 mmol) in dichloromethane (25 mL). The reaction mixture was held at -15 0C for18 h then stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, EtOAc/hexanes) gave 0.55 g (63percent) of product that was used in the next step.
Reference: [1] Patent: WO2007/58850, 2007, A2, . Location in patent: Page/Page column 44
  • 15
  • [ 135065-69-9 ]
  • [ 765914-78-1 ]
YieldReaction ConditionsOperation in experiment
37% With triphenylphosphine In dichloromethane Step B:
2-Bromomethylmorpholine-4-carboxylic acid tert-butyl ester
To a cooled (0° C.) solution of 2-hydroxymethylmorpholine-4-carboxylic acid tert-butyl ester (1.04 g, 4.79 mmol, see Step 1) in dichloromethane (20 mL) was added CBr4 (1.98 g, 5.98 mmol).
After stirring the mixture for 10 minutes, triphenylphosphine (2.20 g, 8.38 mmol) was added portion-wise.
The reaction mixture was stirred at 0° C. for 6 hours and then allowed to warm to room temperature and stirred for 60 hours.
The mixture was concentrated under reduced pressure and then diluted with ether.
The crude mixture was filtered and the filtrate was concentrated to afford the crude product, which was chromatographed on Biotage eluding with dichloromethane.
The desired fractions were combined and concentrated to yield 0.50 g of product (37percent yield).
Reference: [1] Patent: US2004/192653, 2004, A1,
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