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[ CAS No. 106973-36-8 ] {[proInfo.proName]}

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Chemical Structure| 106973-36-8
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Product Details of [ 106973-36-8 ]

CAS No. :106973-36-8 MDL No. :MFCD12031258
Formula : C12H13NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :LAHROJZLGLNLBT-SNVBAGLBSA-N
M.W : 235.23 Pubchem ID :13543371
Synonyms :

Calculated chemistry of [ 106973-36-8 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 17
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.33
Num. rotatable bonds : 3
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 63.2
TPSA : 66.84 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) : -7.38 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.39
Log Po/w (XLOGP3) : 0.5
Log Po/w (WLOGP) : -0.03
Log Po/w (MLOGP) : 0.23
Log Po/w (SILICOS-IT) : 0.92
Consensus Log Po/w : 0.6

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.68
Solubility : 4.95 mg/ml ; 0.0211 mol/l
Class : Very soluble
Log S (Ali) : -1.47
Solubility : 7.9 mg/ml ; 0.0336 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.03
Solubility : 2.21 mg/ml ; 0.0094 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.39

Safety of [ 106973-36-8 ]

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 [ 106973-36-8 ]

* 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 [ 106973-36-8 ]
  • Downstream synthetic route of [ 106973-36-8 ]

[ 106973-36-8 ] Synthesis Path-Upstream   1~6

  • 1
  • [ 106910-77-4 ]
  • [ 79-04-9 ]
  • [ 106973-36-8 ]
YieldReaction ConditionsOperation in experiment
91.2%
Stage #1: With potassium carbonate In tetrahydrofuran; water at 0 - 4℃; for 2 h; Industry scale
Stage #2: With sodium hydroxide In tetrahydrofuran; water at 3 - 10℃; for 4.83333 h; Industry scale
Stage #3: With hydrogenchloride In water at 3 - 6℃; Industry scale
(3/?)-4-benzyl-5-oxomorpholine-3-carboxylic acid .A 300 gallon hastelloy reactor was charged with N-benzyl-D-serine (50.0 kg) followed by the addition of tetrahydrofuran (THF, 271.2 kg). This solution was then cooled to 0 0C and a potassium carbonate (53.1 kg) solution in water (152.5 L) was added in one portion while maintaing the temperature between -5 0C and 5 0C. The temperature was adjusted back to 0 0C and then chloroacetyl chloride (40.2 kg) was added portion wise over 1 h while keeping the temperature below 4 0C. The mixture was stirred for 30 min between 0- 4 0C and another portion of chloroacetyl chloride (4.4 kg) was added in one portion. Stirring was continued for and additional 30 min at 0-4 0C. A 50percent aqueous sodium hydroxide (82.0 kg) solution was added over 50min while keeping the reaction temperature below 10 0C. A final pH endpoint of 13-13.5 should be obtained. After the addition is complete, the solution was cooled to 3-5 0C and stirred at this temperature for 4h. After determining the reaction was complete (HPLC), it was warmed to 20-22 0C and heptane (75.0 kg) was added and vigorously stirred. The basic aqueous layer was collected, the heptane was removed, and the aqueous layer was placed back into the reactor. The basic aqueous solution was washed once again with heptane (107.8 kg) and placed back into the reactor where it was cooled to 3 0C and then adjusted down to < pH 2.0 by portion wise addition of 12N HCI (193.8 kg) over 1-1.5h, while keeping the temperature < 6 0C. After the acid addition was complete, the white solid suspension was cooled to 3-5 0C, stirred for an additional 2h, and then filtered. The cake was then rinsed with cold (3-5 0C) water (50.0 L), pulled dry, and then placed under vacuum at 55-60 0C until the LOD is < 0.6percent giving the title compound (54.9 kg, 91.2percent yield) as a white solid. 1H NMR (DMSO-d6) δ 7.37-7.24 (m, 5H), 5.25 (d, J = 15.4 Hz, 1 H), 4.17 (m, 2H), 4.12 (m 1 H), 3.94 (dd, J = 5.6, 3.2 Hz, 1 H), 3.92 (dd, J = 16.8, 3.2 Hz, 1 H), 3.82 (d, J = 15.4 Hz, 1 H).
75%
Stage #1: With potassium carbonate In tetrahydrofuran; water at 0℃; for 1 h;
Stage #2: With sodium hydroxide In tetrahydrofuran; water at 0℃; for 2 h;
Stage #3: With hydrogenchloride In tetrahydrofuran; water at 10℃;
Part B: (3R)-5-Oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid. As per the procedures of WO2005058245, a solution of N-(phenylmethyl)-D-serine (79.51 g, 407.3 mmol) in THF (485 ml.) was cooled to 0 0C, and a precooled 0 0C solution of K2CO3 (168.87 g, 1222 mmol) in water (485 ml.) was added. To the well- stirred mixture was added chloroacetyl chloride (45.4 ml_, 570.0 mmol) slowly while keeping the internal temperature below 5 0C. The mixture was vigorously stirred at 0 0C for 30 min, and then an additional portion of chloroacetyl chloride (4.54 ml_, 57.0 mmol) was slowly added. The mixture was stirred for an additional 30 min at 0 0C. To the mixture was added a sufficient quantity of precooled 0 0C aqueous NaOH (50percent w/w) to adjust the pH > 13.5 while keeping the internal temperature between 5 0C and 10 0C. The mixture was stirred at 0 0C for 2 h, and then warmed to 20 0C. The mixture was washed with heptane (165 ml.) followed by a second portion of fresh heptane (240 ml_). The aqueous phase was cooled to 0 0C, and adjusted to pH < 2 with concentrated aqueous HCI while keeping the internal temperature less than 10 0C. The mixture was placed in a 0 0C freezer overnight, and the solid was collected by vacuum filtration. The solid was washed with water (2 x 300 ml.) and dried in vacuo at 42 0C overnight. The resulting (3R)-5-oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid (72.20 g, 75percent) was isolated as a white solid. LCMS: (M+H)+: 236.1.
75% With potassium carbonate In tetrahydrofuran; water at 0℃; for 1 h; Inert atmosphere Part B: (3 ?)-5-Oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid As per the procedures of WO2005058245, a solution of A/-(phenylmethyl)-D- (79.51 g, 407.3 mmol) in THF (485 mL) was cooled to 0 °C, and a precooled 0 °C solution of K2C03 (168.87 g, 1222 mmol) in water (485 mL) was added. To the well- stirred mixture was added chloroacetyl chloride (45.4 mL, 570.0 mmol) slowly while keeping the internal temperature below 5 °C. The mixture was vigorously stirred at 0 °C for 30 min, and then an additional portion of chloroacetyl chloride (4.54 mL, 57.0 mmol) was slowly added. The mixture was stirred for an additional 30 min at 0 °C. To the mixture was added a sufficient quantity of precooled 0 °C aqueous NaOH (50percent w/w) to adjust the pH > 13.5 while keeping the internal temperature between 5 °C and 10 °C. The mixture was stirred at 0 °C for 2 h, and then warmed to 20 °C. The mixture was washed with heptane (165 mL) followed by a second portion of fresh heptane (240 mL). The aqueous phase was cooled to 0 °C, and adjusted to pH < 2 with concentrated aqueous HCI while keeping the internal temperature less than 10 °C. The mixture was placed in a 0 °C freezer overnight, and the solid was collected by vacuum filtration. The solid was washed with water (2 x 300 mL) and dried in vacuo at 42 °C overnight. The resulting (3R)-5-oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid (72.20 g, 75percent) was isolated as a white solid. LCMS: (M+H)+: 236.1.
62%
Stage #1: With potassium carbonate In tetrahydrofuran; water at -10 - 5℃; for 2 h;
Stage #2: With sodium hydroxide In tetrahydrofuran; water at 0 - 10℃; for 2 h;
Stage #3: With hydrogenchloride In water at -5 - 10℃;
K2CO3 (10.6 g, 76.4 mmol) in H2O (30 mL) precooled to 0° C. was added to N-(phenylmethyl)-D-serine (4.91 g, 25.2 mmol) in THF (30 mL) cooled to -10° C., internal temperature. Chloroacetyl chloride (3.30 mL, 41.4 mmol) was added dropwise, keeping the internal temperature below 5° C. After stirring for 2 h NaOH (10 mL, 50percent w/w in water), precooled to 0° C. was added dropwise, keeping the internal temperature below 10° C. The reaction mixture was stirred for 2 h and subsequently warmed to rt. The reaction mixture was washed twice with heptane (20 mL) and the aqueous layer was cooled to -5° C. Concentrated HCl was added until pH <2, keeping the internal temperature below 10° C. The mixture was placed in a freezer overnight and the solid was filtered, washed twice with cold H2O (20 mL) and dried at 50° C. in a vacuum oven to give the title compound of step B (3.67 g, 15.6 mmol, 62percent). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.78 (d, J=15.4 Hz, 1H), 3.84-3.92 (m, 2H), 4.05-4.15 (m, 3H), 5.21 (d, J=15.2 Hz, 1H), 7.20-7.31 (m, 5H), 13.20 (br. s., 1H). [α]D20° C.=-108.6, I=100 mm, c=1.0 in 1N NaOH.
43%
Stage #1: With sodium hydroxide In water at 0 - 45℃; for 4.5 h;
Stage #2: With hydrogenchloride In water at 10℃;
To a stirred solution of Intermediate 10 (35.0 g, 179.0 mmol) in aqueous NaOH solution (9.3 g, 200.0 mL, 232.5 mmol) at 00C was slowly added chloroacetyl chloride (24.2 g, 17.0 mL, 214.0 mmol). The reaction mixture was allowed to warm to r.t. and then stirred for 30 minutes. Aqueous 1OM NaOH solution (45.0 mL, 450.0 mmol) was added and the reaction mixture heated to 45°C for 4 h. The reaction mixture was then cooled to 100C and acidified to pH 1 with cone. HCl. On standing at 4°C the product crystallised from the mixture and was collected by filtration, washed with cold water and then dried in vacuo to give the title compound (18.0 g, 43percent) as a white solid. 5H (DMSO- d6) 13.51-12.53 (IH, br. s), 7.38-7.25 (5H, m), 5.27 (IH, d, J 15.3 Hz), 4.24-4.10 (3H, m), 3.94-3.88 (2H, m), 3.83 (IH, d, J 15.3 Hz). MS (ES+) 236.0 (M+H)+.
43%
Stage #1: With sodium hydroxide In water at 0 - 45℃; for 4.5 h;
Stage #2: With hydrogenchloride In water at 10℃;
INTERMEDIATE 35(3i?V4-Benzyl-5-oxomorpholine-3-carboxylic acidTo a stirred solution of Intermediate 34 (35.0 g, 179.0 mmol) in aqueous NaOH (9.3 g in 200 mL water, 232.5 mmol) at 00C was slowly added chloroacetyl chloride (17.0 mL, 214.0 mmol). The reaction mixture was allowed to warm to r.t. and stirred for 30 minutes. Aqueous 1OM NaOH (45.0 mL, 465.0 mmol) was added and the reaction mixture heated to 45°C for 4 h. The reaction mixture was then cooled to 100C and acidified to pH 1 with cone. HCl. On standing at 4°C a solid crystallised from the mixture. It was collected by filtration, washed with cold water and dried in vacuo to give the title compound (18.0 g, 43percent) as a white solid. δH (DMSO-df.) 13.51-12.53 (IH, br s), <n="111"/>7.38-7.25 (5H, m), 5.27 (IH, d, J 15.3 Hz), 4.24-4.10 (3H, m), 3.94-3.88 (2H, m), 3.83 (IH, d,V 15.3 Hz).
43%
Stage #1: With sodium hydroxide In water at 0 - 45℃;
Stage #2: With hydrogenchloride In water
To a stirred solution of Intermediate 16 (35.0 g, 179.0 mmol) in aqueous NaOH solution (9.3 g, 200.0 mL, 232.5 mmol) at 0° C. was slowly added chloroacetyl chloride (24.2 g, 17.0 mL, 214.0 mmol). The reaction mixture was allowed to warm to r.t. and then stirred for 30 minutes. Aqueous 10M NaOH solution (45.0 mL, 465.0 mmol) was added and the reaction mixture heated to 45° C. for 4 h. The reaction mixture was then cooled to 10° C. and acidified to pH 1 with conc. HCl. On standing at 4° C. the product crystallised from the mixture and was collected by filtration, washed with cold water and then dried in vacuo to give the title compound (18.0 g, 43percent) as a white solid. δH (DMSO-d6) 13.51-12.53 (1H, br. s), 7.38-7.25 (5H, m), 5.27 (1H, d, J 15.3 Hz), 4.24-4.10 (3H, m), 3.94-3.88 (2H, m), 3.83 (1H, d, J 15.3 Hz). LCMS (ES+) 236.0 (M+H)+.
29%
Stage #1: With sodium hydroxide In water at 0 - 20℃; for 3.25 h;
Stage #2: at 0℃;
Stage #3: for 0.166667 h; Heating / reflux
The title compound was prepared according to the method described by H. H. Otto, Helvetica Chimica Acta, 2004, 87, 90. To an ice cooled solution of N- (phenylmethyl)-D-serine (8.9Og, 45.59mmol) in 2N NaOH solution (5OmL) was added chloroacetyl chloride (4.36mL, 54.71 mmol), dropwise over 15 minutes. The reaction was stirred for 30 minutes before adding 30percent NaOH solution (4.5g in 15mL) and stirring at RT. for 2 and ΛA hours. It was cooled in an ice bath before adding c.HCI solution to pH<1. solid precipitated out. Filtered. Suspended in isopropanol and heated at reflux for 10 minutes. Filtered hot. Solvent evaporated to afford a pale yellow solid. Triturated with Et2O to afford the title compound as a cream solid in 29percent yield. MS (API+): m/z 236.1 (MH+: 100percent) (at) retention time 1.61 min

Reference: [1] Patent: WO2011/23733, 2011, A1, . Location in patent: Page/Page column 19-20
[2] Patent: WO2009/61879, 2009, A1, . Location in patent: Page/Page column 85
[3] Patent: WO2013/82388, 2013, A1, . Location in patent: Page/Page column 74-75
[4] Patent: US2008/300242, 2008, A1, . Location in patent: Page/Page column 93
[5] Patent: WO2008/47109, 2008, A1, . Location in patent: Page/Page column 40
[6] Patent: WO2009/71895, 2009, A1, . Location in patent: Page/Page column 109-110
[7] Patent: US2011/3785, 2011, A1, . Location in patent: Page/Page column 11
[8] Patent: WO2007/28654, 2007, A1, . Location in patent: Page/Page column 64
[9] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1985, p. 2577 - 2580
  • 2
  • [ 1007169-00-7 ]
  • [ 106973-36-8 ]
YieldReaction ConditionsOperation in experiment
59%
Stage #1: With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 110℃; for 3 h;
Stage #2: With hydrogenchloride In water
Step C: To a solution of (R)-2-(N-benzyl-2-chloroacetamido)-3-hydroxypropanoic acid (1.53 g, 5.63 mmol) in tert-butanol was added potassium tert-butanolate and the reaction mixture heated to 110° C. for three h, then cooled to room temperature and concentrated to dryness. The residue was acidified with 1 N HCl to pH 1 and the aqueous solution extracted with EtOAc (3.x.250 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10 to 30percent CH3OH in CH2Cl2 with 1percent acetic acid) to provide (R)-4-benzyl-5-oxomorpholine-3-carboxylic acid (780 mg, 59percent) as a yellow foam. 1H NMR and MS consistent.
Reference: [1] Patent: US2008/255114, 2008, A1, . Location in patent: Page/Page column 31
  • 3
  • [ 79-04-9 ]
  • [ 515156-88-4 ]
  • [ 106973-36-8 ]
YieldReaction ConditionsOperation in experiment
43%
Stage #1: With sodium hydroxide In water at 0 - 45℃; for 4.5 h;
Stage #2: With hydrogenchloride In water at 10℃;
INTERMEDIATE 17 <n="30"/>(3i?)-4-Benzyl-5-oxomoφholine-3-carboxylic acidTo a stirred solution of Intermediate 16 (35.0 g, 179.0 mmol) in aqueous NaOH solution (9.3 g, 200.0 mL, 232.5 mmol) at 00C was slowly added chloroacetyl chloride (24.2 g, 17.0 mL, 214.0 mmol). The reaction mixture was allowed to warm to r.t. and then stirred for 30 minutes. Aqueous 1OM NaOH solution (45.0 mL, 465.0 mmol) was added and the reaction mixture heated to 45°C for 4 h. The reaction mixture was then cooled to 100C and acidified to pH 1 with cone. HCl. On standing at 4°C the product crystallised from the mixture and was collected by filtration, washed with cold water and then dried in vacuo to give the title compound (18.0 g, 43percent) as a white solid. 6H (DMSO- d6) 13.51-12.53 (IH, br. s), 7.38-7.25 (5H, m), 5.27 (IH, d, J 15.3 Hz), 4.24-4.10 (3H, m), 3.94-3.88 (2H, m), 3.83 (IH, d, J 15.3 Hz). LCMS (ES+) 236.0 (M+H)+.
Reference: [1] Patent: WO2009/1089, 2008, A1, . Location in patent: Page/Page column 28-29
  • 4
  • [ 100-52-7 ]
  • [ 106973-36-8 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1985, p. 2577 - 2580
[2] Patent: WO2013/82388, 2013, A1,
  • 5
  • [ 106973-36-8 ]
  • [ 101376-25-4 ]
YieldReaction ConditionsOperation in experiment
87% With dimethylsulfide borane complex; triethylamine In tetrahydrofuran for 12 h; Heating / reflux To a stirred solution of Intermediate 11 (17.7 g, 75.3 mmol) in THF (300 mL) was added NEt3 (7.3 g, 10.0 mL, 72.0 mmol). The solution was then cooled to 00C and BH3.Me2S complex (1OM in THF, 45.0 mL, 450.0 mmol) was added slowly. The reaction mixture was heated at reflux for 12 h and, after cooling to r.t., the excess borane was destroyed by slow addition of MeOH at 00C. The reaction mixture was concentrated in vacuo and the resultant white solid was dissolved in EtOAc (120 mL) and washed with aqueous NaOH solution (20percent v/v, 2 x 100 mL). The organic fraction was then extracted into aqueous 2M HCl (2 x 150 mL). The combined acidic aqueous fractions were then basifed to pH 14 (addition of solid NaOH) and were re-extracted with EtOAc (2 x 150 mL). The combined organic fractions were washed with brine (150 mL), dried (MgSO4), <n="42"/>filtered and concentrated in vacuo to give the title compound (13.5 g, 87percent) as a clear oil that required no further purification. δH (CDCl3) 7.29-7.16 (5H, m), 4.05 (IH, d, J 12.8 Hz), 3.88 (IH, dd, J 11.5 Hz and J 4.5 Hz), 3.78 (IH, m), 3.70-3.53 (2H, m), 3.51-3.40 (2H, m), 3.20 (IH, d, J 13.2 Hz), 2.68 (IH, dt, J 12.1 Hz and J2.8 Hz), 2.48 (IH, m), 2.27 (IH, m), 2.20-2.15 (IH, br. s).
87%
Stage #1: With dimethylsulfide borane complex; triethylamine In tetrahydrofuran for 12 h; Heating / reflux
Stage #2: With methanol In tetrahydrofuran at 0℃;
INTERMEDIATE 18r(35V(4-Benzylmorpholin-3-yl)1methanolTo a stirred solution of Intermediate 17 {\\1.1 g, 75.3 mmol) in THF (300 mL) was added NEt3 (7.3 g, 10.0 mL, 72.0 mmol). The solution was then cooled to O0C and BH3-Me2S complex (1OM in THF, 45.0 mL, 450.0 mmol) was added slowly. The reaction mixture was heated at reflux for 12 h and, after cooling to r.t., the excess borane was destroyed by slow addition of MeOH at 00C. The reaction mixture was concentrated in vacuo and the resultant white solid was dissolved in EtOAc (120 mL) and washed with aqueous NaOH solution (20percent v/v, 2 x 100 mL). The organic fraction was then extracted into aqueous 2M HCl (2 x 150 mL). The combined acidic aqueous fractions were then basified to pH 14 (addition of solid NaOH) and were re-extracted with EtOAc (2 x 150 mL). The combined organic fractions were washed with brine (150 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (13.5 g, 87percent) as a clear oil that required no further purification. δH (CDCl3) 7.29-7.16 (5H, m), 4.05 (IH, d, J 12.8 Hz), 3.88 (IH, dd, J 11.5 and J4.5 Hz), 3.78 (IH, m), 3.70-3.53 (2H, m), 3.51-3.40 (2H, m), 3.20 (IH, d, J 13.2 Hz), 2.68 (IH, dt, J 12.1 and J2.8 Hz), 2.48 (IH, m), 2.27 (IH, m), 2.20-2.15 (IH, br. s).
87%
Stage #1: With dimethylsulfide borane complex; triethylamine In tetrahydrofuran at 0℃; for 12 h; Heating / reflux
Stage #2: With methanol In tetrahydrofuran at 0℃;
INTERMEDIATE 36[(3-SV(4-Benzylmorpholin-3-yl)]methanolTo a stirred solution of Intermediate 35 (17.7 g, 75.3 mmol) in THF (300 mL) was added triethylamine (10.0 mL, 72.0 mmol). The solution was then cooled to O0C and borane-dimethylsulfide complex (1OM in THF, 45.0 mL, 450.0 mmol) was added slowly. The reaction mixture was heated at reflux for 12 h. After cooling to r.t., excess borane was destroyed by slow addition of MeOH at 00C. The reaction mixture was concentrated in vacuo. The resulting white solid was dissolved in EtOAc (120 mL) and washed with aqueous NaOH solution (20percent v/v, 2 x 100 mL). The organic fraction was extracted with aqueous 2M HCl (2 x 150 mL). The combined acidic aqueous fractions were then basified to pH 14 (by addition of solid NaOH) and were re-extracted with EtOAc (2 x 150 mL). The combined organic fractions were washed with brine (150 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (13.5 g, 87percent) as a clear oil. δH (CDCl3) 7.29-7.16 (5H, m), 4.05 (IH, d, J 12.8 Hz), 3.88 (IH, dd, J 11.5, 4.5 Hz), 3.80-3.76 (IH, m), 3.70-3.53 (2H, m), 3.51-3.40 (2H, m), 3.20 (IH, d, J 13.2 Hz), 2.68 (IH, dt, J 12.1, 2.8 Hz), 2.48-2.45 (IH, m), 2.27-2.24 (IH, m), 2.17 (IH, br s).
87% With dimethylsulfide borane complex; triethylamine In tetrahydrofuran at 0℃; Reflux To a stirred solution of Intermediate 17 (17.7 g, 75.3 mmol) in THF (300 mL) was added NEt3 (7.3 g, 10.0 mL, 72.0 mmol). The solution was then cooled to 0° C. and BH3.Me2S complex (10M in THF, 45.0 mL, 450.0 mmol) was added slowly. The reaction mixture was heated at reflux for 12 h and, after cooling to r.t., the excess borane was destroyed by slow addition of MeOH at 0° C. The reaction mixture was concentrated in vacuo and the resultant white solid was dissolved in EtOAc (120 mL) and washed with aqueous NaOH solution (20percent v/v, 2.x.100 mL). The organic fraction was then extracted into aqueous 2M HCl (2.x.150 mL). The combined acidic aqueous fractions were then basified to pH 14 (addition of solid NaOH) and were re-extracted with EtOAc (2.x.150 mL). The combined organic fractions were washed with brine (150 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (13.5 g, 87percent) as a clear oil that required no further purification. δH (CDCl3) 7.29-7.16 (5H, m), 4.05 (1H, d, J 12.8 Hz), 3.88 (1H, dd, J 11.5 and J 4.5 Hz), 3.78 (1H, m), 3.70-3.53 (2H, m), 3.51-3.40 (2H, m), 3.20 (1H, d, J 13.2 Hz), 2.68 (1H, dt, J 12.1 and J 2.8 Hz), 2.48 (1H, m), 2.27 (1H, m), 2.20-2.15 (1H, br. s).
68%
Stage #1: With dimethyl sulfide borane; triethylamine In tetrahydrofuran at 0℃; for 6.25 h; Heating / reflux
Stage #2: With water In tetrahydrofuran at 0℃; for 0.5 h;
Step D: To a solution of (R)-4-benzyl-5-oxomorpholine-3-carboxylic acid (780 mg, 3.32 mmol) and triethylamine (567 mL, 4.08 mmol) in anhydrous THF (15 mL) at 0° C. was added borane dimethylsulfide complex over 15 min. The reaction mixture was warmed to room temperature and heated to reflux for 6 hours, then cooled in an ice bath. To this mixture was added H2O (4 mL) drop wise over 30 min., then 2 N NaOH (6 mL) and the mixture concentrated to 30percent of the volume. The residue was extracted with EtOAc (3.x.150 mL), the organic layer dried (MgSO4) and concentrated. The residue was purified by flash chromatography (silica gel, 0 to 5percent CH3OH in CH2Cl2) to provide (S)-(4-benzylmorpholine-3-yl)CH3OH (470 mg, 68percent) as a colorless oil. 1H NMR and MS consistent.

Reference: [1] Patent: WO2008/47109, 2008, A1, . Location in patent: Page/Page column 40-41
[2] Patent: WO2009/1089, 2008, A1, . Location in patent: Page/Page column 29
[3] Patent: WO2009/71895, 2009, A1, . Location in patent: Page/Page column 110
[4] Patent: US2011/3785, 2011, A1, . Location in patent: Page/Page column 11
[5] Patent: US2008/255114, 2008, A1, . Location in patent: Page/Page column 31
[6] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1985, p. 2577 - 2580
  • 6
  • [ 106973-36-8 ]
  • [ 218594-79-7 ]
Reference: [1] Patent: WO2011/23733, 2011, A1,
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5-Phenylmorpholin-3-one

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Chemical Structure| 287930-73-8

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4-Benzyl-2-hydroxymorpholin-3-one

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Chemical Structure| 91641-50-8

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2-Morpholino-2-phenylacetic acid hydrochloride

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Chemical Structure| 18085-37-5

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Methyl 1-benzylazetidine-2-carboxylate

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Amides

Chemical Structure| 1235639-75-4

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(R)-Methyl 4-benzyl-5-oxomorpholine-3-carboxylate

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Chemical Structure| 1260672-03-4

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5-Phenylmorpholin-3-one

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Chemical Structure| 287930-73-8

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4-Benzyl-2-hydroxymorpholin-3-one

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Chemical Structure| 88150-75-8

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Ethyl 4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-3-oxobutanoate

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Chemical Structure| 4702-13-0

[ 4702-13-0 ]

N-Phthaloylglycine

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Carboxylic Acids

Chemical Structure| 91641-50-8

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2-Morpholino-2-phenylacetic acid hydrochloride

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Chemical Structure| 4702-13-0

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N-Phthaloylglycine

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Chemical Structure| 88784-33-2

[ 88784-33-2 ]

(S)-5-(Benzyloxy)-2-(1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid

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Chemical Structure| 21319-53-9

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1-Benzylpiperidine-2-carboxylic acid

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Chemical Structure| 62642-62-0

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4-(Morpholinomethyl)benzoic acid

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Related Parent Nucleus of
[ 106973-36-8 ]

Aliphatic Heterocycles

Chemical Structure| 1235639-75-4

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(R)-Methyl 4-benzyl-5-oxomorpholine-3-carboxylate

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Chemical Structure| 1260672-03-4

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5-Phenylmorpholin-3-one

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4-Benzyl-2-hydroxymorpholin-3-one

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2-Morpholino-2-phenylacetic acid hydrochloride

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Chemical Structure| 18085-37-5

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Methyl 1-benzylazetidine-2-carboxylate

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Morpholines

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(R)-Methyl 4-benzyl-5-oxomorpholine-3-carboxylate

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Chemical Structure| 1260672-03-4

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5-Phenylmorpholin-3-one

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4-Benzyl-2-hydroxymorpholin-3-one

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2-Morpholino-2-phenylacetic acid hydrochloride

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(S)-(4-Benzylmorpholin-3-yl)methanol

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