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[ CAS No. 135065-71-3 ] {[proInfo.proName]}

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Chemical Structure| 135065-71-3
Chemical Structure| 135065-71-3
Structure of 135065-71-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 135065-71-3 ]

CAS No. :135065-71-3 MDL No. :MFCD09260605
Formula : C10H19NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :FJYBLMJHXRWDAQ-MRVPVSSYSA-N
M.W : 217.26 Pubchem ID :1512576
Synonyms :

Calculated chemistry of [ 135065-71-3 ]

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) : 2.44
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 : 0.63

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 [ 135065-71-3 ]

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 [ 135065-71-3 ]

* 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 [ 135065-71-3 ]
  • Downstream synthetic route of [ 135065-71-3 ]

[ 135065-71-3 ] Synthesis Path-Upstream   1~14

  • 1
  • [ 135097-68-6 ]
  • [ 135065-71-3 ]
YieldReaction ConditionsOperation in experiment
100% for 16 h; Intermediate 111 (19.8 g, 64.4 mmol) was stirred under an atmosphere of hydrogenin the presence of 10percent Pd/C (1.98 g, 1.86 mmol) for 16 h. The catalyst wasremoved by vacuum filtration and the filtrate concentrated at reduced pressure to give 13.98 g (100percent yield) of the title compound as a colourless viscous oil, which crystallised on standing.1H NMR (250 MHz, chloroform-d): 6 [ppm] 3.98 - 3.75 (m, 3H), 3.73 - 3.41 (m, 4H),3.03- 2.83 (m, 1H), 2.82-2.65 (m, 1H), 2.12 (t, J = 5.9 Hz, 1H), 1.45 (5, 9H).
99% With hydrogen In ethanol at 20℃; To a solution of (R)-tert-buty{ 2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd-C (wet, 3.6 g), and the resulting mixture was stirred at rt under a H2 balloon overnight. After filtration, the solvent was removed under vacuum, and the residue was purified by flash column chromatography to give (R)-tert-buty\\ 2-(hydroxymethyl)morpholine-4-carboxylate (5.84 g, 99 percent) as a clear oil. 1H NMR (400MHz, CDCl3): 3.88 (d, 2 H), 3.82 (br, 1 <n="115"/>H), 3.64 (d, 1 H), 3.56 (m, 3 H), 2.94 (m, 1 H), 2.76 (m, 1 H), 1.90 (br, 1 H), 1.44 (s, 9 H); MS m/z 218 (M+H+).
99% With hydrogen In ethanol Step 3.
(R)-tert-Butyl 2-(hydroxymethyl)morpholine-4-carboxylate
To a solution of (R)-tert-butyl 2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd-C (wet, 3.6 g), and the resulting mixture was stirred at rt under a H2 atmosphere overnight.
After filtration, the solvent was removed under vacuum and the residue was purified by flash column chromatography to give (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5.84 g, 99percent) as a clear oil. 1H NMR (400 MHz, CDCl3): δ=3.88 (d, 2H), 3.82 (br, 1H), 3.64 (d, 1H), 3.56 (m, 3H), 2.94 (m, 1H), 2.76 (m, 1H), 1.90 (br, 1H), 1.44 (s, 9H); MS m/z 218 (M+H+).
99% With hydrogen In 20 C To a solution of (K)-tert-butyl 2-(benzyloxymethyl)rnorpholine-4-carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd-C (wet, 3.6 g), and the resulting mixture was stirred at rt under a H2 balloon overnight. After filtration, the solvent was removed under vacuum, and the residue was purified by flash column chromatography to give (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5.84 g, 99 percent) as a clear oil. 1H NMR (400MHz, CDCl3): 3.88 (d, 2 H), 3.82 (br, 1 H), 3.64 (d, 1 H), 3.56 (m, 3 H), 2.94 (m, 1 H), 2.76 (m, 1 H), 1.90 (br, 1 H), 1.44 (s, 9 H); MS m/z 218 (M+H*).
99% With hydrogen In ethanol at 20℃; To a solution of (R)-tert-butyl 2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd-C (wet, 3.6 g), and the resulting mixture was stirred at rt under a H2 balloon overnight. After filtration, the solvent was removed under vacuum, and the residue was purified by flash column chromatography to give (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5.84 g, 99percent) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.88 (d, 2H), 3.82 (br, 1H), 3.64 (d, 1H), 3.56 (m, 3H), 2.94 (m, 1H), 2.76 (m, 1H), 1.90 (br, 1H), 1.44 (s, 9H); MS m/z 218 (M+H+).
99% With hydrogen In ethanol at 20℃; Step 3. (R)-tert-Buty\\ 2-(hydroxymethyl)morpholine-4-carboxylate: To a solution of (R)-tert-buty\\ 2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd-C (wet, 3.6 g), and the resulting mixture was stirred at rt under a H2 balloon overnight. After filtration, the solvent was removed under vacuum, and the residue was purified by flash column chromatography to give (R)- tert-butyi 2-(hydroxymethyl)morpholine-4-carboxylate (5.84 g, 99 percent) as a clear oil. 1H NMR (400MHz, CDCl3): 3.88 (d, 2 H), 3.82 (br, 1 H), 3.64 (d, 1 H), 3.56 (m, 3 H), 2.94 (m, 1 H), 2.76 (m, 1 H), 1.90 (br, 1 H), 1.44 (s, 9 H); MS m/z 218 (M+H+).
99% With hydrogen In methanol at 20℃; To a solution of (K)-lert-buy\\ 2-(benzyloxymethyl)morpholine-4- carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd-C (wet, 3.6 g), and the resulting mixture was stirred at rt under a H2 balloon overnight. After filtration, the solvent was removed under vacuum and the residue was purified by flash column chromatography to give (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5.84 g, 99 percent) as a clear oil. 1H NMR (400MHz, CDCl3): 3.88 (d, 2 H)5 3.82 (br, 1 H)3 3.64 (d, 1 H)3 3.56 (m3 3 H), 2.94 (m, 1 H), 2.76 (m, 1 H), 1.90 (br, 1 H), 1.44 (s3 9 H); MS m/z 218 (M+H+).
99% With hydrogen In ethanol at 20℃; Step 3. (R)-tert-Butyl 2-(hydroxymethyl)morpholine-4-carboxylate. To a solution of (R)-ter/-butyl 2-(benzyloxymethyl)morpholine-4- carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd-C (wet, 3.6 g), and the resulting mixture was stirred at rt under a H2 balloon overnight. After filtration, the solvent was removed under vacuum and the residue was purified by flash column chromatography to give (R)-.erf-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5.84 g, 99 percent) as a clear oil. 1H NMR (400MHz, CDCl3): 3.88 (d, 2 H), 3.82 (br, 1 H), 3.64 (d, 1 H), 3.56 (m, 3 H), 2.94 (m, 1 H), 2.76 (m, 1 H), 1.90 (br, 1 H), 1.44 (s, 9 H); MS m/z 218 (M+H+).
92% With hydrogen In ethanol for 16 h; Step b) 2R-Hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester The oil (1.80 g) was dissolved in 50 ml ethanol and 100 mg palladium on carbon (10percent) was added. The mixture was hydrogenated at 1 atm H2- EPO <DP n="30"/>pressure for 16 h, filtered through silica/alumina (5 cm and 0.5 cm, respectively) and concentrated in vacuo yielding 1.18 g (92percent) 2R- hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester as a white crystalline solid.
92% With hydrogen In ethanol at 20℃; for 16 h; The oil (1.80 g) was dissolved in 50 ml ethanol and 100 mg palladium on carbon (10percent) was added. The mixture was hydrogenated at 1 atm H2-pressure for 16 h, filtered through silica/alumina (5 cm and 0.5 cm, respectively) and concentrated in vacuo yielding 1.18 g (92percent) 2R-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester as a white crystalline solid.
59% With hydrogen In ethanol at 70℃; (R)-2-Benzyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester 1c (1.02 g, 3.32 mmol) and 0.45 g of palladium on activated carbon were added to a reaction flask. The reaction flask was purged with hydrogen for three times. 10 mL of ethanol was added under hydrogen atmosphere. The reaction mixture was stirred overnight at 70°C and monitored by thin layer chromatography until the disappearance of the starting materials. The resulting mixture was purified by silica gel column chromatography to obtain the title compound (R)-2-hydroxymethyl-morpholine-4-carboxylate acid tert-butyl ester 1d (0.428 g, yield 59percent) as a colorless oil. MS m/z (ESI): 240.3 [M+1]. 1H NMR (CDCl3, 400 MHz) δ 3.92-3.88 (m, 3H), 3.7-3.64 (m, 1H), 3.60-3.48 (m, 3H), 2.936 (m, 1H), 2.75 (m, 1H), 2.06 (m, 1H), 1.46 (s, 9H).
59% With hydrogen In ethanol at 70℃; (R)-2-Benzyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester 1c (1.02 g, 3.32 mmol) and 0.45 g of palladium on activated carbon were added to a reaction flask. The reaction flask was purged with hydrogen for three times. 10 mL of ethanol was added under hydrogen atmosphere. The reaction mixture was stirred overnight at 70° C. and monitored by thin layer chromatography until the disappearance of the starting materials. The resulting mixture was purified by silica gel column chromatography to obtain the title compound (R)-2-hydroxymethyl-morpholine-4-carboxylate acid tert-butyl ester 1d (0.428 g, yield 59percent) as a colorless oil.MS m/z (ESI): 240.3 [M+1].1H NMR (CDCl3, 400 MHz) δ 3.92-3.88 (m, 3H), 3.7-3.64 (m, 1H), 3.60-3.48 (m, 3H), 2.936 (m, 1H), 2.75 (m, 1H), 2.06 (m, 1H), 1.46 (s, 9H).

Reference: [1] Heterocycles, 1993, vol. 35, # 1, p. 105 - 109
[2] Patent: WO2016/91776, 2016, A1, . Location in patent: Page/Page column 290
[3] Patent: WO2008/124575, 2008, A1, . Location in patent: Page/Page column 112; 113-114
[4] Patent: US2010/184805, 2010, A1, . Location in patent: Page/Page column 30-31
[5] Patent: WO2007/70201, 2007, A1, . Location in patent: Page/Page column 176
[6] Patent: US2010/317697, 2010, A1, . Location in patent: Page/Page column 51
[7] Patent: WO2008/124582, 2008, A1, . Location in patent: Page/Page column 93-97
[8] Patent: WO2007/117560, 2007, A2, . Location in patent: Page/Page column 182; 189
[9] Patent: WO2007/117557, 2007, A2, . Location in patent: Page/Page column 79
[10] Patent: WO2007/6715, 2007, A1, . Location in patent: Page/Page column 28-29
[11] Patent: WO2007/6714, 2007, A1, . Location in patent: Page/Page column 120
[12] Patent: EP2189451, 2010, A1, . Location in patent: Page/Page column 10
[13] Patent: US2010/210640, 2010, A1, . Location in patent: Page/Page column 9
[14] Patent: EP411912, 1991, A2,
[15] Patent: WO2007/11292, 2007, A1, . Location in patent: Page/Page column 29-30
[16] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4836 - 4843
[17] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 757 - 770
  • 2
  • [ 24424-99-5 ]
  • [ 156925-22-3 ]
  • [ 135065-71-3 ]
YieldReaction ConditionsOperation in experiment
64% With triethylamine In dichloromethane at 20℃; for 16 h; Di-tert-butyl dicarbonate (0.558 g, 2.55 mmol) was added to a solution of (f?)-morpholin-2- ylmethanol (0.291 g, 2.48 mmol) and triethylamine (0.47 mL, 3.42 mmol) in dichloromethane (11 mL). The reaction mixture was stirred for 16 h at room temperature. The organic solution was washed with 2M HCI (10 mL), and the aqueous phase was extracted with dichloromethane (2 * 10 mL). The combined organic extracts were dried (MgSO4) and solvent was removed in vacuo. The crude product was purified by flash column chromatography on silica gel, eluting with ethyl acetate / hexane (1 / 1). to give the title compound as a colourless oil (0.360 g, 64percent). <n="266"/>1H NMR (CDCI3, 500 MHz) δ 3.91-3.86 (m, 3H), 3.68-3.65 (m, 1H), 3.59-3.49 (m, 3H), 2.95-2.93 (m, 1 H), 2.77-2.75 (m, 2H), 2.10 (s, 1 H), 1.46 (s, 9H).
Reference: [1] Patent: WO2009/44162, 2009, A1, . Location in patent: Page/Page column 263-264
[2] Patent: WO2007/6715, 2007, A1, . Location in patent: Page/Page column 32
[3] Tetrahedron, 2010, vol. 66, # 11, p. 2010 - 2014
  • 3
  • [ 929278-92-2 ]
  • [ 24424-99-5 ]
  • [ 135065-71-3 ]
YieldReaction ConditionsOperation in experiment
82%
Stage #1: With naphthalene; sodium In tetrahydrofuran at 0℃; for 0.0833333 h;
Stage #2: With hydrogenchloride In tetrahydrofuran; water
Stage #3: With sodium hydroxide; sodium hydrogencarbonate In 1,4-dioxane; water at 20℃;
Sodium metal (2.78 g, 121 mmol) was placed in a flask with naphthalene (17.0 g, 133 mmol) in tetrahydrofuran (140 ml_) and sonicated for 2.5 h to give a dark green solution. In a separate flask {(2/t)-4-[(4-methylphenyl)sulfonyl]- 2-morpholinyl}methanol (1.64 g, 6.04 mmol) was dissolved in tetrahydrofuran (40 ml_) and cooled to 0 2C. 20 ml_ of the sodium naphthalenide solution was added slowly ι//a syringe, and the reaction was checked by TLC. An additional 5 ml_ of the sodium naphthalenide solution was added slowly via syringe. The reaction was stirred for 5 min and quenched by the addition of 2 N aqueous hydrochloric acid solution (~150 mL). The mixture was poured into a separatory funnel and extracted with diethyl ether (2x). The diethyl ether layers were discarded. The aqueous layer was basified with solid sodium hydroxide and extracted with dichloromethane, 4:1 dichloromethane:isopropanol, and 4:1 ethyl acetate:isopropanol. These combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Very little material was obtained and was thus discarded. To the aqueous layer was added 100 mL of dioxane and butyl dicarbonate (1.32 g, 6.05 mmol). The addition of three large scoops of solid sodium bicarbonate and additional di-te/?-butyl dicarbonate (1.32 g, 6.05 mmol) was followed by one large scoop of solid sodium hydroxide. The mixture was stirred overnight, and the majority of the dioxane was removed in vacuo. The aqueous layer was extracted with dichloromethane (2x) and ethyl acetate (1x). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography provided 1.07 g (82percent) of the title compound. 1H NMR (400 MHz, CDCI3): δ 3.96-3.75 (m, 3H), 3.66 (dd, 1 H, J= 3.4, 11.4 Hz), 3.60-3.43 (m, 3H), 2.92 (m, 1H), 2.74 (m, 1H), 1.45 (s, 9H).
Reference: [1] Patent: WO2007/30366, 2007, A1, . Location in patent: Page/Page column 107
[2] Patent: WO2008/157330, 2008, A1, . Location in patent: Page/Page column 100-101
  • 4
  • [ 98-59-9 ]
  • [ 135065-64-4 ]
  • [ 135065-71-3 ]
YieldReaction ConditionsOperation in experiment
77% With dmap; triethylamine In dichloromethane at 20℃; for 2 h; A mixture of the (R) -tert-butyl 2- (hydroxymethyl) morpholine-4-carboxylate (2.0 g, 9.21 mmol) , DMAP (114 mg, 0.92 mmol) , Tosyl chloride (TsCl, 1.93 g, 10.13 mmol) and Et3N (2.65 mL, 18.42 mmol) in DCM (20 mL) was stirred at rt for 2 h. The resulting solution was washed by water, extracted with DCM (10 mL x 3) . The combined organic layer was washed by brine, dried over anhydrous sodium sulfate then concentrated and purified by silica gel column chromatography eluting with PE: EA2: 1 to get the desired product (2.62g, 77) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.80 (d, J8.4 Hz, 2H) , 7.35 (d, J8.4 Hz, 2H) , 4.10–3.94 (m, 2H) , 3.94–3.72 (m, 3H) , 3.65-3.55 (m, 1H) , 3.53–3.38 (m, 1H) , 3.01–2.80 (m, 1H) , 2.69-2.61 (m, 1H) , 2.45 (s, 3H) , 1.45 (s, 9H) ppm. MS: M/e 372 (M+1)+
Reference: [1] Patent: WO2016/8411, 2016, A1, . Location in patent: Paragraph 0246
  • 5
  • [ 884512-77-0 ]
  • [ 135065-71-3 ]
Reference: [1] Patent: WO2008/121685, 2008, A1, . Location in patent: Page/Page column 39-40
  • 6
  • [ 135065-70-2 ]
  • [ 135065-71-3 ]
Reference: [1] Heterocycles, 1993, vol. 35, # 1, p. 105 - 109
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4836 - 4843
[3] Patent: WO2016/91776, 2016, A1,
[4] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 757 - 770
[5] Patent: WO2007/117560, 2007, A2,
[6] Patent: WO2007/117557, 2007, A2,
[7] Patent: WO2008/124582, 2008, A1,
  • 7
  • [ 24424-99-5 ]
  • [ 135065-71-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4836 - 4843
[2] Patent: WO2007/117560, 2007, A2,
  • 8
  • [ 929278-86-4 ]
  • [ 135065-71-3 ]
Reference: [1] Patent: WO2008/157330, 2008, A1,
  • 9
  • [ 929278-88-6 ]
  • [ 135065-71-3 ]
Reference: [1] Patent: WO2008/157330, 2008, A1,
  • 10
  • [ 929278-90-0 ]
  • [ 135065-71-3 ]
Reference: [1] Patent: WO2008/157330, 2008, A1,
  • 11
  • [ 919286-65-0 ]
  • [ 135065-71-3 ]
Reference: [1] Patent: WO2009/44162, 2009, A1,
  • 12
  • [ 919286-64-9 ]
  • [ 135065-71-3 ]
Reference: [1] Patent: WO2009/44162, 2009, A1,
  • 13
  • [ 135065-71-3 ]
  • [ 884512-77-0 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With sodium hydrogencarbonate In water; acetone at 0℃;
Stage #2: With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium bromide In water; acetone at 0℃;
Satd aq NaHCO3 ( 15 niL) was added to a solution of (R)-tert-butyl 2-(hydroxymethyl)-morpholine-4-carboxylate (1.09 g, 5.0 mmol) in acetone (50 mL), stirred and maintained at O0C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g, 10.0 mmol) was then added slowly within 20 min at O0C. After addition, the mixture was warmed to rt and stirred overnight. 2-Propanol (3 mL) was added, and the resulting solution was stirred at rt for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with satd aq Na2CO3 (15 mL). The aqueous solution was washed with EtOAc (5 mL), acidified with 6 N HCl, and extracted with EtOAc (5 x 10 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed to give (R)-4-(tert- butoxycarbonyl)morpholine-2-carboxylic acid (1.07 g, 92 percent) as a white solid. 1H NMR (400MHz, CDCl3): 4.20 (br, 1 H), 4.12 (d, 1 H), 4.02 (d, 1 H), 3.84 (m, 1 H), 3.62 (m, 1 H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 232 (M+H+).
92%
Stage #1: With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide In water; acetone at 0 - 20℃;
Stage #2: With hydrogenchloride In water; ethyl acetate
Step 4.
(R)-4-(tert-Butoxycarbonyl)morpholine-2-carboxylic acid
Satd aq NaHCO3 (15 mL) was added to a solution of (R)-tert-butyl 2-(hydroxymethyl)-morpholine-4-carboxylate (1.09 g, 5.0 mmol) in acetone (50 mL), and stirred at 0° C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added.
Trichloroisocyanuric acid (2.32 g, 10.0 mmol) was then added slowly over 20 min at 0° C.
After addition, the mixture was warmed to rt and stirred overnight. 2-Propanol (3 mL) was added and the resulting solution was stirred at rt for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with satd aq Na2CO3 (15 mL).
The aqueous solution was washed with EtOAc (5 mL), acidified with 6 N HCl, and extracted with EtOAc (5*10 mL).
These EtOAc extracts were combined, dried over Na2SO4 and concentrated to give (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.07 g, 92percent) as a white solid. 1H NMR (400 MHz, CDCl3): δ=4.20 (br, 1H), 4.12 (d, 1H), 4.02 (d, 1H), 3.84 (m, 1H), 3.62 (m, 1H), 3.04 (m, 2H), 1.44 (s, 9H); MS m/z 232 (M+H+).
92% With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide In water; acetone at 0 - 20℃; Sat'd aq NaHCO3 (15 mL) was added to a solution of (R)-tert-buty\\ 2- (hydroxymethyl)-morpholine-4-carboxylate (1.09 g, 5.0 mmol) in acetone (50 mL), <n="178"/>stirred and maintained at O°C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g, 10.0 mmol) was then added slowly within 20 min at O°C. After addition the mixture was warmed to rt and stirred overnight. 2-Propanol (3 mL) was added, and the resulting solution was stirred at rt for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with sat'd aq Na2CO3 (15 mL). The aqueous solution was washed with EtOAc (5 mL), acidified with 6 N HCl, and extracted with EtOAc (5 x 10 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed to give (R)-4-(tert- butoxycarbonyl)morpholine-2-carboxylic acid (1.07 g, 92 percent) as a white solid. 1H NMR (400MHz, CDCl3): 4.20 (br, 1 H), 4.12 (d, 1 H), 4.02 (d, 1 H), 3.84 (m, 1 H), 3.62 (m, 1 H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 232 (M+H*).
92%
Stage #1: With sodium hydrogencarbonate In acetone at 0℃;
Stage #2: With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium bromide In acetone at 0 - 20℃;
Satd aq NaHCO3 (15 mL) was added to a solution of (R)-tert-butyl 2-(hydroxymethyl)-morpholine-4-carboxylate (1.09 g, 5.0 mmol) in acetone (50 mL), stirred and maintained at 0° C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g, 10.0 mmol) was then added slowly within 20 min at 0° C. After addition, the mixture was warmed to rt and stirred overnight. 2-Propanol (3 mL) was added, and the resulting solution was stirred at rt for 30 min, filtered through a pad of Celite.(R)., concentrated under vacuum, and treated with satd aq Na2CO3 (15 mL). The aqueous solution was washed with EtOAc (5 mL), acidified with 6 N HCl, and extracted with EtOAc (5.x.10 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed to give (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.07 g, 92percent) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.20 (br, 1H), 4.12 (d, 1H), 4.02 (d, 1H), 3.84 (m, 1H), 3.62 (m, 1H), 3.04 (m, 2H), 1.44 (s, 9H); MS m/z 232 (M+H+).
92% With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide In water; acetone at 0 - 20℃; Step 4. (i?)-4-(tert-Butoxycarbonyl)morpholine-2-carboxylic acid: Satd aq NaHCO3 (15 mL) was added to a solution of (R)-tert-buty\\ 2-(hydroxymethyl)- morpholine-4-carboxylate (1.09 g, 5.0 mmol) in acetone (50 mL), stirred and maintained at O0C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g, 10.0 mmol) was then added slowly within 20 min at O0C. After addition, the mixture was warmed to rt and stirred overnight. 2-Propanol (3 mL) was added, and the resulting solution was stirred at rt for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with satd aq Na2CO3 (15 mL). The aqueous solution was washed with EtOAc (5 mL), acidified with 6 N HCl, and extracted with EtOAc (5 x 10 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed to give (R)-4-(tert- butoxycarbonyl)morpholine-2-carboxylic acid (1.07 g, 92 percent) as a white solid. 1H <n="99"/>NMR (400MHz, CDCl3): 4.20 (br, 1 H), 4.12 (d, 1 H), 4.02 (d, 1 H), 3.84 (m, 1 H), 3.62 (m, 1 H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 232 (M+H+).
92%
Stage #1: With sodium hydrogencarbonate In water; acetone at 0℃;
Stage #2: With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium bromide In water; acetone at 0 - 20℃; for 0.333333 h;
Satd aq NaHCO3 ( 15 mL) was added to a solution of (R)-/er/-butyl 2-(hydroxymethyl)-rnorphoIine-4-carboxylate (1.09 g, 5.0 mmol) in acetone (50 mL), stirred and maintained at O0C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g3 10.0 mmol) was then <n="184"/>added slowly within 20 min at O0C. After addition the mixture was warmed to rt and stirred overnight. 2-Propanol (3 mL) was added, and the resulting solution was stirred at rt for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with satd aq Na2CO3 (15 mL). The aqueous solution was washed with EtOAc (5 mL), acidified with 6 N HCl, and extracted with EtOAc (5 x 10 mL). These EtOAc extracts were combined, dried over Na2SO4 and concentrated to give (R)-4-(/e/7-butoxycarbonyl)morpholine-2-carboxylic acid (1.07 g, 92 percent) as a white solid. 1H NMR (400MHz, CDCl3): 4.20 (br, 1 H), 4.12 (d, 1 H), 4.02 (d, 1 H), 3.84 (m, 1 H), 3.62 (m, 1 H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 232 (M+H+).
92%
Stage #1: With 2,2,6,6-tetramethyl-piperidine-N-oxyl; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide In water; acetone at 0 - 20℃;
Stage #2: at 20℃; for 0.5 h;
Step 4. (R)-4-(tert-Butoxycarbonyl)morpholine-2-carboxylic acid. Satd aq NaHCO3 (15 mL) was added to a solution of (R)-tert-buty\\ 2-(hydroxymethyl)-morpholine-4-carboxylate (1.09 g, 5,0 mmol) in acetone (50 mL), stirred and maintained at O0C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g, 10.0 mmol) was then added slowly within 20 min at O0C. After addition the mixture was warmed to rt and stirred overnight. 2-Propanol (3 mL) was added, and the resulting solution was stirred at rt for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with satd aq Na2CO3 (15 mL). The aqueous solution was washed with EtOAc (5 mL), acidified with 6 N HCl, and extracted with EtOAc (5 x 10 mL). These EtOAc extracts were combined, dried over Na2SO4 and concentrated to give (R)-4-(ter/-butoxycarbonyl)morpholine-2-carboxylic acid (1.07 g, 92 percent) as a white solid. 1U NMR (400MHz, CDCl3): 4.20 (br, 1 H)5 4.12 (d5 1 H), 4.02 (d, 1 H), 3.84 (m, 1 H), 3.62 (m, l H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 232 (M+H+).

Reference: [1] Patent: WO2008/124575, 2008, A1, . Location in patent: Page/Page column 112; 114
[2] Patent: US2010/184805, 2010, A1, . Location in patent: Page/Page column 30-31
[3] Patent: WO2007/70201, 2007, A1, . Location in patent: Page/Page column 176-177
[4] Patent: US2010/317697, 2010, A1, . Location in patent: Page/Page column 51
[5] Patent: WO2008/124582, 2008, A1, . Location in patent: Page/Page column 96-98
[6] Patent: WO2007/117560, 2007, A2, . Location in patent: Page/Page column 182-183; 189-190
[7] Patent: WO2007/117557, 2007, A2, . Location in patent: Page/Page column 79-80
[8] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4836 - 4843
  • 14
  • [ 135065-71-3 ]
  • [ 879403-42-6 ]
Reference: [1] Patent: WO2011/62550, 2011, A1,
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