[ CAS No. 884512-77-0 ] {[proInfo.proName]}

Name: 884512-77-0|(R)-4-(tert-Butoxycarbonyl)morpholine-2-carboxylic acid|95%
Brand: Ambeed
SKU: A140815
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Quality Control of [ 884512-77-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 884512-77-0 ]

SDS Specification

Alternatived Products of [ 884512-77-0 ]

Product Details of [ 884512-77-0 ]

CAS No. :	884512-77-0	MDL No. :	MFCD09260604
Formula :	C₁₀H₁₇NO₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LGWMTRPJZFEWCX-SSDOTTSWSA-N
M.W :	231.25	Pubchem ID :	6559076
Synonyms :

Calculated chemistry of [ 884512-77-0 ] Expand+

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 Å²

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) :	1.93
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 :	0.49

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 [ 884512-77-0 ]

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 [ 884512-77-0 ]

* 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 [ 884512-77-0 ]
Downstream synthetic route of [ 884512-77-0 ]

[ 884512-77-0 ] Synthesis Path-Upstream 1~6

1
[ 884512-77-0 ]
[ 135065-71-3 ]

Reference： [1] Patent: WO2008/121685, 2008, A1, . Location in patent: Page/Page column 39-40

2
[ 135065-71-3 ]
[ 884512-77-0 ]

Yield	Reaction Conditions	Operation 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 Na₂SO₄and 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

3
[ 941710-15-2 ]
[ 884512-77-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	Stage #1: With lithium hydroxide; water In 1,4-dioxane at 20℃; for 3 h; Stage #2: With hydrogenchloride In water; ethyl acetate	A mixture of 10 g of (-)-(2J?)-2,4-morpholinedicarboxylic acid, 4-(l,l-dimethylethyl) 2-ethyl ester, 150 mL of dioxane, 40 mL of water and 6.8 g of lithium hydroxide monohydrate was stirred at room temperature for 3 hrs then under reduced pressure. The rersidue was partitioned between 3 x 50 mL of ethyl acetate and 200 mL of ice cold IN hydrochloric acid. The extracts were dried over magnesium <n="29"/>sulfate and concentrated under reduced pressure. Drying under vacuum gave the product as a white solid (96percent): [α]_D^{25 °c}= -44.7 ° (c = 1.0, MeOH); IH NMR (400 MHz, CDC13) 4.08 (d, IH), 4.0 (d, IH)₅ 3.8 (d, IH), 3.6 (t, IH), 3.08 (t, 2H), 2.95 (d, IH), 1.45 (s, 9H).

Reference： [1] Patent: WO2007/67511, 2007, A2, . Location in patent: Page/Page column 28-29

4
[ 135065-70-2 ]
[ 884512-77-0 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4836 - 4843
[2] Patent: WO2007/117560, 2007, A2,
[3] Patent: WO2007/117557, 2007, A2,
[4] Patent: WO2008/124582, 2008, A1,

5
[ 135097-68-6 ]
[ 884512-77-0 ]

6
[ 24424-99-5 ]
[ 884512-77-0 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4836 - 4843
[2] Patent: WO2007/117560, 2007, A2,

[ 884512-77-0 ] Synthesis Path-Downstream 1~109

1
[ 884512-77-0 ]
[ 6638-79-5 ]
[ 952593-44-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	To a solution of (i?)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid(1.05 g, 4.54 mmol) in DMF (10 mL) at O0C, was added DIEA (3.9 mL, 22.7 mmol), followed by HBTU (1.89 g, 4.99 mmol) and HOBt (0.67 g, 4.99 mmol).MeONHMeetaCl (0.48 g, 4.92 mmol) was added and the resulting solution was warmed to rt and stirred until no starting material remained (~ 2 h). The mixture was diluted with H2O (10 mL) and extracted with EtOAc (4 x 10 mL). The combined organic layers were washed with 1 N aq HCl (10 mL), 1 N aq NaOH (3 x 10 mL), water (2 x 10 mL) and brine (10 mL), and dried over Na2SO4. The solvent was removed under vacuum to give {R)-tert-hvXy 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.40 g, quant.), which was used without further purification. 1U NMR (400MHz, CDCl3): 4.36 (br, 1 H), 4.08(m, 1 H), 4.00 (d, 1 H), 3.84 (m, 1 H), 3.76 (s, 3 H), 3.58 (m, 1 H), 3.20 (s, 3 H), 3.04(m, 2 H), 1.44 (s, 9 H); MS m/z 297 (M+Na+).
100%	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	Step 5. (R)-tert-Butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate To a solution of <strong>[884512-77-0](R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid</strong> (1.05 g, 4.54 mmol) in DMF (10 mL) at 0 C. were added N,O-dimethylhydroxylamine hydrochloride (1.36 g, 13.62 mmol), DIEA (3.9 mL, 22.7 mmol), HBTU (1.89 g, 4.99 mmol) and HOBt (0.67 g, 4.99 mmol). The resulting solution was warmed to rt and stirred until no starting material remained (~2 h). The mixture was diluted with H2O (10 mL) and extracted with EtOAc (410 mL). The combined organic layers were washed with 1 N aq HCl (10 mL), 1 N aq NaOH (310 mL), water (2*10 mL) and brine (10 mL), and dried over Na2SO4. The solvent was removed under vacuum to give (R)-t-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.40 g, quant.), which was used for the next step without further purification; 1H NMR (400 MHz, CDCl3) delta: 4.36 (br, 1H), 4.08 (m, 1H), 4.00 (d, 1H), 3.84 (m, 1H), 3.76 (s, 3H), 3.58 (m, 1H), 3.20 (s, 3H), 3.04 (m, 2H), 1.44 (s, 9H); MS m/z 297 (M+Na+).
100%	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃;	To a solution of <strong>[884512-77-0](R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid</strong> (1.05 g, 4.54 mmol) in DMF (10 mL) at 0 C., was added DIEA (3.9 mL, 22.7 mmol), followed by HBTU (1.89 g, 4.99 mmol) and HOBt (0.67 g, 4.99 mmol). MeONMHMe.HCl (0.48 g, 4.92 mmol) was added and the resulting solution was warmed to rt and stirred until no starting material remained (2 h). The mixture was diluted with H2O (10 mL) and extracted with EtOAc (4×10 mL). The combined organic layers were washed with 1 N aq HCl (10 mL), 1 N aq NaOH (3×10 mL), water (2×10 mL) and brine (10 mL), and dried over Na2SO4. The solvent was removed under vacuum to give (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.40 g, quant.), which was used without further purification. 1H NMR (400 MHz, CDCl3) delta ppm 4.36 (br, 1H), 4.08 (m, 1H), 4.00 (d, 1H), 3.84 (m, 1H), 3.76 (s, 3H), 3.58 (m, 1H), 3.20 (s, 3H), 3.04 (m, 2H), 1.44 (s, 9H); MS m/z 297 (M+Na+).

100%	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃;	Step 5. (R)-tert-Buty 2-(methoxy(methyl)carbamoyl)morpholine-4- carboxylate: To a solution of (i?)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.05 g, 4.54 mmol) in DMF (10 mL) at O0C C, was added DIEA (3.9 niL, 22.7 mmol), followed by HBTU (1.89 g, 4.99 mmol) and HOBt (0.67 g, 4.99 mmol). MeONHMeetaCl (0.48 g, 4.92 mmol) was added and the resulting solution was warmed to rt and stirred until no starting material remained (~ 2 h). The mixture was diluted with H2O (10 mL) and extracted with EtOAc (4 x 10 mL). The combined organic layers were washed with 1 N aq HCl (10 mL), 1 N aq NaOH (3 x 10 mL), water (2 x 10 mL) and brine (10 mL), and dried over Na2SO4. The solvent was removed under vacuum to give (R)-tert-buty 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.40 g, quant.), which was used without further purification. 1U NMR (400MHz, CDCl3): 4.36 (br, 1 H), 4.08 (m, 1 H), 4.00 (d, 1 H), 3.84 (m, 1 H), 3.76 (s, 3 H), 3.58 (m, 1 H), 3.20 (s, 3 H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 297 (M+Na+).
100%	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	To a solution of (R)-4-(/er/-butoxycarbonyl)morpholine-2-carboxylic acid (1.05 g, 4.54 mmol) in DMF (10 mL) at O0C were added N,O- dimethylhydroxylamine hydrochloride (1.36 g, 13.62 mmol), DIEA (3.9 mL, 22.7 mmol), HBTU (1.89 g, 4.99 mmol) and HOBt (0.67 g, 4.99 mmol). The resulting solution was warmed to rt and stirred until no starting material remained (~ 2 h). The mixture was diluted with H2O (10 mL) and extracted with EtOAc (4 x 10 mL). The combined organic layers weie washed with 1 N aq HCl (10 mL), 1 N aq NaOH (3 x 10 mL), water (2 x 10 mL) and brine (10 mL), and dried over Na2SO4. The solvent was removed under vacuum to give (R)-/-butyl 2-(methoxy(methyl)carbamoyl)morphoIine-4-carboxyIate (1.40 g, quant.), which was used for the next step without further purification; 1H NMR (400MHz, CDCl3) delta: 4.36 (br, 1 H), 4.08 (m, 1 H), 4.00 (d, 1 H), 3.84 (m, 1 H), 3.76 (s, 3 H), 3.58 (m, 1 H), 3.20 (s, 3 H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 297 (M+Na+).
100%	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	Step 5. (R)-tert-Butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate. To a solution of <strong>[884512-77-0](R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid</strong> (1.05 g, 4.54 mmol) in DMF (10 mL) at O0C were added N,O- dimethylhydroxylamine hydrochloride (1.36 g, 13.62 mmol), DIEA (3.9 mL, 22.7 mmol), HBTU (1.89 g, 4.99 mmol) and HOBt (0.67 g, 4.99 mmol). The resulting solution was warmed to rt and stirred until no starting material remained (~ 2 h). The mixture was diluted with H2O (10 mL) and extracted with EtOAc (4 x 10 mL). The combined organic layers were washed with 1 N aq HCl (10 mL), 1 N aq NaOH (3 x 10 mL), water (2 x 10 mL) and brine (10 mL), and dried over Na2SO4. The solvent was removed under vacuum to give (R)-t~butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.40 g, quant.), which was used for the next step without further purification; 1H NMR (400MHz, CDCl3) delta: 4.36 (br, 1 H), 4.08 (m, 1 H), 4.00 (d, 1 H), 3.84 (m, 1 H), 3.76 (s, 3 H), 3.58 (m, 1 H), 3.20 (s, 3 H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 297 (M+Na+).
1150 mg	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h;	Step 1 : (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate To a 25 ml one necked round bottom flask was charged with N,0 - dimethylhydroxylamine hydrochloride (633 mg, 6.49 mmol), CH2CI2 (10 ml), Hunig'sBase (996 mg, 8.65 mmol) and <strong>[884512-77-0](R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid</strong> (1000 mg, 4.32 mmol). The mixture was stirred and then propylphosphoric cyclic anhydride (4128 mg, 12.97 mmol) was added. The resulting reaction mixture was then stirred at room temperature for 18 hrs overnight. The reaction was quenched by addition of water (3 mL) and stirred at room temperature for 10 min. Then the mixture was partitioned between NaHCC (sat, 30 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer was extracted by ethyl acetate (2x 50 ML). The combined organic phases were washed with water (30 ML), brine, dried over MgS04, filtered and concentrated. The crude was purified by MPLC (40 g silica gel, 30 to 100% ethyl acetate in hexanes 18 CV) to afford a colorless stick oil as the Title product (1 150 mg). LC-MS (275.19).

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: US2010/317697,2010,A1 .Location in patent: Page/Page column 51-52
[4]Patent: WO2008/124582,2008,A1 .Location in patent: Page/Page column 96; 98
[5]Patent: WO2007/117560,2007,A2 .Location in patent: Page/Page column 183; 190
[6]Patent: WO2007/117557,2007,A2 .Location in patent: Page/Page column 80
[7]Patent: WO2015/95102,2015,A1 .Location in patent: Page/Page column 51

2
[ 941710-13-0 ]
[ 884512-77-0 ]
C₂₄H₃₆N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane;	A mixture of 5.6 g of N-(3,4-dihydro-2eta-l,5-be?zodioxepin-7-ylmethyl)-2-methyIpropan-l- amine, 5.0 g of (-)-(2i?)-4-(^er/-butoxycarbonyl)morphoIine-2-carboxylic acid, 0.8 g of 1- hydroxybenzotriazole hydrate and 5 g of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 3 mL of triethylamine in 100 mL in dichloromethane was stirred overnight. The mixture was concentrated under reduced pressure and partitioned between 100 mL of ethyl acetate and 100 mL of saturated sodium carbonate, dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography (20%-50% ethyl acetate/hexanes gradient elution) gave the product as a resin: MS (m+1) = 449.3; H NMR (400 MHz, CDC13) 7.3-6.7 (complex m, 5H), 4.6 (br d, IH), 6.8-6.7 (m, 2H), 4.4 (d, IH), 4.2 (m, 4H), 4.15 (q, IH), 4.08 (br d, IH), 3.95 (m, IH)3 3.5 (m, IH), 3.2 (m, IH), 3.0 (dd, IH), 2.2 (m, IH), 2.0 (m, IH.) 1.45 (2xs, 9H), 0.9 (dd, 6H).

Reference： [1]Patent: WO2007/67511,2007,A2 .Location in patent: Page/Page column 28

3
[ 941710-15-2 ]
[ 884512-77-0 ]

Yield	Reaction Conditions	Operation in experiment
96%		A mixture of 10 g of (-)-(2J?)-2,4-morpholinedicarboxylic acid, 4-(l,l-dimethylethyl) 2-ethyl ester, 150 mL of dioxane, 40 mL of water and 6.8 g of lithium hydroxide monohydrate was stirred at room temperature for 3 hrs then under reduced pressure. The rersidue was partitioned between 3 x 50 mL of ethyl acetate and 200 mL of ice cold IN hydrochloric acid. The extracts were dried over magnesium <n="29"/>sulfate and concentrated under reduced pressure. Drying under vacuum gave the product as a white solid (96%): [alpha]D25 c= -44.7 (c = 1.0, MeOH); IH NMR (400 MHz, CDC13) 4.08 (d, IH), 4.0 (d, IH)5 3.8 (d, IH), 3.6 (t, IH), 3.08 (t, 2H), 2.95 (d, IH), 1.45 (s, 9H).

Reference： [1]Patent: WO2007/67511,2007,A2 .Location in patent: Page/Page column 28-29

4
[ 884512-77-0 ]
[ 1117-97-1 ]
[ 952593-44-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843
[2]Tetrahedron Letters,2009,vol. 50,p. 389 - 391

5
[ 884512-77-0 ]
[ 952593-49-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843
[2]Patent: WO2008/124582,2008,A1

6
[ 884512-77-0 ]
C₂₈H₃₈ClNO₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843

7
[ 884512-77-0 ]
C₂₉H₄₀FNO₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843

8
[ 884512-77-0 ]
C₂₉H₄₀ClNO₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843

9
[ 884512-77-0 ]
C₃₀H₄₂ClNO₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843

10
[ 884512-77-0 ]
C₂₈H₃₈ClNO₅S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843

11
[ 884512-77-0 ]
C₃₄H₄₇FN₂O₇ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843

12
[ 884512-77-0 ]
C₃₄H₄₇ClN₂O₇ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843

13
[ 884512-77-0 ]
((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((R)-2-((R)-1-(6-fluoro-3'-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843

14
[ 884512-77-0 ]
((1S,3R,4S)-3-amino-4-hydroxycyclopentyl)((R)-2-((R)-1-(6-chloro-3'-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)morpholino)methanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843

15
[ 884512-77-0 ]
[ 952593-45-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843
[2]Patent: WO2007/117560,2007,A2
[3]Patent: WO2007/117557,2007,A2
[4]Patent: WO2008/124582,2008,A1

16
[ 884512-77-0 ]
(R)-1-(6-fluoro-3'-methylbiphenyl-2-yl)-5-methoxy-1-((R)-morpholin-2-yl)-pentan-1-ol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843
[2]Patent: WO2008/124582,2008,A1

17
[ 884512-77-0 ]
[ 1219939-39-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843

18
[ 884512-77-0 ]
[ 1219939-61-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843

19
[ 884512-77-0 ]
[ 1070871-60-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843

20
[ 884512-77-0 ]
[ 1219939-79-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843

21
[ 884512-77-0 ]
[ 1219939-87-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843

22
C₁₂H₁₉NO₆S [ No CAS ]
[ 884512-77-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843
[2]Patent: WO2007/117560,2007,A2

23
[ 24424-99-5 ]
[ 884512-77-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843
[2]Patent: WO2007/117560,2007,A2

24
[ 135065-70-2 ]
[ 884512-77-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843
[2]Patent: WO2007/117560,2007,A2
[3]Patent: WO2007/117557,2007,A2
[4]Patent: WO2008/124582,2008,A1

25
[ 135097-68-6 ]
[ 884512-77-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843
[2]Patent: WO2007/117560,2007,A2
[3]Patent: WO2007/117557,2007,A2
[4]Patent: WO2008/124582,2008,A1

26
[ 884512-77-0 ]
[ 952593-27-0 ]