[ CAS No. 769087-80-1 ] {[proInfo.proName]}

Name: 769087-80-1|4-Benzylmorpholine-2-carboxylic acid|98%
Brand: Ambeed
SKU: A984260
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Quality Control of [ 769087-80-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 769087-80-1 ]

Product Details of [ 769087-80-1 ]

CAS No. :	769087-80-1	MDL No. :	MFCD06410628
Formula :	C₁₂H₁₅NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UJDWIUOGWSDEFP-UHFFFAOYSA-N
M.W :	221.25	Pubchem ID :	2776353
Synonyms :

Safety of [ 769087-80-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P264-P271-P280-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P362-P403+P233-P405-P501	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 769087-80-1 ]

* 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 [ 769087-80-1 ]
Downstream synthetic route of [ 769087-80-1 ]

[ 769087-80-1 ] Synthesis Path-Upstream 1~3

1
[ 769087-80-1 ]
[ 40987-24-4 ]

Reference： [1] Patent: US2010/63022, 2010, A1, . Location in patent: Page/Page column 29

2
[ 147767-51-9 ]
[ 769087-80-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrogenchloride; water In toluene at 20 - 110℃; Inert atmosphere	Step B. 4-Benzylmorpholine-2-carboxylic acid. To a solution of 4- benzylmorpholine-2-carbonitrile (20.2 g, 100 mmol) in toluene (60 mL) was added 6M HC1 (100 mL, 600 mmol). The reaction mixture was ref uxed at 110 C for 1.5 h and then cooled to rt and stirred for 18 h. The solid was filtered to give the title compound (22 g, 99percent) as a white solid.

Reference： [1] Patent: WO2015/164508, 2015, A1, . Location in patent: Page/Page column 48-49
[2] Patent: WO2011/58478, 2011, A1, . Location in patent: Page/Page column 54-55

3
[ 104-63-2 ]
[ 769087-80-1 ]

Reference： [1] Patent: WO2015/164508, 2015, A1,

[ 769087-80-1 ] Synthesis Path-Downstream 1~19

1
[ 769087-80-1 ]
[ 40987-24-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 32A(4-benzylmorpholin-2-yl)methanolTo a solution of 4-benzylmorpholine-2-carboxylic acid (5 g, 22.6 mmol) and triethylamine (3.35 mL, 24 mmol) in THF (100 mL) at -10 C. in a flask equipped with a condenser was added ethyl carbonochloridate (2.5 g, 23 mmol) dropwise and the mixture was stirred at -10 C. to -5 C. for 20 min. Sodium borohydride (2.27 g, 60 mmol) was added followed by methanol (25 mL) from the top of the condenser at such rate to maintain the temperature between 0-5 C. The reaction mixture was allowed to warm to room temperature, acidified to pH 5 with the addition of 10% aqueous citric acid, and concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with water, brine, and dried with MgSO4. Purification of the residue by column chromatography (SiO2, eluted with EtOAc) afforded 3 g of the title compound. MS (DCI/NH3) m/z 208 (M+H)+.

Reference： [1]Patent: US2010/63022,2010,A1 .Location in patent: Page/Page column 29

2
[ 769087-80-1 ]
[ 613-89-8 ]
[ 1227912-01-7 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 167; Lambda/-(2-Oxo-2-phenylethyl)-4-(phenylmethyl)-2-morpholinecarboxamide; Oxalyl chloride (1.187 ml_, 13.56 mmol) was added to a suspension of 4-(phenylmethyl)- 2-morpholinecarboxylic acid (2.0 g, 9.04 mmol) in CH2CI2 (70 ml.) at 0 0C in 10 minutes, and the resulting mixture was stirred at 25 0C for 2 hours. The mixture was concentrated, and the resulting residue was treated with CH2CI2 (70 ml_), triethylamine (2.77 ml_, 19.89 mmol) and 2-amino-1-phenylethanone (1.551 g, 9.04 mmol) at 0 0C. The reaction mixture was stirred at 25 0C for 3 hours. Water (150 ml.) was added, and the resulting aqueous mixture was extracted with EtOAc (3 x 80 ml_). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography to afford the title compound (1.0 g) as a brown solid. LC-MS (ES) m/z = 339 [M+H]+.

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 232

3
[ 769087-80-1 ]
2-amino-1-(3-chloro-phenyl)-ethanone [ No CAS ]
[ 1227912-07-3 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 173; Lambda/-r2-(3-Chlorophenyl)-2-oxoethyll-4-(phenylmethyl)-2-morpholinecarboxamide; Oxalyl chloride (1.32 ml_, 15.03 mmol) was added to the suspension of 4-(phenylmethyl)- 2-morpholinecarboxylic acid (2.218 g, 10.02 mmol) and DMF (0.155 ml_, 2.005 mmol) in CH2CI2 (100 ml.) at 0 0C in 10 minutes, and the resulting mixture was stirred at 25 0C for 2 hours. The mixture was concentrated, and the resulting residue was dissolved in CH2CI2 (100 ml.) and triethylamine (3.07 ml_, 22.05 mmol). 2-Amino-1-(3-chlorophenyl)ethanone (1.7 g, 10.02 mmol) was added to the brown solution at 0 0C, and the reaction mixture was stirred at 25 0C for 3 hours. Water (150 ml.) was added to the reaction mixture, and the aqueous mixture was extracted with EtOAc (3 x 100 ml_). The combined organic layers were dried (Na2SO4), filtered, and evaporated. The resulting residue was purified by silica gel chromatography using as eluent 50% EtOAc in petroleum ether to afford the title compound (800 mg) as a pale yellow solid. LC-MS (ES) m/z = 373 [M+H]+.

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 235-236

4
[ 769087-80-1 ]
[ 931-15-7 ]
[ 1227911-94-5 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 159; Lambda/-r(1R2/?)-2-Hvdroxycvclohexyll-4-(phenylmethyl)-2-morpholinecarboxamide; To a mixture of <strong>[769087-80-1]4-(phenylmethyl)-2-morpholinecarboxylic acid</strong> (5 g, 22.60 mmol) and DMF (0.1 mL) in CH2CI2 (113 mL) was added oxalyl chloride (2.97 mL, 33.9 mmol) at 25 0C.The mixture was stirred at this temperature for 1 hour and the mixture turned clear. The solvent and excess of oxalyl chloride were removed in vacuo, and the resulting residue was dissolved in CH2CI2 (1 13 mL). (1 R,2R)-2-Aminocyclohexanol (2.60 g, 22.60 mmol) and triethylamine (12.60 mL, 90 mmol) were added, and the resulting mixture was stirred overnight. Water (80 mL) was added to quench the reaction, the organic layer was separated and the aqueous layer was extracted with CH2CI2 (2 x 80 mL). The combined organics were washed with sat. NaHCO3(aq ) (80 mL), then brine (2 x 80 mL), dried(MgSO4), and evaporated to afford the title compound (5.3 g). LC-MS(ES) m/z = 319[M+H]+.

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 228

5
[ 769087-80-1 ]
[ 7644-03-3 ]
[ 1227911-88-7 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 154; Lambda/-[2-(4-Chlorophenyl)-2-oxoethyl1-4-(phenylmethyl)-2-morpholinecarboxamide; To a mixture of <strong>[769087-80-1]4-(phenylmethyl)-2-morpholinecarboxylic acid</strong> (1.61 g, 7.28 mmol) and DMF (0.1 mL) in CH2CI2 (70 mL) was added oxalyl chloride (0.956 mL, 10.92 mmol) at 25 0C. The mixture was stirred at this temperature for 1 hour and the mixture turned clear. The solvent and excess of oxalyl chloride were removed in vacuo, and the resulting residue was dissolved in CH2CI2 (70 mL). 2-Amino-1-(4-chlorophenyl)ethanone (1.5 g, 7.28 mmol) and triethylamine (4.06 mL, 29.1 mmol) were added, and the resulting mixture was stirred overnight. Water (80 mL) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with CH2CI2 (2 x 80 mL). The combined organics were washed with sat. NaHCOs aq. (80 mL), then brine (2 x 80 mL), dried (MgSO4), and evaporated to get 3.4 g yellow residue, which was chromatographed (EtOAc-petroleum ether, 1 :1 ) to afford the title compound (2.5 g). LC-MS (ES) m/z = 373 [M+H]+.

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 225-226

6
[ 769087-80-1 ]
[ 40513-43-7 ]
[ 1227912-13-1 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 180; Lambda/-{2-r4-(Methyloxy)phenyll-2-oxoethyl}-4-(phenylmethyl)-2-morpholinecarboxamide; Oxalyl chloride (2.385 ml_, 27.2 mmol) was added to a suspension of 4-(phenylmethyl)-2- morpholinecarboxylic acid (4.02 g, 18.16 mmol) and DMF (0.703 ml_, 9.08 mmol) in CH2CI2 (100 ml.) at 0 0C in 10 minutes, and the reaction mixture was stirred at 25 0C for 2 hours. The mixture was concentrated, and the resulting residue was dissolved in CH2CI2 (100 ml.) and triethylamine (5.57 ml_, 40.0 mmol). 2-Amino-1-[4- (methyloxy)phenyl]ethanone (3.0 g, 18.16 mmol) was added to the brown solution at 0 0C, and the reaction mixture was stirred at 25 0C for 3 hours. Water (150 ml.) was added to the reaction mixture, and the aqueous mixture was extracted with EtOAc (3 x 100 ml_). The combined organic layers were dried (Na2SO4), filtered, and evaporated to afford the title compound (3.4 g) as a brown solid. LC-MS(ES) m/z = 369 [M+H]+.

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 238-239

7
[ 769087-80-1 ]
(2R,3S)-3-amino-1-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-ol; dihydrochloride salt [ No CAS ]
4-benzyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-morpholine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 29: 4-BenzyI-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocycIopentylchroman-4-yIamino)-3- hydroxy-l-phenylbutan-2-yl)morpholine-2-carboxamide. Racemic <strong>[769087-80-1]4-benzylmorpholine-2-carboxylic acid</strong> (16 mg) was dissolved in DMF (0.5 mL) in a reaction flask (1) and DBPEA (0.1 mL) and HATU (42 mg, 0.11 mmol) were added. In a separate flask (2) was placed (2R,3S)-3-amino-l-((S)-6-ethyl-2,2- spirocyclopentylchroman-4-ylamino)-4-rhohenylbutan-2-ol,bis HCl salt (35 mg, 0.075 mmol), DIPEA (0.1 mL) and DMF (0.5 mL) and the reaction was allowed to stir for 10 min before the solution was added to flask (1). The reaction in flask (1) was allowed to stir for 1 h and then diluted with MeOH (2.0 mL), filtered. The filtrate was injected directly onto a reverse phase HPLC purification (80 mL/min on a 30.0 x 150.0 mm C-18(2)Luna Phenomonex column, 10% CH3CN gradient to 100% over 30 min). The pure fractions were evaporated to give the title compound. MS m/z: 598 (M+ 1).

Reference： [1]Patent: WO2007/62007,2007,A1 .Location in patent: Page/Page column 85-86

8
[ 769087-80-1 ]
[ 1117-97-1 ]
[ 852237-32-2 ]

Yield	Reaction Conditions	Operation in experiment
		4-Benzyl-/V-methoxy-/V-methylmorphoNne-2-carboxamide (82) A mixture of carboxylic acid 81 (7.73 g, 30 mmol), /V-methylmorpholine (12.3 g, 120 mmol), and Nu,Omicron- dimethyl hydroxylamine (8.96 g, 90 mmol) in DCM (200 mL) was treated with EDCI (17.6 g, 90 mmol)at RT. The reaction mixture was stirred for 16 h and then poured into saturated aqueous sodium bicarbonate solution and extracted with CH2CI2. The combined extracts were dried over MgS04, filtered, and concentrated to provide 7.90 g of 82 as a light yellow oil. LCMS m/z 265.1 (M+1 ). H NMR (400 MHz, CDCI3) delta 7.18 - 7.35 (m, 5H) 3.94 - 4.03 (m, 1 H) 3.68 - 3.77 (m, 2H) 3.65 (s, 3H) 3.48 - 3.59 (m, 2H) 3.17 (s, 3H) 2.91 (d, J = 1 1.2 Hz, 1 H) 2.66 (dd, J = 1 1.6, 2.1 Hz, 1 H) 2.19 - 2.34 (m, 2H).

Reference： [1]Patent: WO2011/58478,2011,A1 .Location in patent: Page/Page column 55

9
[ 147767-51-9 ]
[ 769087-80-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrogenchloride; water; In toluene; at 20 - 110℃;Inert atmosphere;	Step B. 4-Benzylmorpholine-2-carboxylic acid. To a solution of 4- benzylmorpholine-2-carbonitrile (20.2 g, 100 mmol) in toluene (60 mL) was added 6M HC1 (100 mL, 600 mmol). The reaction mixture was ref uxed at 110 C for 1.5 h and then cooled to rt and stirred for 18 h. The solid was filtered to give the title compound (22 g, 99%) as a white solid.
	With hydrogenchloride; In water; at 90℃; for 16h;Sealed;	4-Benzylmorpholine-2-carboxylic acid (81) Nitrile 80 (10 g, 49.44 mmol) was combined with concentrated HCI (50 imL) at RT in a sealed glass bottle with magnetic stirbar. The mixture was heated to 90 C for 16 h and then cooled to RT. A precipitate formed and the slurry was concentrated and then azeotroped from toluene to provide 15.0 g of 81 as a light pink solid. LCMS m/z 222.1 (M+1 ). H NMR (400 MHz, CD3OD) delta 7.41 - 7.63 (m, 5H) 4.43 (q, 2H) 4.14 (br s, 11-1) 3.94 (d, J = 12.9 Hz, 1 H) 3.68 (br s, 1 H) 3.32 - 3.42 (m, 2H) 3.13 - 3.28 (m, 2H).

Reference： [1]Patent: WO2015/164508,2015,A1 .Location in patent: Page/Page column 48-49
[2]Patent: WO2011/58478,2011,A1 .Location in patent: Page/Page column 54-55

10
[ 769087-80-1 ]
[ 852237-34-4 ]

Reference： [1]Patent: WO2011/58478,2011,A1
[2]Patent: WO2018/137573,2018,A1

11
[ 769087-80-1 ]
[ 1305117-43-4 ]

Reference： [1]Patent: WO2011/58478,2011,A1

12
[ 769087-80-1 ]
[ 67-64-1 ]
1-(4-benzylmorpholin-2-yl)butane-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%		Step C. l-(4-Benzylmophiholin-2-yl)butane-l,3-dione. To a solution of z'-Pr2NH (7 mL, 50 mmol) in THF (40 mL) was added -BuLi (20 mL, 50 mmol) at 0 C and stirred for 0.5 h. The solution was cooled to -78 C, acetone (2.9 g, 50 mmol) was added drop wise mixture was allowed to stir at -78 C for 1 h. A solution of <strong>[769087-80-1]4-benzylmorpholine-2-carboxylic acid</strong> (5.52 g, 25 mmol) in THF (40 mL) with CDI (4.48 g, 27.5 mmol) stirred for 3 h, was added drop wise at -78 C. The mixture was stirred for 1 h, and allowed to warm to rt, then neutoralized with 10% critic acid. The organic mixture was extracted with EtOAc and the organic phase was washed with and aq. NaHC03, dried (Na2S04), filtered, and concentrated under reduced pressure. Purification (FCC, Si02, PE/EtOAc, 5/1) afforded the title compound (3.5 g, 53%) as a colorless oil. 1H NMR (CDC13, 400 MHz) delta 7.25-7.19 (m, 5H), 5.77 (s, 1H), 4.06-4.03 (d, 1H), 3.88-3.84 (d, 1H), 3.66-3.60 (m, 1H), 3.50-3.41 (m, 2H), 3.01-2.97 (d, 1H), 2.61-2.58 (d, 1H), 2.16-2.10 (m, 2H), 2.02-1.97 (m, 4H).

Reference： [1]Patent: WO2015/164508,2015,A1 .Location in patent: Page/Page column 49

13
[ 104-63-2 ]
[ 769087-80-1 ]