171753-74-5

Basic information

• Product Name: Morpholine, 2,6-diMethyl-, (2R,6R)-
• Synonyms: Morpholine, 2,6-diMethyl-, (2R,6R)-;(2R,6R)-2,6-Dimethylmorpholine;(2R-trans)-2,6-Dimethylmorpholine;Trans (2S,6S)-2,6-diMethyl Morpholine;(2R,6R)-2,6-Dimethylmorphline
• CAS NO: 171753-74-5
• Molecular Formula: C₆H₁₃NO
• Molecular Weight: 115.17352
• Mol File: 171753-74-5.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 147℃
• Flash Point: 49℃
• Appearance: /
• Density: 0.862
• Storage Temp.: 2-8°C
• PKA: 9.04±0.60(Predicted)
• CAS DataBase Reference: Morpholine, 2,6-diMethyl-, (2R,6R)-(CAS DataBase Reference)
• NIST Chemistry Reference: Morpholine, 2,6-diMethyl-, (2R,6R)-(171753-74-5)
• EPA Substance Registry System: Morpholine, 2,6-diMethyl-, (2R,6R)-(171753-74-5)

Safety Data

• Hazardous Substances Data: 171753-74-5(Hazardous Substances Data)

Usage

General Description

Morpholine, 2,6-dimethyl, (2R,6R)- is a chemical compound with the molecular formula C6H13NO. It is a colorless liquid with a slightly amine-like odor. Morpholine, 2,6-diMethyl-, (2R,6R)- is used as a solvent, a corrosion inhibitor, and in the production of pharmaceuticals and agricultural chemicals. It is also used in the synthesis of rubber accelerators and optical brighteners. Additionally, it is utilized in the manufacturing of adhesives, sealants, and coating materials. It is important to handle and store this compound carefully, as it can cause irritation to the skin, eyes, and respiratory tract and may be harmful if ingested or inhaled.

Synthetic route

(2R,6R)-4-Benzyl-2,6-dimethyl-morpholine (171753-77-8) → (2R,6R)-2,6-dimethylmorpholine (171753-74-5)

Conditions	Yield
With hydrogen; acetic acid; palladium on activated charcoal In methanol	96.6%
With hydrogen; acetic acid; palladium on activated charcoal In methanol under 760 Torr; for 16h; Ambient temperature;	84%

C6H13NO*C8H8O3 → (2R,6R)-2,6-dimethylmorpholine (171753-74-5)

Conditions	Yield
Stage #1: C6H13NO*C8H8O3 With hydrogenchloride In water pH=1.5; Stage #2: With sodium hydroxide In water pH=14;	78%

(R)-2-((R)-2-Hydroxy-1-methyl-ethoxy)-propan-1-ol (171753-76-7) → (2R,6R)-2,6-dimethylmorpholine (171753-74-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 98 percent / pyridine / 0 deg C to room t., 4 h 2: 97.6 percent / dioxane / 12.5 h / Heating 3: 96.6 percent / H2, AcOH / 10percent Pd/c / methanol View Scheme
Multi-step reaction with 3 steps 1: 94 percent / pyridine / 4 h / 0 - 20 °C 2: 85 percent / dioxane / Heating 3: 84 percent / H2, AcOH / 5percent Pd/C / methanol / 16 h / 760 Torr / Ambient temperature View Scheme

Methanesulfonic acid (R)-2-((R)-2-methanesulfonyloxy-1-methyl-ethoxy)-propyl ester (171561-11-8) → (2R,6R)-2,6-dimethylmorpholine (171753-74-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 97.6 percent / dioxane / 12.5 h / Heating 2: 96.6 percent / H2, AcOH / 10percent Pd/c / methanol View Scheme
Multi-step reaction with 2 steps 1: 85 percent / dioxane / Heating 2: 84 percent / H2, AcOH / 5percent Pd/C / methanol / 16 h / 760 Torr / Ambient temperature View Scheme

R,R-dilactic acid diethyl ester (171753-75-6) → (2R,6R)-2,6-dimethylmorpholine (171753-74-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 97 percent / LiAlH4 / diethyl ether / 0.5 h / Heating 2: 94 percent / pyridine / 4 h / 0 - 20 °C 3: 85 percent / dioxane / Heating 4: 84 percent / H2, AcOH / 5percent Pd/C / methanol / 16 h / 760 Torr / Ambient temperature View Scheme

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + 3,7-dichloro-6-fluorobenzo[d]isoxazole-5-carbaldehyde → 3,7-dichloro-6-((2R,6R)-2,6-dimethylmorpholino)benzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With potassium carbonate In water for 6h; Reflux;	100%
With potassium carbonate In water for 6h; Reflux;	100%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (1224944-77-7) → ethyl 5-[(2R,6R)-2,6-dimethylmorpholin-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 16h; Inert atmosphere;	96%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + 2-fluoro-5-nitrobenzaldehye (27996-87-8) → 2-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-5-nitrobenzaldehyde (1135561-41-9)

Conditions	Yield
With triethylamine In acetonitrile for 22h; Inert atmosphere; Reflux;	93%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + (R)-3-(6,7-difluoro-5-formylbenzo[d]isoxazol-3-yl)-N,N-dimethyl-2-oxooxazolidine-4-carboxamide → (R)-3-(6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-5-formylbenzo[d]isoxazol-3-yl)-N,N-dimethyl-2-oxooxazolidine-4-carboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 16h;	92%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + (R)-6,7-difluoro-3-(2-oxo-5-((trifluoromethoxy)methyl)thiazolidin-3-yl)benzo[d]isoxazole-5-carbaldehyde → 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-((R)-2-oxo-5-((trifluoromethoxy)methyl)thiazolidin-3-yl)benzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 12h;	91%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + 6-fluoro-5-formyl-3-(((1-hydroxycyclopropyl)methyl)amino)benzo[d]isoxazole-7-carbonitrile → 6-((2R, 6R)-2,6-dimethylmorpholinyl)-5-formyl-3-(((1-hydroxycyclopropyl)methyl)amino)benzo[d]isoxazole-7-carbonitrile

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 40℃; for 2h;	88%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 40℃; for 2h;	42%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + 6,7-difluoro-3-(2-oxo-1-oxa-3-azaspiro[4.4]nonan-3-yl)benzo[d]isoxazole-5-carbaldehyde → 6-((2R,6R)-2,6-dimethylmorpholinyl)-7-fluoro-3-(2-oxo-1-oxa-3-azaspiro[4.4]nonane-3-yl)benzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 12h;	88%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + tert-butyl N-[2-[[4-(3-bromophenyl)thiazol-2-yl]amino]-2-oxo-ethyl]carbamate → tert-butyl (2-((4-(3-((2R,6R)-2,6-dimethylmorpholino)phenyl)thiazol-2-yl)amino)-2-oxoethyl)carbamate

Conditions	Yield
With t-BuXPhos Pd G3; sodium t-butanolate In tert-Amyl alcohol at 60℃; for 4h;	87.88%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + p-methoxybenzyl chloride (824-94-2) → (2R,6R)-4-(4-methoxybenzyl)-2,6-dimethylmorpholine

Conditions	Yield
With potassium carbonate In acetonitrile at 55℃; for 42h;	87%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + 6,7-difluoro-3-(5-oxo-4-oxa-6-azaspiro[2.4]heptane-6-yl)benzo[d]isoxazole-5-carbaldehyde → 6-((2R,6R)-2,6-dimethylmorpholinyl)-7-fluoro-3-(5-oxo-4-oxa-6-azaspiro[2.4]heptane-6-yl)benzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 12h;	87%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 10h;	31%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + (S)-6,7-difluoro-3-(4-methyl-2-oxothiazolidin-3-yl)benzo[d]isoxazole-5-carbaldehyde → 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-((S)-4-methyl-2-oxothiazolidin-3-yl)benzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 12h;	87%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + (S)-3-(4-cyclopropyl-2-oxooxazolidin-3-yl)-6,7-difluorobenzo[d]-isoxazole-5-carbaldehyde → 3-((4S)-4-cyclopropyl-2-oxooxazolidin-3-yl)-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 16h;	86%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + 2,3,4,-trifluorobenzoic acid (61079-72-9) → 2-((2R,6R)-2,6-dimethylmorpholino)-3,4-difluorobenzoic Acid

Conditions	Yield
Stage #1: 2,3,4,-trifluorobenzoic acid With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.75h; Inert atmosphere; Stage #2: (2R,6R)-2,6-dimethylmorpholine In tetrahydrofuran at -78 - 20℃; for 19.75h; Inert atmosphere;	85%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + (R)-6,7-difluoro-3-(5-methyl-2-oxooxazolidin-3-yl)benzo[d]-isoxazole-5-carbaldehyde → 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-((5R)-5-methyl-2-oxooxazolidin-3-yl)benzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With potassium carbonate In water at 100℃; Microwave irradiation;	81%
With potassium carbonate In water; acetonitrile at 100℃; for 2h; Microwave irradiation;	73%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + (S)-3-(4-ethyl-2-oxothiazolidin-3-yl)-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde → 6-((2R,6R)-2,6-dimethylmorpholino)-3-((S)-4-ethyl-2-oxothiazolidin-3-yl)-7-fluorobenzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 12h;	80%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + bromopropionitrile (2417-90-5) → trans N-(2-cyanoethyl)-2,6-dimethylmorpholine

Conditions	Yield
With triethylamine In methanol; ethanol; chloroform	79%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + (R)-6-fluoro-5-formyl-3-((2-hydroxypropyl-2-yl)amino)benzo[d]isoxazole-7-carbonitrile → 6-((2R,6R)-2,6-dimethylmorpholinyl)-5-formyl-3-(((R)-2-hydroxypropyl)amino)benzo[d]isoxazole-7-carbonitrile

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 40℃; for 2h;	79%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 40℃; for 2h;	79%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + 6,7-difluoro-3-(6-oxo-5-oxa-7-azaspiro[3.4]octan-7-yl)benzo[d]isoxazole-5-carbaldehyde → 6-((2R,6R)-2,6-dimethylmorpholinyl)-7-fluoro-3-(6-oxo-5-oxa-7-aza-spiro[3.4]octane-7-yl)benzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 12h;	79%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + 6,7-difluoro-3-((R)-4-((R)-1-hydroxyethyl)-2-oxooxazolidin-3-yl)benzo[d]isoxazole-5-carbaldehyde → 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-((R)-4-((R)-1-hydroxyethyl)-2-oxooxazolidin-3-yl)benzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 6h; Sealed tube;	77%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + 3-chloro-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde → 3-chloro-6-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazole-5-carbaldehyde

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 85℃; for 12h; Sealed tube; Cooling with ice;	76%
With base In water for 2h; Reflux;

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + (S)-6,7-difluoro-3-(4-methyl-2-oxooxazolidin-3-yl)benzo[d]-isoxazole-5-carbaldehyde → 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-((S)-4-methyl-2-oxooxazolidin-3-yl)benzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	73%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + (R)-6,7-difluoro-3-(4-methyl-2-oxothiazolidin-3-yl)benzo[d]isoxazole-5-carbaldehyde → 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-((R)-4-methyl-2-oxothiazolidin-3-yl)benzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 12h;	71%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + (S)-3-(4-benzyl-2-oxothiazolidin-3-yl)-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde → 3-((S)-4-benzyl-2-oxothiazolidin-3-yl)-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 12h;	71%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + 6,7-difluoro-3-((3aR,6aS)-2-oxotetrahydro-2H-cyclopentane[d]thiazol-3(3aH)-yl)benzo[d]isoxazole-5-carbaldehyde → 6-((2R,6R)-2,6-dimethylmorpholine)-7-fluoro-3-((3aR,6aS)-2-oxotetrahydro-2H-cyclopentane[d]thiazol-3(3aH)-yl)benzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 12h;	71%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + (S)-6-fluoro-5-formyl-3-((1-hydroxypropan-2-yl)amino)benzo[d]isoxazole-7-carbonitrile → 6-((2R,6R)-2,6-dimethylmorpholino)-5-formyl-3-(((S)-1-hydroxypropan-2-yl)amino)benzo[d]isoxazole-7-carbonitrile

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 40℃; for 2h;	70%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + (R)-3-(5-ethyl-2-oxothiazolidin-3-yl)-6,7-difluorobenzo[d]isoxazole-5-carbaldehyde → 6-((2R,6R)-2,6-dimethylmorpholino)-3-((R)-5-ethyl-2-oxothiazolidin-3-yl)-7-fluorobenzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 12h;	69%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + 6,7-difluoro-3-(5-oxo-6-thia-4-azaspiro[2.4]heptan-4-yl)benzo[d]isoxazole-5-carbaldehyde → 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-(5-oxo-6-thia-4-azaspiro[2.4]heptan-4-yl)benzo[d]isoxazole-5-carbaldehyde

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 12h;	68%

(2R,6R)-2,6-dimethylmorpholine (171753-74-5) + (4S)-7-chloro-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b] [1,4]diazepine → (2R,6R)-2,6-dimethyl-4-((4S)-2,3,4,5-tetrahydro-1,4-methanopyrido[2,3-b][1,4]diazepin-7-yl)morpholine

Conditions	Yield
With (1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene)chloro(3-phenylallyl)palladium(II); potassium tert-butylate In 1,2-dimethoxyethane at 90℃; for 16h; Inert atmosphere;	67.3%
With potassium tert-butylate In 1,2-dimethoxyethane at 20℃; for 0.25h; Inert atmosphere;	67.3%

Upstream product

• 171753-75-6 R,R-dilactic acid diethyl ester 
• 171561-11-8 Methanesulfonic acid (R)-2-((R)-2-methanesulfonyloxy-1-methyl-ethoxy)-propyl ester 
• 171753-76-7 (R)-2-((R)-2-Hydroxy-1-methyl-ethoxy)-propan-1-ol 
• 171753-77-8 (2R,6R)-4-Benzyl-2,6-dimethyl-morpholine 

Downstream Products

• 1620458-09-4 AZD0914 
• 1135561-41-9 2-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-5-nitrobenzaldehyde 

Relevant articles and documents

Asymmetric Synthesis of (-)-(2R,6R)-2,6-Dimethylmorpholine

The title compound was prepared efficiently by O-alkylation of (R)-ethyl lactate with the O-trifluoromethylsulfonyl derivative of (S)-ethyl lactate and further transformations of the two ester functionalities of the homochiral ether thus obtained.

Improved Synthesis of (-)-(2R,6R)-2,6-Dimethylmorpholine

An improved procedure for obtaining the enantiomerically pure title amine is described, using a convergent synthesis, starting from the easily available (R)- and (S)-1,2-propanediols.