287930-75-0

Basic information

• Product Name: (2R)-4-BENZYL-2-{(1R)-1-[3,5-BIS(TRIFLUOROMETHYL)PHENYL]ETHOXY}MORPHOLIN-3-ONE
• Synonyms: (2R)-4-BENZYL-2-{(1R)-1-[3,5-BIS(TRIFLUOROMETHYL)PHENYL]ETHOXY}MORPHOLIN-3-ONE;(R)-4-benzyl-2-((R)-1-(3,5-bis(trifluoroMethyl)phenyl)ethoxy)Morpholin-3-one;(R)-2-((R)-1-(3,5-bis(trifluoroMethyl)phenyl)ethoxy)-4-benzylMorpholin-3-one;(2R)-4-benzyl-2-((R)-1-(3,5-bis(trifluoroMethyl)phenyl)ethoxy)Morpholin-3-one;(2R)-2-[(1R)-1-[3,5-Bis(trifluoroMethyl)phenyl]ethoxy]-4-(phenylMethyl)-3-Morpholinone;3-Morpholinone,2-[(1R)-1-[3,5-bis(trifluoroMethyl)phenyl]ethoxy]-4-(phenylMethyl)-, (2R)-;(R)-2-((R)-1-(3,5-bi;Fosaprepitant Impurity C
• CAS NO: 287930-75-0
• Molecular Formula: C₂₁H₁₉F₆NO₃
• Molecular Weight: 447.38
• EINECS: 1312995-182-4
• Mol File: 287930-75-0.mol
• Article Data: 9

Chemical Properties

• Boiling Point: 457.438 °C at 760 mmHg
• Flash Point: 230.45 °C
• Appearance: /
• Density: 1.37
• Storage Temp.: 2-8°C
• PKA: -2.18±0.40(Predicted)
• CAS DataBase Reference: (2R)-4-BENZYL-2-{(1R)-1-[3,5-BIS(TRIFLUOROMETHYL)PHENYL]ETHOXY}MORPHOLIN-3-ONE(CAS DataBase Reference)
• NIST Chemistry Reference: (2R)-4-BENZYL-2-{(1R)-1-[3,5-BIS(TRIFLUOROMETHYL)PHENYL]ETHOXY}MORPHOLIN-3-ONE(287930-75-0)
• EPA Substance Registry System: (2R)-4-BENZYL-2-{(1R)-1-[3,5-BIS(TRIFLUOROMETHYL)PHENYL]ETHOXY}MORPHOLIN-3-ONE(287930-75-0)

Safety Data

• Hazardous Substances Data: 287930-75-0(Hazardous Substances Data)

Usage

Uses

(2R)-2-[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-4-(phenylmethyl)-3-morpholinone, is the key 3-(4-Fluorophenyl)morpholine moiety used in the synthesis of NK1 receptor antagonist Aprepitant (A729800).

Synthetic route

(R)-[3,5-bis(trifluoromethyl)phenyl]ethanol (368-63-8, 68120-60-5, 127852-28-2) + 4-benzyl-2-hydroxy-morpholin-3-one (287930-73-8) → (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0)

Conditions	Yield
Stage #1: 4-benzyl-2-hydroxy-morpholin-3-one With trifluoroacetic anhydride In acetonitrile at 5 - 30℃; for 1h; Stage #2: (R)-[3,5-bis(trifluoromethyl)phenyl]ethanol With boron trifluoride diethyl etherate In acetonitrile for 3h; Further stages;	96%
Stage #1: 4-benzyl-2-hydroxy-morpholin-3-one With trifluoroacetic anhydride In acetonitrile at 5 - 30℃; for 1h; Stage #2: (R)-[3,5-bis(trifluoromethyl)phenyl]ethanol With boron trifluoride diethyl etherate In acetonitrile for 2h; Stage #3: With tetrahydrolinalool; potassium tert-butylate In hexane at -10 - -5℃; for 14h; Solvent;	96%
Stage #1: 4-benzyl-2-hydroxy-morpholin-3-one With trifluoroacetic anhydride In acetonitrile at 5℃; for 1h; Stage #2: (R)-[3,5-bis(trifluoromethyl)phenyl]ethanol With boron trifluoride diethyl etherate In acetonitrile at 25℃; for 4h; Temperature; Reagent/catalyst;

(R)-4-benzyl-2-hydroxy-morpholin-3-one + (R)-[3,5-bis(trifluoromethyl)phenyl]ethanol (368-63-8, 68120-60-5, 127852-28-2) → (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0)

Conditions	Yield
With di-chlorobenzyl azodicarboxylate; triphenylphosphine In dichloromethane at 10 - 20℃; for 12h; Concentration; Solvent; Reagent/catalyst;	91.5%

(R)-[3,5-bis(trifluoromethyl)phenyl]ethanol (368-63-8, 68120-60-5, 127852-28-2) + 2,2,2-trichloro-acetimidic acid 4-benzyl-3-oxo-morpholin-2-yl ester (502536-97-2) → C22H24N2O5 + (2S,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (327623-36-9) + (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0)

Conditions	Yield
With boron trifluoride diethyl etherate In n-heptane; toluene at 20℃; for 1h;

(2S,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (327623-36-9) → (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0)

Conditions	Yield
With potassium tert-butylate In hexane; tert-butyl alcohol at 22℃; for 16h;

(R)-[3,5-bis(trifluoromethyl)phenyl]ethanol (368-63-8, 68120-60-5, 127852-28-2) + trifluoro-acetic acid 4-benzyl-3-oxo-morpholin-2-yl ester (502537-07-7) → (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0)

Conditions	Yield
With boron trifluoride diethyl etherate In acetonitrile at 20℃; for 2h;	3.51 kg
Stage #1: (R)-[3,5-bis(trifluoromethyl)phenyl]ethanol; trifluoro-acetic acid 4-benzyl-3-oxo-morpholin-2-yl ester With boron trifluoride diethyl etherate In acetonitrile at 25℃; Stage #2: With sodium hydroxide at 20℃; for 0.25h; Stage #3: With linalool potassium at 92℃;

3,5-bis(trifluoromethyl)phenyl methyl ketone (30071-93-3) → (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 97 percent / borane-methyl sulfide complex; (S)-Me-CBS / various solvent(s); toluene / 1 h / -5 °C 2: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: 97 percent / borane-methyl sulfide complex; (S)-Me-CBS / various solvent(s); toluene / 1 h / -5 °C 2: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 3: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C View Scheme
Multi-step reaction with 2 steps 1: 97 percent / borane-methyl sulfide complex; (S)-Me-CBS / various solvent(s); toluene / 1 h / -5 °C 2: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: dimethylsulfide borane complex / tert-butyl methyl ether / 1 h / -10 - -5 °C / Inert atmosphere 2.1: trifluoroacetic anhydride / acetonitrile / 1 h / 25 °C / Inert atmosphere 2.2: 2 h / 20 - 30 °C View Scheme

(R)-[3,5-bis(trifluoromethyl)phenyl]ethanol (368-63-8, 68120-60-5, 127852-28-2) → (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 2: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C View Scheme

4-benzyl-morpholine-2,3-dione (110843-90-8) → (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 80 percent / lithium tri(sec-butyl)borohydride; sodium hydroxide; hydrogen peroxide / tetrahydrofuran; H2O / 1 h / 10 °C 2: acetonitrile / 5 - 34 °C 3: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: 80 percent / lithium tri(sec-butyl)borohydride; sodium hydroxide; hydrogen peroxide / tetrahydrofuran; H2O / 1 h / 10 °C 2: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 3: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 4: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C View Scheme
Multi-step reaction with 3 steps 1: 80 percent / lithium tri(sec-butyl)borohydride; sodium hydroxide; hydrogen peroxide / tetrahydrofuran; H2O / 1 h / 10 °C 2: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 3: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C View Scheme

N-Benzylethanolamine (104-63-2) → (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 76 percent / tetrahydrofuran; H2O / 21 h / Heating 2: acetonitrile / 5 - 34 °C 3: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: 76 percent / tetrahydrofuran; H2O / 21 h / Heating 2: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 3: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 4: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C View Scheme
Multi-step reaction with 3 steps 1: 76 percent / tetrahydrofuran; H2O / 21 h / Heating 2: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 3: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C View Scheme

4-benzyl-2-hydroxy-morpholin-3-one (287930-73-8) → (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetonitrile / 5 - 34 °C 2: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 2: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 3: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C View Scheme
Multi-step reaction with 2 steps 1: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 2: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C View Scheme

2,2,2-trichloro-acetimidic acid 4-benzyl-3-oxo-morpholin-2-yl ester (502536-97-2) → (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 2: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C View Scheme

C12H7F9O2 + 4-benzyl-2-hydroxy-morpholin-3-one (287930-73-8) → (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0)

Conditions	Yield
With potassium tetrahydrolinalool; triphenylphosphine at -10℃; for 6h; Reagent/catalyst; Temperature;	80.2 g

(R)-[3,5-bis(trifluoromethyl)phenyl]ethanol (368-63-8, 68120-60-5, 127852-28-2) + 4-benzyl-2-hydroxy-morpholin-3-one (287930-73-8) → (2S,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (327623-36-9) + (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0)

Conditions	Yield
Stage #1: 4-benzyl-2-hydroxy-morpholin-3-one With trifluoroacetic anhydride In acetonitrile at 25℃; for 1h; Inert atmosphere; Stage #2: (R)-[3,5-bis(trifluoromethyl)phenyl]ethanol With boron trifluoride diethyl etherate In acetonitrile at 20 - 30℃; for 2h; stereoselective reaction;	A 39.5 g B 23.2 g

N-Benzylethanolamine (104-63-2) → (2S,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (327623-36-9) + (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: water; tetrahydrofuran / 8 h / 60 - 65 °C / Inert atmosphere 2.1: trifluoroacetic anhydride / acetonitrile / 1 h / 25 °C / Inert atmosphere 2.2: 2 h / 20 - 30 °C View Scheme

(2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → C14H13F6NO3

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In methanol; water at 50 - 60℃; under 26252.6 Torr; for 4.5h;	99%

4-flourophenylmagnesium bromide (352-13-6) + (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride

Conditions	Yield
Stage #1: 4-flourophenylmagnesium bromide; (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one In tetrahydrofuran; methanol at 15 - 20℃; for 0.916667h; Stage #2: With palladium 10% on activated carbon; ammonium formate; toluene-4-sulfonic acid In tetrahydrofuran; methanol Stage #3: With hydrogenchloride In di-isopropyl ether; water for 0.5h; Reflux;	94.7%
With hydrogenchloride; hydrogen; toluene-4-sulfonic acid; palladium on activated charcoal In tetrahydrofuran; methanol at 20 - 25℃; under 1034.32 Torr; for 3h;	47.6 g
Stage #1: 4-flourophenylmagnesium bromide; (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one With toluene-4-sulfonic acid In tetrahydrofuran; methanol at 0 - 10℃; Stage #2: In methanol at 20 - 30℃; under 1034.32 Torr; for 4h; High pressure;

1-Bromo-4-fluorobenzene (460-00-4) + (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride

Conditions	Yield
Stage #1: 1-Bromo-4-fluorobenzene; (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one With palladium on activated charcoal; hydrogen; magnesium In tetrahydrofuran Stage #2: With hydrogenchloride In tetrahydrofuran; water Reagent/catalyst;	93.1%

phenylmagnesium bromide (100-58-3) + (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-phenylmorpholine (171338-33-3)

Conditions	Yield
Stage #1: phenylmagnesium bromide; (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one In tetrahydrofuran at 15 - 25℃; for 0.5h; Stage #2: With 5%-palladium/activated carbon; hydrogen; toluene-4-sulfonic acid In tetrahydrofuran; methanol at 10 - 35℃; under 258.581 Torr; for 4h;	53%

4-flourophenylmagnesium bromide (352-13-6) + (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine (171338-27-5)

Conditions	Yield
Stage #1: 4-flourophenylmagnesium bromide; (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one In tetrahydrofuran at 20℃; Stage #2: With hydrogen; 5 percent Pd/C In methanol Further stages.;
Stage #1: 4-flourophenylmagnesium bromide; (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one In tetrahydrofuran at 15 - 25℃; for 0.5h; Stage #2: With 5%-palladium/activated carbon; hydrogen; toluene-4-sulfonic acid In tetrahydrofuran; methanol at 0 - 25℃; under 1034.32 Torr; for 3h;

4-flourophenylmagnesium bromide (352-13-6) + (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → [1S,2R,(2αR*)]-2-(2-aminoethoxy)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-1-(4-fluorophenyl)ethan-1-ol + [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine (171338-27-5)

Conditions	Yield
Stage #1: 4-flourophenylmagnesium bromide; (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one In tetrahydrofuran at 20 - 30℃; Stage #2: With hydrogen; 10 percent Pd/C In tetrahydrofuran; methanol Further stages.;	A 5.96 g B n/a

4-flourophenylmagnesium bromide (352-13-6) + (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → (3R*)-4-benzyl-3-[(1S*)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-3-(4-fluorophenyl)morpholin-2-one

Conditions	Yield
In tetrahydrofuran at 20℃;

4-flourophenylmagnesium bromide (352-13-6) + (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → (3R*)-4-benzyl-3-[(1S*)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-3-(4-fluorophenyl)morpholin-2-one + (3R*)-4-benzyl-3-[(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-3-(4-fluorophenyl)morpholin-2-one

Conditions	Yield
In tetrahydrofuran at 20℃; for 3h;	A 0.76 g B 0.96 g

(2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → (2R)-2-[(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-3-dehydromorpholine

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr 2.1: NaHCO3 / ethyl acetate 2.2: 84 percent / K2CO3; N-chlorosuccinimide; DBU / toluene; dimethylformamide / 5 h / 20 °C View Scheme

(2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → C34H32F7NO3

Conditions	Yield
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 20 - 30 °C 1.2: 5.96 g / H2 / 10 percent Pd/C / methanol; tetrahydrofuran 2.1: K2CO3 / dimethylformamide / 120 h / 20 °C View Scheme

(2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → C36H32F7NSO7

Conditions	Yield
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 20 - 30 °C 1.2: 5.96 g / H2 / 10 percent Pd/C / methanol; tetrahydrofuran 2.1: ethyl acetate; aq. NaHCO3 / 2 h / 20 °C 2.2: triehtylamine / CH2Cl2 / 2 h / 0 °C View Scheme

(2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → aprepitant (170729-80-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr View Scheme
Multi-step reaction with 3 steps 1: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr 2: potassium carbonate / toluene; dimethylsulfoxide / 2 h / 15 °C 3: 0.96 kg / Darco / methanol / 1 h / 60 °C View Scheme
Multi-step reaction with 4 steps 1.1: 5%-palladium/activated carbon; hydrogen / methanol; water / 4.5 h / 50 - 60 °C / 26252.6 Torr 2.1: sodium hydroxide / acetonitrile / 2.5 h / 30 - 40 °C 3.1: tetrahydrofuran / 1 h / 15 - 25 °C 3.2: 1 h / 20 - 65 °C 4.1: triethylsilane; boron trifluoride diethyl etherate / acetonitrile / 5 h / 0 - 35 °C View Scheme

(2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → (2R,3R)-2-[(1R)-1-(3,5-bis-trifluoro-methylphenyl)ethoxy]-3-(4-fluorophenyl)morpholine (380499-06-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 20 - 30 °C 1.2: 5.96 g / H2 / 10 percent Pd/C / methanol; tetrahydrofuran 2.1: ethyl acetate; aq. NaHCO3 / 2 h / 20 °C 2.2: triehtylamine / CH2Cl2 / 2 h / 0 °C 3.1: 46 mg / triethylamine / acetonitrile / 20 °C View Scheme

(2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-4-fluorophenyl-4-2-(N-methylcarboxyactamidrazono)morpholine (219821-37-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr 2: potassium carbonate / toluene; dimethylsulfoxide / 2 h / 15 °C View Scheme

(2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 0.5 h / 15 - 25 °C 1.2: 3 h / 0 - 25 °C / 1034.32 Torr 2.1: hydrogenchloride / water View Scheme

(2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → [2R-[2α(R*),3α]]-N-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine

Conditions	Yield
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 0.5 h / 15 - 25 °C 1.2: 3 h / 0 - 25 °C / 1034.32 Torr 2.1: hydrogenchloride / water 3.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C View Scheme

(2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-phenylmorpholine hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 0.5 h / 15 - 25 °C 1.2: 4 h / 10 - 35 °C / 258.58 Torr 2.1: hydrogenchloride / water View Scheme

(2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one (287930-75-0) → [2R-[2α(R*),3α]]-N-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride

Conditions	Yield
Multi-step reaction with 4 steps 1.1: tetrahydrofuran / 0.5 h / 15 - 25 °C 1.2: 3 h / 0 - 25 °C / 1034.32 Torr 2.1: hydrogenchloride / water 3.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 4.1: hydrogenchloride / water View Scheme

Upstream product

• 368-63-8 (R)-[3,5-bis(trifluoromethyl)phenyl]ethanol 
• 502536-97-2 2,2,2-trichloro-acetimidic acid 4-benzyl-3-oxo-morpholin-2-yl ester 
• 104-63-2 N-Benzylethanolamine 
• 287930-73-8 4-benzyl-2-hydroxy-morpholin-3-one 
• 110843-90-8 4-benzyl-morpholine-2,3-dione 
• 30071-93-3 3,5-bis(trifluoromethyl)phenyl methyl ketone 
• 502537-07-7 trifluoro-acetic acid 4-benzyl-3-oxo-morpholin-2-yl ester 
• 327623-36-9 (2S,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one 

Downstream Products

• 171338-27-5 [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine 
• 171482-05-6 [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride 
• 171482-05-6 [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride 
• 171338-33-3 [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-phenylmorpholine 
• 219821-37-1 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-4-fluorophenyl-4-2-(N-methylcarboxyactamidrazono)morpholine 
• 380499-06-9 (2R,3R)-2-[(1R)-1-(3,5-bis-trifluoro-methylphenyl)ethoxy]-3-(4-fluorophenyl)morpholine 
• 170729-80-3 aprepitant 

Relevant articles and documents

Production process of aprepitant key intermediate

The invention relates to the field of chemical pharmacy, in particular to a production process of an aprepitant key intermediate, which comprises the following steps: dissolving a glyoxylic acid aqueous solution in tetrahydrofuran, adding benzyl ethanolamine, distilling to recover tetrahydrofuran, crystallizing, filtering, washing and drying to obtain an intermediate AR-B; dissolving the intermediate AR-B in acetonitrile, adding trifluoroacetic anhydride and boron trifluoride acetonitrile, carrying out reduced pressure distillation to obtain acetonitrile, carrying out extraction, washing, configuration overturning and acetic acid quenching, adding a sodium bicarbonate solution, and carrying out extraction, filtration, washing and drying to obtain an intermediate AR-0; dropwise adding a tetrahydrofuran solution of p-phenylfluoro magnesium bromide into a mixture of the intermediate AR-0 and tetrahydrofuran, adding methanol and toluenesulfonic acid, filtering, adding toluenesulfonic acid and palladium carbon, hydrogenating, filtering out palladium carbon, extracting, washing and drying to obtain the key intermediate AR-1. The synthesis efficiency of the aprepitant key intermediate can be effectively improved, and the production cost is reduced.

A preparation method of the midbody arab league swiss tanzania (by machine translation)

The invention discloses a method of preparing intermediates of arab league swiss tanzania, the method to (R)- 1 - [3, 5 - di (trifluoromethyl) phenyl] ethanol as the starting material, and trifluoroacetic anhydride reaction the compound of formula II, the formula II compound in the catalyst and under strongly alkaline conditions with 4 - benzyl - 2 - hydroxy - morpholine - 3 - one the response results in the type I the target compound (2 R) - 4 - benzyl - 2 - [(1 R) - 1 - [3, 5 - double-(trifluoromethyl) phenyl] ethoxy] morpholine - 3 - one. The method of simple process steps, operation is simple and easy, the resulting product has high purity, high yield, low production cost, and the reagent for economic and environmental protection, and is suitable for industrial production. (by machine translation)

Preparation method of morpholine derivative

The invention provides a preparation method of a morpholine derivative represented as the formula (I), wherein the preparation method includes the steps of: (1) dissolving trialkyl (aryl) phosphine, azodicarboxylic acid diester, (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl-1-ol, and (R)-4-benzyl-2-hydroxyl-morpholine-3-one in a reaction solvent; (2) adding the azodicarboxylic acid diester so that the trialkyl (aryl) phosphine and the azodicarboxylic acid diester are subjected to an addition reaction quickly in the reaction solvent to generate zwitter-ions, which are then converted into quaternary phosphonium salt by means of a hydrogen proton supplied by the hydroxyl group in the (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl-1-ol; (3) enabling the hydroxyl group on the 2-position of the (R)-4-benzyl-2-hydroxyl-morpholine-3-one to be reacted with the quaternary phosphonium salt to generate morpholine oxy-phosphonium salt; and (4) with the (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl-1-ol, which loses the hydrogen proton, as a nucleophilic reagent, performing an SN2 reaction with the morpholine oxy-phosphonium salt to obtain a product which has turned configuration. The method has high stereo-selectivity, avoids generation of an isomer byproduct during the reaction process, and reduces the load of separation and purification of the product in the later period.