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CAS No. :219821-37-1 MDL No. :
Formula : C24H25F7N4O4 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 566.47 Pubchem ID :-
Synonyms :

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Application In Synthesis of [ 219821-37-1 ]

* 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.

  • Downstream synthetic route of [ 219821-37-1 ]

[ 219821-37-1 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 171482-05-6 ]
  • [ 155742-64-6 ]
  • [ 219821-37-1 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In dimethyl sulfoxide; toluene at 15℃; for 2h;
With potassium carbonate In dimethyl sulfoxide; toluene at 15℃; 1 EXAMPLE 1 [2R- [2oc (R*), 3cc]]-5- [ [2- [1- [3, 5-bis (trifluoromethyl) phenyl] ethoxy]-3- (4- fluorophenyl)-4-morpholinyllmethyll-1, 2-dihydro-3H-1, 2, 4-triazol-3-one A mixture of the starting material as the hydrochloride salt of (2R, 2- alpha-R, 3a)-2- [l- [3, 5-bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl)-1, 4- oxazine (2a) (1.00 kg; 2.11 mol) and potassium carbonate (1.02 kg; 7.39 mol) in DMSO (2.2 L) and toluene (1.0 L) was cooled to 15°C. A slurry of amidrazone 3 (367 g; 2.22 mol) in toluene (1.5 L) was added. The mixture was stirred and then partitioned between toluene (4.0 L) and water (5.0 L). The phases were separated at 40°C. The organic layer (containing 4a) was washed with water (5.0 L) at 40°C and then partially concentrated at atmospheric pressure, providing intermediate 4a, which is used in the next step without isolation. The resulting solution containing intermediate 4a was heated to 140°C for 3 h and then allowed to cool to RT. The solids were filtered and dried in vacuo at 40 °C. The product (1.00 kg) was dissolved in methanol (10.0 L) and 50 g of Darco was added. The mixture was heated at 60°C for 1 h and then filtered at this temperature. The filtrates were allowed to cool slowly to RT. Water (5.0 L) was added slowly over 1 h. The slurry was cooled to 5 °C and the solids were filtered and dried in vacuo at 40 °C to yield 0.96 kg (85% overall yield) of the product [2R- [2oc (R*), 3cc]]-5- [ [2- [1- [3, 5-bis (trifluoromethyl) phenyl]- ethoxy]-3- (4-fluorophenyl)-4-morpholinyl] methyl]-1, 2-dihydro-3H-1, 2,4-triazol-3- one (i. e. 5- [ [2 (R)- [l (R)- [3, 5-bis (trifluoromethyl) phenyl]ethoxy]-3(S)-(4-fluorophenyl) -4-morpholinyl] methyl]-1, 2-dihydro-3H-1, 2, 4-triazol-3-one). Intermediate 4a: [a] D25=+84° (c=1.02, methanol) ;'H NMR (400 MHz, CDC13) 8 7. 64 (s, 2H), 7.34 (brt, J~7, 2H), 7.16 (s, 1H), 7.03 (t, J = 8. 4,2H), 5.8 (very br s, 2H), 4.88 (q, J = 6. 6,1H), 4.33 (d, J = 2. 8, 1H), 4.24 (td, J = 11. 6,2. 0, 1H), 3.77 (s, 2H), 3.66 (ddd, J= 11.6, 3.2, 1.6, 1H), 3.46 (d, J= 2.8, 1H), 3.31 (d, J = 14.5, 1H), 2.96 (brd, J= 11.6, 1H), 2.59 (d, J = 14.5, 1H), 2.50 (td, J = 12.1, 3.2, 1H), 1.47 (d, J = 6.6, 3H). Anal. Calc. for C24H2sF7N404 : C, 50.89 ; H, 4.45 ; F, 23.48 ; N, 9.89. Found: C, 50.48 ; H, 4.40 ; F, 23.43 ; N, 9.84. Final product la : Mp: 255 °C ; [α] = +69° (c=1.00, methanol) ;'H NMR (400 MHz, CD30D) 8 7.70 (s, 1H), 7.51 (m, 2H), 7.32 (s, 2H), 7.04 (t, J= 8.7, 2H), 4.94 (q, J= 6.3, 1H), 4.35 (d, J= 2.8, 1H), 4.28 (td, J = 11. 5,2. 8, 1H), 3.66 (ddd, J = 11. 5,3. 3,1. 6, 1H), 3.54 (d, J = 14. 3, 1H), 3.48 (d, J = 2.8, 1H), 2. 88 (br d, J = 11. 9,1H), 2.86 (d, J = 14.3, 1H), 2.49 (td, J = 11. 9,3. 6, 1H), 1.44 (d, J = 6.3, 3H) ;"C NMR (100 MHz, CD30D) 8 164.1 (d, J = 245.9), 158. 7,147. 6,147. 0,134. 1 (d, J= 3.1), 132.7 (d, J= 33.4), 132.4 (d, J= 8.0), 127.8 (m), 124.6 (q, J= 272.0), 122.3 (m), 116.1 (d, J = 21.6), 97.1, 73.7, 70.5, 60.4, 53.6, 52.2, 24.7. Anal. Calc. for C23H2lF7N403 : C, 51.69 ; H, 3.96 ; F, 24.88 ; N, 10.48. Found: C, 51.50 ; H, 3.82 ; F, 24.73 ; N, 10.44. HRMS : 534. 1480 (meas. ); 534.1502 (calc. for C23H21F7N4O3).
  • 2
  • [ 219821-37-1 ]
  • [ 170729-80-3 ]
YieldReaction ConditionsOperation in experiment
In toluene; at 140℃; for 3h; EXAMPLE 1 [2R- [2oc (R*), 3cc]]-5- [ [2- [1- [3, 5-bis (trifluoromethyl) phenyl] ethoxy]-3- (4- fluorophenyl)-4-morpholinyllmethyll-1, 2-dihydro-3H-1, 2, 4-triazol-3-one A mixture of the starting material as the hydrochloride salt of (2R, 2- alpha-R, 3a)-2- [l- [3, 5-bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl)-1, 4- oxazine (2a) (1.00 kg; 2.11 mol) and potassium carbonate (1.02 kg; 7.39 mol) in DMSO (2.2 L) and toluene (1.0 L) was cooled to 15C. A slurry of amidrazone 3 (367 g; 2.22 mol) in toluene (1.5 L) was added. The mixture was stirred and then partitioned between toluene (4.0 L) and water (5.0 L). The phases were separated at 40C. The organic layer (containing 4a) was washed with water (5.0 L) at 40C and then partially concentrated at atmospheric pressure, providing intermediate 4a, which is used in the next step without isolation. The resulting solution containing intermediate 4a was heated to 140C for 3 h and then allowed to cool to RT. The solids were filtered and dried in vacuo at 40 C. The product (1.00 kg) was dissolved in methanol (10.0 L) and 50 g of Darco was added. The mixture was heated at 60C for 1 h and then filtered at this temperature. The filtrates were allowed to cool slowly to RT. Water (5.0 L) was added slowly over 1 h. The slurry was cooled to 5 C and the solids were filtered and dried in vacuo at 40 C to yield 0.96 kg (85% overall yield) of the product [2R- [2oc (R*), 3cc]]-5- [ [2- [1- [3, 5-bis (trifluoromethyl) phenyl]- ethoxy]-3- (4-fluorophenyl)-4-morpholinyl] methyl]-1, 2-dihydro-3H-1, 2,4-triazol-3- one (i. e. 5- [ [2 (R)- [l (R)- [3, 5-bis (trifluoromethyl) phenyl]ethoxy]-3(S)-(4-fluorophenyl) -4-morpholinyl] methyl]-1, 2-dihydro-3H-1, 2, 4-triazol-3-one). Intermediate 4a: [a] D25=+84 (c=1.02, methanol) ;'H NMR (400 MHz, CDC13) 8 7. 64 (s, 2H), 7.34 (brt, J~7, 2H), 7.16 (s, 1H), 7.03 (t, J = 8. 4,2H), 5.8 (very br s, 2H), 4.88 (q, J = 6. 6,1H), 4.33 (d, J = 2. 8, 1H), 4.24 (td, J = 11. 6,2. 0, 1H), 3.77 (s, 2H), 3.66 (ddd, J= 11.6, 3.2, 1.6, 1H), 3.46 (d, J= 2.8, 1H), 3.31 (d, J = 14.5, 1H), 2.96 (brd, J= 11.6, 1H), 2.59 (d, J = 14.5, 1H), 2.50 (td, J = 12.1, 3.2, 1H), 1.47 (d, J = 6.6, 3H). Anal. Calc. for C24H2sF7N404 : C, 50.89 ; H, 4.45 ; F, 23.48 ; N, 9.89. Found: C, 50.48 ; H, 4.40 ; F, 23.43 ; N, 9.84. Final product la : Mp: 255 C ; [alpha] = +69 (c=1.00, methanol) ;'H NMR (400 MHz, CD30D) 8 7.70 (s, 1H), 7.51 (m, 2H), 7.32 (s, 2H), 7.04 (t, J= 8.7, 2H), 4.94 (q, J= 6.3, 1H), 4.35 (d, J= 2.8, 1H), 4.28 (td, J = 11. 5,2. 8, 1H), 3.66 (ddd, J = 11. 5,3. 3,1. 6, 1H), 3.54 (d, J = 14. 3, 1H), 3.48 (d, J = 2.8, 1H), 2. 88 (br d, J = 11. 9,1H), 2.86 (d, J = 14.3, 1H), 2.49 (td, J = 11. 9,3. 6, 1H), 1.44 (d, J = 6.3, 3H) ;"C NMR (100 MHz, CD30D) 8 164.1 (d, J = 245.9), 158. 7,147. 6,147. 0,134. 1 (d, J= 3.1), 132.7 (d, J= 33.4), 132.4 (d, J= 8.0), 127.8 (m), 124.6 (q, J= 272.0), 122.3 (m), 116.1 (d, J = 21.6), 97.1, 73.7, 70.5, 60.4, 53.6, 52.2, 24.7. Anal. Calc. for C23H2lF7N403 : C, 51.69 ; H, 3.96 ; F, 24.88 ; N, 10.48. Found: C, 51.50 ; H, 3.82 ; F, 24.73 ; N, 10.44. HRMS : 534. 1480 (meas. ); 534.1502 (calc. for C23H21F7N4O3).
at 135 - 137℃; for 2h; To a stirred mixture of (2R,3S)-2-{(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy} -3-(4-fluorophenyl) morpholine 4- methylbenzenesulphonate (10 g), powdered potassium carbonate (8 g) in dimethyl sulfoxide (40 ml) was added a solution of N-methylcarboxyl-2-chloroacetamidrazone (2.9 g) in dimethyl sulfoxide (40 ml) at 20-230C over 20-30 minutes. After stirring the reaction mixture at the same temperature for 1 hour, the reaction mixture was quenched with water (80 ml) and extracted with toluene (100 ml). The organic layer was washed twice with water (50 ml) and concentrated at atmospheric pressure upto maximum extent. The viscous liquid residue was heated at 135-1370C for 2 hours to get the solid residue. After completion of reaction , toluene (50 ml) was added and the slurry was cooled to room temperature. Then it was filtered, washed with toluene (20 ml). The wet solid was dissolved in methanol (70 ml) at 5O0C and treated with activated carbon (1 g) at 60-620C for 1 hour, filtered and washed with methanol (30 ml). The combined filtrate was cooled to 250C and water (50 ml) was added slowly over I hour. The slurry was stirred at 25-3O0C for 1 hour and filtered. The wet solid was washed with 2:1 mixture of methanol : water (30 ml) and dried at 5O0C under reduced pressure to get the title compound. Yield: 6 g HPLC purity:99.8 %
  • 3
  • [ 219821-37-1 ]
  • [ 170729-80-3 ]
YieldReaction ConditionsOperation in experiment
98.4% In 5,5-dimethyl-1,3-cyclohexadiene; for 3h;Reflux; The product of the previous step is xylene (30ml) Reflux 3h to complete reaction. Cooled with stirring, filtered and washed with toluene. Filter cake and methanol (100ml), reflux to the solution, stirring cooling, ice bath stirring 20min, filtration, washing, drying white solid V (11.1 g, 98.4%).
97.7% In 5,5-dimethyl-1,3-cyclohexadiene; at 130 - 139℃; for 4h; The reaction bottle (II) compound is added (100.0 g), anhydrous potassium carbonate (102.0 g), dimethyl sulfoxide (200 ml), xylene (200 ml), 0 - 10 C stirring for 10 - 15 minutes, adding the compound (III) (39.0 g), stirring for about 16 hours, plus xylene and water, stirring 10 minutes, layered, the organic layer is washed with water, dried with anhydrous sodium sulfate, filtered, washing the filter cake for xylene, filtrate 130 C -139 C reaction 4 hours. Stirring cooling to 0 C -10 C, filtering, the filter cake is xylene washing. Solid vacuum drying 20 hours, to obtain compound (I) 109.0 g, molar yield 97.7%. HPLC: 99.97%, total isomer 0.017%.
50 - 60% With sodium carbonate; In N,N-dimethyl-formamide; xylene; at 120 - 130℃; for 3h;Product distribution / selectivity; Alternate process for APT-5:APT-4 was dissolved in 3V of xylene:DMF (2.5:0.5) and 0.25g sodium carbonate was added to the reaction mass and heated to 120 to 130 0C for 3 hours. After completion of reaction the reaction mass was cooled to 30 0C and 20 mL of ethyl acetate was added. *The pH of organic layer was adjusted to 6 with dil.HCl (1 :10). The organic layer was washed with water followed by brine. Charcoal (0.05 g) was added to the organic layer, stirred, filtered through hyflow and distilled to the syrupy mass. Heptane (30 mL) was added to the mass and heated to 500C. and stirred. The mass was cooled to 30 0C and filtered and washed the wet cake with hexane .Wet wt=0.6g.0.6g of crude aprepitant and 6 mL of ethyl acetate: methanol (1.5:0.15) was stirred, heated to reflux for dissolution and cooled to 500C. 18mL of hexane was added slowly for 30 minutes and stirred for 30hours. The reaction mass cooled to room temperature and stirred for 2hours. The solid was filtered and washed with hexane. The solid was dried under vacuum for 8hours.Wt=0.35gPurity: 99.5 % Yiled=50-60%
With N-ethyl-N,N-diisopropylamine; In xylene;Reflux; Compound of formula- VIII (10 grams) was taken in a mixture of xylene (55.5 ml) and N,N-diisopropylethyl amine (34.4 ml) and then refluxed for 4-6 hrs then cooled the reaction mixture. Filtered the precipitated compound and washed with xylene (5 ml) to get the crude Aprepitant. The crude compound was crystallized from a mixture of methanol and water to get Aprepitant. Yield: 6.5 grams.
In xylene; at 135 - 140℃; for 5h;Product distribution / selectivity; Example 6; Process for the preparation 5-[2(R)-[l(R)-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]- 3(S)-(4-fluorophenyl)morpholin-4-ylmethyl]-3,4-dihydro-2H-l,2,4-triazol-3-one :APT-4 was dissolved in xylene and heated the reaction mass to 135 to 140 0C for about 5 hours. After completion of reaction the reaction mass was cooled to 30 0C. The solid was filtered and washed with 300 mL of heptane to get APT-5 as crude. Wet wt=75g
With potassium hydroxide; In ethanol; water; at 90 - 100℃; for 0.2h; EXAMPLE 8 A mixture of starting materials (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride 2 (5 g; 10.5 mmol) and potassium carbonate (2.7 g; 20 mmol) was cooled to about 10 C. in tha solvent DMF. A slurry of amidrazone 3c (1.91 g; 11.6 mol) dissolved in DMF was added. The reaction mixture was stirred at room temperature. The mixture was extracted with ethyl acetate and water and phases were separated after the reaction was completed. The layer of ethyl acetate was washed with saturated aqueous solution of NaCl and combined. Ethyl acetate was concentrated under reduced pressure to obtain oily substance 4c, which was dissolved in a mixed solution of ethanol and water (1:1) and 2 g of solid potassium hydroxide was added. The reaction was performed at 90-100 C. for about 2 hours. The majority of ethanol was removed by concentrating under reduced pressure. The solution left was poured into a large amount of ice water, and a large amount of solid precipitated, which was then purified according to the method of Example 1 to obtain aprepitant (336 g, yield 60%).
With water; In dimethyl sulfoxide; at 90 - 110℃; To a 1L round bottom flask charged the compound of formula II (40g), dimethylsulfoxide (100ml) and potassium carbonate (35g) and stirred the reaction mixture for 15 minutes at a temperature of 20C to 30C. The reaction mixture is then cooled to a temperature of 10C to 30C. To the reaction mixture then charged the compound of formula III (14.9g) and stirred the reaction mixture at a temperature of 10C to 30C for 4 to 5 hour. Then charged water (195 ml) to the reaction mixture and heated at a temperature of 90C to 110C and maintained for 6-10 hours. To the resulting reaction mixture then added water and stirred for 15 minutes at a temperature of 90C to 95C. The reaction mixture is then cooled to the temperature of 40C to 45C and then added 50% acetic acid solution in water (~41ml) to the reaction mixture and stirred for 15 minutes, at this stage pH of the reaction mixture is 6 to 7. The reaction mixture is then heated at a temperature of 65 C to 90C with stirring for 30 minutes and then cooled to a temperature of 20C to 30C and maintained with stirring for 1 hour to obtain the solid. Filter the solid obtained under vacuum and washed with water and suck dry to obtain the solid. To the solid then add toluene (280ml) and heated the reaction mixture at a temperature of 75C to 95C for 1 hour. The reaction mixture is then cooled to a temperature of 20C to 35 C with stirring for 30 minutes to yield the solid. Filter the solid obtained under vacuum and washed with toluene and suck dry to obtain aprepitant. Yield 79% and purity 99.8%.
8.15 g With 4-methyl-2-pentanone; for 7h;Reflux; Potash (5. 10g, 36.90 mmol, 1.75 equiv.) was added to a suspension of the hydrochloride 11 ( 10 g, 21 . 10 mmol) in DMF (20 ml) at the laboratory temperature and the suspension was stirred for 30 mins and then addition of a suspension of amidrazone (3.83 g, 23.19 mmol, 1 .1 equiv.) in DMF (10 mL) was started within ca. 10 min. Stirring at the laboratory temperature followed for 4 h. The reaction was monitored with HPLC. The reaction mixture was then diluted with MIBK ( 100 ml) and water ( 100 ml) and brine (20 ml) were added under intensive stirring; the phases were thoroughly mixed and then separated. The aqueous phase was still washed with MIBK (50 ml). The combined organic phase was washed with water (50 ml) and brine (20 ml). The solution of the intermediate obtained this way was heated up to boil and the residual water was removed by azeotropic distillation. Reflux for 17 h, the mixture was concentrated by distillation, ca. 85 mL of MIBK removed. The solution was slowly cooled to the laboratory temperature while being stirred and then cooled to 5 C; crystals were removed by filtration and washed with cold MIBK (3 x 10 ml) and air-dried. 8. 15 g (72%) of crystals were obtained, purity 99.80 %, polymorph form I.
In 5,5-dimethyl-1,3-cyclohexadiene; at 135 - 141℃; for 2h;Inert atmosphere; The specific process of step (2) is:1) The 2R- [1R- [3,5- bis (trifluoromethyl) phenyl] ethoxy] -3S- (4- fluorophenyl) -4- (N- methoxycarbonyl Ki -2-amino Ethylhydrazone) - morpholine in toluene was transferred to a 50 L reactor and heated under nitrogen atmosphere and stirred at 135-141 C for 2 hours. After the reaction, the solution was slowly cooled to 2-8 C and stirred for 60 min.2) filter, wash the cake with xylene, dry, and then mixed with methanol and purified water, washing cake, white towhite crystalline powder;3) The resulting crystalline powder was transferred to a vacuum oven for drying, vacuum ?-0.08Mp, temperature 52-58 C, drying under reduced pressure 8-10h to constant weight, regular rolling, 2h recording of primary temperature, vacuum , Received a sharp piclidine

  • 4
  • [ 1228018-30-1 ]
  • [ 155742-64-6 ]
  • [ 219821-37-1 ]
YieldReaction ConditionsOperation in experiment
The compound of formula VII (20 grams) was converted in to its free base by treating it with 10% sodium hydroxide solution. The free base was extracted into dichloromethane (50 ml) then the solvent distilled off to get the free base of formula- VII. The free base was dissolved in dimethylsulfoxide (60 ml) and added sodium carbonate (10 grams). To the above mixture a solution of <strong>[155742-64-6]N-methylcarboxy-2-chloroacetamidrazone</strong> dissolved in DMSO (40 ml) was added. The reaction mixture was stirred for 30-60 min and then quenched with aqueous sodium carbonate solution and then stirred for 2 hours. The solid obtained was filtered and washed with water. The wet solid stirred in water (100 ml) for 60 min. Filtered the solid, washed with water and dried to get the title compound as an amorphous solid. The amorphous compound of formula- VIII is characterized by its PXRD spectrum shown in figure-4: Yield: 21 grams. Purity: 98.65 % by HPLC.
  • 5
  • [ 171482-05-6 ]
  • [ 155742-64-6 ]
  • [ 219821-37-1 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 10 - 20℃; 8 EXAMPLE 8 EXAMPLE 8 A mixture of starting materials (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride 2 (5 g; 10.5 mmol) and potassium carbonate (2.7 g; 20 mmol) was cooled to about 10° C. in tha solvent DMF. A slurry of amidrazone 3c (1.91 g; 11.6 mol) dissolved in DMF was added. The reaction mixture was stirred at room temperature. The mixture was extracted with ethyl acetate and water and phases were separated after the reaction was completed. The layer of ethyl acetate was washed with saturated aqueous solution of NaCl and combined. Ethyl acetate was concentrated under reduced pressure to obtain oily substance 4c, which was dissolved in a mixed solution of ethanol and water (1:1) and 2 g of solid potassium hydroxide was added. The reaction was performed at 90-100° C. for about 2 hours. The majority of ethanol was removed by concentrating under reduced pressure. The solution left was poured into a large amount of ice water, and a large amount of solid precipitated, which was then purified according to the method of Example 1 to obtain aprepitant (336 g, yield 60%).
Stage #1: [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride With potassium hydroxide In N,N-dimethyl-formamide for 0.5h; Stage #2: N'-(1-amino-2-chloroethylidene)hydrazine carboxylic acid methyl ester In N,N-dimethyl-formamide for 4.16h; 1 Potash (5. 10g, 36.90 mmol, 1.75 equiv.) was added to a suspension of the hydrochloride 11 ( 10 g, 21 . 10 mmol) in DMF (20 ml) at the laboratory temperature and the suspension was stirred for 30 mins and then addition of a suspension of amidrazone (3.83 g, 23.19 mmol, 1 .1 equiv.) in DMF (10 mL) was started within ca. 10 min. Stirring at the laboratory temperature followed for 4 h. The reaction was monitored with HPLC. The reaction mixture was then diluted with MIBK ( 100 ml) and water ( 100 ml) and brine (20 ml) were added under intensive stirring; the phases were thoroughly mixed and then separated. The aqueous phase was still washed with MIBK (50 ml). The combined organic phase was washed with water (50 ml) and brine (20 ml). The solution of the intermediate obtained this way was heated up to boil and the residual water was removed by azeotropic distillation. Reflux for 17 h, the mixture was concentrated by distillation, ca. 85 mL of MIBK removed. The solution was slowly cooled to the laboratory temperature while being stirred and then cooled to 5 °C; crystals were removed by filtration and washed with cold MIBK (3 x 10 ml) and air-dried. 8. 15 g (72%) of crystals were obtained, purity 99.80 %, polymorph form I.
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In 5,5-dimethyl-1,3-cyclohexadiene; dimethyl sulfoxide at 20 - 25℃; Inert atmosphere; wherein the specific process of step (1) is:1) The 100L reaction vessel with nitrogen, dimethyl sulfoxide, (2R, 3S) -2 - [(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy (3-fluorophenyl) morpholine hydrochloride and xylene, stirred and dissolved, potassium carbonate was added, stirred at20-25 ° C, and then (AR-3) 2- (2-chloro-1- Iminoethyl) hydrazinecarboxylate, benzyltriethylammonium chloride for 18-22h;2) After step 1) After the reaction was completed, xylene and water were added to the reaction system, and the mixture wasallowed to standat 37-43 ° C for 30 minutes. The mixturewas collected and separated. After the addition of saturated brine, the organic layer was added at 32-38 ° C After stirring for 5 min, the separatedlayers were collected and the organic phases were separated. The combined aqueous phase was transferred into a kettle. The xylene was added at 32-38 ° C for 5 min. Theaqueous phase was separated and the organic phase was combined. dried over anhydrous magnesium sulfate was stirred for 30min, the drying agent was removed by filtration, leaching using xylenewash, to give a pale yellow filtrate to give 2R- [1R- [3,5- bis (trifluoromethyl) phenyl] ethoxy] - 3S- (4-fluorophenyl) -4-(N-methoxycarbonyl-2-aminoethhydrazono) -morpholine in xylene.
With potassium carbonate In 5,5-dimethyl-1,3-cyclohexadiene; dimethyl sulfoxide at 0 - 10℃; for 16h; 1 Example 1 The reaction bottle (II) compound is added (100.0 g), anhydrous potassium carbonate (102.0 g), dimethyl sulfoxide (200 ml), xylene (200 ml), 0 - 10 °C stirring for 10 - 15 minutes, adding the compound (III) (39.0 g), stirring for about 16 hours, plus xylene and water, stirring 10 minutes, layered, the organic layer is washed with water, dried with anhydrous sodium sulfate, filtered, washing the filter cake for xylene, filtrate 130 °C -139 °C reaction 4 hours. Stirring cooling to 0 °C -10 °C, filtering, the filter cake is xylene washing. Solid vacuum drying 20 hours, to obtain compound (I) 109.0 g, molar yield 97.7%. HPLC: 99.97%, total isomer 0.017%.

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