* 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.
With hydrogen In methanol; toluene at 20℃; for 1.5 h;
hi yet another variation, the reduction of the double bond and amide carbonyl of (E)-N-((i?)-l-naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-acrylamide is carried out in a stepwise manner. Either the carbonyl group or the alkene double bond can be reduced first. For example, the reduction of the alkene double bond is achieved by hydrogenation in the presence of a metal catalyst.[0123] A suspension of (E)-N-((i?)-l-naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)- acrylamide (1.0 equiv.; 0.67 mmol; 250 mg) and Pd/C 10 wtpercent (25 mg) was stirred in a mixture of methanol and toluene (7 mL/lmL). The reaction flask was evacuated and back filled using a hydrogen filled balloon (three times). The reaction mixture is stirred at room temperature and the progress of the reaction was monitored using high performance liquid chromatography. After 90 minutes, the reaction mixture was filtered over a bed of celite and the solvent from the filtrate was removed in vacuo. The resulting solid was dried overnight at 450C using a vacuum oven. Isolated yield: 91.2percent (229 mg). The identity of the amide was confirmed by 1H NMR and mass spectrometry. (400MHz, CDCl3) δ ppm 1.60 (d, 3H) 2.39- 2.53 (m, 2H) 2.96-3.13 ( m, 2H) 5.55 (br. S., IH) 5.87-5.96 (m, IH) 7.29-7.38 (m, 2H) 7.39- 7.46 (m, 4H) 7.46-7.55 (m, 2H) 7.76-7.82 (m, IH) 7.83-7.89 (m, IH) 8.00-8.07 (m, IH) and HRMS (M+l): 372.1
Stage #1: With thionyl chloride; N,N-dimethyl-formamide In toluene at 25 - 75℃; for 2 h; Stage #2: With triethylamine In dichloromethane; toluene at 0 - 5℃; for 1.5 - 2 h;
Example 3: Preparation of N-[I -(R)-(I -naphthyl) ethyl]-3-[3-(trifluoromethyl) phenyl]-l- propanamide(X). Thionyl chloride (6.69 ml, 0.0917 moles) was added dropwise to a solution of 3-[3- (trifluoromethyl) phenyl]-2-propanoic acid (10 gm, 0.045 moles), dimethylformamide (0.5 ml) and dry toluene (100 ml) at 25 - 30 0C under nitrogen atmosphere. The reaction mixture was heated to 70 - 75 0C for 2.0 h. After 2.0 h the toluene was distilled under reduced pressure at 50 - 55 0C. Fresh toluene (100 ml) was further added to reaction mixture to get clear solution. This solution was added dropwise to a solution of ( 1 R)- 1(1- naphthyl)ethane amine (4.88 gm, 0.0285 moles), triethylamine (1 1.53 gm, 0.1 14 moles) in methylene chloride (200 ml) at 0 - 5 0C for 1.5 - 2.0 h under nitrogen atmosphere. After completion of the reaction (by TLC)5 water (50 ml) was added in the reaction mixture and the layers were separated, the organic layer was washed again with water (50 ml). The organic layer was evaporated under reduced pressure to get a crude solid, which was then dissolved in a mixture of hexane (25 ml) and ethyl acetate (30 ml) at reflux and the cooled to O - 5 0C to get solids which was filtered and dried at 50-550C to get the title compound (10 gm, 70.87 percent).Melting point: 108-1110C.IR (KBr) (ν(max), cm-1): 3298.38, 3082.35, 2970.48, 2357.09, 1643.41, 1554.68, 1450.52,1330.93, 1122.61, 1072.48, 798.56, 775.41, 705.97.1H NMR (CDCl3-DMSO-d6) (δ ppm): 7.26 - 8.03 (HH, m), 5.91 (IH, m), 5.58 (IH, bd),3.03 (2H, m), 2.46 (2H, m), 1.60 (3H, d).MS (m/z): 372 [M+l].
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 7, p. 2187 - 2194
[2] Patent: WO2008/117299, 2008, A1, . Location in patent: Page/Page column 16-17
[3] Advanced Synthesis and Catalysis, 2013, vol. 355, # 1, p. 47 - 52
[4] Patent: WO2008/58235, 2008, A2, . Location in patent: Page/Page column 26
[5] Patent: WO2008/35381, 2008, A2, . Location in patent: Page/Page column 26-27
3
[ 1095393-72-8 ]
[ 1005450-55-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydrogen In methanol at 20℃; for 1 h;
Cinacalcet is obtained by reducing the alkyne-amide precursor. In one embodiment, the alkyne was reduced by metal catalyzed hydrogenation. Specifically, to a methanolic solution (7 mL) of 3-(3-trifluoromethyl-phenyl)-propynoic acid ((R)-I- naphthalen-l-yl-ethyl)-amide (1.0 equiv.; 0.68 mmol; 250mg) in a two necked round bottom <n="43"/>flask was added Pd/C 10 wtpercent (28 mg). The flask was evacuated and back filled using a hydrogen filled balloon (three times) before stirring the reaction mixture at room temperature under a positive pressure of hydrogen. Progress of the reaction was monitored by HPLC and LC/MS, with complete reduction of the alkyne group after 1 hour. The reaction was stopped by filtering the reaction mixture over a bed of celite, and the solvent was removed to give a solid that was further dried at 450C overnight in vacuo. Product identity was confirmed by 1H NMR and LC/MS. A quantitative yield of the product was obtained (224mg). (400MHz, CDCl3) δ ppm 1.60 (d, 3H) 2.39-2.53 (m, 2H) 2.96-3.13 ( m, 2H) 5.55 (br. S., IH) 5.87-5.96 (m, IH) 7.29-7.38 (m, 2H) 7.39-7.46 (m, 4H) 7.46-7.55 (m, 2H) 7.76-7.82 (m, IH) 7.83-7.89 (m, IH) 8.00-8.07 (m, IH) and LC/MS (M+l): 372.0.
With potassium carbonate; In acetonitrile; for 22h;Heating / reflux;
The acid chloride (III) is dissolved in Acetonitrile [4 volumes per gram of (III)]. (R)-1-Naphtylethyl amine (1.0 eq) and anhydrous K2CO3 (1.0 eq) are added and the reaction mixture is heated to reflux temperature for about 22 hours. Then salts are filtered out and the solvent is removed under reduced pressure. The residue is dissolved in Toluene (7 volumes per gram of residue after evaporation) and 32% HCl (2 volumes per gram of residue after evaporation) to obtain pH=0-1. The organic phase is then washed with water (2-3×1.5 volumes per gram of residue after evaporation). The solvent is evaporated under reduced pressure until dryness to give the amide (IV).
With triethylamine; In dichloromethane; at 0 - 5℃;Product distribution / selectivity;
Example 17: Preparation of (R)-N-(l-naphthvIen-l-vIethvO-3-f3IYtrifluoromethyl- phenyl] propionamide; A mixture of m-trifluoromethylhydrocinnamic acid (5g) in toluene (25ml) and thionyl chloride (2.5ml) was initially stirred at room temperature for half an hour and then heated at 100-1100C for 4-5 hours. The solvent was distilled and reaction mass was cooled to room temperature and to this methylenechloride (20ml) was added. In a separate flask R-(+)-l(l-naphthyl)ethylamine (3.9g) was taken in methylenedichloride(25 ml), cooled to 0-5 0C and triethylamine (4.8 ml) was added at 0-50C. To this chilled solution, acid chloride solution in methylenedichloride prepared above, was added at 0-50C and stirred. After completion of reaction, chilled concentrated hydrochloric acid (20 ml) was added, stirred and the layers were separated. The organic layer was washed with water and solvent was distilled to isolate 7.96 g of (R)-N-(I- naphthylen- 1 -ylethyl)-3-[3 [(trifluoromethyl- phenyl] propionamide.
With sodium carbonate; In tert-butyl methyl ether; water; at 5 - 25℃; for 1.5h;Product distribution / selectivity;
Example 18: Preparation of (R)-N-(l-naphthaIen-l-yl-ethyl)-3-(3-trifluoromethyl-phcnvI)- propionamide; A mixture of m-trifluoromethylhydrocinnamic acid (24Og, 1.1 mole), toluene (1.2 1) and thionylchloride (120ml) was heated to 85-900C for 4 hours. Toluene and thionylchloride were distilled off under reduced pressure. After complete removal of thionylchloride, methyl- tertiarybutylether (1.1 litre) was added to the acid chloride at 20-250C. This Acid chloride solution in methyltertiarybutylether was added to a prestirred mixture of aqueous sodium carbonate (199g in 800ml of water), R-(+)-l(l-naphthyl)ethylamine (179g) and methyltertiarybutyl- ether (1.63 1) at 5 to 100C over of 30 minutes. Stirring was continued for 1.0 hour at 20-250C, methyltertiarybutylether layer was separated, washed with aqueous sodium carbonate, IN hydrochloric acid (720ml) and demineralized water (720ml). The organic layer was distilled under vacuo and dried in oven at 45-5O0C to afford 35Og of the title compound.
With triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h;
Weigh 15.70g R-1-(1-naphthyl)ethylamineand 13. 91 g of triethylamine, Was dissolved in 150 ml of dichloromethane, The acid chloride obtained in the previous step was dissolved in 50 ml of dichloromethane, Slowly dripping into the reaction system, Control the reaction temperature is 0 ~ 20 C, 30min reaction is completed, Adding 200ml dilute hydrochloric acid solution to quench the reaction, The organic phase was washed once with 200 ml of saturated brine, Dried over anhydrous sodium sulfate, evaporated to remove the solvent, the solid added to 300ml n-hexane beating, stirring and filtering, The solids were dried at 50 C overnight after vacuum drying N - ((1R) -1 - (1-naphthyl) ethyl) -3- (3- (trifluoromethyl) phenyl) propanamide as a white solid
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 10h;
LiAlH4 (114.0 mg, 3.0 mg) was weighed into a 25 mL Shrek tube, and under argon, THF (3 mL) was added and stirred.The temperature of the mixture was lowered to 0 C, and (R)-N-(1-naphthylethyl)-3-(3-trifluoromethylphenyl)propanamide (7) (210.0 mg, 0.6 mmol) was slowly added dropwise. THF (2 mL) solution.The temperature of the reaction mixture was raised to room temperature, and the reaction was stirred for 10 h.After completion of the reaction, a saturated sodium potassium tartrate solution (10 mL) was added to the reaction mixture, and stirring was continued for 6 h.The layers were separated and the aqueous extracted with dichloromethane (3×20 mL).The organic phase was washed with brine (30 mL)Finally purified by silica gel column chromatography (dichloromethane: ethyl acetate / 1:2).Obtained a colorless oily liquid (R) - Cinacalcet(185.5 mg, 92% yield, >99% ee).
The amide (IV) is dissolved in THF [30 volumes per gram of amide (IV)]. The solution is cooled to 0 C. and a 1M solution of BH3 in THF (2.5 eq) is added drop-wise. The reaction mixture is allowed to warm to room temperature and stirred at this temperature for 16 hours. Then it is quenched carefully with 6.0M aqueous HCl and heated to reflux for 1 hour. After cooling to room temperature, the mixture is basified with 1.0N aqueous NaOH. The phases are separated and the aqueous layer is extracted with EtOAc. The combined organic phase is dried over MgSO4, filtered and the solvent is removed under reduced pressure to obtain Cinacalcet base which can be used as it is for the next step or can be purified by column chromatography on silica gel using a gradient from Dichloromethane to a mixture of 2.5-5% Methanol/97.5-95% Dichloromethane as eluent.
EXAMPLE 8: PROCESS FOR THE PREPARATION OF CINACALCET:Tetrahydrofuran (50 ml) and N-[(1 R)-1-(1-napthyl) ethyl]-3-(3- trifluoromethyl) phenyl] propanamide (10 g) were taken into a round bottom flask followed by stirring for about 5 minutes under nitrogen atmosphere. Lithium aluminium hydride (1.73 g) was added over a period of 20 minutes followed by heating to about 64 0C. The resultant reaction solution was stirred for about 3 hours followed by cooling to about 10 C. The reaction solution was quenched by the addition of ethyl acetate (150 ml) followed by addition of water (150 ml) over a period of about 15 minutes. The organic layer was separated, and the aqueous layer extracted with ethyl acetate (50 ml). The combined organic layer was washed with saturated sodium chloride solution (2*50 ml). The organic layer was separated followed by drying over anhydrous sodium sulphate (10 g). The solvent was distilled completely at about 40 0C under vacuum to afford 7.5 g of the title compound.Purity by HPLC: 90.33%.Specific optical rotation (SOR) : [alpha]D25 = + 9.62. (C =1% Methanol). Mass (m/z) : 357 amu.
EXAMPLE 9: PREPARATION OF CINACALCET HYDROCHLORIDE STARTING FROM N-[(1 R)-1-(1 -NAPTHYL) ETHYL]-3-(3-TRIFLUROMETHYL) PHENYL] PROPANAMIDE WITHOUT ISOLATING CINACALCET FREE BASE:N-[(1 R)-1-(1-napthyl) ethyl]-3-(3-trifluromethyl) phenyl] propanamide (200 g) was taken into a round bottom flask and toluene (2000 ml) was added to it. The contents were heated to about 50 to 600C and checked for clear dissolution. Vitride (670 ml) was added to the above reaction mass between 500C to 600C. The reaction mass was stirred at about 50 to 600C for 25-30 min. Reaction EPO <DP n="30"/>completion was checked using thin layer chromatography. After the rection was completed, the reaction mass was cooled to 0-50C. A solution of 10% sodium potassium tartarate (4000 ml) precooled to 5-100C was added slowly to the above reaction mass below 15C. The reaction mass was stirred at 25-35C for 15-30 min. The organic layer was separated and the aqueous layer was extracted into toluene (1000 ml). The combined organic layer was washed with 1% acetic acid solution (2 x 1000ml) at 50-60C followed by washing with water (2 x 1000 ml) at 50-600C. The organic layer was distilled off completely at below 600C under vacuum. The residue obtained was cooled to 25-35C and ethyl acetate (200 ml) was added to it. The solution was stirred for 5-10 minutes and then filtered through Hyflow bed, and the bed was washed with ethyl acetate (400 ml). The filtrate was distilled off completely under vaccum at 50-600C.20 g of the crude obtained above and ethyl acetate (20 ml) were taken into another round bottom flask and stirred for 10 minutes at 25 to 35 0C. The mixture was heated to 50 to 60 0C and HCI dissolved in ethyl acetate (20 ml) was added at the same temperature slowly. The reaction mass was stirred for about 20 minutes at 50 to 60 C and then 300 ml of di-idopropyl ether was added to it. The reaction mass was maintained at the same temperature for another 20 minutes and then 200 ml of water was added to it. The reaction contents were stirred for another 20 minutes and then cooled to 25 to 35 C. The reaction mass was maintained at 25 to 35 0C for about 60 minutes and then filtered. The filtered solid was washed with di-idopropyl ether (40 ml) and the wet solid was dried at about 70 C for 6 to 8 hours to yield 16.9 g of the title compound. Purity By HPLC: 99.5%. Impurity 1 : (Desfluro impurity): 0.04%. Impurity 2: (at RRT 0.90): 0.17%. Impurity 3: (amide of Formula V): 0.05%.
Step (iii) Preparation of (R)-alpha-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-1-naphthalene methanamine [Cinacalcet base]: Compound-III (15.0g) was dissolved in tetrahydrofuran and 7.5g of sodium borohydride was added to the solution. The reaction mass was cooled to 5C and 30.0mL of boron trifluoride-etherate was added drop wise. The reaction mass was then heated to 30C and stirred for 20 h. The reaction mass was quenched in 10% aqueous hydrochloric acid solution. The reaction mass was then refluxed for 2 h and cooled to 30C. To this reaction mixture was added ethyl acetate. Phase separation was done. The organic phase was washed with water, 10% sodium bicarbonate solution and water successively. The organic phase was dried over sodium sulphate and the solvent was evaporated to dryness to obtain cinacalcet free base. Step (iii) Preparation of (R)-alpha-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-1-naphthalene methanamine [Cinacalcet base]:; Compound-III (15.0g) is dissolved in tetrahydrofuran and 7.5g of sodium borohydride is added to the solution. The reaction mass is cooled to 5C and 30.0mL of boron trifluoride-etherate is added drop wise. The reaction mass is then heated to 30C and stirred for 5 h. The reaction mass is quenched in 10% aqueous hydrochloric acid solution. The reaction mass is then refluxed for 2 h and cooled to 30C. Ethyl acetate is added to this reaction mixture. Phase separation is carried out. The organic phase is washed with water, 10% sodium bicarbonate solution and water successively. The organic phase is dried over sodium sulphate and the solvent is evaporated to dryness to obtain cinacalcet free base.; Preparation of (R)-alpha-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-1- naphthalene methane amine [Cinacalcet base]: Compound-III (15.0g) is dissolved in tetrahydrofuran and 7.5g of sodium borohydride was added to the solution. The reaction mass is cooled to 5C and 30.0mL of boron trifluoride-etherate is added drop wise. The reaction mass is then heated to 30C and stirred for 20 h. The reaction mass is quenched in 10% aqueous hydrochloric acid solution. The reaction mass is then refluxed for 2 h and cooled to 30C. To this reaction mixture ethyl acetate is added and phase separation is performed. The organic phase is washed with water, 10% sodium bicarbonate solution and water successively. The organic phase is dried over sodium sulphate and the solvent is evaporated to dryness to obtain cinacalcet free base.
Step (iii) Preparation of (R)-alpha-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-1-naphthalene methane amine [Cinacalcet base]:; Dissolve 5.0gm of compound-III in tetrahydrofuran and add 17.0gm Lithium aluminium hydride to the solution under nitrogen. Cool the reaction mass to 10C ,stir at 10C for 2 hours and reflux for 2 hrs. Cool the reaction mass to 10C and slowly add water at 10C. Stir for 30.0 min. Distill out tetrahydrofuran below 40C. To this reaction mixture add ethyl acetate. Separate the organic phase. Wash the organic phase with 10% sodium bicarbonate solution and water successively. Dry the organic phase over sodium sulphate and then evaporate the solvent under vacuum to get title compound IV.; Step (iii) Preparation of (R)-alpha-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-1-naphthalene methane amine [cinacalcet base]:; Dissolve 5.0gm of compound-III in tetrahydrofuran and add 17.0gm Lithium aluminium hydride to the solution under nitrogen. Cool the reaction mass to 10C and stir at 10C for 2 hours and then at reflux for 2 hrs. Cool the reaction mass to 10C slowly add water at 10C. Stir for 30.0 min. Distill out tetrahydrofuran below 40C. To this reaction mixture add ethyl acetate. Separate the organic phase. Wash the organic phase with 10% sodium bicarbonate solution and water successively. Dry the organic phase over sodium sulphate and then evaporate the solvent under vacuum to get title compound IV.
Example 3: Preparation of N-[I -(R)-(I -naphthyl) ethyl]-3-[3-(trifluoromethyl) phenyl]-l- propanamide(X). Thionyl chloride (6.69 ml, 0.0917 moles) was added dropwise to a solution of 3-[3- (trifluoromethyl) phenyl]-2-propanoic acid (10 gm, 0.045 moles), dimethylformamide (0.5 ml) and dry toluene (100 ml) at 25 - 30 0C under nitrogen atmosphere. The reaction mixture was heated to 70 - 75 0C for 2.0 h. After 2.0 h the toluene was distilled under reduced pressure at 50 - 55 0C. Fresh toluene (100 ml) was further added to reaction mixture to get clear solution. This solution was added dropwise to a solution of ( 1 R)- 1(1- naphthyl)ethane amine (4.88 gm, 0.0285 moles), triethylamine (1 1.53 gm, 0.1 14 moles) in methylene chloride (200 ml) at 0 - 5 0C for 1.5 - 2.0 h under nitrogen atmosphere. After completion of the reaction (by TLC)5 water (50 ml) was added in the reaction mixture and the layers were separated, the organic layer was washed again with water (50 ml). The organic layer was evaporated under reduced pressure to get a crude solid, which was then dissolved in a mixture of hexane (25 ml) and ethyl acetate (30 ml) at reflux and the cooled to O - 5 0C to get solids which was filtered and dried at 50-550C to get the title compound (10 gm, 70.87 %).Melting point: 108-1110C.IR (KBr) (nu(max), cm-1): 3298.38, 3082.35, 2970.48, 2357.09, 1643.41, 1554.68, 1450.52,1330.93, 1122.61, 1072.48, 798.56, 775.41, 705.97.1H NMR (CDCl3-DMSO-d6) (delta ppm): 7.26 - 8.03 (HH, m), 5.91 (IH, m), 5.58 (IH, bd),3.03 (2H, m), 2.46 (2H, m), 1.60 (3H, d).MS (m/z): 372 [M+l].
With potassium carbonate; dicyclohexyl-carbodiimide; In dichloromethane; for 3.5h;Product distribution / selectivity;
EXAMPLE 6: ALTERNATE PROCESS FOR THE PREPARATION OF N-[(1 R)-1- (1 -NAPTHYL) ETHYL]-3-(3-TRIFLUROMETHYL) PHENYL] PROPANAMIDE WITHOUT USING HOBT:3-[3-(trifluoromethyl) phenyl] propanoic acid (2 g) and dichloromethane (10 ml) were charged into a round bottom flask and stirred for about 5 minutes. To the reaction solution, DCC (2.3 g) dissolved in dichloromethane (500 ml) was added over a period of about 15 minutes. Potassium carbonate (1.24 g) was charged followed by addition of R-(+)-1-(1-naphthyl) ethylamine of Formula IV (1.5 g) dissolved in dichloromethane (10 ml) over about 15 minutes. The resultant reaction mixture was stirred for about 2 hours.After the completion of the reaction the by-product DCU was filtered through celite and washed with dichloromethane (5 ml) and the filtrate was distilled completely at about 39 0C under vacuum. To the residue 16 ml of n- hexane was charged followed by raising the temperature to about 70 0C. The resultant reaction solution was stirred for about 10-15 minutes and then cooled to 25 to 35 0C. The separated solid was filtered and washed with n-hexane (4 ml). The solid obtained was dried at about 75 0C under vacuum for about 9 hrs to afford 2.5 g of the title compound. Mass (m/z) : 371 amu.Purity By HPLC: 83.77%
With boric acid; In toluene; for 12h;Heating / reflux;Product distribution / selectivity;
Example 16: Preparation of (R)-N-(l-naphthaIen-l-yl-ethvI)-3-(3-trifluoromethyI-phenyI)- propionaniide; A mixture of m-trifluoromethylhydrocinnamic acid (5g), toluene (50ml), boric acid (7mg) and R-(+)-l(l-naphthyl)ethylamine (3.7g) was refluxed azeotropically for 12 hours and cooled to ambient temperature. The product was filtered, washed with lN-hydrochloric acid and water and dried to afford 8.5g of (R)-N-(l-Naphthalen-l-yl-ethyl)-3-(3-trifliotaiotaoromethy]-phenyl)- propionamide.Melting point: 116-119C MS (m/z): 372.2[M+1]IR (KBr) (vmax, cm'1): 3301(N-H stretching), 1643(C=O stretching), 1556(aromatic C=C stretching).1H NMR (CDCl3) (deltapptn): 7.2-8.0(1 IH, m, Ar-H), 5.84(1H, m, C-H), 5.84(1H, m, N-H), 3.00(2H, m, CH2), 2.39(2H, t, CH2), 1.54(3H, m, CH3). <n="28"/>13C-NMR (CDCl3) (deltappm): 20.57, 31.27, 37.87, 44.60, 122.49, 122.82, 123.10, 123.30, 124.99, 125.17, 125.53, 125.89, 126.56, 128.36, 128.80, 128.89, 131.02, 131.94, 133.88, 138.08, 141.72, 170.38, 130.52.
2-bromo-N-((R)-1-naphthalen-1-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-propionamide[ No CAS ]
[ 1005450-55-4 ]
Yield
Reaction Conditions
Operation in experiment
Example 20: Preparation of (R)-N-(l-Naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl- phenvQ-propionamideZinc powder (0.22g) was added to a mixture of (R)-2-bromo-N-(l-naphthalen-l-yI-ethyl)-3-(3- trifliotaiotaorornethyl-phenyl)~piOpionamide (0.5g), acetic acid (2ml) and demineralized water (0.1ml) at 20-250C. Reaction mass was then heated at 60-650C for 4.5 hours. Acetic acid was distilled off under reduced pressure. To the residue, toluene and cone, hydrochloric acid were added, stirred for 10 minutes and the layers were separated. Organic layer was washed with water and toluene was removed under vacuo to afford 0.4g of the title compound.
Example 4: Preparation of (R)-alpha-methyl-N- [3-[3-(trifluoromethyl)phenyl] propyl]-1-naphthalenemethanamine hydrochloride. To a suspension of N-[l-(R)-(l-naphthyl) ethyl]-3-[3-(trifluoromethyl) phenyl]-l- propanamide (50 gm, 0.134 moles) and NaBH4 (50 gm, 1.313 moles) in dry THF (600 ml) under nitrogen atmosphere was added a solution of iodine (167.5 gm, 0.66 moles) in dry THF (800 ml) at 0 - 5 0C for 2.5 hours. The reaction mixture was then brought to room temperature and then refluxed (70 - 75 0C) for 4.0 h. The reaction mass was cooled to 0-50C and the excess borohydride destroyed by careful addition of 3 N HCl (150 ml). The reaction mixture was basified using 3 N NaOH (225 ml). The organic layer was separated and the aqueous layer was extracted with methylene chloride (2 x 100 ml). The combined organic extracts were washed with water (100 ml) and dried over Na2SO4 The organic layer was evaporated to dryness under vacuum at 40 - 45 0C to get a residue, which was dissolved in hexane (300 ml) and 10 % HCl solution (300 ml) was added at room temperature and stirred for 1 h. The solids separated were filtered and washed with hexane (5 x 25 ml) and dried to get the crude product. The crude product was dissolved in acetonitrile (450 ml) at reflux temperature and then cooled to room temperature, filtered the solids and dried at 50 - 55 0C for 8 h to get Cinacalcet HCl (51.0 gm, 96.22 %).Melting point: 180-1840C.IR (KBr) (nu(max), cm-1) 3437.26, 3363.97, 2962.76, 2796.88, 2750.58, 2712.01, 2511.40,1585.54, 1450.52, 1327.07, 1168.90, 1130.32, 1072.46, 798.56, 775.41, 702.11. 1H NMR (CDCl3-DMSO-d6) (delta ppm): 10.62 (IH, bs), 10.07 (IH, bs), 7.16 - 8.5 (1 IH, m), 5.19 (IH5 q), 2.75 (2H, t), 2.52 (2H, m), 2.28 (2H5 m), 1.98 (3H, d). MS (m/z): 358 [M+l].
EXAMPLE 10: ALTERNATIVE PROCESS FOR THE PREPARATION OF CINACALCET HYDROCHLORIDE:A solution of N- [(1 R)-1-(1-napthyl) ethyl]-3-(3-trifluoromethyl) phenyl] propanamide (40 g) in tetrahydrofuran was stirred for about 10 minutes under nitrogen atmosphere at about 30 C. Lithium aluminium hydride (7.91 g) was slowly added over about 30 minutes. The resultant reaction mixture was heated to about 65 0C followed by stirring for about 5 hours. After the completion of the reaction, reaction mass was cooled to about 0 0C followed by quenching the reaction mass with 10% aqueous hydrochloric acid (400 ml) slowly over about 15 minutes. The reaction mass was extracted with dichloromethane (400 ml) followed by separation of organic and aqueous layers. The aqueous layer was extracted with dichloromethane (200 ml) followed by separation of organic and aqueous layers.The combined organic layers were washed with saturated sodium chloride solution (2x200 ml). The organic layer was dried over 40 g of anhydrous sodium sulphate. The solvent was distilled off completely at about 40 0C under vacuum to afford a residue. To the residue ethyl acetate (200 ml) was added and stirred at about 40 0C for about 15 minutes. To this solution n-heptane (320 ml) was added followed by cooling to about 25 0C. The resultant suspension was stirred for about 45 minutes. The separated solid was filtered and washed with n-heptane (80 ml). The wet solid was dried at about 75 0C for about 4 hours to afford 25.8 g of the title compound.
Example 21: Preparation of Cinacalcet hydrochloride; To a solution of (R)-N-(l-naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-piOpionamide (350g) in tetrahydrofuran (1.4 1) at 0-50C, borane dimethylsulphide complex (179 ml) was added, and heated at 60-650C for 4 hours. Tetrahydrofuran was distilled off under vacuo. Methanol (1.05 1) was added at 00C and stirred for another 30 minutes. Methanol was distilled off under vacuo and the residue was treated with hydrochloric acid (2.1 1) at 0-50C. The reaction mixture was stirred at 25-300C for 2.0 hours and further at 85-900C for 2.0 hours. The reaction mass was then cooled to 25-3O0C, filtered, washed with water and dried to afford 37 Ig of the title compound. The product so obtained was recrystallized with acetonitrile to afford pure cinacalcet hydrochloride having purity of 99.67% by HPLC.
<strong>[1005450-55-4]N-((1R)-1-(1-naphthyl)ethyl)-3-(3-(trifluoromethyl)phenyl)propanamide</strong>lO.Og Add 200ml of tetrahydrofuran, stirring evenly after cooling 0-5 C, To the reaction system, 3. 0 g of sodium borohydride solid was added portionwise, Weighed 22. 9g boron trifluoride ether slowly drip into the reaction system, Droplet heating to 65 C reflux 3h. TLC detection reaction is completed, cooling to 0-5 C, To the reaction system, 1 mol / L dilute hydrochloric acid was slowly added dropwise to pH = 2-3, Heating to 65 C reflux 1h, down to room temperature, To the reaction system by adding 2mol / L NaOH solution dissolved, and adjust the pH = 8-9. The organic solvent was removed by distillation under reduced pressure, and the residue was extracted with 200 ml of ethyl acetate. The aqueous phase was discarded and the organic phase was washed once with the addition of saturated brine, The organic solvent was removed by evaporation under reduced pressure, To give N - ((1R) _1_naphthyl) ethyl) -3- (3- (bistrifluoromethyl) phenyl) propanamine.(1R) -1- (1-naphthyl) ethyl) -3- (3- (trifluoromethyl) phenyl) Propan-1-amine by adding lml n-hexane dissolved, After stirring, 50 ml of 1 mol / L dilute hydrochloric acid was added dropwise to the reaction system. Stirring at room temperature lh, filtration, filter cake washed with a small amount of n-hexane, The solid was dried under vacuum overnight at 50 C to give N - ((1R) -1- (1-naphthyl) ethyl) -3- (3- (trifluoromethyl) phenyl) Salt as a white solid.
45 g
In a 1000 ml reaction flask, 47.7 g of an amide represented by Formula IV, 143 g of tetrahydrofuran, 12.4 g of sodium borohydride, and mechanical stirring were added. 68 g of a boron trifluoride complex was added dropwise at 40-60 C. The reaction was carried out at 40-60 C for 3 hours. 270 g of water was added to quench the reaction, 290 g of toluene was added for extraction, the organic phase was retained, and 270 g of water was used for washing, 17.3 g of concentrated hydrochloric acid was added for salt formation, and 190 g of n-heptane was crystallized at 70 degrees, cooled to normal temperature, and filtered. After drying, 45 g of crystals of cinacalcet hydrochloride were obtained, with a purity of 99.8%, wherein the impurities shown by formula II and formula III were not detected (the corresponding content of the detection limit was less than 0.01%).
With potassium carbonate; In dichloromethane; at 25 - 27℃; for 0.5 - 3h;Product distribution / selectivity;
EXAMPLE 5: PREPARATION OF N- [(1 R)-1-(1 -NAPTHYL) ETHYL]-3-(3- TRIFLUROMETHYL) PHENYL] PROPANAMIDE:3-[3-(trifluoromethyl) phenyl] propanoic acid (100 g) and dichloromethane (500 ml) were taken into a round bottom flask and stirred for about 5 minutes. To the reaction solution HOBT (77.76 g) was added followed by addition of DCC (118.65 g) dissolved in dichloromethane (500 ml) over a period of about 15 minutes. The resultant reaction mixture was stirred for about 1 hour.After the completion of the reaction, the reaction mass was cooled to about 5 0C followed by stirring for about 40 minutes. The by-product dicyclohexyl urea (DCU) was filtered through celite and the filtrate was distilled completely at about 39 0C under vacuum. The complex residue obtained was dissolved in dichloromethane (800 ml) and stirred for about 5 minutes. Potassium carbonate (66.24 g) was charged followed by addition of R -(+)-1-(1-naphthyl) ethylamine of Formula IV (82.08 g) dissolved in dichloromethane (200 ml) over about 15 minutes.The resultant reaction solution was stirred at about 25 0C for about 15 minutes. After the completion of the reaction, the reaction mixture was cooled to about 5 0C followed by stirring for about 40 minutes. Solid separated was filtered and the filtrate was distilled completely at about 39 0C under vacuum. To the residue 500 ml of n-hexane was charged followed by raising the temperature to about 45 0C. The resultant reaction solution was stirred for about 40 minutes. The separated solid was filtered and washed with n-hexane (200 ml). The wet EPO <DP n="27"/>solid was dried at about 75 0C under vacuum for about 9 hrs to afford 141.5 g of title compound. Mass (m/z): 371 amu.; EXAMPLE 7: PREPARATION OF N-[(1 R)-1-(1 -NAPTHYL) ETHYL]-3-(3- TRIFLUROMETHYL) PHENYL] PROPANAMIDE OF FORMULA V STARTING FROM 3-[3-(TRIFLUROMETHYL) PHENYL] PROPENOIC ACID3-[3-(trifluromethyl) phenyl] propenoic acid (50 g) and toluene (500 ml were taken into an autoclave vessel and 5% Pd/C (5 g) was added to it. The reaction EPO <DP n="28"/>mass was heated to about 42 0C and a pressure of 5 Kg/cm2 was applied and maintained for about 4 hours. After the reaction was completed, the reaction mass was filtered over a celite bed and the bed was washed with 200 ml of toluene. The filtrate was distilled at a temperature of about 60 0C under vacuum to get a residue. To the residue obtained dichloromethane (250 ml) was added and stirred at 28 0C. HoBt (37.45 g) was added to the above mixture followed by addition of a solution of DCC (57.25 g) in dichloromethane (450 ml). The reaction mass was maintained at about 28 0C for about 3 hours and then cooled to about 5 C and maintained for about 30 minutes. The reaction mass was then filtered over a celite bed and the bed was washed with dichloromethane (100 ml). The filtrate was taken into a fresh round bottom flask and stirred at about 27 C for about 30 minutes. K2CO3 (31.9 g) was added to the filtrate followed by the addition of a solution of R-(+)-1-(1-naphthyl) ethylamine of Formula IV (39.5 g) in dichloromethane (100 ml). The reaction mass was maintained at about 27 C for about 3 hours.After the reaction was completed, water (400 ml) was added to the reaction mass and cooled to about 5C. The reaction mass was maintained at about 5 0C for about 30 minutes, and then filtered over a hyflow bed. The bed was washed with dichloromethane (100 ml). The organic layer was separated from the filtrate and washed with water (2X200 ml). The organic layer was then distilled and ethyl acetate (800 ml) was added to it and cooled to about 10 0C. The reaction mass was maintained at about 10 0C for about 30 minutes and then filtered over a celite bed. The bed was washed with ethyl acetate (50 ml). The combined organic layer was distilled off completely at about 60 C, and then n-hexane (100 ml) was added to it at the same temperature. Another 350 ml of n-hexane was added to the crude obtained and heated to about 40 0C. The reaction mass was maintained at the same temperature for about 30 minutes followed by addition of another 150 ml of n-hexane. The reaction mass was then cooled to about 30 C and maintained for about 30 minutes. The separated solid was filtered and EPO <DP n="29"/>washed with n-hexane (150 ml). The wet solid was dried at about 42 0C for about 6 hours to yield 68.7 g of the title compound. Purity By HPLC: 97.7%
EXAMPLE 29: PREPARATION OF [3-(3-DIFLUOROMETHYL-PHENYL)- PROPYL]-(I -NAPHTHALEN-1-YL-ETHYL)-AMINE FROM N- [(1 R)-1-(1- NAPTHYL) ETHYL]-3-(3-TRIFLUROMETHYL) PHENYL] PROPANAMIDE:N-[(1 R)-1-(1-napthyl) ethyl]-3-(3-trifluromethyl) phenyl] propanamide (75 g) and tetrahydrofuran (750 ml) were taken into a round bottom flask and heated to about 40 0C. lithium aluminium hydride (59.82 g) was added to it slowly at the same temperature. The reaction mass was further heated to about 65 C and maintained for about 50 hours. The reaction mass was then cooled to about 5 0C. The cooled reaction mass was slowly added to ethyl acetate (750 ml) cooloed to a temperature of about 5 0C. and stirred for about 30 minutes. Water (750 ml) was then added to the above reaction mass and stirred at about 28 C for 30 minutes. The reaction mass was fltered over a celite bed and the organic layer was separated. The organic layer was distilled off completely at about 45 0C under a vacuum of about 650 mm/Hg to yield 72.0 g of the title compound in crude form.Mass (m/z): 339.
With hydrogen;palladium on activated carbon; In methanol; toluene; at 20℃; for 1.5h;Product distribution / selectivity;
hi yet another variation, the reduction of the double bond and amide carbonyl of (E)-N-((i?)-l-naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-acrylamide is carried out in a stepwise manner. Either the carbonyl group or the alkene double bond can be reduced first. For example, the reduction of the alkene double bond is achieved by hydrogenation in the presence of a metal catalyst.[0123] A suspension of (E)-N-((i?)-l-naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)- acrylamide (1.0 equiv.; 0.67 mmol; 250 mg) and Pd/C 10 wt% (25 mg) was stirred in a mixture of methanol and toluene (7 mL/lmL). The reaction flask was evacuated and back filled using a hydrogen filled balloon (three times). The reaction mixture is stirred at room temperature and the progress of the reaction was monitored using high performance liquid chromatography. After 90 minutes, the reaction mixture was filtered over a bed of celite and the solvent from the filtrate was removed in vacuo. The resulting solid was dried overnight at 450C using a vacuum oven. Isolated yield: 91.2% (229 mg). The identity of the amide was confirmed by 1H NMR and mass spectrometry. (400MHz, CDCl3) delta ppm 1.60 (d, 3H) 2.39- 2.53 (m, 2H) 2.96-3.13 ( m, 2H) 5.55 (br. S., IH) 5.87-5.96 (m, IH) 7.29-7.38 (m, 2H) 7.39- 7.46 (m, 4H) 7.46-7.55 (m, 2H) 7.76-7.82 (m, IH) 7.83-7.89 (m, IH) 8.00-8.07 (m, IH) and HRMS (M+l): 372.1
With hydrogen;nickel; In methanol; at 45 - 50℃; under 3677.86 Torr; for 3h;Product distribution / selectivity;
EXAMPLE 16: PARTIAL REDUCTION OF N-(1 -NAPHTHALENE-I-YL-ETHYLJ-S -(3-TRIFLUROMETHYL-PHENYL) ACRYLAMIDE TO GIVE N- [(1 R)-1-(1- NAPTHYL) ETHYL]-3-(3-TRIFLUROMETHYL) PHENYL] PROPANAMIDE:A solution of N-(1-naphthalene-1-yl-ethyl)-3-(3-trifluromethyl-phenyl) acryl amide (2 g) dissolved in methanol (150 ml)was taken into an autoclave vessel followed by addition of Raney nickel (2 g) and 5 kg/cm2 of anhydrous hydrogen gas pressure was passed into the reaction suspension under agitation at about 45 -50 0C for about 3 hours. After the completion of the reaction, the reaction suspension was filtered on celite and the celite bed was washed with methanol (10 ml). The filtrate was distilled completely at about 50 0C under vacuum. N- hexane (16 ml) was added followed by raising the temperature to about 45 0C. The resultant reaction solution was stirred for about 40 minutes. The separated solid was filtered and washed with n-hexane (4 ml). The wet solid was dried at about 75 0C under vacuum for about 5 hrs to afford 1.6 g of title compound. Purity By HPLC: 96.88% Mass (m/z) : 371 amu.
With hydrogen;palladium on activated charcoal; at 20℃; under 3677.86 Torr; for 3h;Product distribution / selectivity;
Methanolic solution of Compound II(20gm in 200ml of methanol) is hydrogenated (5.0kg/cm2 of H2) in the presence of 2gm palladium on carbon (10% w/w of compd III) for 3 hours at room temperature. Then the catalyst was filtered out and the solvent is evaporated to dryness to give 19g of titled compound-III.
In ethyl acetate; at 0 - 30℃; for 3h;Product distribution / selectivity;
Step (ii) Preparation of N-(1-Naphthalen-1-yl-ethyl)-3-(3-tritluoromethyl-phenyl)-propionamide [Compound-III]:; 20.0gm of compound-I was dissolved in ethyl acetate and 10.20gm of triethylamine was added and stirred for 15.0 min. A solution of 9.95 gm of ethyl chloroformate in ethyl acetate was prepared and was added slowly in the reaction mass at 0-5C. The reaction mass was stirred at 0-5C for 2 hours to form mixed anhydride[ compound-II] . A solution of 17.27gm of (R)-(+)-1-(1-Napthyl) ethyl amine in ethyl acetate was prepared and added to the reaction mass at 0-5C. The reaction mixture was stirred at 0-5C for 1 hour .Water was added to this reaction mixture and stirred and the organic phase was separated. The organic phase was washed with 10% hydrochloric acid, water, 10% sodium bicarbonate solution and water successively. The organic phase was dried over sodium sulphate and the solvent was evaporated under vacuum to give crude titled compound-III. To this residue, n-hexane was added and heated the reaction mass to reflux for 30.0 min, cooled gradually to room temperature and stirred for 30.0 min. It was filtered and washed with chilled n-hexane. Wet compound on drying yields 26.0 gm of titled compound-III. Mass spectra is a depicted in figure I [Show Image] Analytical Data- 1HNMR (CDCl3, 400 MHz) of compound-II: delta 1.213-1.248 (triplet, 3H); delta 2.627-2.665 (triplet, 2H); delta 2.994-3.032 (triplet, 2H); delta 4.102-4.156 (quartet, 2H); delta 7.395-7.472 (broad multiplet, 4H). 1HNMR (CDCl3, 400 MHz) of compound-III: delta 1.727-1.837 (doublet, 3H); delta 1.754-2.083 (broad multiplet, 2H); delta 2.653-2.713 (broad multiplet, 1H); delta 2.873-2.994 (broad multiplet, 1H); delta 5.183-5.243 (quartet, 1H); delta 7.146-7.321 (broad multiplet, 4H); delta 7.554-7.663 (broad multiplet, 3H); delta 7.809-8.007 (broad multiplet, 4H).; Step (ii) Preparation of N-(1-Naphthalen-1-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-propionamide [Compound-III]: Dissolve 14.0gm of compound-I in tetrahydrofuran and cool to 10C.Add 18.2gm of triethylamine and then 9.8gm of ethyl chloroformate slowly. Stir the reaction mass at 30C for 2 hours. To this reaction mixture, add 12.0gm of (R)-(+)-1-(1-Napthyl) ethyl amine at 30C and stir for 1 hour. Heat the reaction mass to reflux and stir at reflux for 2 hours. Cool the reaction mass to 30C and distill out tetrahydrofuran below 40C. To this reaction mixture add water and ethyl acetate. Separate the organic phase. Wash the organic phase with 10% hydrochloric acid, water, 10% sodium bicarbonate solution and water successively. Dry the organic phase over sodium sulphate and then evaporate the solvent under reduced pressure to get title compound III.; Step (ii) Preparation of N-(1-Naphthalen-1-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-propionamide [Compound-III]:; Dissolve 14.0gm of compound-I in tetrahydrofuran and cool to 10C.Add 18.2gm of triethylamine and then 9.8gm of ethyl chloroformate slowly. Stir the reaction mass at 30C for 2 hours. To this reaction mixture, add 12.0gm of (R)-(+)-1-(1-Napthyl) ethyl amine at 30C and stir for 1 hour. Heat the reaction mass to reflux and stir at reflux for 2 hours. Cool the reaction mass to 30C and distill out tetrahydrofuran below 40C. To this reaction mixture add water and ethyl acetate. Separate the organic phase. Wash the organic phase with 10% hydrochloric acid, water, 10% sodium bicarbonate solution and water successively. Dry the organic phase over sodium sulphate and then evaporate the solvent under reduced pressure to get title compound III.; Step (ii) Preparation of N-(1-Naphthalen-1-yl-ethyl)-3-(3-trifluoromethyl-phenylpropionamide [Compound-III]:; Dissolve 14.0gm of compound-I in tetrahydrofuran and cool to 10C.Add 18.2gm of triethylamine and then 9.8gm of ethyl chloroformate slowly. Stir the reaction mass at 30C for 2 hours. To this reaction mixture, add 12.0gm of (R)-(+)-1-(1-Napthyl) ethyl amine at 30C and stir for 1 hour. Heat the reaction mass to reflux and stir at reflux for 2 hours. Cool the reaction mass to 30C and distill out tetrahydrofuran below 40C. To this reaction mixture add water and ethyl acetate. Separate the organic phase. Wash the organic phase with 10% hydrochloric acid, water, 10% sodium bicarbonate solution and water successively. Dry the organic phase over sodium sulphate and then evaporate the solvent under reduced pressure to get title compound III.
With hydrogen;palladium on activated carbon; In methanol; at 20℃; for 1h;Product distribution / selectivity;
Cinacalcet is obtained by reducing the alkyne-amide precursor. In one embodiment, the alkyne was reduced by metal catalyzed hydrogenation. Specifically, to a methanolic solution (7 mL) of 3-(3-trifluoromethyl-phenyl)-propynoic acid ((R)-I- naphthalen-l-yl-ethyl)-amide (1.0 equiv.; 0.68 mmol; 250mg) in a two necked round bottom <n="43"/>flask was added Pd/C 10 wt% (28 mg). The flask was evacuated and back filled using a hydrogen filled balloon (three times) before stirring the reaction mixture at room temperature under a positive pressure of hydrogen. Progress of the reaction was monitored by HPLC and LC/MS, with complete reduction of the alkyne group after 1 hour. The reaction was stopped by filtering the reaction mixture over a bed of celite, and the solvent was removed to give a solid that was further dried at 450C overnight in vacuo. Product identity was confirmed by 1H NMR and LC/MS. A quantitative yield of the product was obtained (224mg). (400MHz, CDCl3) delta ppm 1.60 (d, 3H) 2.39-2.53 (m, 2H) 2.96-3.13 ( m, 2H) 5.55 (br. S., IH) 5.87-5.96 (m, IH) 7.29-7.38 (m, 2H) 7.39-7.46 (m, 4H) 7.46-7.55 (m, 2H) 7.76-7.82 (m, IH) 7.83-7.89 (m, IH) 8.00-8.07 (m, IH) and LC/MS (M+l): 372.0.
N‐(1‐(naphthalen‐1‐yl)ethyl)‐3‐(3‐trifluoromethylphenyl)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3-(Trifluoromethyl) phenylpropionic acid (6) (327.3 mg, 1.5 mmol) was weighed into a 50 mL reaction flask.Dichloromethane (10 mL) and DMF (3 drops) were added and stirred to dissolve.The temperature of the mixture was lowered to 0 C, oxalyl chloride (0.27 mL, 3.0 mmol) was added, the reaction mixture was warmed to room temperature, and the reaction was stirred for 2 h.The solvent and excess oxalyl chloride were removed under reduced pressure.The crude (R)-N-(1-naphthylethyl)-3-(3-trifluoromethylphenyl)propanoyl chloride was obtained. The crude (R)-N-(1-naphthylethyl)-3-(3-trifluoromethylphenyl)propanoyl chloride was dissolved in dichloromethane (10 mL).The temperature of the solution was then lowered to 0 C, and pyridine (120 muL) and (R)-1-naphthylethylamine (5) (342.0 mg, 2.0 mmol) were slowly added.Stirring was continued for 2 h at 0 C.After completion of the reaction, the reaction mixture was extracted with dichloromethane (3×20 mL).The organic phase was washed with saturated aqueous sodium hydrogen sulfate (30 mL).(dichloromethane: ethyl acetate/2:1) purified,Obtained a white solid (R)-N-(1-naphthylethyl)-3-(3-trifluoromethylphenyl)propaneAmide (7) (690.0 mg, 93% yield, 87% ee).Amide 7 was recrystallized from n-hexane:ethyl acetate/10:1.Its optical purity is increased to >99% and the recovery is 53%.
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