Name: 3886-70-2|(R)-1-(Naphthalen-1-yl)ethanamine|98%
Brand: Ambeed
SKU: A311072
Price: 5.0 USD
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1
[ 42882-31-5 ]
[ 3886-70-2 ]

Yield	Reaction Conditions	Operation in experiment
88.3%	With p-chlorophenyl pentanoate; hydrogen; In toluene; at 55℃; under 75.0075 Torr; for 15h;Enzymatic reaction;	In a 250 mL three-necked flask, mechanical stirring was slow,Toluene, 4 g of racemic naphthylethylamine, 5.2 g of acyl donor p-chlorophenol valerate, 1 g of Pd / LDH-SA and 0.4 g of lipaseNovozym 435, hydrogen pressure of 0.01MPa, 55 C under the conditions of reaction 15h, gas chromatography, Naphthylamine reaction completely, The catalyst (lipase and racemic catalyst) was removed by filtration and used in the next reaction, and the toluene solution was dissolved with sodium hydroxide(R) -amide; and the resulting (R) -amide was stirred at room temperature for 2 hours to remove p-chlorophenol, then dried and evaporated to dryness under reduced pressure to give2mol / L dilute hydrochloric acid hydrolysis 80 C 10h, then add ammonia to adjust pH> 10,0.5h after the dichloromethane burning extraction, drying, rotary steamTo give 3.538 (10-1- (1-naphthyl) ethylamine in a yield of 88.3%.

Reference： [1]Patent: CN104592037,2016,B .Location in patent: Paragraph 0040
[2]Diss.<Lund 1923>S.51,
[3]Synthetic Communications,2011,vol. 41,p. 341 - 346
[4]Patent: WO2014/178068,2014,A2

2
[ 5709-98-8 ]
[ 3886-70-2 ]
(1R)-N-<(1R)-1-(1-naphthyl)ethyl>cyclohex-3-ene-carboxamide [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1985,vol. 68,p. 2100 - 2114

3
[ 371-27-7 ]
[ 42882-31-5 ]
[ 3886-70-2 ]
[ 87782-88-5 ]

Reference： [1]Journal of the American Chemical Society,1989,vol. 111,p. 3094 - 3095
[2]Journal of Organic Chemistry,1997,vol. 62,p. 3488 - 3495

4
[ 42882-31-5 ]
[ 10420-89-0 ]
[ 3886-70-2 ]

Yield	Reaction Conditions	Operation in experiment
	With chiral stationary phase including isopropyl-functionalized CF6; In methanol; acetic acid; triethylamine; acetonitrile; at 20℃;Purification / work up;	In addition to the foregoing, numerous other chromatographic separations using a column bonded with a CSP including a derivatized cyclofructan residue were carried out. Tables 5-9 list some additional examples of chromatographic separations using a column bonded with a CSP of the present invention. AU examples of chromatographic separations using columns bonded with CSPs of the present invention were carried out using the following experimental conditions and procedures.\|0132\| The high performance liquid chromatography (HPLC) column packing system was composed of an air driven fluid pump (HASKEL, DSTV- 122), an air compressor, a pressure regulator, a low pressure gauge, two high-pressure gauges (10,000 and 6,000 psi), a slurry chamber, check valves, and tubings. The CSPs were slurry packed into a 25 cm x 0.46 cm (inner diameter, I. D.) stainless steel column.\|0133\| The HPLC system was an Agilent 1 100 system (Agilent Technologies, Palo Alto,CA), which consisted of a diode array detector, an autosampler, a binary pump, a temperature- controlled column chamber, and Chemstation software. All chiral analytes were dissolved in ethanol, methanol, or other appropriate mobile phases, as indicated. For the LC analysis, the injection volume and flow rate were 5 muL and 1 mL/min, respectively. Separations were carried out at room temperature (~20 0C) if not specified otherwise. The wavelengths of UV detection were 195, 200, 210, and 254 nm. The mobile phase was degassed by ultrasonication under vacuum for 5 min. Each sample was analyzed in duplicate. Three operation modes (the normal phase mode, polar organic mode, and reversed phase mode) were tested, unless indicated otherwise. In the normal phase mode, heptane with ethanol or isopropanol was used as the mobile phase. In some cases, trifluoroacetic acid (TFA) was used as an additive, as indicated. The mobile phase of the polar organic mode was composed of acetonitrile/methanol and small amounts of acetic acid and triethylamine. Water/acetonitrile or acetonitrile/acetate buffer (20 mM, pH = 4.1 ) was used as the mobile phase in the reversed-phase mode.\|0134\| Two different supercritical fluid chromatographic instruments were used. One was a Berger SFC unit with an FCM 1200 flow control module, a TCM 2100 thermal column module, a dual pump control module, and a column selection valve. The flow rate was 4 mL/min. The cosolvent was composed of methanol/ethanol/isopropanol = 1 : 1 : 1 and 0.2% diethylamine (DEA). The gradient mobile phase composition was 5% cosolvent hold during 0- 0.6 min, 5-60% during 0.6-4.3 min, 60% hold during 4.3-6.3 min, 60%-5% during 6.3-6.9 min, and 5% hold during 6.9-8.0 min. The other SFC system was a Jasco (MD, USA) system comprised of an autosampler unit (AS-2059-SF Plus), a dual pump module (PU-2086 Plus), a column thermostat module (CO-2060 Plus), a UV/Vis detector (UV-2075 Plus), and a back pressure regulator module (SCH-Vch-BP). Unless otherwise specified, the mobile phase was composed of CCVmethanol (0.1 % TFA or 0.1% diethylamine). The flow rate was 3 mL/min.\|0135\| For the calculations of chromatographic data, the "dead time" to was determined by the peak of the refractive index change due to the sample solvent or determined by injecting l ,3,5-tri-/e/-/-butylbenzene in the normal phase mode.
82.9 g; 81.32 g		2.5 L isopropanol was added 171.2 g (1 mol) of 1-naphthylethylamine and 237.4 g (0.98 mol)(+) - 4-phenyl-2-light-5,5-ene-methyl-2-oxo-1,3,2-oxy ether, 5.53 g (0.02 mol)(+) - 4- (2-chlorophenyl) -2-hydroxy-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorane, heated to refluxClarification, stirring lh, cooling crystallization, filtration, washing with 200mL isopropanol filter cake, get 202.4g white solid, namely (R) -l-1_naphthalene ethylamine complex salt. The above filter cake was dissolved in 500 mL of water,With 10% K0H solution adjusted rhoH- = 8,Stirring at room temperature lh,Extracted three times with methylene chloride,Each time the amount of 100mL,Drying the organic layer,(R) - (+) - l-naphthylethylamine (81.32 g) Yield 95%99.2% e.Solid optically active f: + 47.2 (c = l methanol) was measured.Water layer with hydrochloric acid to adjust the pH to strong acid,Stirring a large amount of solid at room temperature,Filter, recovery split agent. The filtrate and the washing liquid in step a are combined,The organic solvent was distilled off,The resulting solid was dissolved in 500 mL of water,With 10% Na0H solution adjusted rhoH- = 8,Stirring at room temperature lh,Extracted three times with methylene chloride,Each time the amount of 100mL,Drying the organic layer,The organic solvent was distilled off,To obtain -(i) -naphthalene ethylamine 82.9g,The yield was 96.8%96.3% e.Water layer transferred to strong acidity,Stir at room temperature, suction filtration, recovery of the remaining resolving agent

Reference： [1]Tetrahedron Asymmetry,2002,vol. 13,p. 2277 - 2282
[2]Tetrahedron,1994,vol. 50,p. 10309 - 10320
[3]Tetrahedron Asymmetry,1994,vol. 5,p. 817 - 820
[4]Journal of the Chemical Society. Perkin Transactions 2 (2001),2000,p. 1339 - 1347
[5]Journal of the Chinese Chemical Society,2009,vol. 56,p. 1163 - 1167
[6]Patent: WO2010/148191,2010,A2 .Location in patent: Page/Page column 45-49; 61
[7]Chemistry - An Asian Journal,2016,vol. 11,p. 3513 - 3519
[8]Patent: CN104829459,2017,B .Location in patent: Paragraph 0040-0044; 0045-0049; 0050-0054; 0075-0078

5
[ 3886-70-2 ]
[ 74103-06-3 ]
[ 100466-56-6 ]
[ 100466-55-5 ]

Reference： [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 589 - 591

6
[ 626-51-7 ]
[ 3886-70-2 ]
[ 374624-47-2 ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 8995 - 9001

7
[ 3886-70-2 ]
[ 20767-04-8 ]
[ 350233-97-5 ]
(E)-3-(3,5-Dimethoxy-phenyl)-N-{(2R,3R,4S,5R)-4-hydroxy-5-hydroxymethyl-2-[6-((R)-1-naphthalen-1-yl-ethylamino)-purin-9-yl]-tetrahydro-furan-3-yl}-acrylamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 2080 - 2093

8
[ 698-76-0 ]
[ 3886-70-2 ]
[ 483287-64-5 ]
(S)-5-Hydroxy-octanoic acid ((R)-1-naphthalen-1-yl-ethyl)-amide [ No CAS ]

Reference： [1]Enantiomer,2002,vol. 7,p. 33 - 39

9
[ 3886-70-2 ]
[ 455-03-8 ]
[ 1005450-55-4 ]

Yield	Reaction Conditions	Operation in experiment
	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

Reference： [1]Patent: US2007/259964,2007,A1 .Location in patent: Page/Page column 3-5
[2]Patent: WO2008/35381,2008,A2 .Location in patent: Page/Page column 27
[3]Patent: WO2008/35381,2008,A2 .Location in patent: Page/Page column 27
[4]Patent: CN103739500,2016,B .Location in patent: Paragraph 0039; 0047; 0048

10
[ 181289-15-6 ]
[ 3886-70-2 ]
[ 1001296-58-7 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; ethyl acetate; at 25 - 68℃;Heating / reflux;	Example 1 Preparation of the (R)-(+)-l-(l-naphthyl)ethylamine salt of (S)~(+)-3- (carbamoylmethyl)-5-methylhexanoic acid.1O g (53.4 mmoles) of <strong>[181289-15-6]3-(carbamoylmethyl)-5-methylhexanoic acid</strong> racemate are added to a mixture of ethyl acetate (60 ml) and methanol (8 ml) at 25C. 8.8 g (51.4 rnmoles) of (R)-(+)-l-(l-naphthyl)ethylamine are added dropwise over 10 minutes in order to obtain complete dissolution. The solution is heated at reflux temperature (68C). The mixture is cooled slowly to 1O0C to obtain the crystallisation of the salt. The solid is filtered and washed with 30 ml of ethyl acetate. The wet product is dried at 4O0C for 6 hours giving 8 g of the (R)-(+)-l-(l- naphthyl)ethylamine salt of (S)-(+)-<strong>[181289-15-6]3-(carbamoylmethyl)-5-methylhexanoic acid</strong> as a white solid. The filtration mother liquor (approx. 80 ml) is used to obtain the desired (R)-(-)-<strong>[181289-15-6]3-(carbamoylmethyl)-5-methylhexanoic acid</strong> enantiomer.

Reference： [1]Patent: WO2008/4044,2008,A1 .Location in patent: Page/Page column 7

11
[ 3886-70-2 ]
[ 585-50-2 ]
[ 1005450-55-4 ]

Yield	Reaction Conditions	Operation in experiment
70.87%		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.

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,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,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

12
[ 3886-70-2 ]
[ 1127-76-0 ]

Reference： [1]Tetrahedron Asymmetry,2001,vol. 12,p. 2121 - 2127
[2]Tetrahedron Asymmetry,2001,vol. 12,p. 2121 - 2127

13
[ 3886-70-2 ]
pent-4-enoylation reagent [ No CAS ]
[ 1127-76-0 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 8821 - 8828
[2]Journal of Organic Chemistry,1999,vol. 64,p. 8821 - 8828

14
[ 3886-70-2 ]
[ 15297-33-3 ]

Reference： [1]Journal of Organic Chemistry,1998,vol. 63,p. 2022 - 2030
[2]European Journal of Medicinal Chemistry,2013,vol. 68,p. 482 - 496
[3]Organic and Biomolecular Chemistry,2015,vol. 13,p. 6082 - 6102
[4]European Journal of Organic Chemistry,2018,vol. 2018,p. 1975 - 1983

15
[ 35310-75-9 ]
[ 3886-70-2 ]
C₂₁H₂₀BrNO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	titanium(IV) isopropylate;	The synthesis of the title compound (26G) was accomplished in a four-step, three-pot reaction sequence. Commercially available 3-bromo-4-methoxybenzaldehyde was reacted with methylmagnesium bromide to provide its phenylethanol derivative. This alcohol was then oxidized to the corresponding ketone in the usual manner with pyridinium chlorochromate (PCC). This ketone was subsequently reacted with (R)-naphthyl-1-ethylamine in the presence of Ti(i-PrO)4 to provide the imine. This imine was reduced in high diastereoselective yield using diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate. In a manner similar to the synthesis of 26D, a mixture of <strong>[35310-75-9]3-bromo-4-methoxyacetophenone</strong> (3.0 g, 13.1 mmol), (R)-naphthyl-1-ethylamine (2.1 mL, 13.1 mmol), and Ti(i-PrO)4 (4.7 mL, 15.7 mmol) in abs. EtOH (100 mL) was reduced with diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate in the presence of Mg(ClO4)2. The resulting crude material was converted to its hydrochloride salt. The salt was purified by precipitation from diethyl ether/hexane to provide GC/MS-pure material (0.6 g, 11%) as a white solid.

Reference： [1]Patent: US6342532,2002,B1 .Location in patent: Page column 20

16
[ 3886-70-2 ]
[ 13574-13-5 ]
[ 370594-93-7 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) at 20℃; for 24h;	57.1 1.12g of commercially available Nα-Boc-L-glutamate γ-benzylester was dissolved in 21.0 ml of DMF, and then 0.853 g of commercially available (R)-1-(1-naphthyl) ethylamine, 0.955 g of WSCI hydrochloride and 0.673 g of HOBt were added to the solution and the whole was left standing for 1 day at room temperature. The termination of a reaction was confirmed using TLC. After that, the reaction system was concentrated without modification under reduced pressure, and then a 1N hydrochloric acid was added to a residue, followed by separatory extraction with chloroform. The resulting organic phase was washed with a saturated sodium bicarbonate solution and was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. A residue was subjected to silica gel column chromatography (50 g, chloroform/ethyl acetate = 5/1) , and 1.63 g of the above-mentioned compound was obtained as a white solid. MS(FAB,Pos.):m/z=491[M+1]+1H-NMR(500MHz,CDCl3): δ=1.33(9H,s),1.63(3H,d,J=6.8Hz),1.88-1.98 (1H,m),2.12-2.22(1H,m),2.45(1H,dt,J=6.8,16.6Hz),2.50-2.58(1H, m),4.08-4.20(1H,m),5.11(2H,s),5.04-5.09(1H,m),5.88(1H,t,J=7.1 Hz),6.48-6.62(1H,m),7.23-7.53(9H,m),7.78(1H,d,J=7.8Hz),7.84(1 H,d, J=7.8Hz), 8.04 (1H,d, J=8.3Hz).

Reference： [1]Current Patent Assignee: KUREHA CORP. - EP1389460, 2004, A1 Location in patent: Page/Page column 73-74

17
[ 546-68-9 ]
ethereal HCl [ No CAS ]
EtOH (abs.) [ No CAS ]
Sodium cyanoborohydride (NaCNBH₃) [ No CAS ]
[ 4903-09-7 ]
[ 3886-70-2 ]
N-(3-chloro-4-methoxybenzyl)-(R)-1-(1-naphthyl) ethylamine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	In diethyl ether; hexane; water;	(R)-N-(3-Chloro-4-methoxybenzyl)-1-(1-naphthyl)ethylamine hydrochloride A mixture of (R)-(+)-1-(1-naphthyl)ethylamine (6.6 g, 39 mmol), <strong>[4903-09-7]3'-chloro-4'-methoxybenzaldehyde</strong> (6.6 g, 39 mmol), titanium (IV) isopropoxide (13.8 g, 48.8 mmol), and EtOH (abs.) (30 mL) was heated to 80° C. for 30 minutes and then stirred at room temperature for 3 hours. Sodium cyanoborohydride (NaCNBH3) (2.45 g, 39 mmol) was then added and the reaction mixture was stirred at room temperature for an additional 18 hours. Diethyl ether (100 mL) and H2O (2 mL) were then added to the reaction mixture and the resulting precipitate was removed by centrifugation. The supernatant was evaporated under vacuum and the crude product was chromatographed on silica gel (50 mm*30 cm column) (elution with CH2C2). The chromatographed material was then dissolved in hexane (500 mL), decolorized with NoritO, filtered (0.2 muM), and then ethereal HCl was added to precipitate the product as a while solid (10.2 g, 56percent yield), m.p. 241-242° C. (dec.).
56%	In hexane; water;	N-(3-chloro-4-methoxybenzyl)-(R)-1-(1-naphthyl) ethylamine hydrochloride A mixture of (R)-(+)-1-(1-naphthyl)ethylamine (6.6 g, 39 mmol), <strong>[4903-09-7]3'-chloro-4'-methoxybenzaldehyde</strong> (6.6 g, 39 mmol), and titanium (IV) isopropoxide (13.8 g, 48.8 mmol), and EtOH (abs.) (30 mL) was heated to 80° C. for 30 minutes then allowed to stir at room temperature for 3 hours. Sodium cyanoborohydride (NaCNBH3) (2.45 g, 39 mmol) was then added. The reaction mixture was stirred at room temperature for 18 hours. Ether (100 mL) and H2O (2 mL) were added to the reaction mixture and the resulting precipitate was then removed by centrifugation. The supernatant was evaporated under vacuum and the crude product was chromatographed on silica gel (50 mm*30 cm column) (elution with CH2Cl2). The chromatographed material was then dissolved in hexane (500 mL), decolorized with Norit.(R). filtered (0.2 muM), and then ethereal HCl was added to precipitate the product as a while solid (10.2 g, 56percent yield), m.p.: 241-242° C. (dec.).

Reference： [1]Patent: US6313146,2001,B1
[2]Patent: US6211244,2001,B1

18
[ 546-68-9 ]
ethereal HCl [ No CAS ]
EtOH (abs.) [ No CAS ]
Sodium cyanoborohydride (NaCNBH₃) [ No CAS ]
[ 4903-09-7 ]
[ 3886-70-2 ]
[ 7732-18-5 ]
N-(3-chloro-4-methoxybenzyl)-(R)-1-(1-naphthyl) ethylamine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	In diethyl ether; hexane;	(R)-N-(3-Chloro-4-methoxybenzyl)-1-(1-naphthyl)ethylamine hydrochloride A mixture of (R)-(+)-1-(1-naphthyl)ethylamine (6.6 g, 39 mmol), <strong>[4903-09-7]3'-chloro-4'-methoxybenzaldehyde</strong> (6.6 g, 39 mmol), titanium (IV) isopropoxide (13.8 g, 48.8 mmol), and EtOH (abs.) (30 mL) was heated to 80° C. for 30 minutes and then stirred at room temperature for 3 hours. Sodium cyanoborohydride (NaCNBH3) (2.45 g, 39 mmol) was then added and the reaction mixture was stirred at room temperature for an additional 18 hours. Diethyl ether (100 mL) and H2 O (2 mL) were then added to the reaction mixture and the resulting precipitate was removed by centrifugation. The supernatant was evaporated under vacuum and the crude product was chromatographed on silica gel (50 mm*30 cm column) (elution with CH2 Cl2). The chromatographed material was then dissolved in hexane (500 mL), decolorized with Norit.(R)., filtered (0.2 muM), and then ethereal HCl was added to precipitate the product as a while solid (10.2 g, 56percent yield), m.p. 241-242° C. (dec.).
56%	In diethyl ether; hexane;	(R)-N-(3-Chloro-4-methoxybenzyl)-1-(1-naphthyl)ethylamine hydrochloride A mixture of (R)-(+)-1-(1-naphthyl)ethylamine (6.6 g, 39 mmol), <strong>[4903-09-7]3'-chloro-4'-methoxybenzaldehyde</strong> (6.6 g, 39 mmol), titanium (IV) isopropoxide (13.8 g, 48.8 mmol), and EtOH (abs.) (30 mL) was heated to 80° C. for 30 minutes and then stirred at room temperature for 3 hours. Sodium cyanoborohydride (NaCNBH3) (2.45 g, 39 mmol) was then added and the reaction mixture was stirred at room temperature for an additional 18 hours. Diethyl ether (100 mL) and H2 O (2 mL) were then added to the reaction mixture and the resulting precipitate was removed by centrifugation. The supernatant was evaporated under vacuum and the crude product was chromatographed on silica gel (50 mm*30 cm column) (elution with CH2 Cl2). The chromatographed material was then dissolved in hexane (500 mL), decolorized with Norit.(R)., filtered (0.2 muM), and then ethereal HCl was added to precipitate the product as a while solid (10.2 g, 56percent yield), m.p. 241°-242° C. (dec.).
56%	In diethyl ether; hexane;	(R)-N-(3-Chloro-4-methoxybenzyl)-1-(1-naphthyl)ethylamine hydrochloride A mixture of (R)-(+)-1-(1-naphthyl)ethylamine (6.6 g, 39 mmol), <strong>[4903-09-7]3'-chloro-4'-methoxybenzaldehyde</strong> (6.6 g, 39 mmol), titanium (IV) isopropoxide (13.8 g, 48.8 mmol), and EtOH (abs.) (30 mL) was heated to 80° C. for 30 minutes and then stirred at room temperature for 3 hours. Sodium cyanoborohydride (NaCNBH3) (2.45 g, 39 mmol) was then added and the reaction mixture was stirred at room temperature for an additional 18 hours. Diethyl ether (100 mL) and H2 O (2 mL) were then added to the reaction mixture and the resulting precipitate was removed by centrifugation. The supernatant was evaporated under vacuum and the crude product was chromatographed on silica gel (50 mm*30 cm column) (elution with CH2 Cl2). The chromatographed material was then dissolved in hexane (500 mL), decolorized with Norit.(R)., filtered (0.2 muM), and then ethereal HCl was added to precipitate the product as a while solid (10.2 g, 56percent yield), m.p. 241-242° C. (dec.).

Reference： [1]Patent: US6031003,2000,A
[2]Patent: US5763569,1998,A
[3]Patent: US6011068,2000,A

19
[ 546-68-9 ]
ethereal HCl [ No CAS ]
EtOH (abs.) [ No CAS ]
Sodium cyanoborohydride (NaCNBH₃) [ No CAS ]
[ 4903-09-7 ]
[ 3886-70-2 ]
[ 7732-18-5 ]
N-(3-chloro-4-methoxybenzyl)-(R)-1-(1-naphthyl)ethylamine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	In hexane;	N-(3-chloro-4-methoxybenzyl)-(R)-1-(1-naphthyl)ethylamine hydrochloride A mixture of (R)-(+)-1-(1-naphthyl)ethylamine (6.6 g, 39 mmol), <strong>[4903-09-7]3'-chloro-4'-methoxybenzaldehyde</strong> (6.6 g, 39 mmol), and titanium (IV) isopropoxide (13.8 g, 48.8 mmol), and EtOH (abs.) (30 mL) was heated to 80° C. for 30 minutes then allowed to stir at room temperature for 3 hours. Sodium cyanoborohydride (NaCNBH3) (2.45 g, 39 mmol) was then added. The reaction mixture was stirred at room temperature for 18 hours. Ether (100 mL) and H2 O (2 mL) were added to the reaction mixture and the resulting precipitate was then removed by centrifugation. The supernatant was evaporated under vacuum and the crude product was chromatographed on silica gel (50 mm*30 cm column) (elution with CH2 Cl2). The chromatographed material was then dissolved in hexane (500 mL), decolorized with Norit.(R). filtered (0.2 muM), and then ethereal HCl was added to precipitate the product as a while solid (10.2 g, 56percent yield), m.p.: 241-242° C. (dec.).

Reference： [1]Patent: US6001884,1999,A

20
[ 39629-86-2 ]
[ 3886-70-2 ]
[ 915390-66-8 ]

Reference： [1]Patent: WO2006/123725,2006,A1 .Location in patent: Page/Page column 64

21
[ 3886-70-2 ]
[ 82258-76-2 ]
[ 226256-56-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 81.7℃; for 5 - 22h;Heating / reflux;Product distribution / selectivity;	Example 22; [00090] 1.7 g of compound VI were dissolved in Acetonitrile (30 ml). (R)-I- Naphtylethyl amine (1.03 g) and anhydrous K2CO3 (1.66 g) were added and the reaction mixture was heated to reflux temperature for 7 hours. Then salts were filtered out and the solvent was removed under reduced pressure to give 2.4 g of crude Cinacalcet base. The crude product was 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 23; [00091] 2.2 g of chloride (VI) were dissolved in Acetonitrile (17.5 ml). (R)-I-Naphtylethyl amine (1.5 ml) and anhydrous K2CO3 (2.7 g) were added and the EPO <DP n="31"/>reaction mixture was heated to reflux temperature for 5 hours. Potassium iodide (230mg) was added and the reaction mixture was stirred at reflux for additional 19 hours. Then salts were filtered out and the solvent was removed under reduced pressure. The residue was dissolved in DCM (16 ml). The obtained solution was washed with 5% aqueous HCl solution (1x17 ml), saturated solution OfNaHCO3 (1x16 ml) and finally with water (2x16 ml). The organic phase was dried over Na2SO4, filtered and the solvent was evaporated until dryness to obtain 1.6 g of Cinacalcet base.Example 24; [00092] 25.5 g of compound VI were dissolved in Acetonitrile (204 ml). (R)-I- Naphtylethyl amine (14.5 ml) and anhydrous K2CO3 (24.9 g) were added and the reaction mixture was heated to reflux temperature for 16 hours. Then salts were filtered out and the solvent was removed under reduced pressure. The residue was dissolved in DCM (75 ml). The obtained solution was washed with 5% aqueous HCl solution (pH=l), saturated solution OfNaHCO3 (pH=8-9) and finally with water. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated until dryness to obtain 33.4 g of Cinacalcet base.Example 25; [00093] 25.5 g of compound VI were dissolved in Acetonitrile (204 ml). (R)-I- Naphtylethyl amine (14.5 ml) and anhydrous K2CO3 (24.9 g) were added and the reaction mixture was heated to reflux temperature for 16 hours. Then salts were filtered out and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (75 ml). The obtained solution was washed with 5% aqueous HCl solution (pH=l), saturated solution OfNaHCO3 (pH=8-9) and finally with water. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated until dryness to obtain 33.4 g of Cinacalcet base.Example 26; [00094] 25.5 g of compound VI were dissolved in Acetonitrile (204 ml). (R)-I-Naphtylethyl amine (14.5 ml) and anhydrous K2CO3 (24.9 g) were added and the EPO <DP n="32"/>reaction mixture was heated to reflux temperature for 16 hours. Then salts were filtered out and the solvent was removed under reduced pressure. The residue was dissolved in toluene (75 ml). The obtained solution was washed with 5% aqueous HCl solution (pH=l), saturated solution OfNaHCO3 (pH=8-9) and finally with water. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated until dryness to obtain 33.4 g of Cinacalcet base.Example 27; [00095] 25.5 g of compound VI were dissolved in Acetonitrile (204 ml). (R)- 1 - Naphtylethyl amine (14.5 ml) and anhydrous K2CO3 (24.9 g) were added and the reaction mixture was heated to reflux temperature for 16 hours. Then salts were filtered out and the solvent was removed under reduced pressure. The residue was dissolved in DCM (75 ml). The obtained solution was washed with 5% aqueous HCl solution (pH=l), saturated solution OfNaHCO3 (pH=8-9) and finally with water. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated until dryness to obtain 33.4 g of Cinacalcet base. No further purification by column chromatography was needed.Example 28; [00096] 25.5 g of compound VI were dissolved in Acetonitrile (204 ml). (R)-I- Naphtylethyl amine (14.5 ml) and anhydrous K2CO3 (24.9 g) were added and the reaction mixture was heated to reflux temperature for 16 hours. Then salts were filtered out and the solvent was removed under reduced pressure. The residue was dissolved in DCM (75 ml). The obtained solution was washed with 5% aqueous HCl solution (pH=l), saturated solution OfNaHCO3 (pH=8-9) and finally with water. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated until dryness to obtain 33.4 g of Cinacalcet base. Example 31; [00099] 5.0 g of compound VI were dissolved in Acetonitrile (20 ml). (R)- 1 -Naphtylethyl amine (R-NEA) (1 eq) and anhydrous K2CO3 (1 eq) were added and the reaction mixture was heated to reflux temperature for 22 hours. Then salts were filtered out and the solvent was removed under reduced pressure. The residue was dissolved in Toluene or Ethyl acetate (7 volumes per gram of residue after evaporation). The obtained solution was heated to 7O0C and 32% HCl (2 volumes per gram of residue after evaporation) was added to obtain pH=0-l. Th...
	With potassium carbonate; In water; toluene; at 85℃; for 20h;Product distribution / selectivity;	Example 32; [000100] Compound VI (10 g, leq) and (R)-I -Naphtylethyl amine (R-NEA) (4.7 ml, leq) were dissolved in Toluene (20 ml, 2vol.). K2CO3 (4 g, leq) was dissolved in distilled H2O (20 ml, 2vol.) and the obtained solution was added under N2 to the toluenic solution of Compound VI and R-NEA. The reaction mixture was heated to reflux temperature (850C) for 20 hours. Then it was cooled to room temperature and phase separation was done. The organic phase was heated to 7O0C and the obtained solution was washed with 10% aqueous HCl solution (2x10 ml) (pH=0), saturated solution OfNaHCO3 (1x20 ml) (rhoH=8-9) and finally with water (pH=7). The solvent was evaporated under reduced pressure until dryness to give Cinacalcet base.
	With potassium carbonate; In toluene; for 14h;Heating / reflux;Product distribution / selectivity;	Example 29; [00097] 10.0 g of compound VI (1 eq) were dissolved in Toluene (60 ml). (R)- 1 - Naphtylethyl amine (0.98 eq) and anhydrous K2CO3 (2 eq) were added and the reaction mixture was heated to reflux temperature for 14 hours. Then salts were EPO <DP n="33"/>filtered out and the solvent was removed under reduced pressure. The residue was dissolved in DCM (75 ml). The obtained solution was washed with 5% aqueous HCl solution (pH=l), saturated solution OfNaHCO3 (pH=8-9) and finally with water. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated until dryness to obtain 11.0 g of Cinacalcet base.

Example 30; [00098] 5.0 g of compound VI (1 eq) were dissolved in Toluene (80 ml). (R)-I- Naphtylethyl amine (0.98 eq) and anhydrous K2CO3 (2 eq) were added and the reaction mixture was heated to 8O0C for 12 hours. Then Tetrabutyl ammonium bromide (TBAB) (5% per moles of (VI)) was added. The mixture was heated for additional hour at 8O0C. Salts were filtered out and the solvent was removed under reduced pressure. The residue was dissolved in DCM (75 ml). The obtained solution was washed with 5% aqueous HCl solution (pH=l), saturated solution OfNaHCO3 (pH=8-9) and finally with water. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated until dryness to obtain of Cinacalcet base.

Reference： [1]Patent: WO2006/125026,2006,A2 .Location in patent: Page/Page column 29-31; 32; 33
[2]Patent: WO2006/125026,2006,A2 .Location in patent: Page/Page column 33
[3]Patent: WO2006/125026,2006,A2 .Location in patent: Page/Page column 31-32
[4]Patent: WO2006/125026,2006,A2 .Location in patent: Page/Page column 31-32

22
[ 61995-20-8 ]
[ 3886-70-2 ]
[ 870859-10-2 ]

Yield	Reaction Conditions	Operation in experiment
		(3) To a solution of 83.7 g of <strong>[61995-20-8]1-benzyloxycarbonyl-3-piperidone</strong> dissolved in 1.2 liters of methylene chloride was added 55.0 g of (R)-(+)-1-(1-naphthyl)ethylamine, and after the mixture was stirred at room temperature for 2 hours, 69 ml of acetic acid and 160 g of sodium triacetoxy borohydride were added to the mixture, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added an aqueous sodium hydroxide to make the mixture basic, and then, chloroform was added to the mixture, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=4:1?0:1) to obtain 98.7 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]-piperidine-1-carboxylate. MS·APCI (m/z): 389 [M+H]+

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2055 - 2060
[2]Patent: EP1757582,2007,A1 .Location in patent: Page/Page column 35-36

23
[ 3886-70-2 ]
[ 105258-93-3 ]
[ 870859-07-7 ]

Yield	Reaction Conditions	Operation in experiment
		(3) To a solution of 8.51 g of <strong>[105258-93-3]benzyl 3-oxoazetidine-1-carboxylate</strong> and 7.10 g (R)-(+)-1-(1-naphthyl)ethylamine dissolved in 170 ml of methylene chloride, 7.49 g of magnesium sulfate was added to the solution. The mixture was stirred at room temperature for 3 hours, and then, 9.5 ml of acetic acid and 13.18 g of sodium triacetoxy borohydride were added thereto, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution to make the mixture basic, chloroform was added to the same and the mixture was stirred, and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1?1:1) to obtain 7.90 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]-azetidine-1-carboxylate.

Reference： [1]Patent: EP1757582,2007,A1 .Location in patent: Page/Page column 34-35

24
[ 455-24-3 ]
[ 3886-70-2 ]
[ 164470-64-8 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
C₄₇H₅₁F₃N₆O₆S [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2006,vol. 4,p. 2354 - 2357

25
[ 129254-76-8 ]
[ 3886-70-2 ]
[ 226256-56-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dichloromethane; at 38℃; for 1.25h;Product distribution / selectivity;	EXAMPLE 19: PROCESS FOR THE PREPARATION OF Cl NACALCET FROM THE COMPOUND:1-(3-bromo-propyl)-3-trifluoromethyl-benzene (2 g) and dichloromethane (10 ml) were taken into a round bottom flask followed by stirring for about 10 minutes. To the reaction solution R-(+)-1-(1-naphthyl) ethylamine of Formula IV (1.3 g) and potassium carbonate (0.75 g) were charged. The resultant reaction mixture was heated to about 38 C followed by stirring for about 1 hour, 15 minutes. After the completion of the reaction, the solvent was distilled completely at about 40 0C under vacuum. To the residue methyl isobutyl ketone (10 ml) was EPO <DP n="37"/>charged followed by heating to about 78 0C and stirring for about 1 hour, 15 minutes.Potassium iodide (0.2 g) was charged followed by heating to about 78 0C and stirring for about 8 hours. The reaction mass was cooled to about 26 0C followed by addition of 10% hydrochloric acid solution (100 ml). The resultant reaction suspension was stirred for about 10 minutes. The organic layer was separated and distilled completely at about 39 0C, to afford a solid. Ethyl acetate (30 ml) and n-heptane (100 ml) were added followed by stirring at about 45 0C for about 20 minutes. The separated solid was filtered and washed with n-heptane (20 ml). The wet solid was dried at about 70 0C under vacuum for about 3 hours to afford 0.9 g of the title compound.
	With potassium carbonate; potassium iodide; In acetonitrile; at 60 - 70℃; for 23h;	3L reaction flask in three sequentially added 187.3g (1.0939mol) R - (+) - 1- naphthylethylamine (type ), 252g (1.832mol) of anhydrous potassium carbonate, 0.36g of potassium iodide, 2.4L acetonitrile, and the reaction the system was heated to an internal temperature of 60-70 deg.] C, and then 248.5g purified intermediate (formula ) was added over 1 hour, maintaining an inner temperature of 60-70 deg.] C the reaction, 22 hours, TLC inspection (eluent: petroleum ether / ethyl acetate = 10: 1) the reaction solution intermediates (formula ) substantially complete the reaction, the reaction mixture was filtered, recovered acetonitrile was concentrated to give cinacalcet free base oil; the oil was dissolved in ethyl acetate were added 1mol L hydrochloric acid / 2% sodium hydroxide solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give cinacalcet free base crude product (formula ) as a brown liquid, weight: 324.7g, 99.69% crude yield, purity by gas chromatography (peak area% of the total) was: 86.94%.

Reference： [1]Patent: WO2008/58235,2008,A2 .Location in patent: Page/Page column 35-36
[2]Patent: CN104774134,2016,B .Location in patent: Paragraph 0048; 0050; 0051

26
[ 3886-70-2 ]
[ 779-89-5 ]
[ 1095393-66-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; dicyclohexyl-carbodiimide; In dichloromethane; for 1.5 - 2.5h;Product distribution / selectivity;	EXAMPLE 12: ALTERNATE PROCESS FOR THE PREPARATION OF N-(1- NAPHTHALENE-I -YL-ETHYL)-S-(S-TRIFLUROMETHYL-PHENYL) ACRYLAMIDE WITHOUT USING HOBT:3-[3-(trifluoromethyl) phenyl]-2-propenoic acid (2 g) and dichloromethane (10 ml) were taken into a round bottom flask and stirred for about 5 minutes. DCC (2.3 g) dissolved in 10 ml of dichloromethane was added over a period of about 15 minutes, and then potassium carbonate (1.24 g) was added followed by addition of a solution 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 1 to 2 hours. After the completion of the reaction the by-product DCU was filtered through celite, and the celite bed was washed with dichloromethane (4 ml). The filtrate was distilled completely at about 39 0C under vacuum. To the residue obtained, 20 ml of n- EPO <DP n="33"/>heptane was added followed by raising the temperature to about 70 to 75 0C. The resultant reaction solution was stirred for about 10 to 15 minutes and cooled to about 25 to 35 0C. The separated solid was filtered and washed with n-heptane (5 ml). The wet solid was dried at about 75 0C under vacuum for about 9 hours to afford 2.6 g of title compound. Purity By HPLC: 96.73percent. Mas
	With boric acid; In toluene; at 110℃;Product distribution / selectivity;	EXAMPLE 13: PREPARATION OF R-(-)-N-(1-NAPHTHALEN-1-YL-ETHYL)-3-(3- TRIFLUOROMETHYL-PHENYL)-ACRYLAMIDE USING BORIC ACID:3-(trifluoromethyl) cinnamic acid (3Og) was taken into a round bottom flask containing toluene (300 ml) and stirred for about 10 minutes. R-(-)-1-(1-napthyl) ethylamine of Formula IV (0.79 g) was added to the mixture followed by addition of boric acid (1.69 g). The reaction mass was heated to about 110 0C and maintained until completion of the reaction. The separated solid was filtered and washed with toluene 960 ml). The obtained filtrate was distilled completely at about 75 0C under vacuum to afford the title compound as a residue.The obtained solid was charged into a round bottom flask containing n- heptane (90 ml). The mass was heated to about 45 °C and stirred for about 60 minutes. The separated solid was filtered and washed with n-hexane (300 ml) and suction dried for about 15 minutes. The obtained solid was filtered and dried under vacuum at about 50 °C to afford 17 g of the title compound.
		In a variation of the foregoing method, the carboxylic acid can be activated in situ during the coupling reaction. For example, a 3-(trifluoromethyl)-cinnamic acid (1.0 equiv.; 2.3 mmol; 0.5g) was activated using l,l '-carbonyldiimidazole (1.3 equiv.; 3.0 mmol; 0.49g) in ethyl acteate (EtOAc 10 mL). After stirring at room temperature for 3 hours, was added a solution of (R)-(+)-l-(l-napthyl)ethylamine (1.2 equiv.; 2.78 mmol; 0.45 mL). The reaction mixture was stirred at room temperature for an additional hour, with the progress of the coupling reaction monitored by LC/MS. The crude solution yield was 14percent and the identity of the product was confirmed by RRT and LC/MS (M+l): 370.0.

Reference： [1]Patent: WO2008/58235,2008,A2 .Location in patent: Page/Page column 31-32
[2]Patent: WO2008/58235,2008,A2 .Location in patent: Page/Page column 32
[3]Patent: WO2009/2427,2008,A2 .Location in patent: Page/Page column 38

27
C₁₆H₁₂F₃N₃O₂ [ No CAS ]
[ 3886-70-2 ]
[ 1005450-55-4 ]

Yield	Reaction Conditions	Operation in experiment
	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%

Reference： [1]Patent: WO2008/58235,2008,A2 .Location in patent: Page/Page column 25-28

28
[ 3886-70-2 ]
[ 21172-43-0 ]
[ 226256-56-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; at 105℃; for 6h;Product distribution / selectivity;	Preparation of CNC-base under neat conditions. A 1 liter glass lab reactor equipped with mechanical stirrer, and controlled heating/cooling system was purged with Nitrogen. The continuous flow of Nitrogen was maintained during the reaction step. 41.5 g of 3-(3-(trifiuoromethyl)phenyl)propyl methanesulfonate (assay 96.4 percent; 40 g on 100 percent basis), 24.3 g of R-Naphthyl ethyl amine, and 9.8 g of K2CO3 were charged into the reactor. The stirrer was turned on, and the reactor jacket was heated to Tj = 105 C. The reaction mixture was stirred for 5 hours, and then sampled for end of reaction monitoring. The conversion to Cinacalcet-base: 85.3 percent.
	With potassium carbonate; In water; toluene; at 133℃; under 5400.54 Torr; for 4h;Product distribution / selectivity;	Preparation of Cinacalcet-base at elevated pressure in Toluene/water. A 2 liter stainless steel lab reactor, equipped with mechanical stirrer, and controlled heating/cooling system, was purged with Nitrogen.[0043] 84.2 g of 3-(3-(trifluoromethyl)phenyl)propyl methanesulfonate (Assay = 95.0, 80 g on 100 percent basis), 19.6 g K2CO3, 48.6 g of R-Naphthyl ethyl amine, 160 ml of toluene, and 96 ml of water were charged into the reactor. The stirrer was turned on, the vent valve was closed, and the reactor jacket was heated to Tj = 140 C. The reactor pressure has increased up to 7.2 bar, and the reactor temperature has increased to 133 C. After 2 hours, the reaction mixture was sampled for end of reaction monitoring. It was found that the conversion to Cinacalcet-base was 85.2 percent. After an additional 2 hours (total 4 hours), the reaction mixture was sampled again, and it was found that the conversion to Cinacalcet- base was 89.5 percent.
	With potassium carbonate; In toluene; at 118 - 124℃; for 5 - 5.5h;Product distribution / selectivity;	Preparation of CNC-base using toluene. A 1 liter glass lab reactor equipped with mechanical stirrer, and controlled heating/cooling system was purged with Nitrogen. The continuous flow of Nitrogen was maintained during the reaction step.42.1 g of 3-(3-(trifluoromethyl)phenyl)propyl methanesulfonate (FTOMs) (assay 94.7 percent; 40 g on 100 percent basis), 24.3 g of R-Naphthyl ethyl amine, 9.8 g K2CO3, and 40 ml toluene (1 volume vs. FTOMs) were charged into the reactor. The stirrer was turned on, and the reactor jacket was heated to Tj = 13O0C. The obtained reflux temperature: 118 to 1220C. The reaction mixture was stirred for 3 hours, and then sampled for end of reaction monitoring. The conversion to Cinacalcet-base: 85.3 percent. The reaction continued for an additional 2.5 hours (total 5.5 hours), and, then, the reaction mixture was cooled to 250C, and 240 ml of toluene (6 volumes) and 40 ml water (1 volume) were charged. The two phases were stirred, and the aqueous phase was then separated. The organic phase was sampled, and it was found that the conversion to CNC-base was: 91.0 percent. Preparation of Cinacalcet-base starting with FTOMs solution, and evaporating during the reaction. 231 Kg of FTOMs solution in toluene (41.2 Kg on 100 percent basis), 10.2 Kg K2CO3, and 24.9 Kg of R-Naphthyl ethyl amine were charged in to a stainless steel reactor. The stirrer was turned on, and the reactor jacket was heated to Tj = 129.20C.[0048] The solvent was evaporated at atmospheric pressure, until the reactor boiling temperature has increased from 111.6C to 123.10C. At these conditions, the volume of solvent remained in the reactor is about 1 volume.[0049] The reaction mixture was stirred for 5 hours. During the reaction, the reactor temperature was 122-124C. Preparation of Cinacalcet-base starting with 3-(3-(trifluoromethyl)phenyl)propyl methanesulfonate solution, and evaporating during the reaction. 1 liter glass lab reactor, equipped with mechanical stirrer, and controlled heating/cooling system, was purged with Nitrogen. 366 g of 3-(3-(trifiuoromethyl)phenyl)propyl methanesulfonate solution in toluene (68.5 g on 100 percent basis), 15.4 g K2CO3, and 33.3 g of R-Naphthyl ethyl amine were charged into the reactor. The stirrer was turned on, and the reactor jacket was heated to Tj =140 C.[0054] The solvent was evaporated at atmospheric pressure, until the reactor boiling temperature increased from 1090C to 1240C. At these conditions, the volume of solvent remained in the reactor was about 1 volume.[0055] The reaction mixture was stirred for 5 hours. During the reaction the reactor temperature was 121 to 123C.

	With potassium carbonate; In water; acetonitrile; at 131.6℃; under 4650.47 Torr; for 5h;Product distribution / selectivity;	Preparation of Cinacalcet-base starting at elevated pressure in acetonitrile/water. A 2 liter stainless steel lab reactor, equipped with mechanical stirrer and controlled heating/cooling system, was purged with Nitrogen.[0039] 84.2 g of 3-(3-(trifluoromethyl)phenyl)propyl methanesulfonate (Assay = 95.0, 80 g on 100 percent basis), 19.6 g K2CO3, 48.6 g of R-Naphthyl ethyl amine 320 ml of Acetonitrile, and 96 ml of water were charged into the reactor. The stirrer was turned on, the vent valve was closed, and the reactor jacket was heated to Tj = 140 C. The reactor pressure was increased up to 6.2 bar, and the reactor temperature has increased to 131.6 C. After 2 hours the reaction mixture was sampled for end of reaction monitoring. It was found that the conversion to Cinacalcet was 86 percent. After an additional 3 hours (total 5 hours), the reaction mixture was cooled to 25 C, and the excess pressure (3.4 bar, due to CO2 emission) was released.
	at 105℃; for 8.5h;Product distribution / selectivity;	Preparation of CNC-base under neat conditions without using a base. A 1 liter glass lab reactor equipped with mechanical stirrer, and controlled heating/cooling system was purged with Nitrogen. The continuous flow of Nitrogen was maintained during the reaction step.[0032] 43.2 g of 3-(3-(trifluoromethyl)phenyl)propyl methanesulfonate (assay 92.6 percent; 40 g on 100 percent basis) and 24.3 g of R-Naphthyl ethyl amine were charged into the reactor. The stirrer was turned on, and the reactor jacket was heated to Tj = 105 C. The reaction mixture was stirred for 5 hours, and the reaction mixture was then sampled for end of reaction monitoring. The conversion to Cinacalcet-base: 77.5 percent. After 7 hours at 105C, the reaction mixture was sampled again, and tested for end of reaction monitoring. The conversion to Cinacalcet-base: 80.3 percent.
	With potassium carbonate; In water; at 60 - 65℃; for 17h;	Example 7; Preparation of cinacalcet base - from (R)-i-naphthylethylamine free base; Purified water (375 ml) was taken in a reaction vessel. Potassium carbonate (0.88 moles, 121 gms) and the product of Example 3 (0.53 moles, 150 gms) was added under stirring.The reaction mixture was heated to 60-650C. (R)-i-naphthylethylamine (0.44 moles, 75 gms) was added maintaining the temperature of the reaction mass at 60-650C for about 17 hours under stirring. After cooling the mass to a temperature of 20-250C, ethyl acetate (2 x250 ml) was added and stirred. The separated organic layer was washed with purified water (2 x 300 ml) and then with saturated brine solution (2 x 300 ml).The solvent was removed from the organic layer by distillation under vacuum to obtain cinacalcet base (97 gms).
493 g	With potassium carbonate; In acetonitrile; at 65 - 83℃;	425 g of intermediate I, 269.4 g of (R)-( )-1-(1-naphthyl)ethylamine,395.3 g of potassium carbonate and 3 L of acetonitrile were added to a 5 L three-necked flask and stirred.Heating to reflux (80 ~ 83 C), reflux reaction for 16 ~ 17h, cooling to 65 ~ 70 C,197 g of potassium carbonate was added to the reaction system, and the mixture was heated to reflux, and the reaction was further stirred for 7 to 8 hours.The temperature of the reaction system was lowered to 25 ± 5 C, filtered, and the filter cake was washed with 2 L of acetonitrile, the filtrate was combined, and the filtrate was concentrated to dryness under reduced pressure.Stir well and stir, then extract with 5% HCl 1200ml.The organic phase is sequentially treated with 2 x 1200 ml of a saturated solution of NaHCO3, 1200 ml.After washing with water, the organic phase was concentrated to dryness under reduced pressure to give 493 g.The yield was 96.6%.

Reference： [1]Patent: WO2008/63645,2008,A1 .Location in patent: Page/Page column 9
[2]Patent: WO2008/63645,2008,A1 .Location in patent: Page/Page column 14
[3]Patent: WO2008/63645,2008,A1 .Location in patent: Page/Page column 12, 15-17
[4]Patent: WO2008/63645,2008,A1 .Location in patent: Page/Page column 13
[5]Patent: WO2008/63645,2008,A1 .Location in patent: Page/Page column 10-11
[6]Patent: WO2010/100429,2010,A1 .Location in patent: Page/Page column 21
[7]Patent: CN109928881,2019,A .Location in patent: Paragraph 0062-0064

29
[ 3886-70-2 ]
[ 21172-41-8 ]
[ 226256-56-0 ]

Yield	Reaction Conditions	Operation in experiment
89%		Under an argon atmosphere, 1.69 g (9.89 mmol, 1.1 eq.) of (R)- 1 -naphthylethylamine was added to a solution of 2.0 g (8.93 mmol, GC purity: 90.3%) of 3-(3-trifluoro methylphenyOpropanal in 40 mL of tetrahydrofuran. The resulting clear solution was stirred for 15 minutes, and 2 mL of acetic acid and 3.18 g (15.0 mmol) of sodium triacetoxy borohydride were added. The reaction mixture was stirred for two hours, and the solvent was evaporated under vacuum. The resulting residue was dissolved in 30 m L of dichloromethane, and the resulting solution was washed with 30 mL of 10% sodium carbonate solution. The inorganic layer was extracted with 20 mL of dichloromethane, and the solvent of the collected organic phases was evaporated under vacuum. The obtained crude base (3.17 g, 89%)
80%	With sodium tetrahydroborate; iron(III) trifluoromethanesulfonate; In dichloromethane; at 20℃; for 0.0833333h;	General procedure: In typical experimental procedure, to the CH2Cl2 solution (3 ml) of benzaldehyde (0.001 mol) and aniline (0.001mol) were added sodium borohydride (0.001 mol) and Fe(OTf)3 (1 mol% ), and the mixture was allowed to react for 5 min., at room temperature. After that 1 ml methanol was added for complete conversion. The progress of reaction was monitored by TLC. After completion of the reaction, solvent completely distilled at 40 C. Then the reaction mixture was quenched with 5% aqueous NaHCO3 solution and reaction mixture was extracted with dichloromethane twice (2x10 mL). The resulted organic layer was washed with water followed by Na2SO4 drying. The solvent was evaporated under reduced pressure and the crude material was purified by silica gel colum chromatography eluting with 2-10% EtOAc in hexane. All the products were characterized by IR, NMR and Mass spectroscopy. All the new compounds gave satisfactory spectroscopic data in accordance with their structure.
		To a cooled solution (100C) of 19.25 g (1 12 mmol) of (R)-l-(l-naphthyl) ethylamine, 4.5 mL of acetic acid and 500 mL isobutyl acetate, 150 mL of freshly prepared sodium triacetoxyboro hydride and 25.0 g (124.0 mmol, 96.7%) of 3-(3-trifluoromethyl <n="20"/>phenyl)propanal in 100 mL isobutyl acetate were added alternatively within four hours in eight portions, starting with the reducing agent. The borohydride aliquots were added simultaneously, while the aldehyde aliquots were added dropwise over 10 minute periods. Once the additions were complete, the resulting white suspension was stirred for 20 minutes, and then 300 mL of distilled water was added. Next, 100 mL of 10% aqueous sodium carbonate was added dropwise. The organic layer was separated and concentrated to about 250 mL.

		In a 630 L stainless steel reactor (clean, dry and inertised), were added (in sequence): 40.9 Kg of sodium triacetoxyborohydride and 96 Kg of isobutyl acetate. The resulting white suspension was then stirred and cooled to 0-5 C.In a 630 L glass-lined reactor, clean, dry and inertised, were added (in sequence): 22 Kg of (lambda)-(+)-l-(l-naphthyl)ethylamine and 96 Kg of isobutyl acetate. The resulting mixture was cooled to 0-5 C. Over the naphthylethylamine solution, 26.0 Kg of 3-[3- (trifluoromethyl)phenyl]propanal and another portion of 96 Kg of isobutyl acetate were added. The resulting pale yellow mixture was then stirred for 15 minutes at a temperature of 0-5 C.The latter mixture was next transferred to the stainless steel reactor, into the sodium triacetoxyborohydride suspension, over a period of 60 minutes while maintaining the temperature in the 0-5 C range. Once the addition was complete, the reaction mixture was stirred for 2 hours at a temperature of 0-5 C.Deionized water (176 Kg) was then added to the stirred mixture, and the temperature was adjusted to 20-25 C. The mixture was then stirred for a total of 30 minutes at 20-25 C, and the organic phase was separated.A 5% w/w aqueous sodium chloride solution (8.8 Kg Sodium chloride and 167Kg deionized water), previously prepared in a clean 630 L glass-lined reactor, was added to the stirred organic phase, and the temperature was adjusted to 20-25 C. The mixture was stirred for a total of 30 minutes, and the organic phase was separated.The organic phase was men transferred into a 630 L glass-lined reactor, and the transfer line was washed with 5 Kg of isobutyl acetate. The organic phase was then concentrated to half its volume by removing 159 +/- 10 Kg of isobutyl acetate by distillation under vacuum without exceeding a product temperature of 45 C. A white suspension was observed during the final stages of the distillation. The concentrated organic phase was then cooled to 5-10 C while stirring.
		In a 1,000 mL, four-necked round-bottomed reaction vessel, purged with nitrogen and equipped with a SOO mL pressure-equalized addition funnel, thermometer and blade impeller, are added (in sequence): sodium triacetoxyborohydride (27.8S g, 131.4 mmol) and 75 mL of isobutyl acetate. The resulting white suspension was stirred and cooled to 0-5 C.In a separate 500 mL, three-necked round-bottomed reaction vessel, purged with nitrogen and equipped with a 100 mL pressure-equalized addition funnel, thermometer and blade impeller, were added (in sequence) at 0-5 C: (/?)-(+)- 1 -(I -naphthyl)ethylamiotane (15.00 g, 87.6 mmol), 75 mL of isobutyl acetate, <strong>[21172-41-8]3-[3-(trifluoromethyl)phenyl]propanal</strong> (17.71 g, 87.6 mmol), and another portion of 75 mL of isobutyl acetate. The resulting pale yellow mixture was stirred for 15 minutes at 0-5 C.The latter mixture was then added dropwise into the sodium triacetoxyborohydride suspension via a pressure-equalized addition funnel over a period of 30 minutes while maintaining the temperature in the 0-5 C range. Once the addition was complete, the reaction mixture was stirred for 2 hours at 0-5 C. Deionized water ( 120 g) was then added dropwise to the stirred mixture while maintaining the temperature below 25 C. The mixture was stirred for a total of 30 minutes at 20-25 C, and subsequently the organic phase was separated. Aqueous <n="26"/>C. The mixture was then stirred for a total of 30 minutes, and subsequently the organic phase was separated. The organic phase was concentrated to half its volume by removing I IS mL of isobutyl acetate by distillation under vacuum at a vapor temperature of 30 C. The concentrated organic phase was cooled to S- 10 C while stirring.
	With hydrogen; In methanol; at 25 - 40℃; under 1500.15 - 3000.3 Torr;Autoclave;	17 g of (R)-l-(naphthalen-l-yl)ethanamine of Formula (A) is charged in a Autoclave containing methanol (200 ml). To the same 20 g 3-(3- (trifluoromethyl)phenyl) propanal of Formula (B) was added at temperature ranging from 25C to 35C. 2 g of Raney- nickel was charged into the reaction mass and applied 2-4 Kg/cm2 of Hydrogen pressure. Temperature increased to 35C to 40C: The reaction mass was filtered through hyflow bed and washed the bed with methanol.

Reference： [1]Journal of Organic Chemistry,2018,vol. 83,p. 11502 - 11509
[2]Patent: WO2008/68625,2008,A2 .Location in patent: Page/Page column 18
[3]Tetrahedron Letters,2012,vol. 53,p. 4354 - 4356
[4]Patent: WO2008/68625,2008,A2 .Location in patent: Page/Page column 18-19
[5]Patent: WO2008/68625,2008,A2 .Location in patent: Page/Page column 26
[6]Patent: WO2008/68625,2008,A2 .Location in patent: Page/Page column 24-25
[7]Patent: WO2014/178068,2014,A2 .Location in patent: Page/Page column 21

30
[ 1076239-83-2 ]
[ 3886-70-2 ]
[ 1005450-55-4 ]

Yield	Reaction Conditions	Operation in experiment
	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.

Reference： [1]Patent: EP1990333,2008,A1 .Location in patent: Page/Page column 7-8; 9; 10; 11

31
[ 402-24-4 ]
[ 201230-82-2 ]
[ 3886-70-2 ]
[ 226256-56-0 ]

Yield	Reaction Conditions	Operation in experiment
53.8%	With hydrogen;bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In methanol; toluene; at 125℃; for 8h;Product distribution / selectivity;	Example 5 - Hvdroformylation; [0131] hi yet another embodiment, cinacalcet was synthesized via a hydro formylation reaction. <n="44"/>[0132] Accordingly, to a high pressure stainless steel reaction vessel (ChemScan Reactor System) was added 3-(trifluoromethyl)styrene (2.0 equiv.; 3.5 mmol; 0.52OmL), (R)-(+)-l-(l- Napthyl)ethylamine (1.0 equiv.; 1.75 mmol; 0.28ImL), Xantphos (4mol%; 40.5mg) and [Rh(cod)2]BF4 (lmol%; 7.1mg) in a mixture of toluene and methanol (1 :1; 4mL). The vessel was pressurized to 40 bar with SynGas (CO/H2) and heated to 125C for 8 hours. A sample was prepared for analysis by diluting the reaction mixture prior to injection onto an HPLC system. Solution yield: 53.8%. The identity of the product was confirmed by RRT and LCMS (M+l): 358.1.

Reference： [1]Patent: WO2009/2427,2008,A2 .Location in patent: Page/Page column 42-43

32
[ 3886-70-2 ]
[ 132274-70-5 ]
[ 1143520-60-8 ]

Yield	Reaction Conditions	Operation in experiment
		Example 4; Synthesis of (lR)-l-(l-?aphthalenyl)-yV-((l-phenyl-lH-pyrazol-5-yl)methyl)ethanamine; To a solution of 1 -phenyl- l//-pyrazole-5-carbaldehyde 38 (0.517 g, 3 mmol) in DCE ( 10 mL) at room temperature was added (/?)-l-(naphthalen-l-yl)ethanamine 39 (0.625 g, 4 mmol), acetic acid (0.208 g, 3 mmol), and NaBH(OAc)3 (0.946 g, 4 mmol). The reaction mixture was stirred at room temperature for 18 h, quenched with saturated NaHCO3, diluted with EtOAc, washed with saturated NaHCO3 (1 x), brine (1 x), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 20% to 70% EtOAc in hexanes) gave (l/?)-l -(l-naphthalenyl)-N-((l-phenyl-lH-pyrazol-5- yl)methyl)ethanamine 40. Mass spectrum: calculated for C22eta2]nu3 327.2; found 328.2 (M+ + I )-

Reference： [1]Patent: WO2009/51718,2009,A2 .Location in patent: Page/Page column 35

33
[ 3886-70-2 ]
[ 16205-98-4 ]
[ 1157578-72-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 3-oxo-l-cyclohexane carboxylic acid (1.8 g) in 1,2-dichlorethane (60 ml.) were added (+)-(R)-l-naphthalen-l-yl-ethylamine (2.2 g), glacial AcOH (1 eq., 0.75 mL) and NaBH(OAc)3 (1.5 eq., 4.1 g). The mixture was stirred at r.t. for 48 h before removal of the solvent. The residue was treated with IN NaOH (ca 100 mL) and pH was adjusted to 7 by addition of 4N HCI. The mixture was brought to reflux. The solid formed upon cooling was filtered and washed with boiling EtOH to afford the title compound as a fine powder. The filtrate was concentrated in vacuo. The residue was dissolved in hot MeCN and little MeOH. The solid formed upon cooling was filtered and washed with MeCN to afford the title compound.

Reference： [1]Patent: WO2009/65406,2009,A2 .Location in patent: Page/Page column 83

34
[ 930-68-7 ]
[ 850568-67-1 ]
[ 3886-70-2 ]
[ 1157580-33-0 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure M.To a solution of cycloalkenone (400 mumol) in 400 muL DME were added boronic acid (480 mumol, 1.2 eq.), (COD)Rh(l,4-dihydroquinone)BF4 (1 mol%) in 100 muL DME, and LiOH (4 mol%) in 600 muL water. After shaking the mixture overnight at 50 0C, the solvent was removed in vacuo. The crude intermediate ketone was dissolved in DCE containing acetic acid (1.2 eq.). (+)-(/R)-l-naphthalen-l-yl-ethyIamine (1 eq.) in DCE was added <n="136"/>followed by NaBH(OAc)3 (1.2 eq.) The mixture was shaken overnight at r. t., filtered and the solvents were removed in vacuo. The residue was redissolved in 750 mul_ DMSO and purified by HPLC.Example 214: 2-Methyl-2-{4-[3-((beta)-l-naphthalen-l-yl-ethylamino)-cyclohexyl]- phenyl>-propionitrile (compound 1236/1237)General procedure M was followed using 4-(2-cyanopropan-2-yl) phenylboronic acid and 2-cyclohexen-l-one. The title compounds were purified by chromatography on 20 g silica gel in a gradient from 0 to 60% EtOAc in n-heptane, flow rate 30 mL/min. Compound 1236 (1 isomer, less polar, RT ~ 11 min): 13C NMR (75 MHz, DMSO) delta 146.84, 142.38, 138.59, 133.47, 130.84, 128.60, 127.05, 126.42, 125.62, 125.54, 125.15, 124.80, 124.69, 123.04, 122.94, 50.88, 49.99, 38.75, 36.56, 36.17, 33.17, 28.94, 28.26, 24.52, 20.25. Compound 1237 (1 isomer, more polar, RT ~ 13 min): 13C NMR (75 MHz, DMSO) delta 146.76, 142.14, 138.61, 133.39, 130.84, 128.55, 127.18, 126.39, 125.62, 125.50, 125.10, 124.85, 124.66, 122.92, 122.80, 50.11, 49.30, 36.44, 36.28, 36.15, 33.36, 30.74, 28.24, 24.40, 20.50.

Reference： [1]Patent: WO2009/65406,2009,A2 .Location in patent: Page/Page column 134-135

35
[ 27151-65-1 ]
[ 3886-70-2 ]
(R)-3-Methyl-4-((R)-1-naphthalen-1-yl-ethylcarbamoyl)-butyric acid methyl ester [ No CAS ]
(S)-3-Methyl-4-((R)-1-naphthalen-1-yl-ethylcarbamoyl)-butyric acid methyl ester [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2009,vol. 351,p. 547 - 552

36
[ 24424-99-5 ]
[ 3886-70-2 ]
[ 518335-32-5 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 20℃; for 2h;Product distribution / selectivity;	To a solution of (R)-I -naphthalen-1-yl-ethylamine (150g, 0.876mol) in dichloromethane (750ml), di-tertiarybutyl dicarbonate (210.3g, 0.964mol) was added at ambient temperature and stirred for 2 hours. Dichloromethane was distilled off followed by addition of n-heptane (150ml) and then n-heptane was distilled off. Again n-heptane (900ml) was added to the resulting residue and stirred. The resulting product was filtered and dried in vacuum at 45-500C to give 223g of the title compound having purity 99.8% by HPLC.
	In dichloromethane; at 20℃; for 2h;Product distribution / selectivity;	Example 5 Preparation of (R)-(1-naphthalen-1-yl-ethyl)-carbamic acid tert-butyl ester Method A: (R)-1-Naphthalen-1-yl-ethylamine (5.0 g, 0.0292 mol) was added to a mixture of di-tertiarybutyl dicarbonate (10.0 g, 0.04582 mol) in water (25 ml) and tetrahydrofuran (0.5 ml) at 25-30 C. and stirred for 5 hours. Reaction mixture was then extracted with dichloromethane (3*15 ml). The combined extracts were washed with water and the solvent was distilled off to give 8.2 g of title compound having purity 99.2% by HPLC. Method B: To a solution of (R)-1-naphthalen-1-yl-ethylamine (150 g, 0.876 mol) in dichloromethane (750 ml), di-tertiarybutyl dicarbonate (210.3 g, 0.964 mol) was added at ambient temperature and stirred for 2 hours. Dichloromethane was distilled off followed by addition of n-heptane (150 ml) and then n-heptane was distilled off. Again n-heptane (900 ml) was added to the resulting residue and stirred. The resulting product was filtered and dried in vacuum at 45-50 C. to give 223 g of the title compound having purity 99.8% by HPLC.

Reference： [1]Organic and Biomolecular Chemistry,2008,vol. 6,p. 3917 - 3920
[2]Patent: WO2010/4588,2010,A2 .Location in patent: Page/Page column 39
[3]Patent: US2011/172455,2011,A1 .Location in patent: Page/Page column 19

37
[ 3886-70-2 ]
[ 54811-38-0 ]
[ 1184301-79-8 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 5228 - 5240

38
[ 3886-70-2 ]
m-trifluoromethyl cinnamic aldehyde [ No CAS ]
[ 226256-56-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 11; Preparation of R)-alpha-Methyl-N-[3-[3-(trifluoromethyI)phenyl]propyl]-l-naphthaIene methaneamine (Cinacalcet base). To a solution of 3-trifluoromethylcinnamaldehyde (10Og, 1 mole) in methanol (1300 ml) in an autoclave vessel, (R)-(+)-l-(l-naphthyl)ethyl amine (80.56 g, 1.0 mole) was added drop wise at 5-100C. The reaction mixture was stirred for 3 hours at 5-1O0C. 20% wet palladium hydroxide (5.0g) was added to the above reaction mixture and hydrogenated at 3.0 Kg/Cm2 pressure for 3 hours at 25-300C. The catalyst was removed by filtration through a celite bed and the resulting solution was concentrated. Water (300 ml) and ethyl acetate (300 ml) was added to obtained crude and acidified with concentrated HCl (25 ml) at 15-2O0C. The resulting organic layer was separated and washed thrice with 20% HCl solution (200 ml) followed by basification with 10% sodium carbonate solution (100 ml). The resulting organic layer was washed thrice with brine solution (200 ml) and concentrated on rotavapour under vacuum at 500C to yield 123g of the title compound as oil (Purity by HPLC: 91.0%). Content of Impurities: Benzylamine impurity: Not detected; N-oxide impurity: Not detected.

Reference： [1]Patent: WO2010/67204,2010,A1 .Location in patent: Page/Page column 44-45

39
[ 3886-70-2 ]
[ 364782-34-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium carbonate; potassium iodide / isopropyl alcohol / 4 h / 80 - 85 °C / Inert atmosphere 1.2: 1 h / 20 °C / Inert atmosphere 1.3: 20 °C / pH 11 - 12 / Inert atmosphere 2.1: iron acetylacetonate / 1-methyl-pyrrolidin-2-one; tetrahydrofuran / -30 - 0 °C / Inert atmosphere 2.2: 0.25 h / 10 - 35 °C / pH 0 - 1 / Inert atmosphere 3.1: sodium hydrogencarbonate / ethyl acetate; water / 1 h / 20 °C / Inert atmosphere 3.2: 1 h / 20 °C / Inert atmosphere 4.1: hydrogenchloride; hydrogen / 2-5percent w/w palladium on carbon / water; methanol / 20 - 30 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: potassium carbonate; potassium iodide / isopropyl alcohol / 4 h / 80 - 85 °C / Inert atmosphere 1.2: 1 h / 20 °C / Inert atmosphere 1.3: 20 °C / pH 11 - 12 / Inert atmosphere 2.1: iron acetylacetonate / 1-methyl-pyrrolidin-2-one; tetrahydrofuran / 0.17 h / -45 - 0 °C / Inert atmosphere 2.2: 1 h / 25 - 35 °C / Inert atmosphere 3.1: sodium hydroxide / toluene; water / 0.17 h / 20 °C / pH 8 - 8.5 / Inert atmosphere 3.2: 2 h / 20 - 35 °C / Inert atmosphere 3.3: Inert atmosphere
	Multi-step reaction with 3 steps 1.1: potassium carbonate; potassium iodide / isopropyl alcohol / 4 h / 80 - 85 °C / Inert atmosphere 1.2: 1 h / 20 °C / Inert atmosphere 1.3: 20 °C / pH 11 - 12 / Inert atmosphere 2.1: iron acetylacetonate / 1-methyl-pyrrolidin-2-one; tetrahydrofuran / -30 - 0 °C / Inert atmosphere 2.2: 0.25 h / 10 - 35 °C / pH 0 - 1 / Inert atmosphere 3.1: hydrogen / Raney nickel / ethyl acetate; methanol / 20 °C / Inert atmosphere

	Multi-step reaction with 4 steps 1.1: potassium carbonate; potassium iodide / acetonitrile / 4 h / 80 - 85 °C / Inert atmosphere 1.2: 1 h / 20 °C / pH 0.5 - 1 / Inert atmosphere 2.1: sodium hydroxide / water; methanol / 20 °C / pH 11 - 12 / Inert atmosphere 3.1: iron acetylacetonate / 1-methyl-pyrrolidin-2-one; tetrahydrofuran / 0.17 h / -45 - 0 °C / Inert atmosphere 3.2: 1 h / 25 - 35 °C / Inert atmosphere 4.1: sodium hydroxide / toluene; water / 0.17 h / 20 °C / pH 8 - 8.5 / Inert atmosphere 4.2: 2 h / 20 - 35 °C / Inert atmosphere 4.3: Inert atmosphere
	Multi-step reaction with 4 steps 1.1: potassium carbonate; potassium iodide / acetonitrile / 4 h / 80 - 85 °C / Inert atmosphere 1.2: 1 h / 20 °C / pH 0.5 - 1 / Inert atmosphere 2.1: sodium hydroxide / water; methanol / 20 °C / pH 11 - 12 / Inert atmosphere 3.1: iron acetylacetonate / 1-methyl-pyrrolidin-2-one; tetrahydrofuran / -30 - 0 °C / Inert atmosphere 3.2: 0.25 h / 10 - 35 °C / pH 0 - 1 / Inert atmosphere 4.1: hydrogen / Raney nickel / ethyl acetate; methanol / 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: potassium carbonate; potassium iodide / isopropyl alcohol / 4 h / 80 - 85 °C / Inert atmosphere 1.2: 1 h / 20 °C / Inert atmosphere 1.3: 20 °C / pH 11 - 12 / Inert atmosphere 2.1: iron acetylacetonate / 1-methyl-pyrrolidin-2-one; tetrahydrofuran / -30 - 0 °C / Inert atmosphere 2.2: 0.25 h / 10 - 35 °C / pH 0 - 1 / Inert atmosphere 3.1: sodium hydrogencarbonate / ethyl acetate; water / 0.5 h / 20 °C / Inert atmosphere 3.2: Reflux; Inert atmosphere 4.1: hydrogen / 2.5% wt Pd/C / methanol / Inert atmosphere 4.2: 1 h / 25 - 30 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: potassium carbonate; potassium iodide / acetonitrile / 4 h / 80 - 85 °C / Inert atmosphere 1.2: 1 h / 20 °C / pH 0.5 - 1 / Inert atmosphere 2.1: sodium hydroxide / water; methanol / 20 °C / pH 11 - 12 / Inert atmosphere 3.1: iron acetylacetonate / 1-methyl-pyrrolidin-2-one; tetrahydrofuran / -30 - 0 °C / Inert atmosphere 3.2: 0.25 h / 10 - 35 °C / pH 0 - 1 / Inert atmosphere 4.1: sodium hydrogencarbonate / ethyl acetate; water / 0.5 h / 20 °C / Inert atmosphere 4.2: Reflux; Inert atmosphere 5.1: hydrogen / 2.5% wt Pd/C / methanol / Inert atmosphere 5.2: 1 h / 25 - 30 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: potassium carbonate; potassium iodide / acetonitrile / 4 h / 80 - 85 °C / Inert atmosphere 1.2: 1 h / 20 °C / pH 0.5 - 1 / Inert atmosphere 2.1: sodium hydroxide / water; methanol / 20 °C / pH 11 - 12 / Inert atmosphere 3.1: iron acetylacetonate / 1-methyl-pyrrolidin-2-one; tetrahydrofuran / -30 - 0 °C / Inert atmosphere 3.2: 0.25 h / 10 - 35 °C / pH 0 - 1 / Inert atmosphere 4.1: sodium hydrogencarbonate / ethyl acetate; water / 1 h / 20 °C / Inert atmosphere 4.2: 1 h / 20 °C / Inert atmosphere 5.1: hydrogenchloride; hydrogen / 2-5percent w/w palladium on carbon / water; methanol / 20 - 30 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: dichloromethane / 2 h / 20 °C 2.1: sodium hydroxide / dimethyl sulfoxide / 0.5 h / 15 - 20 °C 2.2: 20 h / 20 - 30 °C 3.1: hydrogenchloride / ethyl acetate / 20 - 25 °C
	Multi-step reaction with 3 steps 1.1: dichloromethane / 2 h / 20 °C 2.1: sodium hydride / dimethyl sulfoxide; mineral oil / 0.5 h / 50 - 55 °C 2.2: 1 h / 50 - 55 °C 3.1: hydrogenchloride / ethyl acetate / 20 - 25 °C
	Multi-step reaction with 3 steps 1.1: sodium carbonate / N-benzyl-N,N,N-triethylammonium chloride / dichloromethane / 4 h / 25 - 40 °C 2.1: potassium carbonate / N-benzyl-N,N,N-triethylammonium chloride / 4-methyl-2-pentanone / 1 h / 20 °C 2.2: 15 h / 85 - 90 °C 3.1: potassium carbonate; thiophenol; N-benzyl-N,N,N-triethylammonium chloride / dimethyl sulfoxide / 24 h / 25 - 35 °C 3.2: 2 h / 0 - 25 °C
	Multi-step reaction with 4 steps 1.1: ethanol / 55 - 60 °C 2.1: potassium iodide / 120 - 130 °C 3.1: hydrogenchloride; water / acetonitrile / 1 h / pH 1 - 2 3.2: pH 9 - 10 4.1: hydrogenchloride / n-heptane; toluene; water / 0.5 h / 25 - 30 °C / pH 1 - 2
	Multi-step reaction with 3 steps 1.1: ethanol / 55 - 60 °C 2.1: potassium iodide / 120 - 130 °C 2.2: 1 h / 25 - 35 °C / pH 1 - 2 2.3: pH 9 - 10 3.1: hydrogenchloride / n-heptane; toluene; water / 0.5 h / 25 - 30 °C / pH 1 - 2
	Multi-step reaction with 3 steps 1.1: tetrabutylammomium bromide; potassium carbonate / toluene; water / 60 - 70 °C / Reflux; Large scale 2.1: magnesium; iodine / tetrahydrofuran / 1 h / Reflux 2.2: -55 - 0 °C 3.1: palladium on activated charcoal; hydrogen / water; ethyl acetate / 25 - 30 °C / Large scale
	Multi-step reaction with 5 steps 1: triethylamine / tetrahydrofuran / 12 h / 20 °C / Inert atmosphere 2: 1 h / 0 - 50 °C 3: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium acetate / benzonitrile / 1 h / 20 °C 4: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium acetate; hydrogen / benzonitrile / 12 h 5: hydrogenchloride / water / 12 h / Reflux
	Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 20 °C 2: tetrabutylammomium bromide; potassium carbonate / toluene / Inert atmosphere; Reflux 3: hydrogenchloride / water; tert-butyl methyl ether / 20 °C
	Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 20 °C / Autoclave; Large scale 2: tetrabutylammomium bromide; potassium carbonate / toluene / Inert atmosphere; Reflux; Autoclave; Large scale 3: lithium hydroxide monohydrate; mercaptoacetic acid / acetonitrile / Inert atmosphere; Reflux; Autoclave; Large scale 4: hydrogenchloride / tert-butyl methyl ether; water / 20 °C / Large scale
	Multi-step reaction with 4 steps 1: triethylamine / toluene; acetonitrile / 2 h / 0 °C 2: triphenylphosphine; diethylazodicarboxylate / toluene / 1 h / 50 °C 3: lithium hydroxide monohydrate / toluene; N,N-dimethyl-formamide / 2 h / 25 °C 4: hydrogenchloride / ethyl acetate; water / 45 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / 12 h / 20 °C 2.1: Cu-grafted TiC catalyst / toluene / 24 h / 80 °C / Schlenk technique; Sealed tube 3.1: dichloro bis(acetonitrile) palladium(II); 1,1'-bis-(diphenylphosphino)ferrocene; sodium carbonate / 1,4-dioxane / 18 h / 80 °C 4.1: hydrogen; palladium on carbon / methanol / 12 h / 40 °C / 760.05 Torr 4.2: 0.17 h / 20 °C

Reference： [1]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2011/33473, 2011, A1
[2]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2011/33473, 2011, A1
[3]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2011/33473, 2011, A1
[4]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2011/33473, 2011, A1
[5]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2011/33473, 2011, A1
[6]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2011/33473, 2011, A1
[7]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2011/33473, 2011, A1
[8]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2011/33473, 2011, A1
[9]Current Patent Assignee: IND-SWIFT LABORATORIES LIMITED - US2011/172455, 2011, A1
[10]Current Patent Assignee: IND-SWIFT LABORATORIES LIMITED - US2011/172455, 2011, A1
[11]Current Patent Assignee: IND-SWIFT LABORATORIES LIMITED - US2011/172455, 2011, A1
[12]Current Patent Assignee: AMNEAL PHARMACEUTICALS LLC; MEGAFINE PHARMA (P) LTD. - US2011/319663, 2011, A1
[13]Current Patent Assignee: AMNEAL PHARMACEUTICALS LLC; MEGAFINE PHARMA (P) LTD. - US2011/319663, 2011, A1
[14]Tewari, Neera; Maheshwari, Nitin; Medhane, Roshan; Nizar, Hashim; Prasad, Mohan [Organic Process Research and Development, 2012, vol. 16, # 9, p. 1566 - 1568]
[15]Prediger, Patrícia; Da Silva, Allan Ribeiro; Correia, Carlos Roque Duarte [Tetrahedron, 2014, vol. 70, # 20, p. 3333 - 3341]
[16]Current Patent Assignee: SHANGHAI QINGSONG PHARMACEUTICAL - CN106543008, 2017, A
[17]Current Patent Assignee: SHANGHAI QINGSONG PHARMACEUTICAL - CN106543010, 2017, A
[18]Current Patent Assignee: ASTENA HOLDINGS CO LTD - JP2019/14687, 2019, A
[19]Jing, Hongyu; Li, Jiong; Li, Wen-Hao; Li, Yadong; Wang, Dingsheng; Wang, Yu; Yang, Jiarui; Zhang, Jian; Zhao, Jie [Journal of the American Chemical Society, 2021, vol. 143, # 37, p. 15453 - 15461]

40
[ 3886-70-2 ]
[ 294856-02-3 ]
[ 1005450-55-4 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 2187 - 2194

41
[ 3886-70-2 ]
[ 226256-56-0 ]

Reference： [1]Patent: US2011/172455,2011,A1
[2]Patent: US2011/319663,2011,A1
[3]Patent: US2011/319663,2011,A1
[4]Patent: US2012/309842,2012,A1
[5]Patent: US2012/309842,2012,A1
[6]Patent: CN106543010,2017,A
[7]Patent: CN106810452,2017,A
[8]Patent: JP2019/14687,2019,A

42
[ 3886-70-2 ]
[ 6142-65-0 ]
[ 1332345-01-3 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water; at 20℃; for 4h;	To a stirred solution of <strong>[6142-65-0](trans)-2-(4-bromophenyl)cyclopropanecarboxylic acid</strong> (6.52 g, 27.04 mmol), which can be prepared in accordance with the process set forth on page 82 of WO 2009/024823, in 400 ml of EtOH was added a solution of (R)-(+)-1-(1-Naphthyl)ethylamine (4.63g, 4.37 mL, 27.04 mmol), in 100 ml of EtOH followed by 25 ml of H2O. This was stirred at rt for about 4 h. The solid was collected by filtration and washed with 40 ml of cold EtOH/H2O (20/1) providing 3.18 grams of salt as a white solid (58% recovery) equivalent to 1.86 g of free acid. This was taken up in 2 N NaOH and extracted 5×s with EtOAc. The aq. phase was placed on a rotary evaporator to remove the remaining EtOAc. The resulting clear solution was transferred to an erlenmeyer flask, cooled in an ice bath, and conc. HCl was added dropwise while stirring to pH 4. The resulting solid was collected by filtration providing 1.63 g of Intermediate R. The product was analyzed by chiral SFC (UV detection) using isocratic method (mobile phase: 25% MeOH with 0.1% DMEA, supercritical CO2) on ChiralPak AD-H, 10×250 mm, 5 mum particle size, giving an enantiomeric purity of >95%, Rt 3.88 min (isomer 1) and 4.79 min (isomer 2). 1H NMR (400 MHz, CDCl3) delta ppm 1.37 (ddd, J=8.20, 6.64, 4.69 Hz, 1H), 1.67 (ddd, J=9.28, 5.08, 4.79 Hz, 1H), 1.87 (ddd, J=8.50, 4.69, 4.39 Hz, 1H), 2.48-2.63 (m, 1H), 6.87-7.06 (m, 2H), 7.37-7.46 (m, 2H).

Reference： [1]Patent: US2011/201622,2011,A1 .Location in patent: Page/Page column 19; 20

43
[ 3886-70-2 ]
[ 147526-32-7 ]
[ 1213706-08-1 ]

Yield	Reaction Conditions	Operation in experiment
	In hexane; acetone; at 20℃; for 16h;	Example 9 Synthesis of a compound of formula (IX): (3R,5S,E)-7-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-3,5-dihydroxyhept-6-enoic acid (R)-NEA salt A solution of (II) prepared as in Example 8 (27.9 g, 50.9 mmol) in MeOH (470 mL) is adjusted to 0 C. and 2 M HCl (65 mL, 127.3 mmol, 2.5 equivalents) is added drop by drop. The mixture is left under stirring at 20 C. for 16 hours. Il organic solvent is evaporated off under reduced pressure, AcOEt (500 ml) is added and the organic phase is washed with a NaHCO3 saturated solution, with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The reaction crude is purified by flash silica gel chromatography (eluent: toluene/AcOEt 8:2). The resulting solid (16.3 g, 37.6 mmoles) is dissolved in anhydrous THF (55 mL) and MeOH (55 mL). The solution is then added drop by drop to a suspension of NaBH4 (2.0 g, 52.6 mmol, 1.4 equivalents) and 1 M diethylmethoxyborane in THF (38 mL, 37.6 mmol, 1 equivalent) in anhydrous THF (215 mL) kept at -78 C. The reaction mixture is kept under stirring at -78 C. and after 1 hour is treated with a NaHCO3 saturated solution and extracted with AcOEt. The organic phase is washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue is dissolved in AcOEt (230 mL) and the solution is heated at 50 C. A 35% H2O2 aqueous solution (10.5 ml, 115.8 mmol, 3.08 equivalents) is added and the mixture is left under magnetic stirring a 50 C. for 1 hour. After that, the mixture is added with brine (230 mL) and left to stand at 50 C. for 30 minutes; finally added with a Na2S2O5 aqueous solution (6.6 g in 120 ml of H2O) and kept under stirring a 50 C. for a further 10 minutes. The organic phase is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained solid is dissolved in MeOH (315 mL) and treated with 1 M NaOH (45 ml, 45 mmoles, 1.2 equivalents). The mixture is kept under stirring at 20 C. for 2 hours, then the organic solvent is evaporated off under reduced pressure at 40 C. The resulting aqueous phase is washed with methyl t-butyl ether and AcOEt, treated with 1N HCl to pH=4.5 and extracted with dichloromethane. The organic solution is dried over Na2SO4, filtered and concentrated under reduced pressure; the residue is dissolved in acetone (40 mL) and this solution is added with a solution obtained dissolving (R)-NEA (6.5 mL, 40.5 mmoles, 1.1 equivalents) in acetone (18 mL). After completion of the addition, a white solid precipitates, which is added drop by drop with hexane (50 mL) and the suspension is left under stirring at 20 C. for 16 hours, then filtered and the solid is then repeatedly recrystallized from acetone and isopropanol/water. 7.1 g of the title compound are obtained, as a crystalline white solid, having both chemical and optical purity degree of 99.5%. 1H NMR (300 MHz, CDCl3) delta: 7.97 (d, 1H); 7.95 (d, 1H); 7.82 (d, 1H); 7.76 (d, 1H); 7.64 (d, 1H); 7.61-7.43 (m, 5H); 7.33-7.29 (m, 2H); 7.19-7.08 (m, 4H); 6.55 (d, 1H); 5.54-5.47 (m, 4H); 5.11 (dd, 1H); 4.24-4.14 (m, 1H); 3.82-3.68 (m, 1H); 2.47-2.36 (m, 1H); 1.96 (d, 2H); 1.66 (d, 3H); 1.38-1.19 (m, 3H); 1.15-0.97 (m, 3H).

Reference： [1]Patent: US2011/269962,2011,A1 .Location in patent: Page/Page column 7

44
[ 3886-70-2 ]
[ 21172-41-8 ]
[ 364782-34-3 ]

Yield	Reaction Conditions	Operation in experiment
80%		<strong>[21172-41-8]3-[3-(trifluoromethyl)phenyl]propionaldehyde</strong>(5.9 g, 0.029 mol) was added to (R)-(l-naphthyle)ethylamine (5 g, 0.029 mol) for 30 min at room temperature and stirred for lhour. Mixture of boric acid (1.81g, 0.029 mol) and sodium borohydride (1.08g, 0.029 mol) was slowly added lot wise for 1 hour at room temperature. Stirred for 12 hours at room temperature, Completion of reaction was monitored by TLC. After the completion of reaction slowly added aqeoussodiumbicorbonate (6 g in 100 ml water) for 30min. Extract the reaction mass with ethylacetate (70 ml). Wash the ethylacetate layer with water (20 ml). Distill of ethyl acetate under vaccum and charged hexane (100 ml) and water (20 ml). Slowly added con.HCl for 30 min to get pH 1 to 3.Stirr for 3 hours at room temperature and filter followed by washing with mixure of hexane and water. Crude product is dissolved in acetonitrile (30 ml) and heat to 50-60C. The clear solution was cooled to 0-5C and stir for 2 hours. Filter the reaction mass followed by washing with chilled acetonitrile (10 ml).The wet product was dried under vaccum at 50C to yield Cinacalcet Hydrochloride as a white solid, (9.2 g, 80%).
		-[3-(Trifluoromethyl)phenyl]propionaldehyde (7.07 gm) was dissolved in tetrahydrofuran (25 ml) and then cooled to -45 to -50C. To the solution was added a solution of (R)-(l-naphthyl)ethylamine (5 gm) in tetrahydrofuran (75 ml) at -45 to -50C slowly for 2 hours 30 minutes and then added titanium(IV)isopropoxide (2.07 gm). The reaction mass was stirred for 20 minutes at -45 to -50C and then added a solution of sodium cyanoborohydride (2 gm) in methanol (20 ml) slowly for 20 minutes. The temperature of the reaction mass was raised to room temperature and maintained for 2 hours at room temperature. To the reaction mass was added water (25 ml) and the reaction mass was then filtered through celite bed. The layers were separated and the aqueous layer was extracted with diisopropyl ether. The combined organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain residual mass. To the residual mass was added diisopropyl ether (40 ml) and water (50 ml). The contents were heated to 55 to 60C. Hydrochloride in ethyl acetate (16% HCl, 6.2 ml) was added to the reaction mass at 55 to 60C and maintained for 30 minutes at 55 to 60C. The reaction mass was cooled to room temperature and maintained for 15 hours at room temperature, filtered. The solid obtained was dried to obtain 9.5 gm of cinacalcet hydrochloride.Cinacalcet hydrochloride: 98.6%; 2- [3 -(Trifluoromethyl)phenyl] -5- [3 -(trifluoromethyl)phenyl] -3 -hydroxy pentanal impurity: 1.05%;(R)-l-(Naphthyl)ethylamine impurity: 0.3%.

Reference： [1]Patent: WO2014/16847,2014,A1 .Location in patent: Page/Page column 5; 9
[2]Patent: WO2012/7954,2012,A1 .Location in patent: Page/Page column 13

45
[ 516-09-6 ]
[ 3886-70-2 ]
[ 1352125-80-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	In toluene; at 150℃; for 40h;Inert atmosphere; Sealed vessel;	A 250-mL pressure bottle, charged with R-(+)-α-naphthyl ethyl amine (27.1 g, 0.158 mol), α-methyltetronic acid (18.0 g, 0.158 mol), and toluene (50 mL), was sealed and heated to 150 C. After 40 h, the reaction mixture was cooled, unsealed and diluted with CH2Cl2 (2 L) and filtered through Buchner funnel to remove some undissolved solid. The filtrate was washed with satd. aq NaHCO3 (2×200 mL), H2O (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford the crude yellowish solid. The crude solid was suspended in Et2O (100 mL), filtered through a Buchner funnel, rinsed with Et2O (3×50 mL), and concentrated in vacuo to afford 34.0 g (90%) of product 20 as a white crystalline solid. An analytical sample had: [α]22D -196 (c 1.18, 1:1 CH3OH/CHCl3); 1H NMR (1:1 CD3OD/CDCl3): δ 7.78 (d, J=8.4 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.36-7.20 (m, 4H), 5.10 (q, J=7.8 Hz, 1H), 4.42 (d, J=15.3 Hz, 1H), 4.29 (s, 1H), 3.96 (d, J=15.3 Hz, 1H), 1.45 (d, J=7.8 Hz, 6H); 13C NMR (1:1 CD3OD/CDCl3): δ 178.2, 163.5, 139.0, 133.8, 129.6, 128.8, 127.8, 126.2, 125.5, 125.3, 121.7, 121.6, 88.6, 65.9, 49.8, 22.5, 6.0; IR (CHCl3): 3374, 3017, 2944, 2833, 1635, 1448 cm-1; EIMS: 267 (M+); HRMS calcd for C17H17NO2: m/z 267.1259. Found: 267.1237. Crude 20 was used without further purification.

Reference： [1]Tetrahedron,2011,vol. 67,p. 9787 - 9808

46
[ 129254-76-8 ]
[ 3886-70-2 ]
[ 100-52-7 ]
[ 364782-34-3 ]

Yield	Reaction Conditions	Operation in experiment
52.1%	Stage #1: (R)-1-(1-Naphthyl)ethylamine; benzaldehyde at 25 - 30℃; Stage #2: 1-(3-bromopropyl)-3- (trifluoromethyl)benzene In 1-methyl-pyrrolidin-2-one at 130 - 140℃; for 12h; Stage #3: With hydrogenchloride; water In 1-methyl-pyrrolidin-2-one; toluene	8 Preparation of Cinacalcet Hydrochloride of Formula (VII) Example 8 Preparation of Cinacalcet Hydrochloride of Formula (VII) Solution of (1R)-1-naphthyl ethylamine (Formula II, 100 gm) and benzaldehyde (Formula III, 62.0 gm) was stirred at 25-30° C. for 1-2 hours. After completion of the reaction which was monitored by HPLC, N-methyl-2-pyrrolidinone (300 ml) was added to the reaction mass and stirred the mixture for 15-20 min. 1-(bromopropyl)-3-(trifluoromethyl)benzene (Formula V, 172 gm) was added to the resulting solution. The reaction mixture was further stirred and heated to at 130-140° C. for 12 hrs. After completion of the reaction (by HPLC), the reaction solution was diluted with water (1000 ml) and the pH of the solution was adjusted to 8-9 using aqueous ammonia, toluene (1000 ml) was added to the solution. The mixture was stirred and toluene layer was separated. The toluene layer were washed with water (1000 ml) followed by solution of 10% sodium metabisulphite (1000 ml2). The toluene layer was diluted with water (1000 ml), adjusted pH of the solution to 0.5-2.0 using concentrated hydrochloric acid. The resulting reaction solution was stirred, separated aqueous layer and organic layer. Organic layer washed with water washed with water (1000 ml2). The toluene layer was distilled off completely to obtain the thick syrup, which was further stirred in diisopropylether (600 ml) at 25-30° C. for 6 h isolated the solid by filtration. The obtained solid was suspended in ethyl acetate (500 ml), solution was heated at 55-60° C. for 30 min, cooled to 15-20° C., filter the obtained solid. The product was dried to afford Cinacalcet hydrochloride (Formula VII) as white crystalline solid. Yield of the compound VI 120 gm (52.10%). HPLC purity: 99.85%: Chiral Purity: 99.98% MS; m/z 358.79 (M++1). 1H NMR (DMSO-d6): δ 10.12 (s, 1H), 9.43 (s, 1H), 8.26 (d, 1H), 8.08 (d, 1H), 7.99-8.03 (m, 2H), 7.60-7.63 (m, 3H), 7.53-7.54 (dt, 2H), 7.45-7.48 (dt, 2H). 5.32(q, 1H), 2.93-2.96 (m, 1H), 2.69-2.74 (t, 3H), 1.97-2.07 (m, 2H), 1.68-1.71 (d, 3H).

Reference： [1]Current Patent Assignee: AMNEAL PHARMACEUTICALS LLC; MEGAFINE PHARMA (P) LTD. - US2011/319663, 2011, A1 Location in patent: Page/Page column 18

47
[ 129254-76-8 ]
[ 3886-70-2 ]
[ 364782-34-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: 1-(3-bromopropyl)-3-(trifluoromethyl)benzene; (R)-1-(1-Naphthyl)ethylamine With potassium carbonate In toluene Reflux; Stage #2: With hydrogenchloride In water monomer; toluene at 50℃;
83%	Stage #1: 1-(3-bromopropyl)-3-(trifluoromethyl)benzene; (R)-1-(1-Naphthyl)ethylamine With potassium carbonate In toluene for 7h; Reflux; Stage #2: With hydrogenchloride In water monomer; toluene at 50℃;	8 Example 8 Example 8 [0038] 1-(3-bromopropyl)-3-(trifluoromethyl)benzene (3.8 g), toluene (30 ml), R-(-)-1-naphthyl ethylamine (2.91 g), and potassium carbonate (3.92 g) was charged and refluxed for 7 hours, The mixture was cooled to 20° C.-25° C., water (100 ml) and toluene (30 ml) were added, organic phase was separated and washed with hydrochloric acid (1 mol/L, 40 mL×3) at 50° C., chilled and stirred at 5° C.-10° C. for 1 hour. Solid was collected by filtration to afford cinacalcet hydrochloride, 4.6 g, 83%. Cinacalcet hydroxide obtained in this example was tested and confirmed with the same method as used in Example 1: HPLC purity (Purity): 98.7%; Chiral purity (Purity): 99.0%.
58%	Stage #1: (R)-1-(1-Naphthyl)ethylamine With benzaldehyde at 25 - 30℃; Stage #2: 1-(3-bromopropyl)-3-(trifluoromethyl)benzene In 1-methyl-pyrrolidin-2-one at 125 - 130℃; Further stages;

Reference： [1]Chen, Xinfa; Chen, Zhijie; Cui, Yong; Farha, Omar K.; Gong, Wei; Kirlikovali, Kent O.; Liu, Yan; Nan, Bing; Si, Rui; Zhang, Wenqiang [Journal of the American Chemical Society, 2022, vol. 144, # 7, p. 3117 - 3126]
[2]Current Patent Assignee: XINCHANG KANGLE CHEMICALS CO., LTD. - US2015/80608, 2015, A1 Location in patent: Paragraph 0038
[3]Location in patent: experimental part Shinde, Gorakshanath B.; Niphade, Navnath C.; Deshmukh, Shrikant P.; Toche, Raghunath B.; Mathad, Vijayavitthal T. [Organic Process Research and Development, 2011, vol. 15, # 2, p. 455 - 461]

48
[ 3886-70-2 ]
[ 158966-92-8 ]
[ 1380816-67-0 ]

Yield	Reaction Conditions	Operation in experiment
	In ethyl acetate at 25 - 30℃; for 10h;	8 Example 8: Preparation of montelukast (R)-(+)- l-(l-naphthyl)ethylamine saltTo a stirred solution of montelukast (5.0 g, 0.01 mol ) in ethyl acetate (20 ml), (R)-(+)- 1-(1- naphthyl)ethylamine salt (1.7 g, 0.01 mol) was slowly added at 25-30°C and stirred for 10 hours. Reaction mixture was filtered to remove undissolved particles. To the filtrate thus obtained, acetonitrile (50 ml) was added at 25-30 °C and mixture was stirred for 24 hours. Solid thus precipitated was filtered and washed successively with acetonitrile (10 ml) & n-heptanes (25 ml). Resulting solid was dried under vacuum at 30 °C for 4 hours to give 4.5 g of the title compound showing melting point 1 15-1 18°C.

Reference： [1]Current Patent Assignee: IND-SWIFT LABORATORIES LIMITED - WO2012/77133, 2012, A1 Location in patent: Page/Page column 25

49
[ 3886-70-2 ]
[ 78573-45-2 ]
[ 226256-56-0 ]

Reference： [1]European Journal of Organic Chemistry,2012,p. 2990 - 3000
[2]Advanced Synthesis and Catalysis,2018,vol. 360,p. 2157 - 2165
[3]Organic Letters,2019

50
[ 189321-66-2 ]
[ 3886-70-2 ]
[ 1398394-72-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step-2: tert-Buty-2-(((R)-l -(naphthalen- l-yl)ethyl)carbamoyl)morpholine-4-carboxy late: To a stirred solution of Step-1 of Intermediate-2 (2.9 g, 12.55 mmole) in dichloromethane (100ml), HOBt (2.54 g, 18.83 mmole) was added followed by DIPC (2.92 mL, 18.83 mmole) at RT (room temperature). The reaction mixture was stirred for 15 min and (R)-l- (naphthalen-l-yl)ethanamine (2.41 mL, 15.06 mmole) was added to the reaction mixture and stirred overnight. Solid separated out was filtered, washed with dichloromethane (2 x 30 mL), filtrate collected and washed with brine (2 x 30 mL) and DM water to get crude amide which was further purified by flash chromatography (n-Hexane:ethyl acetate, 8:2) to get the title compound as a white solid (3.4 gm) (m/z-Boc) 285.2

Reference： [1]Patent: WO2012/120476,2012,A1 .Location in patent: Page/Page column 58

51
[ 212650-43-6 ]
[ 3886-70-2 ]
[ 1398394-57-4 ]

Yield	Reaction Conditions	Operation in experiment
		Step-2: ieri-Butyl 3-(((i?)-l-(naphthalen-l-yl)ethyl)carbamoyl)morpholine-4-carbo xylate:To a stirred solution of Step-1 of Intermediate- 1 (1.8 g, 7.79 mmole) in dichloromethane, HOBt (1.57 g, 11.6 mmole) was added followed by DIPC (1.05 mL, 11.6 mmole) at RT. The reaction mixture was stirred for 15 min and (i?)-l-(naphthalen-l-yl)ethanamine (1.49 mL, 9.35 mmole) was added to the reaction mixture and then stirred overnight. Solid separated out was filtered, washed with dichloromethane (2 x 15 mL), filtrate collected and washed with brine (2 x 15 mL) and demineralised water (DM water) to get crude amide, which was further purified by flash chromatography (n-hexane: ethyl acetate, 8:2) to get title compound as a white solid (2.6 gm) (m/z-Boc) 285.1
2.6 g		Step-2: tert-Butyl 3-(((R)-1-(naphthalen-1-yl)ethyl)carbamoyl)morpholine-4-carboxylate To a stirred solution of Step-1 of Intermediate-1 (1.8 g, 7.79 mmole) in dichloromethane, HOBt (1.57 g, 11.6 mmole) was added followed by DIPC (1.05 mL, 11.6 mmole) at RT. The reaction mixture was stirred for 15 min and (R)-1-(naphthalen-1-yl)ethanamine (1.49 mL, 9.35 mmole) was added to the reaction mixture and then stirred overnight. Solid separated out was filtered, washed with dichloromethane (215 mL), filtrate collected and washed with brine (215 mL) and demineralised water (DM water) to get crude amide, which was further purified by flash chromatography (n-hexane:ethyl acetate, 8:2) to get title compound as a white solid (2.6 gm) (m/z-Boc) 285.1

Reference： [1]Patent: WO2012/120476,2012,A1 .Location in patent: Page/Page column 57
[2]Patent: US2013/345213,2013,A1 .Location in patent: Paragraph 0352

52
[ 859155-89-8 ]
[ 3886-70-2 ]
[ 1398396-09-2 ]

Yield	Reaction Conditions	Operation in experiment
71.6%		Step-5 : ieri-Butyl 3 -(2-(((R)- 1 -(naphthalen- 1 -yl)ethyl)amino)-2-oxoethyl)morpholine-4- carboxylateTo a stirred solution of Step-5 intermediate (30ml), HOBt (0.749 g, 4.89 mmol) and DIPC (0.762 ml, 4.89 mmol) were added at RT. The reaction mixture was stirred for 15 min, then (R)-l -(naphthalen- l-yl)ethanamine (0.670 g, 3.91 mmol) was added to the reaction mixture and further stirred overnight. Solid separated out was filtered and filtrate extracted with dichloromethane (2 x 30 mL), washed with brine solution (2 x 30 mL) and DM water. The solvent was evoparated to get the crude compound and it was further purified by flash chromatography (n-Hexane:ethyl acetate, 4: 1 ) to get the title compound as a white solid (930 mg, 71.6%), m/z 399.
71.6%		Step-5: tert-Butyl 3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)-2-oxoethyl)morpholine-4-carboxylate [0383] To a stirred solution of Step-5 intermediate (30 ml), HOBt (0.749 g, 4.89 mmol) and DIPC (0.762 ml, 4.89 mmol) were added at RT. The reaction mixture was stirred for 15 min, then (R)-1-(naphthalen-1-yl)ethanamine (0.670 g, 3.91 mmol) was added to the reaction mixture and further stirred overnight. Solid separated out was filtered and filtrate extracted with dichloromethane (2×30 mL), washed with brine solution (2×30 mL) and DM water. The solvent was evaporated to get the crude compound and it was further purified by flash chromatography (n-Hexane:ethyl acetate, 4:1) to get the title compound as a white solid (930 mg, 71.6%), m/z 399.

Reference： [1]Patent: WO2012/120476,2012,A1 .Location in patent: Page/Page column 66
[2]Patent: US2013/345213,2013,A1 .Location in patent: Paragraph 0383

53
[ 3886-70-2 ]
[ 147118-40-9 ]
[ 1416820-71-7 ]

Yield	Reaction Conditions	Operation in experiment
		7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5- dihydroxy-hept-6-enoic acid methyl ester (1 1.0 g) was dissolved in methanol (1 10 ml) at room temperature and mixture was cooled at 10 - 15°C. Aqueous sodium hydroxide solution (10 percent, 1 1 ml) was added to the reaction mixture at 10-15 °C and stirred for 2 hour at ambient temperature. After completion of reaction, reaction mass was concentrated followed by addition of demineralized water (55 ml) and activated carbon (1.1 g). Reaction mixture was stirred for 15 minutes, filtered through hyflow bed and bed was washed with water. Resulting filtrate was washed with methyl tert-butyl ether (3 x 50ml). Ethyl acetate (1 10 ml) was added to the resulting reaction aqueous layer and pH was adjusted to 1 - 2 by addition of concentrated hydrochloric acid at 10-15 °C. Reaction mixture was stirred for 30 minutes followed by layer separation. Organic layer was washed with brine solution and then concentrated under vacuum. Ethyl acetate (55 ml) was added to resulting residue and cooled reaction to 0 °C. R(+)-l-(l-Naphthyl)ethylamine (3.80 g) in ethyl acetate (1 1 ml) was added to mixture at 0 °C and stirred for 30 minutes at 0 °C. Reaction mixture was stirred at ambient temperature for 12 hours, n- Heptane (44 ml) was added to resulting mixture and cooled reaction mixture at -10 °C. Reaction mixture was stirred for 1 hour at same temperature, filtered, washed with n-heptane and ethyl acetate mixture and dried to give 7.0 g of title compound having purity 98.82 percent by HPLC.

Reference： [1]Patent: WO2012/176218,2012,A1 .Location in patent: Page/Page column 22-23

54
[ 3886-70-2 ]
[ 78573-45-2 ]
[ 364782-34-3 ]

Yield	Reaction Conditions	Operation in experiment
83%		2.51 g (14.7 mmol) of (R)-1-(1-naphthyl)-ethylamine and 3.01 g (14.7 mmol) of 3-[3-(trifluoromethyl)phenyljpropanol are weight into a flask. The mixture is diluted with 6 ml of toluene and 53 mg (0.45 mol percent) of {IrCp*Cl2]2 is added. The mixture is heated in a bath at t=110 °C under a reflux condenser in the nitrogen atmosphere for 20 hours. After cooling down, the reaction mixture is diluted with a mixture of hexane and ethyl acetate. On addition of a solution of hydrogen chloride in diethylether, a solid salt is formed and by sucking it off 4.83 g (83 percent) of Cinacalcet hydrochloride is obtained in a purity of 97.8 percent (HPLC). The method described in Example 1 was used for HPLC determination.

Reference： [1]Patent: WO2013/75679,2013,A1 .Location in patent: Page/Page column 9

55
[ 1643-28-3 ]
[ 3886-70-2 ]
[ 1434603-36-7 ]