[ CAS No. 1012341-50-2 ] {[proInfo.proName]}

Name: 1012341-50-2|(2R,4S)-5-([1,1'-Biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid|95%
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SKU: A644676
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Quality Control of [ 1012341-50-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1012341-50-2 ]

Product Details of [ 1012341-50-2 ]

CAS No. :	1012341-50-2	MDL No. :	MFCD27955981
Formula :	C₂₃H₂₉NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YNELJETWNMPEEH-UZLBHIALSA-N
M.W :	383.48	Pubchem ID :	46193546
Synonyms :

Calculated chemistry of [ 1012341-50-2 ]

Physicochemical Properties

Num. heavy atoms :	28
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.39
Num. rotatable bonds :	10
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	111.2
TPSA :	75.63 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.09 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.39
Log Po/w (XLOGP3) :	5.0
Log Po/w (WLOGP) :	4.9
Log Po/w (MLOGP) :	3.83
Log Po/w (SILICOS-IT) :	4.43
Consensus Log Po/w :	4.31

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-5.02
Solubility :	0.00362 mg/ml ; 0.00000945 mol/l
Class :	Moderately soluble
Log S (Ali) :	-6.33
Solubility :	0.00018 mg/ml ; 0.00000047 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-6.47
Solubility :	0.00013 mg/ml ; 0.00000034 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	3.68

Safety of [ 1012341-50-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1012341-50-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 1012341-50-2 ]
Downstream synthetic route of [ 1012341-50-2 ]

[ 1012341-50-2 ] Synthesis Path-Upstream 1~2

1
[ 1012341-50-2 ]
[ 149690-12-0 ]

Yield	Reaction Conditions	Operation in experiment
96.5%	With thionyl chloride In ethanol at 60℃; for 1 h;	The (2R, 4S) -5- (biphenyl-4-yl) -4 - [(tert-butoxycarbonyl) amino] -2-methyl-pentanoic acid 1.91g (5.0mmol),Ethanol 20mL added to the reaction flask,0.41 mL (5.5 mmol) of thionyl chloride was added dropwise at an elevated temperature of 60 ° C,Continue to maintain the temperature for 1 hour.The reaction was complete by HPLC.The reaction solution was concentrated under reduced pressure to give 1.67 g of compound (II)Yield 96.5percent.

Reference： [1] Patent: CN107468685, 2017, A, . Location in patent: Paragraph 0267; 0268; 0269
[2] Patent: WO2016/135751, 2016, A1, . Location in patent: Page/Page column 30
[3] Patent: CN107082746, 2017, A, . Location in patent: Paragraph 0051; 0055-0060; 0080

2
[ 1012341-50-2 ]
[ 64-17-5 ]
[ 149690-12-0 ]

Yield	Reaction Conditions	Operation in experiment
246 g	at 62 - 65℃; for 2.5 h;	A-1 (300 g) was dissolved in 2400 ml of absolute ethanol at room temperature; heated to 62 ° C,Slowly dripping140 g of sodium sulfoxideThe temperature was raised to 65 ° C for 2.5 h. The residue was distilled under reduced pressure to give a white solid which was dried under reduced pressure by adding 1200 ml of n-hexane.Into a 1200 ml n-hexane ice bath for 60 min; filtered, the solid was rinsed with n-hexane and dried at 35 ° C for 10 h to give a white solid(A-2) 246 g.
172.3 g	at 0 - 60℃; for 6 h;	Thionyl chloride (49.4 ml) was added to a precooled solution containing ethanol (600 ml) and (2R,4S)-5-([ 1,1 ‘-biphenyl] -4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid compound of formula-2 (200 gms) at 0-5°C. Heated the reaction mixture to 55-60°C and stirred for 6 hours at the same temperature. Distilled off the solvent completely under reduced pressure and co-distilled with methyl tertiary butyl ether. Cooled the reaction mixture to 25- 30°C. Methyl tertiary butyl ether (1400 ml) was added to the obtained compound. Heated thereaction mixture to 50-55°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with methyl tertiary butyl ether and dried to get the title compound.Yield: 172.3 grns; M.R: 150-158°C; Purity by HPLC: 99.46percent.

Reference： [1] Patent: WO2008/83967, 2008, A2, . Location in patent: Page/Page column 115-120
[2] Patent: CN106065006, 2016, A, . Location in patent: Paragraph 0051; 0052
[3] Patent: CN106146351, 2016, A, . Location in patent: Paragraph 0035
[4] Patent: WO2017/154017, 2017, A1, . Location in patent: Page/Page column 23; 24

[ 1012341-50-2 ] Synthesis Path-Downstream 1~87

1
[ 1012341-48-8 ]
[ 1012341-50-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogen; under 15001.5 - 18751.9 Torr;	7) To 61.4g (R, E) -5-([1,1'-biphenyl] -4-yl) -4-((tert-butoxycarbonyl) amino) -2-methyl-2-pentene acidHydrogen is introduced (hydrogen partial pressure is 2-2.5 MPa), and hydrogenation catalyzes to obtain 55.2g (2R, 4S) -5- (biphenyl-4-yl) -4-[(Tert-butoxycarbonyl) amino] -2-methylpentanoic acid;(90% yield);
86.9%	With hydrogen;diiodo(p-cymene)ruthenium(II) dimer; (SP,S?P)-1,1?-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2?-bis[(R)-alpha-(dimethylamino)benzyl]ferrocene; In ethanol; at 40.0℃; under 15001.5 Torr; for 6.0h;Product distribution / selectivity;	Example 2: (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid in crystalline form; [Show Image] To a suspension of <strong>[1012341-48-8](E)-(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid</strong> (200 g, 524.3 mmol) in degassed ethanol (900 ml) at 40 C a solution of diiodo(p-cymene)ruthenium(II) dimer (0.052 g, 0.0524 mmol) and (alphaR,alphaR)-2,2'-bis(alpha-N,N-dimethylaminophenylmethyl)-(S,S)-1,1'-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphine]ferrocene (= Mandyphos SL-M004-1) (0.116 g, 0.110 mmol) was added in degassed ethanol (100 ml). The solution was degassed using vacuum and a pressure of 20 bar hydrogen applied. The mixture was stirred at 40 C for 6 h. Vessel was then purged with nitrogen. Ethanol (700 ml) was removed by distillation. Isopropyl acetate (600 ml) was added. Solvent (600 ml) was removed by distillation. Isopropyl acetate (600 ml) was added. Solvent (600 ml) was removed by distillation. Isopropyl acetate (300 ml) was added and the solution heated to reflux. Heptane fraction (1200 ml) was added and the mixture cooled to room temperature. The solid was collected by filtration and washed with heptane fraction-isopropyl acetate 2 : 1 mixture (360 ml). The solid was dried overnight at 50 C under 1-50 mbar vacuum to afford (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (174.7 g, 86.9 %) as a white/off-white solid. Mpt 146-147 C; deltaH (500 MHz; DMSO) 1.07 (3H, d, J 7.0, 1-CH3), 1.34 (9H, s, (CH3)3), 1.38 (1H, m, 3-HA), 1.77 (1H, m, 3-HB), 2.43 (1H, m, 2-H), 2.70 (2H, d, J 7.0, 5-H), 3.69 (1H, m, 4-H), 6.74 (1H, d, J 9.0, NH), 7.27 (2H, d, J 8.0, Ar-ortho-H(Ph)), 7.36 (1H, t, J 7.0, Ar-(Ph)-para-H), 7.46 (2H, t, J 7.5, Ar-(Ph)-meta-H), 7.57 (2H, d, J 8.0, Ar-meta-H(Ph), 7.64 (2H, d, J 7.5, Ar-(Ph)-ortho-H), 12.01 (1H, s, CO2H); deltac (500 MHz, DMSO) 18.1 (1-CH3), 28.3 [(CH3)3], 35.9 (2-C), 37.9 (3-C), 40.7 (5-C), 50.0 (4-C), 77.4 [(C(CH3)3], 126.3, 126.5, 127.2, 128.9, 129.8 (Ar-CH), 137.7 (Ar-ipso-C(Ph)), 138.3 (Ar-para-C(Ph)), 140.1 (Ar-(Ph)-ipso-C), 155.2 (NCO), 177.2 (CO2H); mlz (+ESI) 406 ([MNa]+, 6%), 384 ([MH]+, 31), 328 (100), 284 (19); Found: [MH]+, 384.21691. C23H30NO4 requires MH 384.21693. Figure 1 shows the structure of crystalline (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid measured by x-ray diffraction. The crystals comprise the following unit cell dimensions, measured by 100 K:
73.8%	With palladium 10% on activated carbon; hydrogen; In ethanol; at 25.0℃; under 7500.75 Torr; for 20.0h;	(R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-pentane was added to the hydrogenation vessel with stirring. 2-enoic acid (Compound III) (75 g, 0.20 mol), 10% palladium on carbon (Pd/C) (3.0 g) and 750 ml of ethanol,Hydrogen was introduced and allowed to react (1.0 MPa, 25 C) for 20 hours. Filter and concentrate to dryness,It was recrystallized by adding an appropriate ratio of isopropyl acetate/petroleum ether, and dried to give a white solid (Compound II).

	With diiodo(p-cymene)ruthenium(II) dimer; (SP,S?P)-1,1?-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2?-bis[(R)-alpha-(dimethylamino)benzyl]ferrocene; hydrogen; sodium hydroxide; In dichloromethane; water; at 60.0℃; under 30003 Torr; for 16.0h;Autoclave; Ionic liquid; Inert atmosphere;	General procedure: [Ru(p-cimene)I2]2 (4.85 mg; 4.96 mumol) and (SP,S?P)-1,1?-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2?-bis[(R)-alpha-(dimethylamino)benzyl]ferrocene (Mandyphos, SL-M004-1) (12.0mg; 11.4 mumol) were weighted in two Schlenk tubes inside a glovebox. The Ru precursor was dissolved in CH2Cl2 (5 mL) and the resulting solution was transferred into the Schlenk tube containing the ligand and stirred at r.t. for 1 h. The ionic liquid 1-ethyl-3-methylimidazoliumbis(trifluoromethylsulfonyl)imide [EMIM][NTf2] (5 mL) was added and the CH2Cl2 was slowly evaporated under vacuum. An aliquot of this solution (0.2 mL) was diluted with additional [EMIM][NTf2] (1.8 mL) and the solution was transferred into a 13 mL window autoclave. (R)-1-CO2H (100 mg; 262 mumol) was dissolved in a basic aqueous solution (4 mL, pH 13) (see table 2 for detail) and transferred into the autoclave. The autoclave was heated to reaction temperature and pressurized with H2 (40 bar). The reaction was started by magnetic agitation. After 16 h, the autoclave was cooled to r.t. and gently vented. The upper water phase was removed with a needle and neutralized with an HCl solution (1 M), the white solid precipitated was collected by filtration and analyzed by HPLC.
	With diiodo(p-cymene)ruthenium(II) dimer; hydrogen; In ethanol; under 22502.3 Torr; for 20.0h;	Step 3 0.07853 mol of compound II was added to 130 g of absolute ethanol and 0.030 g of [RuI2] 2 and 0 ? 120 g Mandyphos chiral ligands were added. The hydrogen pressure was 3·0 MPa, and the pressure was stirred for 20 hours. Rate of 95.05%.
340 g	With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; N,N?-(1S,2S)-cyclohexane-1,2-diylbis[2-(diphenylphosphino)-1-naphthamide]; hydrogen; In ethanol; at 40.0℃; under 11251.1 Torr;Autoclave;	To the autoclave is sequentially added in the Embodiment 3: (R, E) -5 - ([1, 1' - biphenyl] -4 - yl) -4 - ((tert-butoxy carbonyl) amino) -2 - methyl -2 - pentenoic acid 381g, ethanol 3.5 kg, double-(dicyclopentadiene) tetra fluoborate rhodium 99 mg and phosphine CK - 04 279 mg, replacing hydrogen, pressure 15 kg, temperature 40 C, stirring to LC in the control reaction is complete, filtering, crude job the filtrate turns on lathe, chiral analysis of II:III=90 the two isomers: 10. The crude product of ethyl acetate and petroleum ether beating, then using ethanol recrystallization, the crude product of ethyl acetate and petroleum ether beating, to obtain the product (2R, 4S) -5 - ([1, 1' - biphenyl] -4 - yl) -4 - ((tert-butoxy carbonyl) amino) -2 - methyl valeric acid 340g

Reference： [1]Patent: CN108299226,2018,A .Location in patent: Paragraph 0016; 0027; 0034; 0037; 0044
[2]Patent: EP1903027,2008,A1 .Location in patent: Page/Page column 17-18
[3]Patent: CN108373423,2018,A .Location in patent: Paragraph 0035-0038
[4]Synthesis,2017,vol. 49,p. 353 - 357
[5]Patent: CN106631903,2017,A .Location in patent: Paragraph 0031; 0034
[6]Patent: CN105061263,2017,B .Location in patent: Paragraph 0037; 0038; 0039; 0040; 0041; 0042; 0043; 0044

2
[ 1012341-50-2 ]
[ 64-17-5 ]
[ 1038924-98-9 ]

Yield	Reaction Conditions	Operation in experiment
	With dibromo sulfoxide; at 65℃; for 1.5h;	1O g (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (3-a, R1 = BOC, R2 = R3 = H) are added to ethanol (100 ml). The mixture is heated to 65 0C. 3 ml of thionyl bromide is then added over 0.5 hour. The mixture is then stirred for a further 1 hour. The ethanol is removed and heptane added. Further azeotropic distillations are performed using heptane to remove any residual ethanol. The solvent is removed in vacuo to afford (2R, 4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrobromide (3-a, R1 = R2 = H1 R3 = Et). 1H NMR (DMSO): 1.11 (6 H)1 1.61 (1 H), 1.87 (1H), 2.73 (1H), 2.84 (1H)1 3.04 (1H), 3.42 (1H), 4.01 (2H), 7.36 (3H), 7.47 (2H)1 7.65 (4H)1 8.03 (3H). m/z (ES+) 312 ([MH]+, 100 %).

Reference： [1]Patent: WO2008/83967,2008,A2 .Location in patent: Page/Page column 150

3
[ 1012341-50-2 ]
[ 64-17-5 ]
(2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrogen sulphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; at 65℃;	1O g (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (3-a, R1 = BOC1 R2 = R3 = H) are added to ethanol (100 ml). The mixture is heated to 65 0C. 2 ml of concentrated sulphuric acid is then added over 0.5 h. The mixture is then stirred overnight. The ethanol is removed and heptane added. Further azeotropic distillations are performed using heptane to remove any residual ethanol.. The solvent is removed in vacuo to afford (2R, 4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrogen sulphate (3-a, R1 = R2 = H, R3 = Et). 1H NMR (DMSO): 1.12 (6H), 1.56 (1 H)1 1.87 (1 H)1 2.67 (1 H)1 2.78 (1H)1 2.98 (1H), 3.76 (2H), 7.34 (3H), 7.47 (2H), 7.64 (4H), 8.57 (3H). m/z (ES+) 312 ([MH]+, 100.

Reference： [1]Patent: WO2008/83967,2008,A2 .Location in patent: Page/Page column 150-151

4
[ 1012341-50-2 ]
[ 64-17-5 ]
[ 1038924-71-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; water; In ethyl acetate; at 130℃; for 1.75h;Product distribution / selectivity;	A mixture of 37 % hydrochloric acid (85 ml), ethyl acetate (100 ml) and water (100 ml) is heated to an external oil bath temperature of 130 0C. 50 g (2R,4S)-5-biphenyl-4-yl-4- tert-butoxycarbonylamino-2-methylpentanoic acid (3-a, R1 = BOC, R2 = R3 = H) in <n="153"/>ethyl acetate (100 ml) is then added to the mixture over 45 min. The mixture is stirred for a further 1 h. The mixture is then cooled to 0 0C and the solid collected by filtration to give (2R1 4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid hydrochloride (3-a, R1 = R2 = R3 = H). Spectroscopic data as given in Example 7.

Reference： [1]Patent: WO2008/83967,2008,A2 .Location in patent: Page/Page column 151-152

5
[ 1012341-50-2 ]
[ 64-17-5 ]
[ 149690-12-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With thionyl chloride;	3.8 g of (2R,4S)-N-tert-butoxycarbonyl-2-methyl-4-amino-5-(4-biphenyl)pentanoic acid (Compound IV-a), 20 ml of ethanol was added to the reaction 2 ml of thionyl chloride was added dropwise to the bottle.The mixture was warmed until the reaction was completed. EtOAc was evaporated.
96%	With thionyl chloride; at 60℃;	2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid (50 g, 0.13 mol) and absolute ethanol (500 ml) were added to a 1 L three-necked flask equipped with a magnetic stirrer and a condenser tube, dissolved by stirring at room temperature, added dropwise with thionyl chloride (23.3 g, 0.195 mol). After the addition was completed, the reaction was carried out for 3-3.5 h when the temperature was raised to 50-60 C. The reaction mixture was cooled and concentrated to dryness under reduced pressure. The residue was washed with ethyl acetate, with not more than 15% residual ethanol detected by GC, then added with ethyl acetate (500 ml), stirred at room temperature to a slurry for 3 h, filtered and dried to give ethyl (2R, 4S)-5-([1,1-biphenyl)-4-amino-2-methylpentanoate hydrochloride, with a yield of 88%-96% and a purity higher than 98.5%.
92.4%	With thionyl chloride; at 4 - 75℃; for 1.5h;	S1. 50g of starting material (2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid (1eq) was dissolved in 380mL anhydrous In ethanol (50eq),Cool to 4C , add 31.0g thionyl chloride (2eq) dropwise,Keep the temperature below 10C , after the drop is heated to reflux,Stir the reaction at 75 C under reflux for 1.5h to obtain the reaction solution; S2. The reaction solution obtained in step S1 is cooled to 50 C,After concentration under reduced pressure until no obvious droplets flow out,Add 500mL of ethyl acetate, warm to 75 C and stir for 60min,After the system is clarified, add 500mL of n-heptane, reduce the temperature to below 5 , stir and crystallize for 60min, and filter with suction.The filter cake was washed with a mixed solution of ethyl acetate and n-heptane mixed at a volume ratio of 1: 1 and dried to obtain 41.91 g of intermediate 1.

89.9%		S1. 100g of starting material(2R, 4S) -5- (biphenyl-4-yl) -4-[(tert-butoxycarbonyl) amino] -2-methylpentanoic acid(1eq) Dissolve in 600g absolute ethanol (50eq), cool to 4 , dropwise add 62g of sulfoxide chloride (2eq), the drop rate is 1mL / min, keep the temperature below 10 , warm up to reflux after dropping Stir the reaction at 75 C under reflux for 1.5h to obtain the reaction solution;S2. Add 35.5 g of imidazole (2 eq) to the reaction liquid obtained in step S1, stir for 10 min, concentrate under reduced pressure until no obvious droplets are added, add 600 g of ethyl acetate, and stir for 10 min,Filtration with suction and concentration of the filtrate under reduced pressure gave 81.6 g of intermediate 1.
85%	With thionyl chloride; at 65℃; for 1h;	8) Dissolve 55.2g (2R, 4S) -5- (biphenyl-4-yl) -4-[(tert-butoxycarbonyl) amino] -2-methylpentanoic acid in 0.55L ethanol,Add 15.8mL of thionyl chloride dropwise, warm up to 65 degrees after addition, keep the reaction for 1 hour,Reduced compression crystallization at 40 to get 38.35g(2R, 4S) -5-([1,1-biphenyl) -4-amino-2-methylvaleric acid ethyl ester hydrochloride;(85% yield);
	With thionyl chloride; at 20 - 70℃; for 3h;Product distribution / selectivity;	15O g (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (3-a, R1 = BOC1 R2 = R3 = H) were dissolved in 1500 ml ethanol at 70 0C. 43 ml of thionyl chloride were then added over about 1 hour. The mixture was then stirred for a further 2 hours. The mixture was concentrated to dryness and then suspended in 3400 ml heptane. The precipitate was collected by filtration, yielding 133 g of (2R1 4S)-4-amino- 5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-a, R1 = R2 = H1 R3 = Et). 1H-NMR (DMSO): 1.05 (3H, t, 1-CH3); 1.08 (3H, t, CH2CH3); 1.61 (1H, m, 3-CHH); 1.85 (1H1 m, 3-CHH); 2.74 (1H, m, 2-CH); 2.81 (1H, dd, 5-CHH); 3.08 (1H, dd, 5-CHH); 3.36 (1 H1 m, 4-CH); 3.95 (2H1 q, CH2CH3); 7.31 (1H, m, aromatic); 7.35 (2H1 m. aromatic); 7.43 (2H, m, aromatic); 7.62 (4H, m, aromatic); 8.30 (3H1 s, NH3+). m/z 312 (MHMOO %); 15O g (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (3-a, R1 = BOC1 R2 = R3 = H) are added to 1500 ml ethanol at room temperature. The mixture is then warmed to an internal temperature of 60-70 C. 42.8 ml Thionyl chloride is then added over a period of 1 h to the reaction mixture. The mixture is then stirred for a further 2 h. 810 ml of the solvent is removed by distillation under reduced pressure. 1460 ml Heptane fraction is then added. 1310 ml of solvent is then removed by distillation under reduced pressure. 1460 ml Heptane fraction is then added. 520 ml of solvent is then removed by distillation under reduced pressure. 1460 ml Heptane fraction is then added. The mixture is then cooled to room temperature over a period of 1 h. The mixture is then stirred at room temperature for 2 h. The solid is then collected by filtration. The solid is <n="118"/>then washed with heptane fraction (600 ml) and dried to give (2R, 4S)-4-amino-5- biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-a, R1 = R2 = H, R3 = Et). Spectroscopic data as given in Example 9-1 Method 1.Significant reflections in the X-ray diffraction pattern show the following interlattice plane intervals (average 2Theta in [] are indicated with error limit of +/-0.2): 2Theta in []: 5.7, 6.2, 7.7, 11.3, 12.5, 17.1, 22.4, 22.9. Data taken using a Bruker D8 Advance diffractometer using Cu-Ka radiation.The X-ray Structure of the obtained crystals is shown in figure 6a and figure 6b. Single crystal for this determination is obtained from acetonitrile as solvent.Crystal data [recorded at 293(2) KI Empirical formula C2oH26CIN02Formula weight 347.87Crystal system MonoclinicSpace group C2Cell parameters a = 40.672(12) A b = 6.543(2) A c = 14.757(4) A alpha = 90 beta = 99.167(13) gamma = 90 Volume of unit cell 3877(2) A3Z* 8Calculated density 1.192 mg rrT3* (number of asymmetric units in the unit cell); (2R, 4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-a, R1 = R2 = H, R3 = Et)(3-a, R1 = R2 = H, R3 = Et) prepared in accordance Example 9-1 and is crystallised according to the following Methods: <n="119"/>Method 1500 mg (2R, 4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-a, R1 = R2 = H, R3 = Et) is added to 3 ml toluene at room temperature. The mixture is then heated to 75 0C and is stirred at this temperature until the material has dissolved. The mixture is then cooled to room temperature and stirred for 16 h. The precipitate is collected by filtration.Significant reflections in the X-ray diffraction pattern show the following interlattice plane intervals (average 2Theta in [] are indicated with error limit of +/-0.2): 2Theta in []: 16.9, 18.2, 22.2, 22.7, 24.0. Data taken using a Bruker D8 Advance diffractometer using Cu-Ka radiation.Method 2500 mg (2R, 4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-a, R1 = R2 = H, R3 = Et) is added to 3 ml xylene at room temperature. The mixture is then heated to 80 0C and is stirred at this temperature until the material is dissolved. The mixture is then cooled to room temperature and stirred for 16 h. The precipitate is collected by filtration.Significant reflections in the X-ray diffraction pattern show the following interlattice plane intervals (average 2Theta in [] are indicated with error limit of +/-0.2): 2Theta in []: 16.9, 18.2, 22.2, 22.7, 23.9. Data taken using a Bruker D8 Advance diffractometer using Cu-Ka radiation.Method 3500 mg (2R, 4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-a, R1 = R2 = H, R3 = Et) is added to 5 ml ethyl acetoacetate at room temperature. The mixture is then heated to 80 0C and is stirred at this temperature until the material is dissolved. The mixture is then cooled to room temperature and stirred for 16 h. The precipitate is collected by filtration. <n="120"/>Significant reflections in the X-ray diffraction pattern show the following interlattice plane intervals (average 2Theta in [] are indicated with error limit of +/-0.2): 2Theta in []: 7.7, 17.2, 18.5, 22.4, 22.9, 24...
246 g	With thionyl chloride; at 62 - 65℃; for 2.5h;	A-1 (300 g) was dissolved in 2400 ml of absolute ethanol at room temperature; heated to 62 C,Slowly dripping140 g of sodium sulfoxideThe temperature was raised to 65 C for 2.5 h. The residue was distilled under reduced pressure to give a white solid which was dried under reduced pressure by adding 1200 ml of n-hexane.Into a 1200 ml n-hexane ice bath for 60 min; filtered, the solid was rinsed with n-hexane and dried at 35 C for 10 h to give a white solid(A-2) 246 g.
		To a 500 ml solution of ethanol in ethanol (250 ml) was added A (383 mg, 1 mmol)SOCl2 (120 mg, 1.1 mmol) was added and the mixture was stirred for 30 minutes.The reaction was allowed to react at room temperature for 24 hours in hydrogen. After careful release of hydrogen,The reaction mixture was washed with methanol and then concentrated in vacuo. JoinSuccinic anhydride (110 mg, 1 mmol) was added and the reaction was stirred for 8 hours. The reaction mixture was washed with ethanol,The residue was removed by short silica gel column. The enantiomeric content was measured by capillary GC or HPLC.The reaction conversion was 100% and the ee% was 98%.
172.3 g	With thionyl chloride; at 0 - 60℃; for 6h;	Thionyl chloride (49.4 ml) was added to a precooled solution containing ethanol (600 ml) and (2R,4S)-5-([ 1,1 ?-biphenyl] -4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid compound of formula-2 (200 gms) at 0-5C. Heated the reaction mixture to 55-60C and stirred for 6 hours at the same temperature. Distilled off the solvent completely under reduced pressure and co-distilled with methyl tertiary butyl ether. Cooled the reaction mixture to 25- 30C. Methyl tertiary butyl ether (1400 ml) was added to the obtained compound. Heated thereaction mixture to 50-55C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with methyl tertiary butyl ether and dried to get the title compound.Yield: 172.3 grns; M.R: 150-158C; Purity by HPLC: 99.46%.
80 g		(2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid of Formula IotaPi (100 gms) and ethanol (200 ml) were added into a round bottom flask at 25-35C and stirred for 60 mins. To this solution cyclohexane (500 ml) was added and then thionyl chloride (38 ml) was added slowly at 25-35C. The temperature of the reaction mass was raised to 42-48C, maintained for 7 hrs and distilled the solvent completely under reduced pressure at below 50C and then co-distilled the resulting residue with cyclohexane (300 ml *2). HPLC analysis revealed the content of amine-acid impurity of Formula A: 0.15%. The resulting solid was further treated with cyclohexane (1000 ml) and ethanol (25 ml) at 42-48C. The reaction mass was cooled to 25-35C and maintained for 1 hr, filtered, washed with cyclohexane. The resulting wet cake was suck dried initially, later dried at 25-35C for 2 hrs and finally dried at 47-53C for 8hrs to obtain title compound as hydrochloride salt. Yield: 80 gms. HPLC Purity: 99.8%; acid-amine impurity of Formula A: less than 0.1%.

Reference： [1]Patent: CN109400493,2019,A .Location in patent: Paragraph 0087-0090
[2]Organic Process Research and Development,2019,vol. 23,p. 102 - 107
[3]Patent: US2020/55812,2020,A1 .Location in patent: Paragraph 0168-0169
[4]Patent: CN110845349,2020,A .Location in patent: Paragraph 0053-0119
[5]Patent: CN110818581,2020,A .Location in patent: Paragraph 0048-0090
[6]Patent: CN108299226,2018,A .Location in patent: Paragraph 0016; 0027; 0035; 0037; 0045
[7]Patent: WO2008/83967,2008,A2 .Location in patent: Page/Page column 115-120
[8]Patent: CN106065006,2016,A .Location in patent: Paragraph 0051; 0052
[9]Patent: CN106146351,2016,A .Location in patent: Paragraph 0035
[10]Patent: WO2017/154017,2017,A1 .Location in patent: Page/Page column 23; 24
[11]Patent: WO2018/69833,2018,A1 .Location in patent: Page/Page column 28-29

6
[ 1038924-71-8 ]
[ 24424-99-5 ]
[ 1012341-50-2 ]

Yield	Reaction Conditions	Operation in experiment
		3.2 g of (2R1 4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid hydrochloride (3-a, R1 = R2 = R3 = H) were mixed with 3.2 g di-tert-butyl-dicarbonate, 5 g potassium carbonate and 50 ml water/iso-propanol mixture 1 : 1 and stirred at room temperature for 1 hour. Afterwards, the mixture was acidified with diluted phosphoric acid, extracted with iso-propyl acetate, washed with water, concentrated and crystallised from iso- propyl acetate/heptane to yield 2.8 g of (2R,4S)-5-biphenyl-4-yl-4-tert- butoxycarbonylamino-2-methylpentanoic acid (3-a, R1 = BOC, R2 = R3 = H). Mpt 146- 147 0C; deltaH (500 MHz; DMSO) 1.07 (3H, d, J 7.0, 1-CH3), 1.34 (9H, s, (CH3J3), 1.38 (1H, m, 3-HA), 1.77 (1H, m, 3-HB), 2.43 (1 H1 m, 2-H), 2.70 (2H, d, J 7.0, 5-H)1 3.69 (1H, m, 4- H), 6.74 (1H, d, J 9.0, NH), 7.27 (2H1 d, J 8.0, Ar-ort/7O-H(Ph)), 7.36 (1H1 1, J 7.0. Ar- (Ph)-para-H), 7.46 (2H1 1, J 7.5, Ar-(Ph)-met°-H), 7.57 (2H1 d, J 8.0, Ar-met°-H(Ph), 7.64 (2H, d, J 7.5, Ar-(Ph)-ortfto-H), 12.01 (1 H, s, CO2H); deltac (500 MHz1 DMSO) 18.1 (1- CH3), 28.3 [(CH3J3], 35.9 (2-C)1 37.9 (3-C), 40.7 (5-C), 50.0 (4-C)1 77.4 [(C(CHa)3]. 126.3, 126.5, 127.2, 128.9, 129.8 (Ar-CH), 137.7 (Ar-/pso-C(Ph))t 138.3 (Ar-para- C(Ph)), 140.1 (Ar-(Ph)-ZpSO-C), 155.2 (NCO)1 177.2 (CO2H); m/z (+ESI) 406 ([MNa]+, 6%), 384 ([MH]+, 31), 328 (100), 284 (19); Found: [MH]+, 384.21691. C23H30NO4 requires MH 384.21693.

Reference： [1]Patent: WO2008/83967,2008,A2 .Location in patent: Page/Page column 115

7
[ 1012341-50-2 ]
[ 75-03-6 ]
[ 149709-60-4 ]

Yield	Reaction Conditions	Operation in experiment
		50 g of (2f?,4S)-5-biphenyl-4-yl-4-te/t-butoxycarbonylamino-2-methylpentanoic acid (3- a, R1 = BOC, R2 = R3 = H) is added to dimethylformamide (80 ml). Cesium carbonate <n="151"/>(69 g) is then added. Ethyl iodide (13.6 g) is then added and the mixture is stirred overnight at room temperature. Water (200 ml) is added to the mixture and the mixture is then extracted with isopropyl acetate (2 x 200 ml). The combined organic phases are washed with brine, dried (MgSO4) and concentrated in vacuo to give (2f?,4S)-5- biphenyl-4-yl-4-te/t-butoxycarbonylamino-2-methylpentanoic acid ethyl ester (3-a, R1 = BOC, R2 = H, R3 = Et) (56 g). 1H NMR (DMSO): 1.12 (3H), 1.19 (3H), 1.36 (9H), 1.53 (1H), 1.84 (1H), 2.55 (1 H), 2.75 (2H)1 3.74 (1H)1 4.05 (2H)1 6.04 (1H), 7.23 (2H)1 7.30 (1H), 7.41 (2H), 7.50 (2H), 7.57 (2H). m/z (ES+): 412 ([MH]+, 100 %), 356 (63), 312 (73).
	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	Example 62: (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid ethyl ester (1-a, R1 = Boc, R2 = H, R3 = CO2Et) <n="285"/>; 2 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1 = Boc, R2 = H1 R3 = CO2H) prepared according to Example 2 in WO/2008/031567 is added to 2.55 g caesium carbonate. Dimethylformamide (4 ml) is then added. Ethyl iodide (0.55 ml) is then added and the mixture is stirred for 16 h at room temperature. Water (10 ml) and isopropyl acetate (10 ml) are added. The phases are separated. The aqueous phase is washed with isopropyl acetate (2 x 10 ml). The combined organic phases are washed with 20 % aqueous sodium chloride solution (15 ml) and then dried (MgSO4). The mixture is concentrated under reduced pressure to afford (2R,4S)-5-biphenyl-4-yl-4-tert- butoxycarbonylamino-2-methylpentanoic acid ethyl ester (1-a, R1 = Boc, R2 = H, R3 = CO2Et). 1H NMR (CDCI3): 1.18 (3H), 1.27 (3H), 1.42 (9H), 1.49 (1H), 1.95 (1H), 2.62 (1H), 2.85 (2H), 3.94 (1H), 4.16 (2H), 4.36 (1H), 7.26 (2H), 7.35 (1H), 7.45 (2H), 7.55 (2H), 7.59 (2H).

Reference： [1]Patent: WO2008/83967,2008,A2 .Location in patent: Page/Page column 149-150
[2]Patent: WO2009/90251,2009,A2 .Location in patent: Page/Page column 283-284

8
[ 1038924-76-3 ]
[ 1012341-50-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium hydroxide; at 60℃;	A mixture of compound 3 (26.54 g, 100 mmol) and DMAP (1.22 g, 10 mmol) were added to the three-necked flask, (21.29 g, 150 mmol) was added, Boc anhydride (22.92 g, 105 mmol) was added and reacted at room temperature for 6 to 8 hours.To the tetrahydrofuran reaction solution of compound 4 was added 10% sodium hydroxide solution (130 mL), and the mixture was heated to60 C for 10 to 16 hours, the reaction is cooled to room temperature, plus methyl tert-butyl ether (130mL) after intense mixing, water box. To the aqueous phase by adding isopropyl acetate (130mL), dropping 2mol / L hydrochloric acid to adjust the pH to 3 ~ 4, liquid separation of organic Phase, and the aqueous phase was extracted once with isopropyl acetate (65 mL). The organic phase was washed with saturated brine once (130 mL), anhydrous sulfuric acid Sodium and dried, and concentrated to give compound 5 (32.98 g, 86%) by column chromatography using petroleum ether ethyl acetate mixed solvent column chromatography.
		5 g (3R, deltaSJ-S-biphenyM-ylmethyl-S-methyl^-oxo-pyrrolidine-i-carboxylic acid tert- butyl ester (2-a, R1 = BOC) was dissolved in 50 ml of a mixture of THF and a 2 M lithium hydroxide solution (ratio 1 :1). After 1 hour at room temperature, phosphoric acid was added to neutralise the excess of lithium hydroxide. The slurry was concentrated under vacuum to remove most of the solvent and extracted with iso-propyl acetate. The organic phase was then washed with water, partially concentrated under vacuum and brought to crystallisation upon addition of heptane. The crystalline solid obtained was collected and dried under vacuum to yield about 3.6 g of [(2R,4S)-5-biphenyl-4-yl-4-tert- butoxycarbonylamino-2-methylpentanoic acid] (3-a, R1 = BOC, R2 = R3 = H). Mpt 146- 147 0C; deltaH (500 MHz; DMSO) 1.07 (3H, d, J 7.0, 1-CH3), 1.34 (9H, s, (CH3)3), 1.38 (1H, m, 3-HA), 1.77 (1H, m, 3-HB), 2.43 (1 H, m, 2-H), 2.70 (2H, d, J 7.0, 5-H), 3.69 (1H, m, 4- <n="127"/>H), 6.74 (1 H1 d, J 9.0, NH), 7.27 (2H, d, J 8.0, Ar-ortho-H(Ph)), 7.36 (1H, t, J 7.0, Ar- (Ph)-para-H), 7.46 (2H1 1, J 7.5, Ar-(Ph)-met°-H), 7.57 (2H1 d, J 8.0. Ar-met°-H(Ph), 7.64 (2H, d. J 7.5, Ar-(Ph)-orf/7o-H), 12.01 (1H, s, CO2H); deltac (500 MHz, DMSO) 18.1 (1- CH3), 28.3 [(CH3J3], 35.9 (2-C)1 37.9 (3-C)1 40.7 (5-C)1 50.0 (4-C), 77.4 [(C(CH3)3], 126.3, 126.5, 127.2, 128.9, 129.8 (Ar-CH), 137.7 (Ar-/pso-C(Ph)), 138.3 (Ar-para- C(Ph)), 140.1 (Ar-(Ph)-/pso-C), 155.2 (NCO), 177.2 (CO2H); m/z (+ESI) 406 ([MNa]+, 6%), 384 ([MH]+, 31), 328 (100), 284 (19); Found: [MH]+. 384.21691. C23H30NO4 requires MH 384.21693.

Reference： [1]Patent: CN106496055,2017,A .Location in patent: Paragraph 0053; 0054; 0055; 0056
[2]Patent: WO2008/83967,2008,A2 .Location in patent: Page/Page column 125-126

9
[ 1012341-50-2 ]
[ 121-44-8 ]
[ 1174130-83-6 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 20℃; for 0.5h;	Example 38: (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid triethylammonium salt (1-a, R1 = Boc, R2 = H, R3 = CO2 [NHEt3J+); 1 g (2R,4S)-5-Biphenyl-4-yl-4-fe/t-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1 = Boc, R2 = H, R3 = CO2H) is added to ethanol (10 ml). Triethylamine (0.264 ml) is then added and the mixture is stirred at room temperature for 30 minutes. The mixture is then concentrated in vacuo to afford (2R,4S)-5-biphenyl-4-yl-4-tert- butoxycarbonylamino-2-methylpentanoic acid triethylammonium salt (1-a, R1 = Boc, R2 <n="200"/>= H, R3 = CO2-[NHEt3]+). 1H NMR (DMSO-d6): 0.95 (9 H), 1.04 (3H), 1.32 (9H), 1.36 (1H), 1.74 (1H), 2.38-2.50 (7 H), 2.67 (2H), 3.65 (1 H), 6.29 and 6.70 (1H), 7.23-7.25 (2H), 7.33-7.37 (1H), 7.43-7.48 (2H), 7.55-7.57 (2H), 7.62-7.64 (2H).

Reference： [1]Patent: WO2009/90251,2009,A2 .Location in patent: Page/Page column 198-199

10
[ 1012341-50-2 ]
[ 74-88-4 ]
[ 1174131-27-1 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	Example 59: (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid methyl ester (1-a, R1 = Boc, R2 = H, R3 = CO2Me); 2 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1 = Boc, R2 = H, R3 = CO2H) prepared according to Example 2 in WO/2008/031567 is added to 2.55 g caesium carbonate. Dimethylformamide (4 ml) is then added. Methyl iodide <n="283"/>(0.55 ml) is then added and the mixture is stirred for 16 h at room temperature. Water (10 ml) and isopropyl acetate (10 ml) are added. The phases are separated. The aqueous phase is washed with isopropyl acetate (2 x 10 ml). The combined organic phases are washed with 20 % aqueous sodium chloride solution (15 ml) and then dried (MgSO4). The mixture is concentrated under reduced pressure to afford (2R,4S)-5-biphenyl-4-yl-4-tert- butoxycarbonylamino-2-methylpentanoic acid methyl ester (1-a, R1 = Boc, R2 = H, R3 = CO2Me). 1H NMR (CDCI3): 1.18 (3H), 1.41 (9H), 1.51 (1H), 1.95 (1H), 2.66 (1H), 2.85 (2H), 3.70 (3H), 3.94 (1H), 4.36 (1H), 7.25 (2H), 7.35 (1H), 7.45 (2H), 7.53 (2H), 7.59 (2H).

Reference： [1]Patent: WO2009/90251,2009,A2 .Location in patent: Page/Page column 281-282

11
[ 1012341-50-2 ]
[ 7087-68-5 ]
[ 1174130-82-5 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 20℃; for 0.5h;	Example 37: (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid diisopropylethylammonium salt (1-a, R1 = Boc, R2 = H, R3 = CO2 [N H JPr2Et]+); 1 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1 = Boc, R2 = H, R3 = CO2H) is added to ethanol (10 ml). Diisopropylethylamine (0.454 ml) is then added and the mixture is stirred at room temperature for 30 minutes. The mixture is then concentrated in vacuo to afford (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino- 2-methylpentanoic acid diisopropylethylammonium salt (1-a, R1 = Boc, R2 = H, R3 = CO2' [NHiPr2Et]+). 1H NMR (DMSO-d6): 0.95-0.98 (15 H), 1.04 (3H), 1.32 (9H), 1.36 (1H), 1.74 (1H), 2.38-2.49 (3 H), 2.67 (2H), 2.99 (2H), 3.66 (1H), 6.29 and 6.70 (1H), 7.23-7.25 (2H), 7.33-7.37 (1 H), 7.42-7.46 (2H), 7.55-7.57 (2H), 7.62-7.64 (2H).

Reference： [1]Patent: WO2009/90251,2009,A2 .Location in patent: Page/Page column 198

12
[ 1012341-50-2 ]
[ 1174130-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In ethanol; at 20℃; for 0.5h;	Example 39: (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid sodium salt (1-a, R1 = Boc, R2 = H, R3 = CO2 Na+); 1 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (R1 = Boc, R2 = H, R3 = CO2H) is added to ethanol (10 ml). Sodium methoxide (141 mg) is then added and the mixture is stirred at room temperature for 30 minutes. The mixture is then concentrated in vacuo to afford (2R,4S)-5-biphenyl-4-yl-4-tert- butoxycarbonylamino-2-methylpentanoic acid sodium salt (1-a, R1 = Boc, R2 = H, R3 = CCVNa+). 1 H NMR (DMSO-d6): 0.91 (3H), 1.29 (1H), 1.34 (9H), 1.61 (1H), 2.12 (1H), 2.68-2.81 (2H), 3.60 (1H), 7.25-7.27 (2H), 7.32-7.36 (1H), 7.43-7.47 (2H), 7.55-7.57 (2H), 7.64-7.66 (2H), 7.76 (1H).

Reference： [1]Patent: WO2009/90251,2009,A2 .Location in patent: Page/Page column 199

13
[ 1012341-50-2 ]
[ 100-39-0 ]
[ 1257266-74-2 ]

Yield	Reaction Conditions	Operation in experiment
88.7%	With potassium carbonate; In acetonitrile; at 60℃; for 0.5h;	The (2R, 4S) -5- (biphenyl-4-yl) -4 - [(tert-butoxycarbonyl) amino] -2-methyl-pentanoic acid 1.91g (5.0mmol),20 mL of acetonitrile,0.35g (2.5mmol) of potassium carbonate was added to the reaction flask,0.85 g (5.0 mmol) of benzyl bromide was added,Warmed to 60 C,Reaction for 30 minutes,HPLC detection reaction was complete,After treatment, the reaction solution was evaporated to dryness,Add 20mL water,Extraction with ethyl acetate,The combined organic phases were dried over anhydrous sodium sulfate,Of 2.09 g of colorless oil (II)Yield 88.7%.
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	Intermediate 2: (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester hydrochloride; To a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (prepared using the procedure described in WO 2008083967)(1 .0 g, 2.61 mmol) and benzyl bromide (468 mg, 2.74 mmol) in DMF (15 ml_) is added potassium carbonate (541 mg, 3.91 mmol) and the mixture is stirred at room temperature for 2 hours. Water is added and the mixture is extracted with ethyl acetate. The combined organic layers are washed with water and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residual oil is purified by column chromatography using heptane/EtOAc (4:1 ) to furnish (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester.Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl- pentanoic acid benzyl ester in THF (5 ml_) is added 4M HCI in dioxane (3 ml_) and the solution is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure to give the title compound. MS 374.4 (M+1 ).

Reference： [1]Patent: CN107468685,2017,A .Location in patent: Paragraph 0287; 0288; 0289
[2]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 169

14
[ 1012341-50-2 ]
[ 3144-09-0 ]
[ 1257266-71-9 ]

Yield	Reaction Conditions	Operation in experiment
55%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	Intermediate 49: ((1 S, 3R)-1-Biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4- oxo-butyl)-carbamic acid tert-butyl ester; To a solution of (2R, 4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (500 mg, 1 .304 mmol) in DMF (10 ml) at room temperature is added methyl sulfonamide (223 mg, 2.347 mmol), EDCHCI (450 mg, 2.347 mmol), 1 -hydroxy-7- azabenzotriazole (284 mg, 2.086 mmol) and DIPEA (0.501 ml, 2.87 mmol). The reaction mixture is stirred at room temperature over night. The reaction is quenched by brine and is extracted with EtOAc. The combined organic layer is washed with brine and is dried over anhydrous sodium sulfate, filtered and concentrated. Reverse phase HPLC [15 to 60% ACN-H2O (0.1 % NH4OH) over 10 min by X-bridge phenyl column] provides ((1 S, 3R)-1 - Biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-carbamic acid tert-butyl ester (333mg, 55%). HPLC retention time = 1 .03 minutes (condition D), MS (m-1 ) = 495.5, MS (m-55) = 405.3, MS (m-99) = 361 .3.

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 195

15
[ 1038924-76-3 ]
(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid [ No CAS ]
[ 1012341-50-2 ]

Reference： [1]Patent: WO2012/25502,2012,A1
[2]Patent: US2013/158275,2013,A1

16
[ 1174130-72-3 ]
(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid [ No CAS ]
[ 1012341-50-2 ]

Reference： [1]Patent: WO2012/25502,2012,A1
[2]Patent: US2013/158275,2013,A1

17
[ 1361408-16-3 ]
(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid [ No CAS ]
[ 1012341-50-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen; triethylamine;5% rhodium-on-charcoal; In Isopropyl acetate; at 20℃; under 760.051 Torr;Product distribution / selectivity;	Example 6: (2 ~,4S)-5-Biphenyl-4-yl-4-ierf-butoxycarbonylamino-2- methylpentanoic acid (2a, R1 = Boc, R2 = H, R3 = C02H) or (2S,4S)-5-Biphenyl-4- yl-4-fert-butoxycarbonylamino-2-methylpentanoic acid (2b, R1 = Boc, R2 = H, R3 = C02H); 1 g (Z)-(f~)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid (5a, R1 = Boc, R2 = H, R3 = C02H) is added to isopropyl acetate (10 ml) at ambient temperature. Triethylamine (0.37 ml) is then added to the mixture. The hetereogeneous catalyst (100 mg or 200 mg) is added to the mixture. Hydrogen gas at ambient pressure Wis applied to the mixture. The mixture is stirred overnight at ambient temperature and pressure.The crude reaction solution is analysed by HPLC to determine the ratio of (2f~,4S)-5- biphenyl-4-yl-4-te/f-butoxycarbonylamino-2-methylpentanoic acid (2a, R1 = Boc, R2 = H, R3 = C02H) to (2S,4S)-5-biphenyl-4-yl-4-ferf-butoxycarbonylamino-2-methylpentanoic acid (2b, R1 = Boc, R2 = H, R3 = C02H).Method 1Heterogeneous Catalyst: Palladium on Carbon (10 % loading, 50 % water wet); 100 mg. Ratio (2a :2b): 54 : 46.Method 2Heterogeneous Catalyst: Platinium on Carbon ( 0 % loading); 100 mg. Ratio (2a : 2b): 42 : 58.Method 3Heterogeneous Catalyst: Rhodium on Carbon (5 % loading); 200 mg. Ratio (2a :2b): 55 : 45.HPLC Method (Example 6)Column: Daicel Chiralpak QN-AX; 150 x 4.6 mm; 5 muetaiota. Mobile Phase A:Methanol/EtOH (1:1), 0.1 % AcOH (v/v), 0.01 % NH4OAc (m/v). Isocratic: 0 min (100 % A); 20 min (100 % A). Flow rate 0.5 ml min"1. Wavelength: 254 nm.Retention times:(2a, R1 = Boc, R2 = H, R3 = C02H): 7.6 min(2b, R1 = Boc, R2 = H, R3 = C02H): 10.3 min
	With hydrogen; triethylamine;palladium 10% on activated carbon; In Isopropyl acetate; at 20℃; under 760.051 Torr;Product distribution / selectivity;	Example 6: (2 ~,4S)-5-Biphenyl-4-yl-4-ierf-butoxycarbonylamino-2- methylpentanoic acid (2a, R1 = Boc, R2 = H, R3 = C02H) or (2S,4S)-5-Biphenyl-4- yl-4-fert-butoxycarbonylamino-2-methylpentanoic acid (2b, R1 = Boc, R2 = H, R3 = C02H); 1 g (Z)-(f~)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid (5a, R1 = Boc, R2 = H, R3 = C02H) is added to isopropyl acetate (10 ml) at ambient temperature. Triethylamine (0.37 ml) is then added to the mixture. The hetereogeneous catalyst (100 mg or 200 mg) is added to the mixture. Hydrogen gas at ambient pressure Wis applied to the mixture. The mixture is stirred overnight at ambient temperature and pressure.The crude reaction solution is analysed by HPLC to determine the ratio of (2f~,4S)-5- biphenyl-4-yl-4-te/f-butoxycarbonylamino-2-methylpentanoic acid (2a, R1 = Boc, R2 = H, R3 = C02H) to (2S,4S)-5-biphenyl-4-yl-4-ferf-butoxycarbonylamino-2-methylpentanoic acid (2b, R1 = Boc, R2 = H, R3 = C02H).Method 1Heterogeneous Catalyst: Palladium on Carbon (10 % loading, 50 % water wet); 100 mg. Ratio (2a :2b): 54 : 46.Method 2Heterogeneous Catalyst: Platinium on Carbon ( 0 % loading); 100 mg. Ratio (2a : 2b): 42 : 58.Method 3Heterogeneous Catalyst: Rhodium on Carbon (5 % loading); 200 mg. Ratio (2a :2b): 55 : 45.HPLC Method (Example 6)Column: Daicel Chiralpak QN-AX; 150 x 4.6 mm; 5 muetaiota. Mobile Phase A:Methanol/EtOH (1:1), 0.1 % AcOH (v/v), 0.01 % NH4OAc (m/v). Isocratic: 0 min (100 % A); 20 min (100 % A). Flow rate 0.5 ml min"1. Wavelength: 254 nm.Retention times:(2a, R1 = Boc, R2 = H, R3 = C02H): 7.6 min(2b, R1 = Boc, R2 = H, R3 = C02H): 10.3 min
	With palladium 10% on activated carbon; hydrogen; triethylamine; In Isopropyl acetate; at 20℃; under 760.051 Torr;	g (Z)-(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid (5a, R1=Boc, R2=H, R3=CO2H) is added to isopropyl acetate (10 ml) at ambient temperature. Triethylamine (0.37 ml) is then added to the mixture. The heterogeneous catalyst (100 mg or 200 mg) is added to the mixture. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred overnight at ambient temperature and pressure. [0461] The crude reaction solution is analysed by HPLC to determine the ratio of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (2a, R1=Boc, R2=H, R3=CO2H) to (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (2b, R1=Boc, R2=H, R3=CO2H).

With 10% Pt/activated carbon; hydrogen; triethylamine; In Isopropyl acetate; at 20℃; under 760.051 Torr;

g (Z)-(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid (5a, R1=Boc, R2=H, R3=CO2H) is added to isopropyl acetate (10 ml) at ambient temperature. Triethylamine (0.37 ml) is then added to the mixture. The heterogeneous catalyst (100 mg or 200 mg) is added to the mixture. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred overnight at ambient temperature and pressure. [0461] The crude reaction solution is analysed by HPLC to determine the ratio of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (2a, R1=Boc, R2=H, R3=CO2H) to (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (2b, R1=Boc, R2=H, R3=CO2H).

Reference： [1]Patent: WO2012/25502,2012,A1 .Location in patent: Page/Page column 65-66
[2]Patent: WO2012/25502,2012,A1 .Location in patent: Page/Page column 65-66
[3]Patent: US2013/158275,2013,A1 .Location in patent: Paragraph 0459; 0460; 0461; 0462
[4]Patent: US2013/158275,2013,A1 .Location in patent: Paragraph 0459; 0460; 0461; 0463

18
[ 1361408-15-2 ]
(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid [ No CAS ]
[ 1012341-50-2 ]

Reference： [1]Patent: WO2012/25502,2012,A1

19
[ 1012341-50-2 ]
[ 1257266-74-2 ]
[ 1257265-27-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; potassium carbonate; In tetrahydrofuran; 1,4-dioxane; n-heptane; water; benzyl bromide; ethyl acetate; N,N-dimethyl-formamide;	(2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester hydrochloride To a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (prepared using the procedure described in WO 2008083967) (1.0 g, 2.61 mmol) and benzyl bromide (468 mg, 2.74 mmol) in DMF (15 mL) is added potassium carbonate (541 mg, 3.91 mmol) and the mixture is stirred at room temperature for 2 hours. Water is added and the mixture is extracted with ethyl acetate. The combined organic layers are washed with water and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residual oil is purified by column chromatography using heptane/EtOAc (4:1) to furnish (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester. Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester in THF (5 mL) is added 4M HCl in dioxane (3 mL) and the solution is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure to give the title compound. MS 374.4 (M+1).

Reference： [1]Patent: US2012/122844,2012,A1

20
[ 1012341-50-2 ]
[ 1257265-30-7 ]

Reference： [1]Patent: EP2640375,2016,B1

21
[ 1012341-50-2 ]
[ 1257265-29-4 ]

Reference： [1]Patent: EP2640375,2016,B1

22
[ 1012341-50-2 ]
[ 1257266-14-0 ]

Reference： [1]Patent: EP2640375,2016,B1

23
[ 1012341-50-2 ]
[ 1257265-46-5 ]

Reference： [1]Patent: EP2640375,2016,B1

24
[ 1012341-50-2 ]
[ 1257265-45-4 ]

Reference： [1]Patent: EP2640375,2016,B1

25
[ 1012341-50-2 ]
[ 100-39-0 ]
[ 1257265-27-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (prepared using the procedure described in WO 2008083967)(1.0 g, 2.61 mmol) and benzyl bromide (468 mg, 2.74 mmol) in DMF (15 mL) is added potassium carbonate (541 mg, 3.91 mmol) and the mixture is stirred at room temperature for 2 hours. Water is added and the mixture is extracted with ethyl acetate. The combined organic layers are washed with water and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residual oil is purified by column chromatography using heptane/EtOAc (4:1) to furnish (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester. Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester in THF (5 mL) is added 4M HCl in dioxane (3 mL) and the solution is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure to give the title compound. MS 374.4 (M+1).

Reference： [1]Patent: EP2640375,2016,B1 .Location in patent: Paragraph 0550

26
C₁₉H₂₇NO₅ [ No CAS ]
[ 1012341-50-2 ]

Reference： [1]Patent: CN105523964,2016,A

27
ethyl(2S,4S)-4-((tert-butoxycarbonyl)amino)-5-(4-hydroxyphenyl)-2-methylpentanoate [ No CAS ]
[ 1012341-50-2 ]

Reference： [1]Patent: CN105523964,2016,A

28
[ 149709-61-5 ]
[ 1012341-50-2 ]

Yield	Reaction Conditions	Operation in experiment
	With water; lithium hydroxide; In ethanol; at 70℃;	1 times the amount of compound VI dissolved in ethanol and stirred clear solution, was added 11 times the amount of water and 0.41 times the amount of LiOH, slowly warming up to about 70 reaction was stirred. TLC control in the completion of the reaction, was cooled to 30 , filtered, and the filter cake was rinsed with ethanol, the filtrate was added dropwise with stirring acetic acid adjusted to pH = 5, some solid precipitated, water was added and stirring was heated to 80 deg.] C down to room temperature and filtered to give the crude product VII. The crude product from ethanol / water (1/1) at room temperature beating, pulling doing fine filterVII,

Reference： [1]Patent: CN105523964,2016,A .Location in patent: Paragraph 0340; 0051; 0052

29
[ 70642-86-3 ]
[ 1012341-50-2 ]

Reference： [1]Patent: CN105523964,2016,A

30
[ 929872-80-0 ]
[ 1012341-50-2 ]

Reference： [1]Patent: CN105523964,2016,A

31
C₁₄H₁₉NO₄ [ No CAS ]
[ 1012341-50-2 ]

Reference： [1]Patent: CN105523964,2016,A

32
(2R,4S)-5-(4-bromophenyl)-4-(tert-butoxycarbonyl) amino-2-methylpentanoic acid [ No CAS ]
[ 98-80-6 ]
[ 1012341-50-2 ]

Yield	Reaction Conditions	Operation in experiment
8 g	With dipotassium hydrogenphosphate; formic acid; palladium diacetate; In water; at 25 - 45℃; for 6h;Inert atmosphere;	(2R, 4S)-5 -(4-bromophenyl)-4- [(tert-butoxycarbonyl) amino] -2-methylpentanoic acid (FormulaXII, 10 g) was dissolved in water (100 mL). Phenylboronic acid (4.7 g), dipotassium hydrogen phosphate (0.5 g), and formic acid (0.059 g) were then added at 25-35 C. The solution was purged with nitrogen for 30 mins after whichpalladium acetate (0.29 g) was added. The reaction mass was stined at 35-45 C for 6 hours. The pH of the reaction mass was adjusted to 10-11 with sodium hydroxide solution, after which ethyl acetate was added. The aqueous and organic layers were separated and the pH of the aqueous layer was adjusted to 3-4 with HC1. The aqueous layer was extracted with ethyl acetate and concentrated completely under vacuum and the residue was dissolved in ethyl acetate (40 mL) at 50-55 C. Hexane (80 mL) was added at 50-55 C and the solution was cooled to ambient temperature. The solution was then filtered to obtain a solid product of (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2- methylpentanoic acid (Formula-XIII, 8 g).

Reference： [1]Patent: WO2016/135751,2016,A1 .Location in patent: Page/Page column 30

33
[ 1012341-50-2 ]
[ 149690-12-0 ]

Yield	Reaction Conditions	Operation in experiment
96.5%	With thionyl chloride; In ethanol; at 60℃; for 1h;	The (2R, 4S) -5- (biphenyl-4-yl) -4 - [(tert-butoxycarbonyl) amino] -2-methyl-pentanoic acid 1.91g (5.0mmol),Ethanol 20mL added to the reaction flask,0.41 mL (5.5 mmol) of thionyl chloride was added dropwise at an elevated temperature of 60 C,Continue to maintain the temperature for 1 hour.The reaction was complete by HPLC.The reaction solution was concentrated under reduced pressure to give 1.67 g of compound (II)Yield 96.5%.
	With thiophosgene; In ethanol; at 70 - 75℃; for 3h;	(2R, 4S)-5-(biphenyl-4-yl)-4- [(tert-butoxycarbonyl) amino] -2-methylpentanoic acid (FormulaXIII, 100 g) was dissolved in ethanol (600 mL) at 70-75 C. Thionylchloride (35.7 g) was added at 70-75 C and the reaction mass was stined for 3 hours, followed by concentration under vacuum to get asolid. Ethyl acetate (500 mL) was added to the solid and the reaction mass was cooled to ambient temperature, stined for 2 hours, then filtered to get (2R,4S)-4-amino-5- (biphenyl)-2-methylpentanoate hydrochloride (hydrochloride salt of Formula-XIV, 80 g).
	With thionyl chloride; In ethanol; tert-butyl methyl ether; at 60 - 70℃; for 3h;	Example 1 discloses a method for preparing a sodium form of AHU sodium salt, which includes the following preparation stages:The first stage: Synthesis of AHU1 includes the following steps:(1) To a three-necked flask equipped with a thermometer and a reflux condenser, respectively, add anhydrous ethanol (20mL) and AHU01 (10 g), magnetic stirring to obtain a white suspension, the system was heated to 60-70 C;(2) 3.26 g of thionyl chloride was slowly added dropwise via a constant pressure dropping funnel, and was added dropwise within 5 minutes. The reaction was stirred at 60-70 C. for 3 hours to obtain a pale yellow clear reaction solution.(3) Sample HPLC detection, AHU01 basic conversion completed,Methyl tert-butyl ether (200 mL) was added, slowly lowered to room temperature, suction-filtered under reduced pressure, and the filter cake was washed several times with methyl tert-butyl ether to obtain an off-white solid, which was blown at 60 C. to obtain AHU1.

Reference： [1]Patent: CN107468685,2017,A .Location in patent: Paragraph 0267; 0268; 0269
[2]Patent: WO2016/135751,2016,A1 .Location in patent: Page/Page column 30
[3]Patent: CN107082746,2017,A .Location in patent: Paragraph 0051; 0055-0060; 0080

34
(2R)-3-(4-bromophenyl)-2-[[(tert-butoxy)carbonyl]amino]propanoic acid [ No CAS ]
[ 1012341-50-2 ]

Reference： [1]Patent: WO2016/135751,2016,A1

35
tert-butyl [(2R)-1-(4-bromophenyl)-3-hydroxypropan-2-yl] carbamate [ No CAS ]
[ 1012341-50-2 ]

Reference： [1]Patent: WO2016/135751,2016,A1

36
[ 62561-74-4 ]
[ 1012341-50-2 ]

Reference： [1]Patent: WO2016/135751,2016,A1

37
[ 24424-99-5 ]
[ 1012341-50-2 ]

Reference： [1]Patent: WO2016/135751,2016,A1
[2]Patent: CN106496055,2017,A

38
[ 1246363-08-5 ]
[ 1012341-50-2 ]

Reference： [1]Patent: WO2016/135751,2016,A1

39
[ 1257266-88-8 ]
[ 1012341-50-2 ]

Reference： [1]Patent: WO2016/135751,2016,A1

40
(2E,4R)-5-(4-bromophenyl)-4-[(tert-butoxycarbonyl) amino-2-methylpent-2-enoic acid] [ No CAS ]
[ 1012341-50-2 ]

Reference： [1]Patent: WO2016/135751,2016,A1

41
[ 1012341-48-8 ]
(2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid [ No CAS ]
[ 1012341-50-2 ]

Yield	Reaction Conditions	Operation in experiment
	With diiodo(p-cymene)ruthenium(II) dimer; (SP,S?P)-1,1?-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2?-bis[(R)-alpha-(dimethylamino)benzyl]ferrocene; hydrogen; In dichloromethane; water; at 60.0℃; under 45004.5 Torr; for 16.0h;Autoclave; Ionic liquid; Inert atmosphere;	General procedure: [Ru(p-cimene)I2]2 (4.85 mg; 4.96 mumol) and (SP,S?P)-1,1?-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2?-bis[(R)-alpha-(dimethylamino)benzyl]ferrocene (Mandyphos, SL-M004-1) (12.0mg; 11.4 mumol) were weighted in two Schlenk tubes inside a glovebox. The Ru precursor was dissolved in CH2Cl2 (5 mL) and the resulting solution was transferred into the Schlenk tube containing the ligand and stirred at r.t. for 1 h. The ionic liquid 1-ethyl-3-methylimidazoliumbis(trifluoromethylsulfonyl)imide [EMIM][NTf2] (5 mL) was added and the CH2Cl2 was slowly evaporated under vacuum. An aliquot of this solution (0.2 mL) was diluted with additional [EMIM][NTf2] (1.8 mL) and the solution was transferred into a 13 mL window autoclave. (R)-1-CO2H (100 mg; 262 mumol) was dissolved in a basic aqueous solution (4 mL, pH 13) (see table 2 for detail) and transferred into the autoclave. The autoclave was heated to reaction temperature and pressurized with H2 (40 bar). The reaction was started by magnetic agitation. After 16 h, the autoclave was cooled to r.t. and gently vented. The upper water phase was removed with a needle and neutralized with an HCl solution (1 M), the white solid precipitated was collected by filtration and analyzed by HPLC.

Reference： [1]Synthesis,2017,vol. 49,p. 353 - 357

42
[ 1012341-50-2 ]
[ 1038924-71-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; water;	General procedure: [Ru(p-cimene)I2]2 (4.85 mg; 4.96 mumol) and (SP,S?P)-1,1?-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2?-bis[(R)-alpha-(dimethylamino)benzyl]ferrocene (Mandyphos, SL-M004-1) (12.0mg; 11.4 mumol) were weighted in two Schlenk tubes inside a glovebox. The Ru precursor was dissolved in CH2Cl2 (5 mL) and the resulting solution was transferred into the Schlenk tube containing the ligand and stirred at r.t. for 1 h. The ionic liquid 1-ethyl-3-methylimidazoliumbis(trifluoromethylsulfonyl)imide [EMIM][NTf2] (5 mL) was added and the CH2Cl2 was slowly evaporated under vacuum. An aliquot of this solution (0.2 mL) was diluted with additional [EMIM][NTf2] (1.8 mL) and the solution was transferred into a 13 mL window autoclave. (R)-1-CO2H (100 mg; 262 mumol) was dissolved in a basic aqueous solution (4 mL, pH 13) (see table 2 for detail) and transferred into the autoclave. The autoclave was heated to reaction temperature and pressurized with H2 (40 bar). The reaction was started by magnetic agitation. After 16 h, the autoclave was cooled to r.t. and gently vented. The upper water phase was removed with a needle and neutralized with an HCl solution (1 M), the white solid precipitated was collected by filtration and analyzed by HPLC.

Reference： [1]Synthesis,2017,vol. 49,p. 353 - 357

43
[ 1038924-70-7 ]
[ 1012341-50-2 ]

Reference： [1]Patent: CN106496055,2017,A

44
[ 1012341-50-2 ]
[ 64-17-5 ]
[ 149709-60-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With thionyl chloride; for 10h;Reflux;	A mixture of compound 5 (38.35 g, 100 mmol) and ethanol (190 mL) was added to the three-To the ethanol melt of compound 5, thionyl chloride (15.8 g, 150 mmol) was slowly added dropwise,After completion of the dropwise addition, the mixture was heated to reflux and the reaction was carried out for 10 hours and then evaporated under reduced pressure Ethanol, and then dichloromethane (95 mL) was steamed twice, after the addition of succinic anhydride (11.01 g, 110 mmol) and dichloromethane(190 mL). After stirring, triethylamine (21.29 g, 150 mmol) was added dropwise and reacted at room temperature for 4 to 6 hours. The reaction is cooled to 0 ~The reaction was quenched by the addition of 1 mol / L dilute hydrochloric acid (190 mL) at 5 C, and the aqueous phase was extracted again with dichloromethane (190 mL). Saturated brine (190 mL) was washed once with sodium sulfate, filtered, concentrated and treated with petroleum ether ethyl acetate mixed solvent column Compound 7 (34.98 g, 85%) was isolated.

Reference： [1]Patent: CN106496055,2017,A .Location in patent: Paragraph 0057; 0058; 0059

45
(3R,5S)-5-(hydroxymethyl)-3-methyl-2-pyrrolidone [ No CAS ]
[ 1012341-50-2 ]

Reference： [1]Patent: CN106496055,2017,A
[2]Patent: CN106496055,2017,A

46
(3R,5S)-5-(bromomethyl)-3-methyl-2-pyrrolidone [ No CAS ]
[ 1012341-50-2 ]

Reference： [1]Patent: CN106496055,2017,A

47
(3R,5S)-5-(tosyloxymethyl)-3-methyl-2-pyrrolidone [ No CAS ]
[ 1012341-50-2 ]

Reference： [1]Patent: CN106496055,2017,A

48
[ 1012341-50-2 ]
N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenyl-methyl)-4-amino-(2R)-methylbutanoic acid ethyl ester calcium salt [ No CAS ]

Reference： [1]Patent: CN106065006,2016,A
[2]Patent: CN107082746,2017,A

49
[ 1012341-50-2 ]
[ 149709-62-6 ]

Reference： [1]Patent: CN106065006,2016,A
[2]Patent: CN107468685,2017,A
[3]Patent: CN107082746,2017,A
[4]Patent: US2020/55812,2020,A1

50
[ 1012341-50-2 ]
[ 149690-05-1 ]

Reference： [1]Patent: CN106065006,2016,A
[2]Patent: CN107082746,2017,A
[3]Patent: US2020/55812,2020,A1

51
[ 149709-68-2 ]
[ 1012341-50-2 ]

Yield	Reaction Conditions	Operation in experiment
	With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; C34H36O2P2; hydrogen; at 20℃; for 24.5h;	To a 500 ml solution of methanol (240 mL) was added [Rh (COD) 2] BF4 (315 mg, 0.78 mmol)The chiral phosphine ligand BICPO (452 mg, 0.84 mmol) was added and the mixture was stirred for 30 minutes,1 (ii-a) (30 g, 0.078 mol) was added successively.The hydrogenation was allowed to react in hydrogen at room temperature for 24 hours. After careful release of hydrogen,The reaction mixture was washed with methanol and then concentrated in vacuo. The residue was removed by means of a short silica gel column.The enantiomeric content was measured by capillary GC or HPLC. The reaction conversion was 100% and the ee% was 99%.
18.5 g	With palladium 10% on activated carbon; (S)-1-phenyl-ethylamine; hydrogen; In ethanol; at 40℃; under 3000.3 Torr; for 2.5h;	Of compound (1) (20.0g, 1.0 eq.) Was dissolved in ethanol (50ml) was added (S) - phenethylamine (5.9g, 1.0 equiv), 10% Pd / C (2.0g), in the 4.0bar under a hydrogen pressure of 40 reaction was placed in an oil bath was heated with stirring for 2.5 hours and then cooled to room temperature, the system is gray suspension was filtered directly to afford an off-white solid, which was placed in a reaction flask was added water (20ml) , methylene chloride (in 80 ml of), hydrochloric acid (6mol / L, 10ml), stirred at room temperature for 1 hour and filtered to remove Pd / C, followed by liquid separation system, the methylene chloride layer was collected, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure solvent, to give a white solid 20.1g. HPLC detection, diastereomeric isomer ratio (2-a) :( 2-b) = 97.62: 2.38. document.write(""); With 100ml ethyl acetate / heptane (1: 4), purified by recrystallization, to give a white solid 18.5g. HPLC detection, diastereomeric isomer ratio (2-a) :( 2-b) = 99.97: 0.03
	With C43H36O6P2Ru; hydrogen; In methanol; 1,2-dichloro-ethane; at 20℃; under 4560.31 Torr; for 24h;Inert atmosphere;	6 (1 mmol) and the catalyst Ru(1a)OAc2 (0.16 mg, 0.0002 mmol) were respectively added to two hydrogenated vials under N2 atmosphere, and finally 5 mL of dichloroethane and trifluoroethanol were added. After 24 hours under a hydrogen atmosphere, the starting materials were all converted to products. The diastereomeric ratio of compound 7 was determined by HPLC to be 98/2, diastereomeric of compound 8.The composition ratio is >99/1.

Reference： [1]Patent: CN106146351,2016,A .Location in patent: Paragraph 0025
[2]Patent: CN105152980,2017,B .Location in patent: Paragraph 0028-0030
[3]Patent: CN109503659,2019,A .Location in patent: Paragraph 0092-0094

52
C₃₃H₃₈N₂O₅ [ No CAS ]
[ 1012341-50-2 ]

Yield	Reaction Conditions	Operation in experiment
95%		Add III-a to the three bottles(10 g, 1 eq) and 100 mL of tetrahydrofuran, cooled to 0 C and added with stirring30 wt% hydrogen peroxide (8.3 g, 4 eq),After the addition was complete, the reaction was continued at 0 C for 0.5 h.Lithium hydroxide (1.53 g, 2 eq) was added in small amounts, and the mixture was stirred at 25 to 30 C for 3 hours. After the completion of the reaction, the saturated sodium bisulfite solution was added to remove the excess peroxide, the aqueous phase was separated and the organic solvent was removed by distillation under reduced pressure, and 2 M hydrochloric acid was added to adjust the pHTo 3 to 4, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to givecrude product.The crude product was recrystallized from a mixed solvent of isopropyl acetate and n-heptane: heated to 100 C to reflux, dissolved, cooled to 70 C, crystallized and further cooled to room temperature,Filtration to get the sand library than the middle(19.95 g, white solid, yield = 95%, ee = 99.8%).

Reference： [1]Patent: CN106699604,2017,A .Location in patent: Paragraph 0061; 0062; 0063

53
(S)-5-(biphenyl-4-yl)-4-(tert-butoxycarbonylamino)pentanoic acid [ No CAS ]
[ 1012341-50-2 ]

Reference： [1]Patent: CN106699604,2017,A

54
(2R/S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid [ No CAS ]
[ 1012341-50-2 ]

Yield	Reaction Conditions	Operation in experiment
37%	With (S)-1-(1-Naphthyl)ethylamine; In methanol; at 60℃; for 1h;	30g compound of formula II and 300ml of methanol were added to a 1L four-necked flask,Warmed to 60 , 13.4g S-naphthylamine was added dropwise,Stirring 1h, reduced to 5 ~ 10 , suction filtration, the filter cake into 500ml four-necked flask, then add 60ml of toluene, warmed to 80 , incubated 0.5h,Down to 0 ~ 5 , stirring 1h, centrifuged, the filter cake to the kettle,Add 17.2g 6 normal concentrations of hydrochloric acid, incubated for 2h,Then add 60ml dichloromethane extraction, liquid separation, the organic phase was washed with 30ml,Concentrated to no distillate, added 30ml of toluene, warmed to 70 , incubated 1h,Down to 0 ~ 5 , heat 1h, suction filtration, filter cake drying to obtain 11.1gThe compound of formula III was obtained in 37% yield, 99.0% pure, 99.1% ee.
	With (S)-1-phenyl-ethylamine; In ethanol; at 20℃; for 2h;	After phenethylamine (6.3g, 1.0 eq), system was gradually precipitated white solid was stirred for 2 hours - the above-mentioned compound (2) (21.0g, 1.0 eq.) Was dissolved in 210ml of ethanol, stirring at room temperature was slowly added (S) The filter cake was washed with 105ml of ethanol. The filter cake was washed into a reaction vessel, water (20ml), methylene chloride (in 80 ml of), hydrochloric acid (6mol / L, 10ml), stirred at room temperature for 1 hour and the system liquid separation, the dichloromethane layer was collected, no over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give a white solid 12.9g. HPLC detection, diastereomeric isomer ratio (2-a) :( 2-b) = 95.03: 4.97.

Reference： [1]Patent: CN106966926,2017,A .Location in patent: Paragraph 0021; 0022; 0023; 0024
[2]Patent: CN105152980,2017,B .Location in patent: Paragraph 0041

55
[ 149818-98-4 ]
[ 1012341-50-2 ]

Reference： [1]Patent: CN105085322,2017,B
[2]Patent: CN105085322,2017,B
[3]Patent: CN108299226,2018,A

56
[ 1426129-50-1 ]
[ 1012341-50-2 ]

Reference： [1]Patent: CN105085322,2017,B
[2]Patent: CN105085322,2017,B
[3]Patent: CN108299226,2018,A

57
C₂₁H₂₇NO₅S [ No CAS ]
[ 1012341-50-2 ]

Reference： [1]Patent: CN105085322,2017,B

58
C₂₀H₂₄INO₂ [ No CAS ]
[ 1012341-50-2 ]

Reference： [1]Patent: CN105085322,2017,B
[2]Patent: CN106966926,2017,A

59
C₃₃H₃₈N₂O₅ [ No CAS ]
[ 1012341-50-2 ]

Yield	Reaction Conditions	Operation in experiment
90%		The compound (IV-a) (30 g, 1 equivalent) was dissolved in 77 ml of tetrahydrofuran,Cooled to 0 C, 30% hydrogen peroxide (25 g, 4 equiv) was added with stirring,Add after stirring 30min. The temperature was added dropwise to the hydrated lithium hydroxide(4.6 g, 2 eq.) Was added dropwise and the mixture was stirred at 20-25 C for 3 hours.After stirring, the aqueous phase was removed,The organic phase is removed with saturated sodium bisulfite solution to remove excess peroxide,The organic phase was removed and the organic phase was evaporated under reduced pressure to remove the solvent to give the crude product.Crude water, with sodium hydroxide solution to adjust the PH value to 12-13,The aqueous phase was washed three times with tert-butyl methyl ether, followed by pH adjusted to 3-4 with concentrated hydrochloric acid,The ethyl acetate extracts were dried over anhydrous sodium sulfate,The desiccant was removed by filtration, and the mother liquor was evaporated under reduced pressure to remove the solvent,To give the title compound (I) (18.9 g, yield 90%, chiral purity 100%).

Reference： [1]Patent: CN105085322,2017,B .Location in patent: Paragraph 0113; 0114; 0115; 0116

60
[ 1012341-50-2 ]
C₂₅H₂₉NO₄ [ No CAS ]

Reference： [1]Patent: CN107216277,2017,A

61
[ 1012341-50-2 ]
[ 1038924-97-8 ]

Reference： [1]Patent: CN107216277,2017,A

62
[ 1012341-50-2 ]
C₂₂H₂₃NO₄ [ No CAS ]

Reference： [1]Patent: CN107216277,2017,A
[2]Patent: CN107216277,2017,A

63
[ 1012341-50-2 ]
[ 64-17-5 ]
[ 752174-62-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	With thionyl chloride; at 78℃;	A solution of 1 g of (2R, 4S) -5- (biphenyl-4-yl) -4- [(tert- butoxycarbonyl) amino] -2-methylpentanoic acid, 15 ml of ethanol, 0.25 ml of thionyl chloride ) Was added to the reaction flask, the reaction was warmed to 78 C, the reaction 4 to 9 hours.The reaction mixture was a colorless and transparent solution. The solvent was concentrated and removed to give 0.75 g of a white solid, that is, a compound represented by Formula I in a yield of 88%.
87.8%	With thionyl chloride; at 40℃; for 4h;	(2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-pentane was added to the reaction flask with stirring. Acid (Compound II) (45 g, 0.12 mol) and 225 ml of ethanol were added dropwise to chlorosulfoxide (69.3 g, 0.58 mol) at 5 C, and the mixture was heated to 40 C for 4 hours. Concentrated to dryness, petroleum ether was beaten, filtered, and dried to give a white solid (Comp. I) (39.5 g).
0.7 g	With thionyl chloride; at 0 - 50℃; for 8h;	In a 100 ml round bottom flask was added 1 g(2R, 4S) -5- (biphenyl-4-yl) -4 - [(tert- butoxycarbonyl) amino]30 ml of ethanol,While adding 0.6ml SOCl2 at 0 C,Stirring and heating to 50 C for 8 hours,The reaction was monitored by thin-layer chromatography (dichloromethane: methanol = 20: 1 mixed solvent as developing solvent)The results show that the consumption of raw materials is complete,Generate strong ultraviolet point, the polarity becomes larger.The solvent was distilled off under reduced pressure,Column chromatography gave 0.7 g of a white solid.

Reference： [1]Patent: CN107311909,2017,A .Location in patent: Paragraph 0026; 0027; 0028; 0041; 0042; 0043; 0044-0049
[2]Patent: CN108373423,2018,A .Location in patent: Paragraph 0039-0041
[3]Patent: CN107216277,2017,A .Location in patent: Paragraph 0020; 0021-0026; 0048; 0049; 0050; 0051; 0052-0055

64
[ 1012341-50-2 ]
[ 67-63-0 ]
(2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid isopropyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With thionyl chloride; at 85℃; for 9h;	(0.0026 mol) of 1 g of (2R, 4S) -5- (biphenyl-4-yl) -4- [(tert- butoxycarbonyl) amino]30 ml isopropanol,0.19ml thionyl chloride (0.0026mol) was added to the reaction flask,Heated to 85 reaction,The reaction time is 9 hours.The reaction solution is a colorless and transparent solution,Concentrated to remove the solvent,A white solid 0.75g,That is, the compound shown in Formula I, the yield was 80%.
0.75 g	With thionyl chloride; at 0 - 80℃; for 8h;	A 100 ml round bottom flask was charged with 1 g of (2R, 4S) -5- (biphenyl-4-yl) -4 - [(tert- butoxycarbonyl) amino]2-methylpentanoic acid,30 ml isopropanol,While adding 0.6ml SOCl2 at 0 C,Stirring heated to 80 C for 8 hours,The reaction was monitored by thin-layer chromatography (dichloromethane: methanol = 20: 1 mixed solvent as developing solvent)The results show that the consumption of raw materials is complete,Generate strong ultraviolet point, the polarity becomes larger.The solvent was evaporated under reduced pressure and the column was chromatographed to give 0.75 g of a white solid.

Reference： [1]Patent: CN107311909,2017,A .Location in patent: Paragraph 0055; 0056; 0057; 0058; 0059
[2]Patent: CN107216277,2017,A .Location in patent: Paragraph 0037; 0038; 0039; 0040; 0041

65
[ 1012341-50-2 ]
D-lysine [ No CAS ]
[ 137862-53-4 ]
C₂₄H₂₈N₅O₃^(1-)*Ca⁽²⁺⁾*C₆H₁₄N₂O₂*C₂₂H₂₃NO₅^(2-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.5%		The (2R, 4S) -5- (biphenyl-4-yl) -4 - [(3-carboxy propionyl) amino] -2-methyl-pentanoic acid 0.95g (2.5mmol),Valsartan 1.08 g (2.5 mmol),20mL acetone was added to the reaction flask,The reaction mixture was stirred for 30 minutes to clarify,After adding 0.36 g (2.5 mmol) of D-lysine,Continue stirring for 10 minutes,After a mixture of 0.20 g (5.00 mmol) of sodium hydroxide and 2 mL of water was added dropwise at room temperature,Stir for 20 minutes,0.27g (2.5mmol) of calcium chloride was added and stirring was continued for 3 hours,Gradual precipitation,The reaction solution was suction-filtered under nitrogen to obtain the final compound z (II) 1.88g,Yield 75.5%.

Reference： [1]Patent: CN107468685,2017,A .Location in patent: Paragraph 0235; 0236; 0237; 0238; 0239

66
[ 1012341-50-2 ]
[ 91339-47-8 ]
C₂₉H₃₆N₂O₂*2ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83.2%	With thionyl chloride; In dichloromethane; for 11h;Reflux;	The (2R, 4S) -5- (biphenyl-4-yl) -4 - [(tert-butoxycarbonyl) amino] -2-methyl-pentanoic acid 3.14g (8.20mmol),(II), 1.47 g (8.20 mmol) and dichloromethane (30 mL)Stirring to raise the temperature to reflux,Thionyl chloride 0.66 mL (9.10 mmol) was dropped,After 1 hour of reaction,The solvent was evaporated to dryness,3.52 g of compound (III)Yield 83.2%.

Reference： [1]Patent: CN107468685,2017,A .Location in patent: Paragraph 0212; 0215; 0216

67
[ 1012341-50-2 ]
C₂₈H₂₈N₂O₄ [ No CAS ]