[ CAS No. 149690-12-0 ] {[proInfo.proName]}

Name: 149690-12-0|(2R,4S)-Ethyl 5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride|95%
Brand: Ambeed
SKU: A249066
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2D 3D

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Quality Control of [ 149690-12-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 149690-12-0 ]

SDS Specification

Alternatived Products of [ 149690-12-0 ]

Product Details of [ 149690-12-0 ]

CAS No. :	149690-12-0	MDL No. :	MFCD27955986
Formula :	C₂₀H₂₆ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MYJTZLYRAWUSLB-WSCVZUBPSA-N
M.W :	347.88	Pubchem ID :	25017086
Synonyms :

Calculated chemistry of [ 149690-12-0 ]

Physicochemical Properties

Num. heavy atoms :	24
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.35
Num. rotatable bonds :	8
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	101.45
TPSA :	52.32 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-4.98 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	4.85
Log Po/w (WLOGP) :	4.61
Log Po/w (MLOGP) :	3.93
Log Po/w (SILICOS-IT) :	4.51
Consensus Log Po/w :	3.58

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-4.89
Solubility :	0.00444 mg/ml ; 0.0000128 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.68
Solubility :	0.000722 mg/ml ; 0.00000208 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-6.31
Solubility :	0.000169 mg/ml ; 0.000000485 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	3.24

Safety of [ 149690-12-0 ]

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 [ 149690-12-0 ]

* 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 [ 149690-12-0 ]
Downstream synthetic route of [ 149690-12-0 ]

[ 149690-12-0 ] Synthesis Path-Upstream 1~27

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
[ 149709-60-4 ]
[ 149690-12-0 ]

Yield	Reaction Conditions	Operation in experiment
98.8%	at 25℃; for 18 h;	Step 7Ethyl (2R,4S)-5-(jI,1 ‘-biphenylj--yl)-4-amino-2-rnethylpentanoate hydrochloride To an ice-bath cooled anhydrous EtOH (300 mE) was added 78.5 g AcCI (1.0 mol) dropwise. After stirred at 20 0 for 5 minutes, a solution of 17.0 g of the product of Step 6 (41.3 mmol, 1.0 eq) in 150 mL anhydrous EtOH was added and the resulting solution was stirred at 25°C for 18 hrs. TLC (PE/EA ::: 2/1) showed the reaction was cornS pIeted and the solution was concentrated to dryness to afford 14.2 of the title compound, yield: 98.8percent.
96%	at 30 - 35℃;	To the reaction flask was added 28.2 g of intermediate V,A solution of 350 mL of hydrogen chloride in ethanol was added,Stirring dissolved,Heated to 35 ° C,And then incubated at 30 to 35 ° C,There is solid precipitation,TLC monitoring reaction;Reaction is completed,Cooling to room temperature,Filter,The filter cake was washed with ethanol,dry,To give 24.6 g of a white solid product.Yield: 96percent.

Reference： [1] Patent: WO2015/154673, 2015, A1, . Location in patent: Page/Page column 16; 17
[2] Patent: CN106478437, 2017, A, . Location in patent: Paragraph 0005; 0021; 0026; 0031

3
[ 64-17-5 ]
[ 149690-12-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	at 0 - 20℃; for 3 h;	To a stirred solution of C2R, 4S)-5-C4-biphenylyl)-4-[CR)-tert-butylsulfinylamino]-2-methylpentanoic acidC50 mg, 134 pmol) in absolute ethanol C0.4 mL), at0 °C thionylchloride C20 pL, 268 pmol) was added.The reaction miure was stirred at room temperaturefor 3 h. The reaction was evaporated to dryness tofurnish C2R, 4S)-5-C4-biphenylyl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride (2R, 4S)1 as a white solid C45 mg, 130 pmol, 99percent). Colourless amorphous solid; 1H NMR C600MHz, DMSO-d6) O 1.06 Cd, J7.1 Hz, 3H, H14), 1.09 Ct, J7.1 Hz, 3H, H16), 1.58 Cddd,J=13.8, 8.1, 5.4 Hz, 1H, H3’), 1.85 Cddd, J=14.3, 9.1, 5.0 Hz, 1H, H3), 2.69-2.76 Cm, 1H, H2),2.80 Cdd, J=13.8, 8.1 Hz, 1H, H5’), 3.03 Cdd, J=13.8, 5.5 Hz, 1H, H5), 3.35-3.41 Cm, 1H, H4),3.98 Cq, J=7.1 Hz, 2H, HiS), 7.35 Cd, J=8.0 Hz, 2H, H7), 7.35 Ct, J=7.4 Hz, 1H, H13), 7.46 Ct,J=7.7 Hz, 2H, H12), 7.64 Cdd, J=7.8 Hz, 2H, H8), 7.66 Cd, J=7.8 Hz, 2H, Hil), 8.16 Cbr. s,3H, NH3), 13C NMR C151 MHz, DMSO-d6) O 13.9 CCH3, C16), 17.5 CCH3, C14), 35.0 CCH,C2), 35.5 CCH2, C3), 38.1 CCH2, CS), 50.4 CCH, C4), 60.1 CCH2, C15), 126.5 C2CH, C8),126.8 C2CH, Cli), 127.4 CCH, C13), 128.9 C2CH, C12), 130.0 C2CH, C7), 135.5 CC, C6),138.7 CC, C9), 139.7 CC, ClO), 174.7 CC, Cl), HRMS-ESl: m/z [M+H] Calcd for C20H26N02:Expected: 312.1964. Found: 312.1967. HPLC CChiralpak AD-H, 250mm, 4.6mm ID., 5.0um; isocratic n-Hexane/ethanol/methanol/triethylamine 80/10/10/0.2; 40°C; 0.8 mI/mm; 254nm; run time 23 mins) (2R,4S)-1 C97.07percent) and isomers, (2S,4R)-1 C0.21percent), (2S,4S)-1 C2.32percent) and (2R,4R)-1 C0.40percent).

Reference： [1] Organic Letters, 2015, vol. 17, # 21, p. 5436 - 5439
[2] Patent: WO2017/51326, 2017, A1, . Location in patent: Page/Page column 47

4
[ 64-17-5 ]
[ 1038924-71-8 ]
[ 149690-12-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	at 65 - 70℃; for 3 h;	(2R, 4S) -5 - ([1,1'-biphenyl] -4-yl) -4-amino-2-methylpentanoic acid hydrochloride, And 60ml of anhydrous ethanol to join the reaction flask, stirring up to 65-70 ; keep 65-70 , 5.6 g of thionyl chloride was added dropwise to the reaction flask with stirring. After completion of the dropwise addition, the mixture was stirred at 65-70 ° C for 3 hours; TCL detection reaction (if not completely complete, plus the appropriate amount of sodium sulfoxide); reaction is completed, vacuum distillation solvent, At a temperature of 50 ° C and evaporated to no more liquid to flow out; 100 ml of n-heptane was added to the residue, Stirring at room temperature for 1 hour; cooling to 0 ~ 10 , stirring crystallization 2 hours; filtration, The filter cake was rinsed with 50 ml of n-heptane and dried in vacuo for 4 hours at a temperature of 50 to 55 ° C. (2R, 4S) -5 - ([1,1'-biphenyl] -4-yl) -4-amino-2- Methylpentanoic acid ethyl ester hydrochloride as a yellow solid in 99percent yield.

Reference： [1] Patent: CN104860894, 2017, B, . Location in patent: Paragraph 0057; 0059; 0060

5
[ 64-17-5 ]
[ 149690-12-0 ]

Yield	Reaction Conditions	Operation in experiment
68%	With hydrogenchloride In waterReflux	4.8 g tert-butyl (2R,4S)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4-phthalimidopentanoate (formula XII) was dissolved in 50 ml ethanol solvent. Then to the reaction system, was added 65 ml hydrochloric acid. After completion of addition, the whole reaction system was heated at reflux until the starting material disappears. Natural cooling to room temperature the reaction system, a high vacuum to remove the solvent, the residue using ethanol/acetic acid ethyl ester is recrystallized to get (2R, 4S) - 5 - ([1,1 '-biphenyl] - 4-yl) - 4-amino-2-methyl valeric acid ethyl ester hydrochloride (2.4 g, 68percent).

Reference： [1] Patent: CN105601524, 2016, A, . Location in patent: Paragraph 0024

6
[ 64-17-5 ]
[ 149709-60-4 ]
[ 149690-12-0 ]

Reference： [1] Patent: WO2017/97275, 2017, A1, . Location in patent: Page/Page column 37; 47

7
[ 64-17-5 ]
[ 1039307-95-3 ]
[ 149690-12-0 ]

Reference： [1] Patent: WO2017/98430, 2017, A1, . Location in patent: Page/Page column 76

8
[ 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

9
[ 64-17-5 ]
[ 1038924-66-1 ]
[ 149690-12-0 ]

Reference： [1] Patent: WO2008/83967, 2008, A2, . Location in patent: Page/Page column 122

10
[ 64-17-5 ]
[ 1038924-70-7 ]
[ 149690-12-0 ]

Reference： [1] Patent: WO2008/83967, 2008, A2, . Location in patent: Page/Page column 123-124

11
[ 1591-31-7 ]
[ 149690-12-0 ]

Reference： [1] Organic Letters, 2015, vol. 17, # 21, p. 5436 - 5439

12
[ 2350-89-2 ]
[ 149690-12-0 ]

Reference： [1] Organic Letters, 2015, vol. 17, # 21, p. 5436 - 5439

13
[ 61502-90-7 ]
[ 149690-12-0 ]

Reference： [1] Organic Letters, 2015, vol. 17, # 21, p. 5436 - 5439

14
[ 76757-90-9 ]
[ 149690-12-0 ]

Reference： [1] Patent: WO2015/154673, 2015, A1,

15
[ 149709-56-8 ]
[ 149690-12-0 ]

Reference： [1] Patent: WO2015/154673, 2015, A1,

16
[ 149818-98-4 ]
[ 149690-12-0 ]

Reference： [1] Patent: WO2015/154673, 2015, A1,

17
[ 149709-59-1 ]
[ 149690-12-0 ]

Reference： [1] Patent: WO2015/154673, 2015, A1,

18
[ 60-18-4 ]
[ 149690-12-0 ]

Reference： [1] Patent: WO2015/154673, 2015, A1,

19
[ 3728-20-9 ]
[ 149690-12-0 ]

Reference： [1] Patent: WO2015/154673, 2015, A1,

20
[ 62561-74-4 ]
[ 149690-12-0 ]

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

21
[ 1246363-08-5 ]
[ 149690-12-0 ]

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

22
[ 1257266-88-8 ]
[ 149690-12-0 ]

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

23
[ 149709-58-0 ]
[ 149690-12-0 ]

Reference： [1] Patent: CN106478437, 2017, A,

24
[ 149709-59-1 ]
[ 149690-12-0 ]

Reference： [1] Patent: CN106478437, 2017, A,

25
[ 31603-77-7 ]
[ 149690-12-0 ]

Reference： [1] Patent: WO2017/98430, 2017, A1,

26
[ 5728-52-9 ]
[ 149690-12-0 ]

Reference： [1] Patent: WO2017/98430, 2017, A1,

27
[ 149709-68-2 ]
[ 149690-12-0 ]

Reference： [1] Patent: CN106146351, 2016, A,

[ 149690-12-0 ] Synthesis Path-Downstream 1~88

1
[ 149690-12-0 ]
[ 3282-30-2 ]
[ 1038924-99-0 ]

Yield	Reaction Conditions	Operation in experiment
		10 g (2S, 4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-a, R1 = R2 = H, R3 = Et) in isopropyl acetate (50 ml) is added to a mixture of pivaloyl chloride (4.1 ml) in isopropyl acetate (50 ml). The mixture is then stirred for 40 min at room temperature. Triethylamine (10.3 ml) in isopropyl acetate (30 ml) is then added over a period of 1 h. The resulting mixture is stirred for 16 h. Citric acid (7.5 g) dissolved in water (30 ml) is added and the phases are separated. The organic phase is washed twice with water (30 ml) and concentrated in vacuo to give (2R,4S)-5- Biphenyl-4-yl-4-(2,2-dimethylpropionylamino)-2-methylpentanoic acid ethyl ester (3-a, R1 = Piv, R2 = H, R3 = Et). 1H NMR (DMSO): 1.05 (9H)1 1.09 (3H)1 1.15 (3H), 1.54 (1H), 1.78 (1H), 2.48 (1H)1 2.72 (2H)1 3.97 (1H), 4.00 (2H), 7.15 (1 H), 7.25 (2H), 7.34 (1H), 7.45 (2H), 7.55 (2H), 7.62 (2H).

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

2
[ 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

3
[ 64-17-5 ]
[ 1038924-66-1 ]
[ 149690-12-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In water; at 80 - 120℃; for 24h;Product distribution / selectivity;	0.5 g (3R, 5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one, 5 ml ethanol and 0.5 ml concentrated hydrochloric acid were heated at about 80-120 0C for about 24 hours. The mixture was evaporated to dryness to obtain (2R, 4S)-4-amino- 5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester (hydrochloride salt). Spectroscopic data as reported in Example 9.

Reference： [1]Patent: WO2008/83967,2008,A2 .Location in patent: Page/Page column 122

4
[ 64-17-5 ]
[ 1038924-70-7 ]
[ 149690-12-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In water; at 80 - 120℃; for 24h;Product distribution / selectivity;	1 g (3R1 5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1 = H)1 10 ml ethanol and 1.4 ml concentrated hydrochloric acid were heated at about 80-120 0C for about 24 hours. The mixture was evaporated to dryness to obtain (2R, 4S)-4-amino-5- <n="125"/>biphenyl-4-yl-2-methylpentanoic acid ethyl ester (hydrochloride salt). Spectroscopic data as reported in Example 9.

Reference： [1]Patent: WO2008/83967,2008,A2 .Location in patent: Page/Page column 123-124

5
[ 149690-13-1 ]
[ 149690-12-0 ]
[ 1038925-00-6 ]
[ 1038924-70-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of (2S, 4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-b, R1 = R2 = H, R3 = Et) [9 : 1 diastereoisomer mixture [(2S, 4S) : (2R, 4S)]] (840 mg) in isopropyl acetate (10 ml) triethylamine (418 mg) is added. The mixture is then stirred at 55 0C for 1 h and then filtered. The filtrate is heated at reflux for 24 hours. To the mixture is added saturated ammonium chloride solution and the phases are separated. The organic layer is concentrated to dryness. The residue is purified by chromatography, eluting first with IPA/Heptane 2:1 then with a mixture 1 :1 to afford (3S1 5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-b, R1 = H) and (3R, 5S)-5-biphenyl- 4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1 = H). Ratio of diastereoisomers determined by 1H NMR to be 9 :1 [(3S, 5S) : (3R, 5S)]. 1H NMR (CDCI3) for (2-b, R1=H): 1.15 (3H)1 1.38 (1H), 2.42 (2H)1 2.63 (1H)1 2.82 (1H), 3.75 (1H)1 5.51 (1H)1 7.17 (2H), 7.28 (1H)1 7.37 (2H)1 7.49 (4H). Spectroscopic data for (2-a, R1=H) as in Example 6.

Reference： [1]Patent: WO2008/83967,2008,A2 .Location in patent: Page/Page column 152-153

6
[ 1918-77-0 ]
[ 149690-12-0 ]
[ 1257265-13-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;	Example 3-1 : Synthesis of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl- acetylamino)-pentanoic acid; To a solution of thiophen-2-yl-acetic acid (0.144 mmol) in DMF (5 ml_) is added HATU (0.216 mmol). After stirring the mixture at room temperature for 10 minutes, (2R,4S)-4- amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (0.144 mmol) and triethylamine (0.359 mmol) is added and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and the mixture is washed with aqueous 1 M HCI and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2- yl-acetylamino)-pentanoic acid ethyl ester which is used directly in the subsequent hydrolysis reaction.Next, to a solution of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)- pentanoic acid ethyl ester (0.287 mmol) in ethanol (10 ml_) is added aqueous 1 M NaOH (2 ml_, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl- acetylamino)-pentanoic acid. HPLC Retention time 1 .23 minutes (condition A); MS 408.3 (M+1 ); 1 H NMR (400 MHz, MeOD-d4) ? ppm 1 .16 (d, J=7.07 Hz, 3H), 1 .50 (m, 1 H), 1 .96 (m, 1 H), 2.52 (m, 1 H), 2.72 (dd, J=7.71 Hz,7.58 Hz, 1 H), 2.84 (dd, J=5.81 Hz, 5.66 Hz, 1 H), 3.64 (d, J=1 .26 Hz, 2H), 4.20 (m, 1 H), 6.82 (m, 1 H), 6.89 (m, 1 H), 7.21 (m, 3H), 7.32 (m, 1 H), 7.42 (m, 2H), 7.46 (m, 2H), 7.57 (m, 2H), 7.95 (d, J=8.59 Hz, 1 H).
	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide;	Example 16-1 Synthesis of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid To a solution of thiophen-2-yl-acetic acid (0.144 mmol) in DMF (5 mL) is added HATU (0.216 mmol). After stirring the mixture at room temperature for 10 minutes, <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (intermediate 29: 0.144 mmol) and triethylamine (0.359 mmol) is added and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and the mixture is washed with aqueous 1M HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid ethyl ester which is used directly in the subsequent hydrolysis reaction.
	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;	To a solution of thiophen-2-yl-acetic acid (0.144 mmol) in DMF (5 mL) is added HATU (0.216 mmol). After stirring the mixture at room temperature for 10 minutes, <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (intermediate 29: 0.144 mmol) and triethylamine (0.359 mmol) is added and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and the mixture is washed with aqueous 1 M HCI and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid ethyl ester which is used directly in the subsequent hydrolysis reaction. (0378) Next, to a solution of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid ethyl ester (0.287 mmol) in ethanol (10 mL) is added aqueous 1 M NaOH (2 mL, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid. HPLC Retention time 1.23 minutes (condition F); MS 408.3 (M+1); 1H NMR (400 MHz, MeOD-d4) delta ppm 1.16 (d, J=7.07 Hz, 3H), 1.50 (m, 1 H), 1.96 (m, 1 H), 2.52 (m, 1 H), 2.72 (dd, J=7.71 Hz,7.58 Hz, 1 H), 2.84 (dd, J=5.81 Hz, 5.66 Hz, 1 H), 3.64 (d, J=1.26 Hz, 2H), 4.20 (m, 1 H), 6.82 (m, 1 H), 6.89 (m, 1 H), 7.21 (m, 3H), 7.32 (m, 1 H), 7.42 (m, 2H), 7.46 (m, 2H), 7.57 (m, 2H), 7.95 (d, J=8.59 Hz, 1 H).

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 70-71
[2]Patent: US2012/122844,2012,A1
[3]Patent: EP2640375,2016,B1 .Location in patent: Paragraph 0376-0378

7
[ 50681-25-9 ]
[ 149690-12-0 ]
[ 1257266-04-8 ]

Yield	Reaction Conditions	Operation in experiment
		Example 47-1 : Synthesis of (2R,4S)-5-Biphenyl-4-yl-2-methyl-4-[(pyridazine-4- carbonyl)-amino]-pentanoic acid; To a stirred solution of <strong>[50681-25-9]pyridazine-4-carboxylic acid</strong> (21 mg, 0.17 mmol) in DMF (6 ml_) is added HOBT (26 mg, 0.17 mmol) and HBTU (65 mg, 0.17 mmol) and the mixture is stirred at room temperature for 10 minutes. (2R,4S)-4-Amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (50 mg, 0.14 mmol) and DIEA (42 mg, 0.56 mmol) are added. After stirring the mixture at room temperature for 18 hours, water is added and the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound; HPLC retention time 1.19 minutes (condition C); MS 390.3 (M+H); 1 H NMR (400 MHz, DMSO-d6): ? ppm 1 .08-1 .10 (d, J=7.07 Hz, 3H), 1 .59-1 .66 (m, 1 H), 1 .88-1 .95 (m, 1 H), 2.46-2.53 (m, 1 H), 2.85-2.87 (d, J=6.82 Hz, 2H), 4.22- 4.30 (m, 1 H), 7.29-7.32 (m, 2H), 7.33-7.36 (m, 1 H), 7.42-7.46 (m, 2H), 7.57-7.59 (m, 2H), 7.62-7.65 (m, 2H), 7.91 -7.93 (q, J=2.27 Hz, 1 H), 8.76-8.78 (d, J=8.59 Hz, 1 H), 9.41 -9.43 (m, 1 H), 9.45-9.46 (m, 1 H), 12.09 (s, 1 H).

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 136-137

8
[ 149690-12-0 ]
[ 4755-77-5 ]
[ 1257266-91-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N,N-dimethyl-formamide; at 20℃;	Intermediate 42: (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2- methylpentanoate ; To a solution of (2R,4S)-ethyl 4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride salt (1 g, 2.87 mmol) in DMF (10 ml_) is added TEA (0.42 ml_, 3.02 mmol) followed by ethyl 2-chloro-2-oxoacetate (392 mg, 2.87 mmol). The crude is stirred at rt for 1 hr. To the crude is added an additional 0.2 ml of ethyl 2-chloro-2-oxoacetate followed by triethylamine (1.26 ml_, 9.06 mmol). The crude is quenched with water and diluted in EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated. The crude is purified via flash chromatography using 30% EtOAc/heptane to 50% EtOAc/heptane to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2-methylpentanoate (970 mg).

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 191-192

9
[ 114832-74-5 ]
[ 149690-12-0 ]
[ 1257265-93-2 ]

Yield	Reaction Conditions	Operation in experiment
		Example 41-1 : Synthesis of 6-((1S,3R)-1-Biphenyl-4-ylmethyl-3-ethoxycarbonyl- butylcarbamoyl)-2-hydroxy-pyrimidine-4-carboxylic acid; To a stirred solution of 2-hydroxypyrimidine-4,6-dicarboxylic acid (71 mg, 0.39 mmol) in DMF (10 ml_) is added HOBT (59 mg, 0.39 mmol) and EDCI (74 mg, 0.39 mmol) and the mixture is stirred at room temperature for 10 minutes then (2R,4S)-4-amino-5-biphenyl-4-yl- 2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 1 ) (120 mg, 0.35 mmol) and triethylamine (0.15 ml, 1 .16 mmol) are added. After stirring the mixture at room temperature for five hours, water is added and the mixture is extracted with ethyl acetate (3x). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and residue is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1 % TFA) to elute the title compound. HPLC retention time 1 .32 minutes (condition C); MS 478.3 (M+H); 1 H NMR (400 MHz, DMSO-d6): ? ppm 1 .05-1 .07 (d, J=7.07 Hz, 3H), 1 .09-1 .12 (t, J=7.07 Hz, 3H), 1 .72-1 .79 (m, 1 H), 1 .81 -1 .89 (m, 1 H), 2.44-2.49 (m, 1 H), 2.77-2.82 (m, 1 H), 2.89-2.95 (m, 1 H), 3.95-4.01 (q, J=7.07 Hz, 2H), 4.16-4.26 (m, 1 H), 7.26-7.28 (m, 2H), 7.31 -7.35 (m, 1 H), 7.41 -7.45 (m, 2H), 7.55-7.57 (m, 2H), 7.62-7.64 (m, 2H), 8.73-8.76 (d, J=9.35 Hz, 1 H).

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 131-132

10
[ 32315-10-9 ]
[ 149690-12-0 ]
[ 1257265-32-9 ]

Yield	Reaction Conditions	Operation in experiment
		Example 6-1 : Synthesis of (S)-1-((1 S,3R)-1-biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-pyrrolidine-2-carboxylic acid; To a vigorously stirred 1 :1 mixture of methylene chloride/8 % aqueous NaHCO3 (30 ml_) at O 0C is added triphosgene (1 14 mg , 0.384 mmol). After stirring the mixture at O 0C for 5 minutes, <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (400 mg, 1 .15 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester. Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester (1.15 mmol) in methylene chloride (10 ml_) is added (S)-pyrrolidine-2-carboxylic acid methyl ester (1.15 mmol) and diisopropylethylamine (2.3 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is washed with aqueous 1 M HCI and the organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography using hexane/methylene chloride to elute the product.Next, to a solution of the obtained residue (0.287 mmol) in ethanol (10 ml_) is added aqueous 1 M NaOH (2 ml_, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1 % TFA). The proper fractions are lyophilized to furnish (S)-1 -((1 S,3R)-1 -biphenyl-4- ylmethyl-3-carboxy-butylcarbamoyl)-pyrrolidine-2-carboxylic acid. HPLC Retention time 0.97 minutes (condition A); MS 425.3 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) ? ppm 1 .03 (d, J=7.07 Hz, 3H), 1 .43 (m, 1 H), 1 .71 (m, 1 H), 1 .86 (m, 3H), 2.09 (m, 1 H), 2.45 (m, 1 H), 2.66- 2.83 (m, 2H), 3.84 (m,1 H), 6.00 (d, J=8.21 Hz, 1 H), 7.27 (d, J=8.08 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.57 (d, J=8.21 Hz, 2H), 7.65 (d, J=7.20, 2H).
		To a vigorously stirred 1:1 mixture of methylene chloride/8 % aqueous NaHCO3 (30 mL) at 0 C is added triphosgene (114 mg , 0.384 mmol). After stirring the mixture at 0 C for 5 minutes, <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (Intermediate 29: 400 mg, 1.15 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester. (0393) Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester (1.15 mmol) in methylene chloride (10 mL) is added (S)-pyrrolidine-2-carboxylic acid methyl ester (1.15 mmol) and diisopropylethylamine (2.3 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is washed with aqueous 1 M HCI and the organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography using hexane/methylene chloride to elute the product. (0394) Next, to a solution of the obtained residue (0.287 mmol) in ethanol (10 mL) is added aqueous 1 M NaOH (2 mL, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (S)-1-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-pyrrolidine-2-carboxylic acid. HPLC Retention time 0.97 minutes (condition F); MS 425.3 (M+1); 1 H NMR (400 MHz, DMSO-d6) delta ppm 1.03 (d, J=7.07 Hz, 3H), 1.43 (m, 1 H), 1.71 (m, 1 H), 1.86 (m, 3H), 2.09 (m, 1 H), 2.45 (m, 1 H), 2.66-2.83 (m, 2H), 3.84 (m,1 H), 6.00 (d, J=8.21 Hz, 1 H), 7.27 (d, J=8.08 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.57 (d, J=8.21 Hz, 2H), 7.65 (d, J=7.20, 2H).

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 106-107
[2]Patent: EP2640375,2016,B1 .Location in patent: Paragraph 0391-0394

11
[ 149690-12-0 ]
[ 319-60-8 ]
[ 1257265-62-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; HATU; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 4h;	Example 15-1 : Synthesis of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy- benzoylamino)-2-methyl-pentanoic acid; To a solution of <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> salt (200 mg, 0.58 mmol) in CH2CI2 (2 ml_) and DMF (2 ml_) at rt is added 3,5 difluoro-4-methoxy benzoic acid (108 mg, 0.58 mmol) followed by an addition of TEA (0.32 ml_, 2.3 mmol) and HATU (262 mg, 0.69 mmol). The mixture is stirred at rt for 4 hours and quenched with saturated NaHCO3 and diluted in ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained material is purified by preparative silica gel thin-layer chromatography plates (eluent: EtOAc/hepane = 3/2) to give 265 mg of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4- methoxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester.Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-methoxy-benzoylamino)-2- methyl-pentanoic acid ethyl ester (125 mg, 0.260 mmol) in DCM (2.6 ml_) is slowly added BBr3 (2.60 ml_, 2.60 mmol) under nitrogen. The reaction is stirred for 18 hours at rt. The reaction is quenched with MeOH, diluted with EtOAc, washed with H2O and brine, dried over MgSO4, and concentrated under reduced pressure. The obtained material is purified by preparative silica gel thin-layer chromatography (7% MeOH in DCM) to give 100 mg (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester.Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2- methyl-pentanoic acid ethyl ester (30mg, 0.064mmol) in MeOH (2 ml_) at room temperature is added aqueous 1 M NaOH (4 ml_, 4.0 mmol). After stirring for 1 hour the reaction is quenched with aqueous 1 M HCI (4 ml_, 4.0 mmol). The mixture is concentrated under reduced pressure and filtered to remove NaCI salt. The obtained residue is purified by preparative silica gel thin-layer chromatography (7% MeOH in DCM) to give 17.1 mg of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid. HPLC Retention time 1 .56 minutes (condition B); MS 440 (M+1 ); 1 H NMR (400 MHz, ACETONITRILE-d3) ? ppm 1 .19 (d, J=7.07 Hz, 3 H) 1 .55 (ddd, J=14.27, 10.74, 3.79 Hz, 1 H) 1 .90 - 1 .96 (m, 1 H) 2.54 - 2.71 (m, 1 H) 2.91 (dd, J=6.69, 3.16 Hz, 2 H) 4.25 - 4.43 (m, 1 H) 6.49 (d, J=9.60 Hz, 2 H) 6.93 (d, J=8.84 Hz, 1 H) 7.33 - 7.42 (m, 3 H) 7.49 (t, J=7.71 Hz, 2 H) 7.61 (d, J=8.34 Hz, 2 H) 7.67 (dd, J=8.34, 1 .26 Hz, 2 H).
	With triethylamine; HATU; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 4h;	To a solution of <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> salt (200 mg, 0.58 mmol) in CH2CI2 (2 mL) and DMF (2 mL) at rt is added 3,5 difluoro-4-methoxy benzoic acid (108 mg, 0.58 mmol) followed by an addition of TEA (0.32 mL, 2.3 mmol) and HATU (262 mg, 0.69 mmol). The mixture is stirred at r.t. for 4 hours and quenched with saturated NaHCO3 and diluted in ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained material is purified by preparative silica gel thin-layer chromatography plates (eluent: EtOAc/hepane = 3/2) to give 265 mg of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-methoxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester. (0414) Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-methoxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester (125 mg, 0.260 mmol) in DCM (2.6 mL) is slowly added BBr3 (2.60 mL, 2.60 mmol) under nitrogen. The reaction is stirred for 18 hours at rt. The reaction is quenched with MeOH, diluted with EtOAc, washed with H2O and brine, dried over MgSO4, and concentrated under reduced pressure. The obtained material is purified by preparative silica gel thin-layer chromatography (7% MeOH in DCM) to give 100 mg (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester. Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester (30mg, 0.064mmol) in MeOH (2 mL) at room temperature is added aqueous 1 M NaOH (4 mL, 4.0 mmol). After stirring for 1 hour the reaction is quenched with aqueous 1 M HCI (4 mL, 4.0 mmol). The mixture is concentrated under reduced pressure and filtered to remove NaCI salt. The obtained residue is purified by preparative silica gel thin-layer chromatography (7% MeOH in DCM) to give 17.1 mg of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid. HPLC Retention time 1.56 minutes (condition G); MS 440 (M+1); 1 H NMR (400 MHz, ACETONITRILE-d3) delta ppm 1.19 (d, J=7.07 Hz, 3 H) 1.55 (ddd, J=14.27, 10.74, 3.79 Hz, 1 H) 1.90 - 1.96 (m, 1 H) 2.54 - 2.71 (m, 1 H) 2.91 (dd, J=6.69, 3.16 Hz, 2 H) 4.25 - 4.43 (m, 1 H) 6.49 (d, J=9.60 Hz, 2 H) 6.93 (d, J=8.84 Hz, 1 H) 7.33 - 7.42 (m, 3 H) 7.49 (t, J=7.71 Hz, 2 H) 7.61 (d, J=8.34 Hz, 2 H) 7.67 (dd, J=8.34, 1.26 Hz, 2 H).

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 118-119
[2]Patent: EP2640375,2016,B1 .Location in patent: Paragraph 0412-0414

12
[ 149690-12-0 ]
[ 3441-03-0 ]
N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane; at 20℃; for 24h;	Example 1-1 : Synthesis of N-((1 S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butyl)- isophthalamic acid; To a mixture of <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (70 mg, 0.201 mmol) and S-chlorocarbonylbenzoic acid methyl ester (0.302 mmol) in methylene chloride (0.5 ml_) is added pyridine (0.5 ml_) and the mixture is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and ethyl acetate is added. The solution is washed with aqueous 1 M HCI and brine and the organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography using methylene chloride to furnish N-((1 S,3R)-1 -biphenyW-ylmethyl-S-ethoxycarbonyl-butyO-isophthalamic acid. Next, to a solution of N-((1 S,3R)-1 -biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)- isophthalamic acid (0.287 mmol) in ethanol (10 ml_) is added aqueous 1 M NaOH (1.2 ml_, 1 .12 mmol) and the mixture is stirred at 50-60 0C for 5 hours. The ethanol is removed under reduced pressure and water is added. The solution is acidified with 1 M HCI and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1 % TFA). The proper fractions are lyophilized to furnish N-((1 S,3R)-1 -biphenyl-4-ylmethyl-3-carboxy-butyl)-isophthalamic acid. HPLC Retention time 1 .05 minutes (condition A); MS 432.3 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) ? ppm 1 .09 (d, J=7.07 Hz, 3H), 1 .60 (m, 1 H), 1 .89 (m, 1 H), 2.47 (m, 1 H), 2.86 (m, 2H), 4.27 (m, 1 H), 7.27- 7.35 (m, 3H), 7.34 (t, 1 H), 7.43 (t, 2H), 7.55-7.66 (m, 5H), 8.01 -8.07 (m, 2H), 8.39 (s, 1 H), 8.47 (d, J=8.46 Hz, 1 H).

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 62-63

13
[ 903558-45-2 ]
[ 149690-12-0 ]
[ 1257265-94-3 ]

Yield	Reaction Conditions	Operation in experiment
	With HATU; In N,N-dimethyl-formamide; at 20℃; for 1h;	Example 42-1 : Synthesis of 6-((1 S,3R)-1-Biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-2-ethoxy-pyrimidine-4-carboxylic acid; To a solution of Intermediate 1 (31 1 mg, 1 mmol) and Intermediate 24 (260 mg, 1 .2 mmol) in DMF (10 ml_) is added HATU (380 mg, 1 mmol) and triethylamine (0.418 ml_, 3 mmol) and the mixture is stirred at room temperature for 1 hour. Water is added and the mixture is extracted with EtOAc. The organic phase is washed wit brine and is dried over magnesium sulfate. The solvent is removed under reduced pressure to give 6-((1 S,3R)-1 -biphenyl-4- ylmethyl-3-ethoxycarbonyl-butylcarbamoyl)-2-chloro-pyrimidine-4-carboxylic acid methyl ester which is used directly in the next reaction.Next, to a solution of the above product in EtOH (7 ml_) is added 1 N NaOH (10 ml_) and the mixture is stirred at room temperature for 18 hours. The mixture is acidified withi N HCI and extracted with EtOAc. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN to elute the title compound; HPLC retention time 1 .15 minutes (condition C); MS 478.3 (M+H); 1 H NMR (400 MHz, MeOD-d4): ? ppm 1 .18-1 .20 (d, J=7.07 Hz, 3H), 1 .43-1 .46 (t, J=7.07 Hz, 3H), 1 .76 - 1 .83 (m, 1 H), 2.02-2.09 (m, 1 H), 2.55-2.61 (m, 1 H), 2.96-2.98 (d, J=6.82 Hz, 2H), 4.42-4.49 (m, 1 H), 4.55-4.61 (q, J=7.07 Hz, 2H), 7.27-7.33 (m, 3 H), 7.37-7.41 (t, J=7.83 Hz, 2H), 7.50-7.52 (d, J=8.34 Hz, 2H), 7.55-7.57 (d, J=7.33 Hz, 2H), 8.1 1 (s, 1 H), 8.58-8.61 (d, J=9.35, 1 H).

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 133

14
[ 149690-12-0 ]
[ 213270-44-1 ]
[ 1257265-54-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example 12-1 : Synthesis of (2S,4S)-5-biphenyl-4-yl-4-((S)-3-carboxy-3-cyclohexyl- propionylamino)-2-methyl-pentanoic acid; To a solution of (S)-2-cyclohexyl-succinic acid 1 -methyl ester (0.144 mmol) in DMF (5 mL) is added HATU (0.216 mmol). After stirring the mixture at room temperature for 10 minutes, <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (0.144 mmol) and triethylamine (0.359 mmol) is added and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and the mixture is washed with aqueous 1 M HCI and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to give the ester product which is used directly in the subsequent hydrolysis reaction.Next, to a solution of the obtained ester product (0.287 mmol) in ethanol (10 ml_) is added aqueous 1 M NaOH (2 ml_, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified, and the diastereomers are separated, by preparative HPLC using a gradient of MeCN/water (0.1 % TFA). The proper fractions are lyophilized to furnish (2S,4S)-5-biphenyl-4-yl-4-((S)-3-carboxy-3-cyclohexyl-propionylamino)-2-methyl- pentanoic acid. HPLC Retention time 1 .21 minutes (condition A); MS 466.4 (M+1 ).

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 115-116

15
[ 149690-12-0 ]
[ 716362-09-3 ]
[ 1257266-41-3 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 38: (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-methoxythiazole-5-carboxamido)- 2-methylpentanoate; To a solution of 2-methoxythiazole-5-carboxylic acid (101 mg, 0.64 mmol) in DMF (6 ml_) is added HOAt (107 mg, 0.58 mmol), EDCI (133 mg, 0.69 mmol), and TEA (0.48 ml_, 3.47 mmol). The crude is stirred at room temperature for 15 mins. To this crude is added (2R,4S)-ethyl 4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride salt. The crude is stirred at room temperature for overnight. The crude is quenched with 1 N HCI and water, diluted in EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated. The residue is purified via flash column chromatography using 30% EtOAc/heptane to 70% EtOAc/heptane to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2- methoxythiazole-5-carboxamido)-2-methylpentanoate (170 mg). HPLC retention time 1 .94 minutes (condition A); MS 453.3 (M+1 ); 1 H NMR (400 MHz, CHLOROFORM-cQ delta ppm 1 .18 (d, J=7.1 Hz, 3 H), 1 .23 (t, J=7.1 Hz, 3 H), 1 .71 (ddd, J=14.0, 9.9, 3.9 Hz, 1 H), 1 .88 - 2.04 (m, 1 H), 2.56 - 2.73 (m, 1 H), 2.78 - 2.96 (m, 1 H), 2.96 - 3.09 (m, 1 H), 4.09 (s, 3 H), 4.09 - 4.18 (m, 2 H), 4.30 - 4.47 (m, 1 H), 6.15 (d, J=8.1 Hz, 1 H), 7.27 (d, J=6.8 Hz, 2 H), 7.29 - 7.36 (m, 1 H), 7.42 (t, J=7.6 Hz, 2 H), 7.49 (s, 1 H), 7.53 (d, J=8.1 Hz, 2 H), 7.57 (d, J=7.3 Hz, 2 H).

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 189-190

16
[ 1605-20-5 ]
[ 149690-12-0 ]
[ 1257266-44-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; HATU; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 2h;	Intermediate 39: (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-methoxyoxazole-5-carboxamido)- 2-methylpentanoate; To a solution of 2-methoxyoxazole-5-carboxylic acid, intermediate 22, (68 mg, 0.47 mmol) in DMF (2 ml_) and DCM (2 ml_) is added (2R,4S)-ethyl 4-amino-5-(biphenyl-4-yl)-2- methylpentanoate hydrochloride (150 mg, 0.43 mmol), HATU (246 mg, 0.65 mmol), and triethylamine (180 mul_, 1 .29 mmol). After stirring the reaction for 2 hours at room temperature, the reaction is quenched with H2O, and the crude is diluted in EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1 % TFA)/CH3CN), and then lyophilized to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2- methoxyoxazole-5-carboxamido)-2-methylpentanoate (175 mg). HPLC retention time = 1 .71 minutes (condition A); MS 437.5 (M+1 ); 1 H NMR (400 MHz, CHLOROFORM-d) delta ppm 1 .20 (d, J=7.1 Hz, 3 H) 1 .25 (t, J=7.1 Hz, 3 H) 1 .65 (ddd, J=14.3, 10.0, 4.3 Hz, 1 H) 1 .96 - 2.10 (m, 1 H) 2.63 (ddd, J=9.4, 7.1 , 4.2 Hz, 1 H) 2.92 (dd, J=13.9, 6.3 Hz, 1 H) 2.99 (dd, J=13.9, 6.3 Hz, 1 H) 4.1 1 (s, 3 H) 4.12 - 4.18 (m, 2 H) 4.34 - 4.54 (m, 1 H) 6.15 (d, J=8.8 Hz, 1 H) 7.28 (d, J=8.3 Hz, 2 H) 7.31 - 7.37 (m, 1 H) 7.40 - 7.47 (m, 3 H) 7.54 (d, J=8.3 Hz, 2 H) 7.59 (dd, J=8.3, 1 .26 Hz, 2 H)

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 190-191

17
[ 17347-61-4 ]
[ 149690-12-0 ]
[ 1257264-86-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 2-1 : Synthesis of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-3-methyl- butyrylamino)-2-methyl-pentanoic acid; A solution of <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (100 mg, 0.287 mmol) and 3,3-dimethyl-dihydro-furan-2,5-dione (0.431 mmol) in 1 :1 methylene chloride/pyridine (1 .4 ml_) is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and obtained residue is used directly in the subsequent hydrolysis reaction.Next, to a solution of the obtained residue (0.287 mmol) in ethanol (10 ml_) is added aqueous 1 M NaOH (2 ml_, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1 % TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-4-(3- carboxy-3-methyl-butyrylamino)-2-methyl-pentanoic acid. HPLC Retention time 1 .03 minutes (condition A); MS 412.4 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) ? ppm 0.97-1 .07 (m, 9H), 1 .32 (m, 1 H), 1 .72 (m, 1 H), 2.25 (q, 2H), 2.45 (m, 1 H), 2.64-2.74 (m, 2H), 3.91 (s, 1 H), 7.25 (d, J=8.08 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.56 (d, J=8.08 Hz, 2H), 7.64 (d, J=7.58 Hz, 2H), 7.88 (s, broad, 1 H).
	In pyridine; ethanol; dichloromethane; water;	Example 15-1 Synthesis of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-3-methyl-butyrylamino)-2-methyl-pentanoic acid A solution of <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (Intermediate 29: 100 mg, 0.287 mmol) and 3,3-dimethyl-dihydro-furan-2,5-dione (0.431 mmol) in 1:1 methylene chloride/pyridine (1.4 mL) is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and obtained residue is used directly in the subsequent hydrolysis reaction. Next, to a solution of the obtained residue (0.287 mmol) in ethanol (10 mL) is added aqueous 1M NaOH (2 mL, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1M HCl, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-3-methyl-butyrylamino)-2-methyl-pentanoic acid. HPLC Retention time 1.03 minutes (condition F); MS 412.4 (M+1); 1H NMR (400 MHz, DMSO-d6) delta ppm 0.97-1.07 (m, 9H), 1.32 (m, 1H), 1.72 (m, 1H), 2.25 (q, 2H), 2.45 (m, 1H), 2.64-2.74 (m, 2H), 3.91 (s, 1H), 7.25 (d, J=8.08 Hz, 2H), 7.34 (t, 1H), 7.45 (t, 2H), 7.56 (d, J=8.08 Hz, 2H), 7.64 (d, J=7.58 Hz, 2H), 7.88 (s, broad, 1H).
		A solution of <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (Intermediate 29: 100 mg, 0.287 mmol) and 3,3-dimethyl-dihydro-furan-2,5-dione (0.431 mmol) in 1:1 methylene chloride/pyridine (1.4 mL) is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and obtained residue is used directly in the subsequent hydrolysis reaction. (0370) Next, to a solution of the obtained residue (0.287 mmol) in ethanol (10 mL) is added aqueous 1 M NaOH (2 mL, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-3-methyl-butyrylamino)-2-methyl-pentanoic acid. HPLC Retention time 1.03 minutes (condition F); MS 412.4 (M+1); 1H NMR (400 MHz, DMSO-d6) delta ppm 0.97-1.07 (m, 9H), 1.32 (m, 1 H), 1.72 (m, 1 H), 2.25 (q, 2H), 2.45 (m, 1 H), 2.64-2.74 (m, 2H), 3.91 (s, 1 H), 7.25 (d, J=8.08 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.56 (d, J=8.08 Hz, 2H), 7.64 (d, J=7.58 Hz, 2H), 7.88 (s, broad, 1H).

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 64-65
[2]Patent: US2012/122844,2012,A1
[3]Patent: EP2640375,2016,B1 .Location in patent: Paragraph 0368-0370

18
[ 149690-12-0 ]
[ 2949-22-6 ]
[ 1257265-41-0 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In N,N-dimethyl-formamide; at 20℃; for 18h;	Example 7-1 : Synthesis of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxymethyl-ureido)-2- methyl-pentanoic acid; To a mixture of <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (50 mg, 0.161 mmol) and Isocyanato-acetic acid ethyl ester (0.161 mmol) in DMF (8 ml_) is added pyridine (0.161 mmol) and the mixture is stirred at room temperature for 18 hours. Water is added and the mixture is extracted with ethyl acetate (3x). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to afford the ester product. This is used in the subsequent hydrolysis reaction.Next, to a solution of the obtained residue (0.287 mmol) in ethanol (10 ml_) is added aqueous 1 M NaOH (2 ml_, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1 % TFA). The proper fractions are lyophilized to furnish (S)-1 -((1 S,3R)-1 -biphenyl-4- ylmethyl-3-carboxy-butylcarbamoyl)-pyrrolidine-2-carboxylic acid. HPLC Retention time 0.91 minutes (condition A); MS 385.4 (M+1 ); 1 H NMR (400 MHz, MeOD-d4) ? ppm 1 .15 (d, J=7.20 Hz, 3H), 1 .40 (m, 1 H), 1 .91 (m, 1 H), 2.60 (m, 1 H), 2.81 (d, J=6.32 Hz, 2H), 3.85 (d, J=1 .89Hz, 2H), 4.00 (m, 1 H), 7.32 (m, 3H), 7.42 (m, 2H), 7.53 (m, 2H), 7.59 (m, 2H).

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 110-111

19
[ 32315-10-9 ]
[ 149690-12-0 ]
[ 1257265-32-9 ]
[ 2577-48-2 ]
[ 144-55-8 ]
(S)-1-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-pyrrolidine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In ethanol; hexane; dichloromethane; water;	Example 18-1 Synthesis of (S)-1-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-pyrrolidine-2-carboxylic acid To a vigorously stirred 1:1 mixture of methylene chloride/8% aqueous NaHCO3 (30 mL) at 0 C. is added triphosgene (114 mg, 0.384 mmol). After stirring the mixture at 0 C. for 5 minutes, <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (Intermediate 29: 400 mg, 1.15 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester. Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester (1.15 mmol) in methylene chloride (10 mL) is added (S)-pyrrolidine-2-carboxylic acid methyl ester (1.15 mmol) and diisopropylethylamine (2.3 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is washed with aqueous 1M HCl and the organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography using hexane/methylene chloride to elute the product. Next, to a solution of the obtained residue (0.287 mmol) in ethanol (10 mL) is added aqueous 1M NaOH (2 mL, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1M HCl, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (S)-1-(1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-pyrrolidine-2-carboxylic acid. HPLC Retention time 0.97 minutes (condition F); MS 425.3 (M+1); 1H NMR (400 MHz, DMSO-d6) delta ppm 1.03 (d, J=7.07 Hz, 3H), 1.43 (m, 1H), 1.71 (m, 1H), 1.86 (m, 3H), 2.09 (m, 1H), 2.45 (m, 1H), 2.66-2.83 (m, 2H), 3.84 (m, 1H), 6.00 (d, J=8.21 Hz, 1H), 7.27 (d, J=8.08 Hz, 2H), 7.34 (t, 1H), 7.45 (t, 2H), 7.57 (d, J=8.21 Hz, 2H), 7.65 (d, J=7.20, 2H).

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

20
[ 149690-12-0 ]
N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid [ No CAS ]
[ 3441-03-0 ]
N-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butyl)-isophthalamic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In ethanol; dichloromethane; water; ethyl acetate;	Example 14-1 Synthesis of N-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butyl)-isophthalamic acid To a mixture of <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (Intermediate 29: 70 mg, 0.201 mmol) and 3-chlorocarbonylbenzoic acid methyl ester (0.302 mmol) in methylene chloride (0.5 mL) is added pyridine (0.5 mL) and the mixture is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and ethyl acetate is added. The solution is washed with aqueous 1M HCl and brine and the organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography using methylene chloride to furnish N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid. Next, to a solution of N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid (0.287 mmol) in ethanol (10 mL) is added aqueous 1M NaOH (1.2 mL, 1.12 mmol) and the mixture is stirred at 50-60 C. for 5 hours. The ethanol is removed under reduced pressure and water is added. The solution is acidified with 1M HCl and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish N-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butyl)-isophthalamic acid. HPLC Retention time 1.05 minutes (condition F); MS 432.3 (M+1); 1H NMR (400 MHz, DMSO-d6) delta ppm 1.09 (d, J=7.07 Hz, 3H), 1.60 (m, 1H), 1.89 (m, 1H), 2.47 (m, 1H), 2.86 (m, 2H), 4.27 (m, 1H), 7.27-7.35 (m, 3H), 7.34 (t, 1H), 7.43 (t, 2H), 7.55-7.66 (m, 5H), 8.01-8.07 (m, 2H), 8.39 (s, 1H), 8.47 (d, J=8.46 Hz, 1H).

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

21
[ 149690-12-0 ]
[ 213270-44-1 ]
[ 1257265-53-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide;	Example 22 Synthesis of (2S,4S)-5-biphenyl-4-yl-4-((S)-3-carboxy-3-cyclohexyl-propionylamino)-2-methyl-pentanoic acid To a solution of (S)-2-cyclohexyl-succinic acid 1-methyl ester (0.144 mmol) in DMF (5 mL) is added HATU (0.216 mmol). After stirring the mixture at room temperature for 10 minutes, <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (0.144 mmol) and triethylamine (0.359 mmol) is added and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and the mixture is washed with aqueous 1M HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to give the ester product which is used directly in the subsequent hydrolysis reaction.

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

22
[ 149690-12-0 ]
[ 1257265-40-9 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In water; N,N-dimethyl-formamide;	Example 19 Synthesis of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxymethyl-ureido)-2-methyl-pentanoic acid To a mixture of <strong>[149690-12-0](2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride</strong> (Intermediate 29: 50 mg, 0.161 mmol) and Isocyanato-acetic acid ethyl ester (0.161 mmol) in DMF (8 mL) is added pyridine (0.161 mmol) and the mixture is stirred at room temperature for 18 hours. Water is added and the mixture is extracted with ethyl acetate (3*). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to afford the ester product. This is used in the subsequent hydrolysis reaction. Next, to a solution of the obtained residue (0.287 mmol) in ethanol (10 mL) is added aqueous 1M NaOH (2 mL, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1M HCl, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (S)-1-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-pyrrolidine-2-carboxylic acid. HPLC Retention time 0.91 minutes (condition F); MS 385.4 (M+1); 1H NMR (400 MHz, MeOD-d4) delta ppm 1.15 (d, J=7.20 Hz, 3H), 1.40 (m, 1H), 1.91 (m, 1H), 2.60 (m, 1H), 2.81 (d, J=6.32 Hz, 2H), 3.85 (d, J=1.89 Hz, 2H), 4.00 (m, 1H), 7.32 (m, 3H), 7.42 (m, 2H), 7.53 (m, 2H), 7.59 (m, 2H).

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

23
[ 149690-12-0 ]
[ 4755-77-5 ]
[ 1432502-05-0 ]

Yield	Reaction Conditions	Operation in experiment
11.2 mg		Comparative Example 1 (2R,4S)-5-Biphenyl-4-yl-2-methyl-4-(oxalyl-amino)-pentanoic Acid (Comparative Compound A; R?-C(O)-COOH) (2R,4S)-4-Amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester (HCl salt; 527 mg, 0.2 mmol) and ethyl oxalyl chloride (18.4 muL, 1.1 eq) were combined with DIPEA (52.2 muL, 0.3 mmol) in DMF (0.3 mL)/DCM (0.3 mL). The mixture was stirred at room temperature until the reaction was complete. The solvent was removed and the residue was dissolved in EtOH (750 muL) and 1 M aqueous NaOH (750 muL), and stirred at room temperature overnight. The solvent was removed and the residue was purified by preparative HPLC to yield Comparative Compound A (11.2 mg, 100% purity). MS m/z [M+H]+ calc'd for C20H21NO5, 356.14; found 356.2.

Reference： [1]Patent: US2013/109639,2013,A1 .Location in patent: Paragraph 0632-0633

24
[ 1591-31-7 ]
[ 149690-12-0 ]

Reference： [1]Organic Letters,2015,vol. 17,p. 5436 - 5439

25
[ 64-17-5 ]
(2R, 4S)-5-(4-biphenylyl)-4-[(S)-tert-butylsulfinylamino]-2-methylpentanoic acid [ No CAS ]
[ 149690-12-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride; at 0 - 20℃; for 3h;	To a stirred solution of C2R, 4S)-5-C4-biphenylyl)-4-[CR)-tert-butylsulfinylamino]-2-methylpentanoic acidC50 mg, 134 pmol) in absolute ethanol C0.4 mL), at0 C thionylchloride C20 pL, 268 pmol) was added.The reaction miure was stirred at room temperaturefor 3 h. The reaction was evaporated to dryness tofurnish C2R, 4S)-5-C4-biphenylyl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride (2R, 4S)1 as a white solid C45 mg, 130 pmol, 99%). Colourless amorphous solid; 1H NMR C600MHz, DMSO-d6) O 1.06 Cd, J7.1 Hz, 3H, H14), 1.09 Ct, J7.1 Hz, 3H, H16), 1.58 Cddd,J=13.8, 8.1, 5.4 Hz, 1H, H3?), 1.85 Cddd, J=14.3, 9.1, 5.0 Hz, 1H, H3), 2.69-2.76 Cm, 1H, H2),2.80 Cdd, J=13.8, 8.1 Hz, 1H, H5?), 3.03 Cdd, J=13.8, 5.5 Hz, 1H, H5), 3.35-3.41 Cm, 1H, H4),3.98 Cq, J=7.1 Hz, 2H, HiS), 7.35 Cd, J=8.0 Hz, 2H, H7), 7.35 Ct, J=7.4 Hz, 1H, H13), 7.46 Ct,J=7.7 Hz, 2H, H12), 7.64 Cdd, J=7.8 Hz, 2H, H8), 7.66 Cd, J=7.8 Hz, 2H, Hil), 8.16 Cbr. s,3H, NH3), 13C NMR C151 MHz, DMSO-d6) O 13.9 CCH3, C16), 17.5 CCH3, C14), 35.0 CCH,C2), 35.5 CCH2, C3), 38.1 CCH2, CS), 50.4 CCH, C4), 60.1 CCH2, C15), 126.5 C2CH, C8),126.8 C2CH, Cli), 127.4 CCH, C13), 128.9 C2CH, C12), 130.0 C2CH, C7), 135.5 CC, C6),138.7 CC, C9), 139.7 CC, ClO), 174.7 CC, Cl), HRMS-ESl: m/z [M+H] Calcd for C20H26N02:Expected: 312.1964. Found: 312.1967. HPLC CChiralpak AD-H, 250mm, 4.6mm ID., 5.0um; isocratic n-Hexane/ethanol/methanol/triethylamine 80/10/10/0.2; 40C; 0.8 mI/mm; 254nm; run time 23 mins) (2R,4S)-1 C97.07%) and isomers, (2S,4R)-1 C0.21%), (2S,4S)-1 C2.32%) and (2R,4R)-1 C0.40%).

Reference： [1]Organic Letters,2015,vol. 17,p. 5436 - 5439
[2]Patent: WO2017/51326,2017,A1 .Location in patent: Page/Page column 47

26
[ 2350-89-2 ]
[ 149690-12-0 ]

Reference： [1]Organic Letters,2015,vol. 17,p. 5436 - 5439

27
[ 61502-90-7 ]
[ 149690-12-0 ]

Reference： [1]Organic Letters,2015,vol. 17,p. 5436 - 5439

28
[2-(4-biphenylyl)ethylidene]((S)-tert-butylsulfinyl)amine [ No CAS ]
[ 149690-12-0 ]

Reference： [1]Organic Letters,2015,vol. 17,p. 5436 - 5439

29
(4R)-5-(4-biphenylyl)-4-[(S)-tert-butylsulfinylamino]-2-methylenepentanoic acid ethyl ester [ No CAS ]
[ 149690-12-0 ]

Reference： [1]Organic Letters,2015,vol. 17,p. 5436 - 5439

30
[ 76757-90-9 ]
[ 149690-12-0 ]