[ CAS No. 623950-02-7 ] {[proInfo.proName]}

Name: 623950-02-7|(S)-2-((tert-Butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)propanoic acid|98%
Brand: Ambeed
SKU: A258975
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Quality Control of [ 623950-02-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 623950-02-7 ]

SDS Specification

Alternatived Products of [ 623950-02-7 ]

Product Details of [ 623950-02-7 ]

CAS No. :	623950-02-7	MDL No. :	MFCD20528368
Formula :	C₁₇H₂₄N₂O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZLUHLTMMROGKKD-ZDUSSCGKSA-N
M.W :	336.38	Pubchem ID :	11847987
Synonyms :		Chemical Name :	(S)-2-((tert-Butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)propanoic acid

Calculated chemistry of [ 623950-02-7 ]

Physicochemical Properties

Num. heavy atoms :	24
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.47
Num. rotatable bonds :	8
Num. H-bond acceptors :	5.0
Num. H-bond donors :	3.0
Molar Refractivity :	89.37
TPSA :	118.72 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.85 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.95
Log Po/w (XLOGP3) :	2.12
Log Po/w (WLOGP) :	1.92
Log Po/w (MLOGP) :	1.69
Log Po/w (SILICOS-IT) :	2.0
Consensus Log Po/w :	1.94

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.92
Solubility :	0.406 mg/ml ; 0.00121 mol/l
Class :	Soluble
Log S (Ali) :	-4.24
Solubility :	0.0192 mg/ml ; 0.000057 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-3.51
Solubility :	0.104 mg/ml ; 0.000309 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.15

Safety of [ 623950-02-7 ]

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 [ 623950-02-7 ]

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

Downstream synthetic route of [ 623950-02-7 ]

[ 623950-02-7 ] Synthesis Path-Downstream 1~38

1
[ 623950-05-0 ]
[ 623950-02-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With lithium hydroxide; water; In tetrahydrofuran;	G. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionic acid. Into an ice-cooled solution of Compound 8c (0.22 g, 0.63 mmol) in THF (3.5 mL) was added an aqueous LiOH solution (1 N, 3.5 mL) and stirred at 0 C. Upon completion of the reaction, the reaction was concentrated and the aqueous phase was neutralized with cooled aqueous 1 N HCl at 0 C., and extracted with EtOAc. The combined extracts were dried over Na2SO4 overnight. Filtration and evaporation of the filtrate to dryness led to Compound 8d (0.20 g, 94%) as a white solid. 1H NMR (300 MHz, DMSO-d6): delta 1.30 (9H, s), 2.32 (6H, s), 2.95(1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd, J=6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s), 7.80 (1H, s); MS(ES+) (relative intensity): 236.9 (6) (M-Boc)+.
87%		D. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic Acid Into an ice-cooled solution of methyl ester from Step C (2.99 g, 8.54 mmol) in THF (50 mL) was added an aqueous LiOH solution (1 N, 50 mL) and stirred at 0 C. Upon disappearance of starting materials monitored by Tlc, the organic solvents were removed and the aqueous phase was neutralized with cooled 1 N HCl at 0 C., and extracted with EtOAc, finally dried over Na2SO4 overnight. Filtration and evaporation to dryness led to the title acid. 2.51 g, 87%; 1H NMR (300 MHz, DMSO-d6): delta 1.30 (9H, s), 2.32 (6H, s), 2.95(1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd, J=6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s), 7.80 (1H, s); MS(ES+) (relative intensity): 236.9 (6) (M-Boc)+.
87 - 94%		D. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid. Into an ice-cooled solution of methyl ester from Step C (2.99 g, 8.54 mmol) in THF (50 mL) was added an aqueous LiOH solution (1N, 50 mL) and stirred at 0 C. Upon consumption of the starting materials, the organic solvents were removed and the aqueous phase was neutralized with cooled 1N HCl at 0 C., and extracted with EtOAc, and dried over Na2SO4 overnight. Filtration and evaporation to dryness led to the title acid (S)-2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid (2.51 g, 87%); 1H NMR (300 MHz, DMSO-d6): delta 1.30 (9H, s), 2.32 (6H, s), 2.95 (1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd, J=6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s), 7.80 (1H, s); MS(ES+) (relative intensity): 236.9 (6) (M-Boc)+. Into an ice-cooled solution of Compound 8c (0.22 g, 0.63 mmol) in THF (3.5 mL) was added an aqueous LiOH solution (1 N, 3.5 mL) and stirred at 0 C. Upon completion of the reaction, the reaction was concentrated and the aqueous phase was neutralized with cooled aqueous 1 N HCl at 0 C., and extracted with EtOAc. The combined extracts were dried over Na2SO4 overnight. Filtration and evaporation of the filtrate to dryness led to Compound 8d (0.20 g, 94%) as a white solid. 1H NMR (300 MHz, DMSO-d6): delta 1.30 (9H, s), 2.32 (6H, s), 2.95(1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd, J=6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s), 7.80 (1H, s); MS(ES+) (relative intensity): 236.9 (6) (M-Boc)+.

64%	With water; lithium hydroxide; In tetrahydrofuran; for 3h;	The above-mentioned example 3 the obtained compound (163.8 g) and tetrahydrofuran (1000 ml) is added to the bottle, the addition of water (750 ml), drop hydrogenation lithia (22 . 79 g)/water (750 ml) solution, reaction 3 hours. Adding ethyl acetate (500 ml * 3) extraction. The aqueous phase is added to ethyl acetate (800 ml), cooled to 0 - 5 C dropwise 1 M hydrochloric acid (400 ml), adjusting pH=2, layered, aqueous phase of ethyl acetate (300 * 3) extraction, the combined organic phase, dried with anhydrous sodium sulfate, filtered, concentrated solids are separated out, filtering to obtain white solid. Vacuum drying to obtain a white powder (70.4 g), yield 64%, purity 99.7%, chiral purity 99.9%.
	With lithium hydroxide; water; In tetrahydrofuran; at 0℃;Product distribution / selectivity;	EXAMPLE 1 (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid Step G: (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionic acid Into an ice-cooled solution of compound 1h (0.22 g, 0.63 mmol) in THF (3.5 mL) was added an aqueous LiOH solution (1 N, 3.5 mL) and the reaction mixture stirred at 0 C. Upon completion of the reaction, the reaction mixture was concentrated and the aqueous phase was neutralized with cooled aqueous 1 N HCl at 0 C., and then extracted with EtOAc. The combined extracts were dried over Na2SO4 overnight. Filtration and evaporation of the filtrate to dryness yielded compound 1j as a white solid. 1H NMR (300 MHz, DMSO-d6): delta 1.30 (9H, s), 2.32 (6H, s), 2.95(1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd, J=6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s), 7.80 (1 H, s); MS(ES+) (relative intensity): 236.9 (6) (M-Boc)+; EXAMPLE 8 (S)-2-tert-Butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionic acid methyl ester Step D. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid Into an ice-cooled solution of methyl ester from Step C (2.99 g, 8.54 mmol) in THF (50 mL) was added an aqueous LiOH solution (1N, 50 mL) and stirred at 0 C. Upon consumption of the starting materials, the organic solvents were removed and the aqueous phase was neutralized with cooled 1N HCl at 0 C., and extracted with EtOAc, and dried over Na2SO4 overnight. Filtration and evaporation to dryness yielded the title acid (S)-2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid. 1H NMR (300 MHz, DMSO-d6): delta 1.30 (9H, s), 2.32 (6H, s), 2.95(1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd, J=6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s), 7.80 (1H, s) MS(ES+) (relative intensity): 236.9 (6) (M-Boc)+.
1.14 g		This example is representative of operation g) of the process of the invention.To the oily residue prepared as described in example 1 (6.0 mmol theoretical) dispersed in tetrahydrofuran (8.6 ml.) and water (8.6 ml_), a 30% (w/w) solution of sodium hydroxide in water (1.4 g, 10.8 mmol) was slowly added monitoring that the internal temperature did not exceed 10 C. The mixture was maintained under stirring at 5 C for 1 hour then toluene (1.7 ml.) and formic acid (0.57 g, 12.4 mmol) were subsequently added thereto. The phases were separated so as to cause precipitation of a solid. The mixture was filtered, the solid washed with water and dried at 40 C under reduced pressure so as to obtain 1.14 g of the desired compound.

Reference： [1]Patent: US2005/203143,2005,A1 .Location in patent: Page/Page column 46
[2]Tetrahedron,2005,vol. 61,p. 6836 - 6838
[3]Patent: US2004/10014,2004,A1 .Location in patent: Page/Page column 32
[4]Patent: US2005/203143,2005,A1 .Location in patent: Page/Page column 38; 46
[5]Patent: CN107129444,2017,A .Location in patent: Paragraph 0038; 0039
[6]Patent: US2006/211861,2006,A1 .Location in patent: Page/Page column 4; 19; 26-27; 32-33
[7]Patent: WO2019/197274,2019,A1 .Location in patent: Page/Page column 32

2
[ 623950-02-7 ]
[ 623949-96-2 ]
[ 623950-28-7 ]

Yield	Reaction Conditions	Operation in experiment
	With (4-dimethylamino-butyl)-ethyl-carbodiimide; benzotriazol-1-ol; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;	A. {1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-carbamic acid tert-butyl ester 2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid (0.42 g, 1.25 mmol) was dissolved in DMF (5 mL) followed by 1-hydroxybenzotriazole (0.34 g, 1.75 mmol), and the resulting solution was cooled to 0 C. To this reaction mixture was added 2-(4-phenyl-1H-imidazol-2-yl)-piperidine (0.31 g, 1.75 mmol) followed by (4-dimethylamino-butyl)-ethyl-carbodiimide (0.34 g, 1.75 mmol). The reaction was then warmed to room temperature and stirred for 16 hours. The reaction mixture was then combined with 2N citric acid and washed multiple times with ethyl acetate. The combined organics were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 600 mg of desired product {1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-carbamic acid tert-butyl ester as a glass which was used as is without further purification. (TLC: 5:1 CHCl3:MeOH Rf=0.6)

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2505 - 2508
[2]Patent: US2004/10014,2004,A1 .Location in patent: Page/Page column 40

3
[ 623950-02-7 ]
[ 422572-64-3 ]
[ 623950-08-3 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); water; at 20℃;	A. {1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamic acid tert-butyl ester To a mixture of 220 mg (0.8 mmol) of 3-(4-phenyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydro-isoquinoline, 269 mg (0.8 mmol) of 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid, 216 mg (1.6 mmol) of of hydroxybenzotriazole hydrate and 184 mg (0.96 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added 3 mL of dimethylformamide. The resulting mixture was allowed to stir overnight at room temperature under argon. The mixture was then partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and concentrated. The product {1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamic acid tert-butyl ester was taken to the next step without further purification.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2505 - 2508
[2]Patent: US2004/10014,2004,A1 .Location in patent: Page/Page column 34

4
[ 623950-02-7 ]
4-{2-amino-3-oxo-3-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-3,5-dimethyl-benzamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2505 - 2508

5
[ 623950-02-7 ]
S,S isomer of 4-{2-amino-3-oxo-3-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3,5-dimethyl-benzamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2505 - 2508

6
[ 623950-04-9 ]
[ 623950-02-7 ]

Reference： [1]Tetrahedron,2005,vol. 61,p. 6836 - 6838

7
[ 623950-03-8 ]
[ 623950-02-7 ]

Reference： [1]Tetrahedron,2005,vol. 61,p. 6836 - 6838
[2]Patent: WO2019/197274,2019,A1

8
[ 137650-15-8 ]
[ 623950-02-7 ]

Reference： [1]Tetrahedron,2005,vol. 61,p. 6836 - 6838
[2]Patent: WO2019/197274,2019,A1

9
[ 1227311-10-5 ]
[ 623950-02-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With dihydrogen peroxide; potassium carbonate; In dimethyl sulfoxide; at 0 - 50℃; for 2h;Inert atmosphere; Green chemistry;	Compound 6A (16.6 g, 0.044 mol), DMSO 440 mL, and K2CO3 (6.6 g, 0.44 mol) were added to the reaction flask under nitrogen, and after cooling to 0 C, 30% Eta2Omicron2 9.67 mL was added dropwise, and then the temperature was raised. The solid was dissolved at room temperature, stirred at 45 to 50 C for 2 h, added to 870 mL of distilled water, stirred and cooled, and the product was filtered, washed with water and dried in vacuo to give compound 7 in total 13.3 g, 80% yield. The HPLC analysis spectrum of the prepared product is shown in Fig. 1. The chiral HPLC spectrum is shown in Fig. 2. The test results show that the purity of the compound 7 prepared in this example is close to 100%, and the ee value is 100%.
	With water; dihydrogen peroxide; potassium carbonate; In dimethyl sulfoxide; at 50℃;Inert atmosphere; Cooling with ice;Product distribution / selectivity;	Example 5Preparation of (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenvD-propionic acidA 5OmL three-necked round bottom flask equipped with magnetic stirrer, and thermocouple was charged under nitrogen with (S)-2-tert- butoxycarbonylamino-3-(4-cyano-2,6-dimethyl-phenyl)-propionic acid methyl ester (166.2 mg, O.deltammol), DMSO (5.0 mL), and K2CO3 (75 mg, 0.5 mmol) and the resulting mixture cooled in an ice bath. To the resulting mixture was then added 30% H2O2 (1 10mul), dropwise via a syringe. The resulting mixture was then allowed to warm up to ambient temperature, with the solids observed to dissolve to yield a clear solution. After stirring for about 2 hours at 45-5O0C, water (1 OmL) was added, cooling was applied, and a precipitated product isolated by filtration. The isolated white solid was washed with water (2 x 25mL), then dried for 24 hours on high vacuum pump to yield the title compound as a white solid.

Reference： [1]Patent: CN110092735,2019,A .Location in patent: Paragraph 0065-0067; 0077-0078
[2]Patent: WO2010/62590,2010,A2 .Location in patent: Page/Page column 31

10
[ 623950-02-7 ]
(S)-2-methoxy-5-([1-(4-phenyl-1H-imidazol-2-yl)ethylamino]methyl)benzoic acid methyl ester [ No CAS ]
5-([2-tert-butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethylphenyl)propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino}methyl)-2-methoxybenzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		48,4g (143,9 mmoles) of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)propanoic acid were dissolved under stirring at the temperature of about 4 C in N,N-dimethylformamide (400 ml) then N-methyl morpholine (23,7 ml; 216 mmoles) was added and the obtained mixture cooled down to 0-5C. 2-chloro- 4,6-dimethoxy-1 ,3,5-triazine (37,9 g; 216 mmoles) was added potion wise in about 20' and the obtained suspension maintained under stirring at 0-5 C for about 1 hours. Then, maintain the reaction mixture under stirring at 0-5 C, the above mentioned solution of (S)-methyl 2-methoxy-5-(((1-(4-phenyl-1 H-imidazol-2- yl)ethyl)amino) methyl) benzoate in DMF (assay value of 50,65g equivalent to 137,64 mmoles) was added in about 25'. The reaction mixture was maintained under stirring at 15-20 C for about 18 hours then was added drop wise in 45-50' in water (2,5 liters) under vigorous stirring at 15-20 C and at the of the addiction maintained in these conditions for about 1 hour. The obtained suspension was filtered by suction and the precipitate washed on the filter with water (3 x 300 ml) to afford a wet product with an assay value of 73,9 g (108 mmoles) of compound 3 (75% of molar yields from (S)-2-((tert-butoxycarbonyl)amino)-3-( (0084) dimethylphenyl)propanoic acid; HPLC purity 91 ,4%) (0085) 1HNMR (500 MHz) in deuterated chloroform at 300K: 0.92 (3H; broad s; CH3-CH), 1.46 (9H; s; (CH3)3C-), 2.30 (6H; s; CH3 aromatics), 2.99-3.03 and 3,32 (2H; 2dd; aromatic-CH2-CH), 3.61 (3H; 1 broad s; 0-CH3), 3.77 (3H; broad s; COOCH3), 3.98 and 4.41 (2H; 2 broad signals; Ar-CH2-N-), 4.79 (1 H; broad s; CH-CH3), 4.99 (1 H; broad s; NH-CH-CO), 6.58 (1 H; d; 3CH aromatic), 7.08-7,68 (10 H; complex system t; 4CH, 6CH, 2'CH? 3'CGH, 4'CH, 5'CH, 6'CH, 3"CH, 5"CH aromatics and CH= imidazole).
145 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃;	To a stirring mixture of 2-tert-butoxycarbonylamino-3 -(4-carbamoyl-2,6-dimethyl-phenyl-propionic acid (100 gm), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (159.4 gm) and 1-hydroxybenzotriazole (45.4 gm) in dimethylformamide (80 ml) & dichloromethane (1920ml) was added 5-( { [2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl] -[1 -(4-phenyl- 1 H-imidazol-2-yl)-ethyl] -amino } -methyl)-2-methoxy-benzoic acid (step 1 product, 146.6 gm). The resulting mixture was stirred at room temperature for overnight and further diluted with water. The separated organic phase was washed sequentially with aqueous Na2CO3 solution, iN HC1 solution, water and brine. After concentration, theresidue was further dissolved in DCM. The resultant solution was washed sequentially with water & iN HC1 solution and then concentrated under vacuum to afford titled compound (yield: 145 gm).
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 25 - 30℃; for 2h;	The oil (obtained from Example 2) was dissolved in N,N-dimethylformamide (150 mL) to obtain a solution. N-(teri-Butoxycarbonyl)-4-carbamoyl-2,6-dimethyl-L- phenylalanine (50 g; prepared as per procedure disclosed in Example 8 of US 7,741,356) was added to the solution and then stirred for 5 minutes at 25C to 27C to obtain a clear solution. l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (42.74 g) was added and then stirred for 2 hours at 28C to 30C. Dichloromethane (500 mL) and water (400 mL) was added to the solution and then stirred for 10 minutes. The layers were separated and the organic layer was washed with de-ionized water (400 mL) and aqueous sodium bicarbonate solution (2x500 mL). The organic layer was collected and de-ionized water (500 mL) was added. The pH was adjusted to 3.0 using 6Nu hydrochloric acid (6 mL). The layers were separated and deionized water (500 mL) was added to the organic layer. The pH was adjusted to 2.98 using 6Nu hydrochloric acid (2 mL). The layers were separated and washed with de-ionized water (500 mL). The organic layer was recovered under vacuum at 40C to 45C to obtain the title compound. Yield: 75.06 g (0302) Chromatographic purity: 79.85%

284.9 g	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In dichloromethane; N,N-dimethyl-formamide; at 0 - 18℃; for 25h;	To a stirring mixture of 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl -propionic acid (156 gm), l-ethoxycarbonyl-2-ethoxy- l, 2-dihydroquinoline ( 152.8 gm) in dimethyl formamide (300 ml) at 0-5C was added a solution of (S)-2-methoxy-5- (((l-(4-phenyl-lH-imidazol-2-yl)ethyl)amino)methyl)benzoate in dichloromethane [the solution of (S)-2-methoxy-5-(((l-(4-phenyl- lH-imidazol-2- yl)ethyl)amino)methyl)benzoate in dichloromethane was obtained by adding dichloromethane (100 ml) and water (100 ml) to (S)-2-methoxy-5-((( l-(4-phenyl-lH- imidazol-2-yl)ethyl)amino)methyl)benzoate hydrochloric acid salt (180 gm obtained in Example 4) followed by addition of 5% aqueous sodium hydroxide solution (500 ml) at 10C to 15C, stirring and separating the dichloromethane layer] in 1 hr. The reaction mixture was stirred for 4hrs at 0-5C, then the temperature was raised to 15-18 C and stirring was continued for 20 hrs. Thereafter dichloromethane (500 ml) and water (500 ml) were added to the reaction mixture and stirred and settled. The phases were separated. The organic layer was washed with 2% aqueous sodium hydroxide (500 ml), cooled to 0- 5C and added dil. hydrochloric acid ( 1000 ml) gradually and stirred the reaction mixture for 3 hrs., filtered and dried under vacuum to afford 284.9 gm of the title compound.
	With propylphosphonic anhydride; triethylamine; In ethyl acetate; at -15 - -10℃; for 1h;	This example is representative of operation b) of the process of the invention.To the solution of methyl (S)-2-methoxy-5-(((1-(4-phenyl-1 H-imidazol-2- yl)ethyl)amino)methyl)benzoate in ethyl acetate prepared as described in example 5 or 6 (33 g of the solution containing 8.45 g, 23.12 mmol of (S)-2-methoxy-5-(((1-(4-phenyl-1 H-imidazol- 2-yl)ethyl)amino)methyl)benzoate in ethyl acetate), (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4- carbamoyl-2,6-dimethylphenyl)propanoic acid prepared as described in example 3 (7.00 g, 20.81 mmol), ethyl acetate (64 ml.) and subsequently triethylamine (7.95 g, 78.60 mmol) were added at 25 C under stirring. The resulting mixture was cooled to -15 C and a 50% w/w solution of T3P in ethyl acetate (22.07 g, 34.68 mmol) added thereto monitoring that the internal temperature did not exceed -10 C. The mixture was maintained under stirring at -15/- 10 C until complete conversion was achieved (about 1 hour) then water (34 ml.) was added thereto monitoring that internal temperature did not exceed 0 C. The resulting phases were heated to 25 C, maintained under stirring at this temperature for 1 hour then separated. The organic layer was washed with water and the combined organic phases concentrated under reduced pressure up to achieve a residual volume of 20 ml_. The resulting residue was co- evaporated with isopropanol in order to remove residual ethyl acetate, then isopropanol (34 ml.) was added thus leading to 41 g of a solution suitable to be used in example 8.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4869 - 4872
[2]Patent: WO2017/153471,2017,A1 .Location in patent: Page/Page column 15-16
[3]Patent: WO2018/20450,2018,A2 .Location in patent: Page/Page column 21; 22
[4]Patent: WO2018/55528,2018,A2 .Location in patent: Page/Page column 33-34
[5]Patent: WO2019/58271,2019,A1 .Location in patent: Page/Page column 15; 25; 30; 31-34; 37; 38
[6]Patent: WO2019/197274,2019,A1 .Location in patent: Page/Page column 34-35; 39-41

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[ 623950-02-7 ]
C₁₈H₁₉N₃ [ No CAS ]
C₃₅H₄₁N₅O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4869 - 4872

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[ 623950-02-7 ]
C₁₉H₁₉N₃O₂ [ No CAS ]
C₃₆H₄₁N₅O₆ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4869 - 4872

13
(S)-2-tert-butoxycarbonylamino-3-(4-methoxycarbonyl-2,6-dimethylphenyl)propionic acid [ No CAS ]
[ 623950-02-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	With 1-methyl-pyrrolidin-2-one; sodium methylate; formamide; In methanol; at 20 - 30℃; for 1h;	A mixture of 0.5 g of (S) -2-tert-butoxycarbonylamino-3- (4-methoxycarbonyl-2,6-dimethylphenyl) propionic acid3 ml of formamide and 1 ml of NMP were added 0.8 g of a methanolic solution of sodium methoxide (30% w / w)The temperature was maintained at 20 C to 30 C for 1 hour. After the reaction is complete, the temperature is lowered to 0 C to 5 C,Water was added to 30 ml of water and stirred at room temperature for 1 hour. The solid was collected by filtration.The resulting solid was recrystallized from a 15% aqueous methanol to give 0.33 g of product as a yield of 69%.

Reference： [1]Patent: CN106866463,2017,A .Location in patent: Paragraph 0117; 0118

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[ 145235-85-4 ]
[ 623950-02-7 ]