Name: 149709-62-6|4-(((2S,4R)-1-([1,1'-Biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid|98%
Brand: Ambeed
SKU: A269433
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1
[ 76757-90-9 ]
[ 149709-62-6 ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 1689 - 1700
[2]Patent: WO2017/141193,2017,A1

2
[ 149709-59-1 ]
[ 149709-62-6 ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 1689 - 1700

3
[ 149709-62-6 ]
[ 137862-53-4 ]
trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3’-methyl-2’-(pentanoyl{2”-(tetrazol-5-ylate)biphenyl-4’-ylmethyl}amino)butyrate]hemipentahydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		LCZ696 is prepared by dissolving 22.96 mmol of <strong>[149709-62-6](2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester</strong> and valsartan (10.00 g; 22.96 mmol) in acetone (300 mL). The suspension is stirred at room temperature for 15 min to obtain a clear solution. A solution of sodium hydroxide (2.76 g; 68.90 mmol) in water (8 mL) is then added to this solution over a period of 10 min. Solids start to precipitate in 10 min. Alternatively, precipitation can be induced by seeding. The suspension is stirred at 20-25 C for 2 h. This suspension is concentrated at 15-30 C under reduced pressure (180-250 mbar) to a batch volume of ca 150 mL. lsopropyl acetate (150 mL) is then added to the batch and the suspension is concentrated again at 15-30 C under reduced pressure (180-250 mbar) to a batch volume of ca 150 mL. This operation (addition of 150 mL of isopropyl acetate to the batch and concentration) is repeated once again. The suspension is stirred at 20-25 C for 1 h. The solids are collected by filtration under nitrogen over a Büchner funnel, washed with isopropyl acetate (20 mL), and dried at 35 C under reduced pressure (20 mbar) to afford trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3’-methyl-2’-(pentanoyl{2’’-(tetrazol-5-ylate)biphenyl-4’-ylmethyl}amino)butyrate] hemipentahydrate.
	With sodium hydroxide; In acetone; at 20℃;Sonication;	To 0.5 mL of acetone was dissolved 104.1 mg of <strong>[149709-62-6]AHU-377</strong> and 107.6 mg of valsartan and 29.4 mg of sodium hydroxide. Sonicated the solution and stirred it at room temperature until solids precipitated out. Added 2.5 mL acetone to it again and stirred at room temperature overnight. The solid was isolated and Form I was obtained, which was analyzed by XRPD, DSC and TGA. The XRPD data obtained in this example is listed in Table 2. The XRPD pattern, DSC thermogram, TGA thermogram of the complex obtained from this example are displayed in FIGs. 2-4, respectively. TGA thermogram of the complex obtained from this example exhibits about 6.7% weight loss when heated up to 150 C.
7.7 g	With sodium hydroxide; In water; acetone; at 25 - 30℃; for 2h;	Sacubitril (4.2 g) and valsartan (4.4 g) were dissolved in acetone (120 mL). Aqueous sodium hydroxide solution (1.25 g NaOH in 4 mL water) was added and the solution was stirred for 2 hours at 25-30 C and stripped off three times with isopropyl acetate (60 mL). Isopropyl acetate (60 mL) was added to result in a clear solution, n- heptane (120 mL) was then added and to get a white solid material. The reaction mixture was stirred for 1 hour and then filtered to yield the amorphous form of trisodium <strong>[149709-62-6]sacubitril</strong> valsartan (7.7 g).

		Example 8: Preparation of crystalline trisodium valsartam<strong>[149709-62-6]sacubitril</strong> form II Valsartan acid (1.0 g) and Sacubitril acid (0.940 g) were dissolved in ethyl acetate and stirred for 15 minutes. Sodium hydroxide (25% aqueous solution, 1.08ml) and the obtained suspension was stirred for 2 hours. Reaction mixture was concentrated under reduced pressure at 40C , and then toluene (15 ml) was added. Reaction mixture was once again concentrated under reduced pressure and 40C followed again by the addition of toluene (15ml). Reaction mixture was heated to 110C, stirred for 10 minutes, cooled down and filtrated off. The wet sample was left at 60% RH for 96 hours and then dried at 40C under reduced pressure for 8 hours and analyzed by XRPD- form II.
220 g		Sacubitril (105 gm) and Valsartan (111 gm) were added to Acetone (2100 ml) at room temperature and stined for 10 minutes. To the obtained clear solution was cooled to - 2 to 5C. To the above solution was added aq.sodium hydroxide solution by dropwise and maintained for two hours at -2 to 5C. Filtered the obtained reaction mass and washed with acetone (210 ml) and the obtained filtrate was concentrated under vacuum at 35 to 45C.The obtained solid was dried at 35 to 45C to yield amorphous solid. To the obtained solidwas added cyclohexane (2 lts) and stined for 2 hour. Filtered the solid and dried at 35 to45C for 12 to 15 hours to yield Amorphous form of Sacubitril I Valsartan trisodium salt(220 gm).Chromatographic purity by HPLC: 99.83%M.C:3.2%wlwContent of Sodium: 6.9% wlw
4.7 g		A mixture of 10 g of ethyl (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoate and 60 ml of acetic acid Isopropyl ester added to the reaction flask, 2 ml of 2N hydrochloric acid was added with stirring; The mixed solution was stirred at room temperature for 2 hours, allowed to stand for 10 minutes, and the lower aqueous phase was separated; The upper organic phase was added to 100 ml of purified water, stirred for 10 minutes, allowed to stand for 10 minutes, Separate the lower aqueous phase; The upper organic phase is evaporated under reduced pressure, the temperature is 40 ~ 45 , Steamed no longer have liquid out; The residue was added to the reaction flask, Add 15 ml of acetonitrile and 15 ml of isopropanol to the reaction flask, Stirring 10.1g valsartan added to the reaction flask, heated to 50 ~ 55 , Stir to dissolve; Insulation 50 ~ 55 , stirring will be 2.8g Sodium hydroxide dissolved in 7 ml of purified water in aqueous sodium hydroxide solution was added to the reaction flask; dropping to a temperature of room temperature, stirred for 1 hour; and then cooled to 0 to 5 C for 1 hour; 30 ml of acetone was added to the reaction flask with stirring, and the mixture was incubated at 0 to 5 C and stirred for 2 hours. The filter cake was rinsed with 15 ml of acetone, dried in vacuo for 8 hours at a temperature of 50-55 C; 16.2 g of LCZ696 as a white powder was obtained in a yield of 72.8% Step 4, 5 g of crude LCZ696 was added to 30 ml of a 1: 3 mixed solvent of n-butanol and o-xylene, and 1 g of Charcoal, heated to reflux for 5 hours, hot filter in addition to activated carbon, stirring at room temperature for 8 hours, precipitation crystallization, filtration and crystallization, with 20ml of n-propanol washed twice, after drying that LCZ696 pure 4.7g.
	With sodium hydroxide; In ethanol; water; at 25 - 30℃; for 0.5h;	Sacubitril (5 g) and valsartan (5.3 g) were dissolved in ethanol (30 ml). In another, flask sodium hydroxide (1.425g) was dissolved in water (4 ml) then diluted with ethanol (10 ml). The sodium hydroxide solution was added to the above clear solution of <strong>[149709-62-6]sacubitril</strong> and valsartan to form a reaction mass, which was stirred for 30 minutes at 25-30C and concentrated under vacuum. Traces of water were removed using ethanol(3xl5 ml) until the moisture level of the residue was to less than 0.5%. Ethyl acetate (30 ml) was added to the residue and the mixture was stirred at 40-45 C until a clear solution was formed, which was then filtered through micron filter and cooled to 25-35C.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 275 - 276
[2]Patent: WO2016/49663,2016,A1 .Location in patent: Page/Page column 17
[3]Patent: WO2016/125123,2016,A1 .Location in patent: Page/Page column 12
[4]Patent: WO2016/201238,2016,A1 .Location in patent: Paragraph 0097
[5]Patent: WO2017/37591,2017,A1 .Location in patent: Page/Page column 12
[6]Patent: CN104860894,2017,B .Location in patent: Paragraph 0057; 0063; 0064
[7]Patent: WO2018/69937,2018,A1 .Location in patent: Page/Page column 28-30

4
[ 108-30-5 ]
[ 149690-12-0 ]
[ 149709-62-6 ]

Yield	Reaction Conditions	Operation in experiment
88.3%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 0.5h;	1.67 g (4.82 mmol) of compound (II),20 mL dichloromethane,Succinic anhydride 0.48g (4.82mmol) was added to the reaction flask was stirred,Diisopropylethylamine 0.84 mL (4.82 mmol) was dropped,Reaction at room temperature for 30 minutes,HPLC detection reaction was complete,Post-processing,The reaction solution was washed with water,Dried over anhydrous sodium sulfate,Suction filtration and evaporated to dryness solvent to give Compound (III) 1.75g,Yield 88.3%.
81.3%	With triethylamine; In Isopropyl acetate; at -5 - 30℃; for 2h;	(2R, 4S) -5 - ([1,1'-biphenyl] -4-yl) -4-amino-2-methylpentanoic acid ethyl ester hydrochloride, 3.4 g succinic anhydride and 60 ml isopropyl acetate were added to the reaction flask and the temperature was lowered to -5 to 0 C with stirring. 3.5 g of triethylamine was added dropwise to the reaction flask to control the dropping rate, keeping the temperature no more than 0 C; Stirring up to 25 ~ 30 stirring 2 hours; TCL detection reaction (if not fully responded, Continue to maintain 25 ~ 30 stirring); reaction is completed, acetic acid aqueous solution (6g acetic acid, 60 ml of purified water) was added to the reaction flask; stirred for 10 minutes, allowed to stand for 10 minutes, and the lower aqueous phase was separated; 60 ml of purified water was added to the upper organic phase, stirred for 10 minutes, allowed to stand for 10 minutes, and the lower aqueous phase was separated; 100 ml of purified water was added to the upper organic phase, and 1N aqueous sodium hydroxide solution was added dropwise with stirring to adjust the pH to 7.5; The mixture was heated to 50 to 55 C with stirring, stirred for 10 minutes, allowed to stand for 10 minutes, and the lower aqueous phase was separated, The upper organic phase do not; to the lower water phase by adding 60ml isopropyl acetate, to maintain 50 ~ 55 , Stirring for 10 minutes, standing for 10 minutes, separating the lower aqueous phase, the upper organic phase do not; The lower aqueous phase was heated to 90-95 & lt; 0 & gt; C, Stirring the calcium chloride aqueous solution (6.4 g of calcium chloride, 20 ml of purified water) into the reaction flask; Cooling to 50 ~ 55 , stirring 2 hours; filtration, filter cake with 20ml purified water rinse, vacuum drying 8 hours, (2R, 4S) -5-biphenyl-4-yl-5- (3-carboxy-propionylamino) -2-methyl-pentanoic acid ethyl ester as a white powder, Yield 81.3%
98.5%Chromat.		100 ml of cliehioromethane and 12 ml of triethylamine was added to 10 g of the hydrochloride of amine (3). The mixture was agitated at the room temperature for approx. 10 minutes. This was followed by addition of 4.3 g of succinic aithydride and agitation of the mixture at the room temperature for 4 hours. 100 ml of IM HCI was added to the mixture, the layers were separated, the organic layer was washed with water and dried over sodium sulphate, Afterfiltration of the desiccant the solvent was evaporated in vacuo (75C, 10 mbar) and the product was obtained in the form of transparent honey. According to HPLC analyses the product usually contained 97.5 to 98.5% of the desired substance.

165 g	With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 3h;	(2R,4S)-4-amino-5-(biphenyl)-2-methylpentanoate hydrochloride (hydrochloride salt of Formula-XIV, 170 g) was dissolved in dichloromethane (1360 mL) and the solution was cooled to 5-10 C. 4-dimethylaminopyridine(1.0 g) and succinic anhydride (61.1 g) were added. A solution of triethylamine (74 g) was added. The reaction mass was stined at ambient temperature for 3 hours. After reaction completion, reaction mass was washed with iN HC1 solution (850 mL) followed by brine solution (850 mL). The organic layer was then concentrated under vacuum to obtain a residue and cooled to ambient temperature. Diisopropylether (850 mL) was added to the residue and stined for2 hours. The solution was filtered to obtain a solid which was dried to get the crystalline material of sacubitril (165 g).
	With triethylamine; In Isopropyl acetate; at 0 - 20℃; for 2h;	To a suspension of ethyl (2R,4S)-5-([1 , 1 -biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride (100 g, 1.00 equiv.), prepared as described in US 5,217,996, and succinic anhydride (33.1 g, 1.15 equiv.) in isopropyl acetate (800 ml) at 0 C, a solution oftriethylamine (51 ml, 1.28 equiv.) in isopropyl acetate (100 ml) is added over 1 h. The reaction mixture is further stirred at 0 C for 1 h, then warmed to room temperature over 1 h. The reaction is quenched by addition of a solution of citric acid (68.5 g, 1 .24 equiv.) in water (300 ml). After phase separation, the organic layer is washed with water (2 x 200 ml) to give a solution of the free acid of AHU277 in isopropyl acetate, which is directlyused without further purification in the next step (see Example 8). The free acid of AHU377 can be obtained as pure substance by concentration of the solution in isopropyl acetate for use without further purification in the next step (see Example 1).
	With triethylamine; In Isopropyl acetate; at 20℃;	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.
	With thionyl chloride; for 8h;	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%.
	With triethylamine; In ethyl acetate; toluene; at 0 - 5℃; for 4.33333h;	The amount of 36.7 g of succinanhydride, dissolved in 580 ml of ethyl acetate, is added to a solution of the hydrochloride of the amine of formula 3 in toluene, prepared according to Example 1, at RT. Being stirred, the mixture is cooled down to 0C. Then, at the temperature of ~2C, a solution of 115 ml of triethylamine in 115 ml of ethyl acetate is slowly added to the stirred mixture during approx. 80 minutes and the obtained mixture is stirred for another 3 hours at a temperature of 0 - 5C. Then, a solution of 41 ml of 36% hydrochloric acid in 280 ml of water is added at ~20C and the emulsion is stirred for about 15 minutes at RT. After the separation of the phases, the top organic layer is further extracted with 200 ml of purified water. The obtained solution of sacubitril in the organic solvent is then concentrated at a slightly reduced pressure (-0.2 bar) by evaporation of about 1100 ml of the solvents. The distillation then continues at simultaneous adding of 280 ml of toluene (approximately the same quantity of the solvents is removed by distillation at the same time). The final solution of sacubitril in toluene achieved the purity of 98.0% according the HPLC while the main contained impurity is the lactam of formula 5, which amounted to 1.85%. The solution of the crude acid of sacubitril is further used for the preparation of the selected salt.
36 g	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 10 - 20℃;	At a controlled temperature of 10 to 20 C, 518 g of dichloromethane, 39 g of SV-A and 12.3 g of succinic anhydride were added sequentially to 1 L of a dry reaction kettle, and 17.4 g of N, N-diisopropyl (DI PEA) was added dropwise, and after completion of addition at control temperature continue to stirring the reaction for 3 ~ 4h; TLC method to monitor the reaction (Developing solvent: ethyl acetate:acetic acid = 100: 1, Rf sv-i = 0.2, Rf sv-2 = 0.6, UV254 nm), when the SV-A disappeared, as the reaction is complete.After completion of the reaction, 40 kg of water was added, and the solvent was distilled off under reduced pressure at 25 to 35 C and vacuum of ? -0.08 MPa. Into the residue was added 350 g of isopropyl acetate, and the organic phase was washed twice with water (100 g / each time), twice with 0.2% sodium bicarbonate (100 g / time) , 2 times with 1.5 N hydrochloric acid and 2 times with saturated sodium chloride(100 g / times), and dried over 39 g Anhydrous sodium sulfate for 0.5 ~ 1h. filtration was carried out , leaching with the suitable amount of isopropyl acetate, solvent was distilled off under reduced pressure at 25 ~ 35 C and vacuum of ? -0.08 MPa to obtain 36g of Sacubitril Crude.
	With triethylamine; In dichloromethane; at 25 - 30℃; for 3h;	Succinic anhydride (43.14 gms) was added to a mixture of dichloromethane (300 ml) and (2R,4S)-ethyl 5 -([1,1 ?-biphenyl] -4-yl)-4-amino-2-methylpentanoate hydrochloride compound of formula-3 (100 gms) at 25-30C. Triethyl amine (60.5 ml) was slowly added to the reaction mixture at 25-30C and stirred for 3 hours at the same temperature. Water wasadded to the reaction mixture at 25-30C and stirred for 15 minutes at the same temperature. Separated the organic and aqueous layers and extracted the aqueous layer with dichioromethane. Combined both the organic layers and washed with water. Distilled off the solvent completely from the organic layer and co-distilled with ethyl acetate under reduced pressure. Ethyl acetate (600 ml) was added to the obtained compound at 25-30C.Tromethamine (38.2 gms) was added to the reaction mixture at 25-30C. Heated the reaction mixture to 60-65C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 25-30C and stirred for 5 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound.
	With triethylamine; In water; ethyl acetate; at 20 - 30℃; for 2.5h;	(1) Add AHU1 (15.2g) in order to the three-vial with a thermometer.Ethyl acetate (45mL) and succinic anhydride (4.82g), magnetic stirring to obtain a white suspension, the water bath to maintain the internal temperature of 20-30 C;(2) Triethylamine (5.30g) was added dropwise in a constant pressure dropping funnel over 5 minutes, and the reaction was incubated for 2 hours at 20-30C. Samples were analyzed by HPLC and AHU1 was basically converted.(3) Add water (100 mL) to the reaction system, stir for 30 minutes, and stand still;(4) Separate the organic layer with a separatory funnel, retain the organic layer, and adjust the pH of the aqueous layer to less than 5 with hydrochloric acid, extract once with ethyl acetate (50 mL), and combine the organic phases.Water (50mL) and sodium hydroxide (2.1g) were added, stirred for 10 minutes, allowed to stand for separation, and the aqueous layer was separated by a separatory funnel, and a 13% calcium chloride aqueous solution (20 g) was added under magnetic stirring to the aqueous layer;(5) Precipitation of solids, stirring, suction filtration under reduced pressure, washing of the filter cake with water several times, and obtaining a white solid obtained by vacuum drying AHU2 calcium salt at 40C;
52.4 g	With pyridine; at 60 - 70℃;	Ethyl (2R,4S)-5-([1,1-biphenyl)-4-amino-2-methylpentanoate hydrochloride (43.6 g, 0.125 mol) and pyridine (87.2 ml) were added to a 250 ml three-necked flask equipped with a magnetic stirrer and a condenser tube, dissolved by stirring at room temperature; added with succinic anhydride (18.7 g, 0.186 mol) at room temperature, and after the addition reacted for 1-1.5 h when the temperature was raised to 60-70 C., cooled, and concentrated under reduced pressure until pyridine-free, dissolved with ethyl acetate (515 ml), adjusted to pH 1-2 with 2N hydrochloric acid, stirred for 20-30 min, allowed to stand for 10-15 min, and separated to different liquid phases; The organic phase was acidified with 0.1N hydrochloric acid (515 ml), washed successively with saturated aqueous sodium chloride (515 ml), water (515 ml) and separated to different liquid phases, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure, added with absolute ethanol (103 ml), concentrated to dryness, then added with acetone (256 ml), concentrated to dryness at 40-45 C. to give a crude product of 52.4 g ethyl (2R,4S)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoate, with a yield of 95%-105% and purity higher than 97.0%.

Reference： [1]Patent: CN107468685,2017,A .Location in patent: Paragraph 0267; 0270; 0271
[2]Patent: CN104860894,2017,B .Location in patent: Paragraph 0057; 0061; 0062
[3]Patent: WO2016/74651,2016,A1 .Location in patent: Page/Page column 20
[4]Patent: WO2016/135751,2016,A1 .Location in patent: Page/Page column 31
[5]Patent: WO2017/3483,2017,A1 .Location in patent: Page/Page column 31
[6]Patent: CN106065006,2016,A .Location in patent: Paragraph 0049; 0050; 0051; 0053
[7]Patent: CN106146351,2016,A .Location in patent: Paragraph 0035
[8]Patent: WO2017/97275,2017,A1 .Location in patent: Page/Page column 38; 48
[9]Patent: CN106674206,2017,A .Location in patent: Paragraph 0031; 0057-0060
[10]Patent: WO2017/154017,2017,A1 .Location in patent: Page/Page column 23; 24
[11]Patent: CN107082746,2017,A .Location in patent: Paragraph 0051; 0064-0069; 0080
[12]Patent: US2020/55812,2020,A1 .Location in patent: Paragraph 170-171

5
[ 149709-62-6 ]
[ 149690-05-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium acetate; at 20℃; for 2h;pH 6 - 9;	Weigh 41.1g (0.1mol) of Shakubituo free acid (purity 97.7%,Impurity 1-3 content 1.2%, impurity 1-4 content 0.8%) placed in 1000mlIn a round-bottomed flask, 400 ml of methyl isobutyrate was added and the mixture was stirred and dissolved.Then, sodium acetate solution was added dropwise so that the pH of the reaction solution was 6.0-9.0.The reaction was stirred for 2 hours at room temperature and concentrated until the remaining volume was 50 ml.Stop this concentration of water,Then add 400ml of methyl isobutyrate to dissolveThen add 600ml n-hexane,The mixture was stirred for 2 hours to precipitate a solid which was then filtered and the filter cake was vacuum dried at 60C for 16 hours.Obtained the sodium sacurbitrate, melting point: 153-156C, yield 90%,Purity 99.92% (content of impurity 1-3 0.04%, impurity 1-4 content 0.03%),Its X-ray powder diffraction pattern is consistent with Figure 1.
90%	With sodium hydroxide; In tetrahydrofuran; ethanol; at 20 - 25℃; for 1h;	Add 50 mL of ethanol, 50 mL of tetrahydrofuran to the reaction flask. Sacubitril free acid oil 4.11g, Stir and dissolve, add 6mL of 2mol / L sodium hydroxide solution, The reaction was carried out at room temperature of 20 to 25 C for 1 hour, and the reaction was completed. After removing 50 mL of the solvent under reduced pressure, a flocculent solid was formed, and the obtained flocculent solid was filtered under a nitrogen stream, and dried under vacuum. Sacubitril sodium salt 3.91g, The yield was 90%, and the chromatographic purity was 99.1%.
80.95%	With sodium carbonate; In acetone; at 30℃; for 2h;	In the reactor,<strong>[149709-62-6]sacubitril</strong> free acid 5.0 g(12.1 mmol)And 35 ml of acetone and stirred.3.2 ml (6.1 mmol) of 20% sodium carbonate aqueous solution was added to the reaction mixture, followed by stirring at 30 for 2 hours.The reaction mixture was concentrated in vacuo at 40, and the gas was removed at 40 for 1 hour.60 ml of isopropyl acetate was then added to the reaction mixture and stirred at 30 overnight.The resulting solid was filtered, washed with isopropyl acetate, and then vacuum-dried at 55 C for 4 hours to obtain 4.25 g (yield: 80.95%) of the desired compound.

80.95%	With sodium carbonate; In acetone; at 30 - 40℃; for 3h;	The reactor was charged with 5.0 g (12.1 mmol) of saccharide free acid and 35 ml of acetone and stirred.3.2 ml (6.1 mmol) of 20% sodium carbonate aqueous solution was added to the reaction mixture, followed by stirring at 30 for 2 hours.The reaction mixture was concentrated in vacuo at 40, and the gas was removed at 40 for 1 hour.60 ml of isopropyl acetate was then added to the reaction mixture and stirred at 30 overnight. The resulting solid was filtered and washed with isopropyl acetate,And dried under vacuum at 50 for 4 hours to obtain 4.25 g (yield: 80.95%) of the desired compound.
	With sodium hydroxide; In tetrahydrofuran; ethanol; water; at 20℃; for 17h;	At room temperature, 330 mg of sakubicin was dissolved in 20 mL of a mixed solvent of ethanol and tetrahydrofuran (1: 1), 5 mL of a 1 N aqueous solution of sodium hydroxide was slowly added dropwise thereto, and the mixture was further stirred at room temperature for 17 hours,, Diluted with water and washed with ether. The aqueous phase was acidified with 1N hydrochloric acid and extracted with ethyl acetateThe organic phase was dried over magnesium sulfate and concentrated. The resulting solid was washed with ether to give the sodium salt of sulbucate.
	With sodium hydroxide; In Isopropyl acetate;	To a mixture of AHU377 free acid (17.7 g) in isopropyl acetate (190 mL), solid sodium hydroxide (1.9 g) is added, thus yielding AHU377 sodium salt which is directly used for manufacture of the calcium salt. The mixture is stirred at 25 C for 70 mm to give a turbidmixture. Addition of solid calcium chloride (2.4 g) is followed by seeding with AHU377 Modification B (obtainable e.g. as described in Example 2) at room temperature. The white suspension is stirred at 25 C for 20 h, then filtered and washed with isopropyl acetate to give solid AHU377 calcium salt after drying at 50 C under reduced pressure.
	With sodium hydroxide; In ethanol; at 40 - 60℃;	Sodium hydroxide 0.10 (2.19 mmol) was dissolved in 2 ml of absolute ethanol at 40 to 45 C; At room temperature, 1.00 g (2.43 mmol) of Sacubitril was dissolved in 10 ml of absolute ethanol.the sodium hydroxide dissolved in ethanol solution added dropwise to the above mentioned Sacubitril dissolved in absolute ethanol solution with stirring to obtain a clear solution. At 55 C - 60 C, methyl tert-butyl ether was added dropwise to a solid precipitate and cooled. Filtration carried out , filter cake was washed by methyl tert-butyl ether and dried at 105 ~ 110 C under reduced pressure to obtain Sacubitril Crystalline Form A.
	With sodium hydroxide; In Isopropyl acetate; at 40℃; for 2h;	Compound 1 Calcium salt1.05 equivalents of an aqueous solution of sodium hydroxide (1 mol / L) was added dropwise to the organic phase obtained in Example 1 at room temperature,40 for 2 h, separated, the water phase with 600mL × 4 IPAC extraction after pressure steaming in addition to IPAC, to get A-4 containing aqueous solution;
19.9 g	With sodium hydroxide; In ethanol; ethyl acetate; toluene; at 20℃; for 0.5h;	Sacubitril free acid (20.16 g, 0.049 mol) is dissolved in a mixture of 55 ml of toluene and 35 ml of ethyl acetate. The solution of 1.93 g of sodium hydroxide (0.048 mol) in 43 ml of ethanol is added to the stirred solution of the acid during 30 min and at the temperature of 20C. The mixture is concentrated in vacuum by evaporation of approx. 100 ml of the solvents. The amount of 50 ml of toluene is added and the mixture is concentrated again by evaporation of approx. 50 ml of the solvents. The concentrated residue is slowly diluted by addition of 230 ml of ethyl acetate. The mixture is stirred for at least 2.5 hours. During this time period the crystalline product is separated. The obtained suspension is gradually cooled down to 15 - 18C and after approximately 30 minutes of stirring the product is filtered off and washed with about 25 ml of ethyl acetate. The isolated product is dried in vacuum at 50C until a constant weight is achieved. The amount of 19.9 g of the crystalline product (yield 94%) was obtained, chemical purity according to HPLC 99.9%, the melting point determined by DSC is 167C (Fig. 7). 1H NMR (DMSO-D6): 1.05 (d, 3H), 1.12 (t, 3H), 1.36 (t, 1H), 1.74 (t, 1H), 2.06 (m, 2H), 2.16 (m, 2H), 2.63-2.72 (m, 3H), 3.89 (m, 1H), 3.99 (q, 2H), 7.27 (d, 2H), 7.36 (t, 1H), 7.45 (t, 2H), 7.57 (d, 2H), 7.65 (d, 2H), 8.65 (d, 1H). The crystalline form was characterized by means of XRPD (Fig. 2, Table 2.).
116 g	With sodium hydroxide; In methanol; water; at 5 - 10℃; for 2h;	Sacubitnl (130.0 g) was added to methanol (520 mL) and the reaction mixture was cooled to 5C to 10C. A solution of sodium hydroxide (12.26 g in 30 mL of water) was added to the reaction mixture at 5C to 10C and the reaction mixture was stirred for 2 hours. Methanol and water (530 mL) were recovered from the reaction mixture under reduced 200 mm to 10 mm of Hg pressure at 40C to 45C. Acetone (390 mL) was added to the reaction mixture at 40C to 45C and the mixture was stirred for 15 minutes.Acetone (390 mL) was recovered from the reaction mixture under reduced 300 mm to 10 mm of Hg pressure at 40C to 45C. Cyclohexane (390 mL) was added to the reaction mixture and stirred for 30 minutes at 20C to 25C. The reaction mixture was filtered and washed with cyclohexane (130 mL) to obtain the solid material (135 g) and dried under vacuum at 650 mm to 680 mm of Hg at 40C to 45C for 20 hours to obtain the titlecompound.Yield: 116.Og
	With sodium hydroxide; In water; ethyl acetate; at 20℃; for 2h;pH 6 - 9;	Weigh 82.2g (0.2mol) AHU377 free acid placed in 3000ml round bottom flask, add 800ml of ethyl acetate, stirring to dissolve, and then dropping 30% aqueous sodium hydroxide solution ρΗ = 6.0-9.0 at room temperature The reaction was stirred for 2 hours, then concentrated to precipitate a solid, and then added 800ml of ethyl acetate and stirred for 2 hours, then filtered, the filter cake was dried in vacuo at 50 C for 16h to give AHU377 sodium salt, the X-ray powder diffraction pattern shown in Figure 1.
49 g	With sodium 2-ethylhexanoic acid; In tert-butyl methyl ether; at 55℃; for 14.25h;	(e) Sacubitril (50 g) was added to methyl t-butyl ether (500 mL) at 20C to 25C and the mixture was stirred for 15 minutes. Sodium-2-ethyl hexonoate (21.6 g) was added to the mixture. The reaction mixture was heated to 50C to 55C for 14 hours. The reaction mixture was cooled to 35C to 40C. The reaction mixture was filtered under nitrogen atmosphere. The reaction mixture was washed with methyl t-butyl ether (400 mL) undernitrogen atmosphere. The product obtained was dried under 650 mm Hg to 680 mm Hg of pressure for 16 hours at 40C to 45C to obtain the title compound.Yield: 49 g.
	With sodium hydroxide; In ethanol; n-heptane; for 0.5h;	Dissolve 112 mg of Sacubitril in 2 mL of ethanol.Add 0.1 mL of ethanol solution containing 0.19 mg of sodium hydroxide per 0.1 mL.Stir for 0.5 hours,Concentrated under reduced pressure,The residue obtained was suspended and stirred in ethanol/n-heptane (1/19, by volume) 300 mL overnight.filter,Dry at 40 C under vacuum,A solid was obtained.The solid was added to 10 mL of isopropanol.After stirring for 72 hours,Centrifuge the supernatant,The obtained solid was dried in an oven at 40 C.Obtained a white solid,That is, type A Sacubitril sodium salt.
1.55 g	With sodium 2-ethylhexanoic acid; In ethyl acetate; at 20℃; for 1h;	Sacubitril (425 g) was added to the reaction flask.Ethyl acetate (3833.5 g) was added and stirred until fully dissolved.Sodium 2-ethylhexanoate (343.4 g) was dissolved in ethyl acetate (3097 g).After completely dissolving, pour into the reaction.The reaction was carried out for 1 hour at room temperature. Pure water (4250 g) was added, and after stirring for 0.5 hour, the layers were separated, and the aqueous layer was collected.The aqueous layer was washed with ethyl acetate (3,840 g), stirred for 0.5 hr and then layered, and the aqueous layer was collected. Isopropanol (3340.5 g) was added, concentrated under reduced pressure, and this procedure was repeated three times.A total of 647 grams of white foamed solid was obtained.HPLC analysis of crude <strong>[149709-62-6]sacubitril</strong> sodium salt with a purity of 99.82%,The impurity diacid was 0.02%, and the impurity in the decylamine was 0.04%. <strong>[149709-62-6]sacubitril</strong> sodium salt recrystallizationThe crude <strong>[149709-62-6]sacubitril</strong> sodium salt(647 g) was added to the reaction flask. Isopropanol (1002 g) was added and stirred until fully dissolved.Add n-heptane (8670 g) and mix well. <strong>[149709-62-6]sacubitril</strong> sodium salt seed crystals (43.0 g) were added. The reaction was carried out at room temperature (20-30 C) for 24 hours.The filter cake was washed with n-heptane (867 g).Dry at 55 C under vacuum (48 hours).A total of 269.93 g of a white solid was obtained after subtracting the weight of the seed crystal.The purity of the product was 99.85% by HPLC analysis. Impure diacid 0.03%, indoleamine 0.00%.The total yield was 60.3%. The crystal form of the obtained product was measured by X powder diffraction method, as shown in FIG. Add <strong>[149709-62-6]sacubitril</strong> crystal salt (1.5 g) to the reaction flask (HPLC analysis product purity is 99.85%,Impure diacid 0.04%, impure indole amine 0.00%).Add isopropanol (15 ml) and pure water (0.1 ml) and stir until fully dissolved.The liquid was concentrated to a foamed solid using a reduced pressure concentrator. Dry using an oil-free pump for 19 hours.A total of 1.55 g of a white solid was obtained. The purity of the product was 99.89% by HPLC and 0.04% of the impurity diacid.The indoleamine is 0.00%. The crystal form of the obtained product was determined by X powder diffraction method, as shown in FIG. 2It is an amorphous <strong>[149709-62-6]sacubitril</strong> sodium salt.
22 g	With sodium hydroxide; In water; acetonitrile; at 20 - 30℃; for 1h;	Sacubitril free acid (24 gms) and acetonitrile (48 ml) were added in to a round bottom at 20- 30C and stirred for 20 min at 20-30C. Sodium hydroxide solution (2.3 gms dissolved in 7.2 ml water) was added to the resulting reaction solution at 20-30C and stirred for 1 hr, distilled out the solvent under vacuum at 40C and degassed for 2 hrs under vacuum at 40C to obtain a solid. Methanol (100 ml) was added to the resulting solid at 25-35C and stirred for 20 min. The solvent was distilled out completely under vacuum at 35-45C, degassed for 1 hr under vacuum at 35-45C and dried the solid under vacuum at 35-45C for 16 hrs to obtain <strong>[149709-62-6]sacubitril</strong> sodium salt. Yield: 22gms.
	With sodium hydroxide; In acetone; at 0 - 10℃; for 1h;	A crude product of ethyl (2R,4S)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoate (52.4 g, 0.125 mol) and acetone (629 ml) were added to a 1 L three-necked flask equipped with a mechanical stirrer, stirred and dissolved at room temperature; cooled to 0-10 C. for 5-10 min and added dropwise with sodium hydroxide solution (25 ml, 5 mol/L), after the addition was completed, kept stirring for 1 h, concentrated to dryness, added with methanol (125 ml) or ethanol (125 ml), concentrated to dryness to give sodium 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutyrate (<strong>[149709-62-6]AHU-377</strong> sodium salt). The product also does not exhibit a good solid form, and is highly hygroscopic despite less hygroscopic than potassium salt.

Reference： [1]Patent: CN107602410,2018,A .Location in patent: Paragraph 0054; 0055; 0062; 0063; 0064-0071
[2]Patent: CN108530371,2018,A .Location in patent: Paragraph 0056; 0057
[3]Patent: KR2018/124428,2018,A .Location in patent: Paragraph 0274-0281
[4]Patent: KR2018/124400,2018,A .Location in patent: Paragraph 0238-0245
[5]Patent: WO2016/74651,2016,A1
[6]Patent: CN105503638,2016,A .Location in patent: Paragraph 0050; 0051
[7]Patent: WO2017/3483,2017,A1 .Location in patent: Page/Page column 24; 30
[8]Patent: CN105837464,2016,A .Location in patent: Paragraph 0214-0215
[9]Patent: CN106065006,2016,A .Location in patent: Paragraph 0056; 0057
[10]Patent: WO2017/97275,2017,A1 .Location in patent: Page/Page column 33; 34; 35; 39; 40
[11]Patent: WO2017/97275,2017,A1
[12]Patent: WO2017/141193,2017,A1 .Location in patent: Page/Page column 53; 54
[13]Patent: CN107188820,2017,A .Location in patent: Paragraph 0040; 0041
[14]Patent: WO2017/191620,2017,A1 .Location in patent: Page/Page column 7; 8
[15]Patent: TW2018/11734,2018,A .Location in patent: Paragraph 0054-0059; 0062-0063; 0066-0067; 0070-0071
[16]Patent: TW2018/11732,2018,A .Location in patent: Paragraph 0031-0035; 0036-0037
[17]Patent: WO2018/69833,2018,A1 .Location in patent: Page/Page column 27-28
[18]Patent: US2020/55812,2020,A1 .Location in patent: Paragraph 0202-0203

6
[ 149709-62-6 ]
N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenyl-methyl)-4-amino-(2R)-methylbutanoic acid ethyl ester calcium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%		The free acid of <strong>[149709-62-6]sacubitril</strong> (0.85 g) was stirred up in 20 ml of water and 20 ml of ethyl acetate. After acidification of the mixture with hydrochloric acid to pH 1 the organic phase containing the acid was separated and the mixture was evaporated on a vacuum evaporator. The evaporation product was dissolved in 20 ml of acetone and 2.43 ml of a suspension of calcium hydroxide was added that had been prepared by suspending (0.74 g) in water (10 ml). The mixture was homogenized in an ultrasonic bath and then it was left to evaporate in a vacuum drier at the room temperature. The amount of 11.3 g of the crystalline salt (96%, 99% HPLC) was obtained. The crystalline calcium salt was characterized by means of XRPD (Fig. 5, Table 4.).
32 g		At a controlled temperature of 10 - 20 C, 58 g of acetone, 65 g of isopropyl acetate and 36 g of the above-mentioned Sacubitril Crude added to the 1 L dry reaction kettle, and the aqueous solution of sodium bicarbonate (8.8 g of sodium bicarbonate dissolved in 50g water) was added dropwise and addition completed in 0.5 ~ 1 h , and at a control temperature 10 ~ 20 C continue to stirring the reaction for 0.5 ~ 1. 0h. then at a control temperature of 10 ~ 20 C, dropwise addition of calcium chloride aqueous solution (9.7g dissolved in 40g water) ,and Control the dropping time to 0. 5 ~ 1h; after addition , stirring the reaction for 1 ~ 2h, then filtration, and with the suitable amount of water wash the filter cake.The 240 g of isopropyl acetate, 110 g of n-heptane and the above-mentioned filter cake were added successively to a 1 L dry reaction kettle, heated to 70 to 80 C, then incubated stirring for 0.5 to 1 h , cool down temperature to 10 to 20 C, and incubated stirring for 3 to 4 h. Filtration was carried out, leaching filter cake with the suitable amount of n-heptane, filter cake was dried at 35 ~ 45 C, vacuum degree ≤ -0.08MPa for 8 ~ 10h;to obtain 32g of Sacubitril Calcium, purity 99.5%.
	With calcium chloride; sodium hydroxide; In water; at 40℃;	(1) Add AHU1 (15.2g) in order to the three-vial with a thermometer.Ethyl acetate (45mL) and succinic anhydride (4.82g), magnetic stirring to obtain a white suspension, the water bath to maintain the internal temperature of 20-30 C;(2) Triethylamine (5.30g) was added dropwise in a constant pressure dropping funnel over 5 minutes, and the reaction was incubated for 2 hours at 20-30C. Samples were analyzed by HPLC and AHU1 was basically converted.(3) Add water (100 mL) to the reaction system, stir for 30 minutes, and stand still;(4) Separate the organic layer with a separatory funnel, retain the organic layer, and adjust the pH of the aqueous layer to less than 5 with hydrochloric acid, extract once with ethyl acetate (50 mL), and combine the organic phases.Water (50mL) and sodium hydroxide (2.1g) were added, stirred for 10 minutes, allowed to stand for separation, and the aqueous layer was separated by a separatory funnel, and a 13% calcium chloride aqueous solution (20 g) was added under magnetic stirring to the aqueous layer;(5) Precipitation of solids, stirring, suction filtration under reduced pressure, washing of the filter cake with water several times, and obtaining a white solid obtained by vacuum drying AHU2 calcium salt at 40C;

105.5 g	With calcium chloride; In water; at 95℃;	(R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoic acid (1) (150 g, 394.2 mmol), LCZ-A (117 mg, 0.12 mmol) and LCZ-B (201 mg, 0.192 mmol) were added to ethanol (750 mL). The mixture was stirred under 3.0 MPa pressure of hydrogen gas at 65 C until starting material 1 was consumed completely (<2% by HPLC). The resulting mixture containing compound 2 (485.14 g) was used in next step without any further purification. After an addition of ethanol (1L), SOCl2 (46.4 g, 391.2 mmol) was added slowly to the solution. The temperature was raised to 38 C, and the mixture was stirred for 24h. Then the reaction mixture was concentrated under vacuum at 50-60 C to obtain a crude solid of (2R, 4S)-ethyl 5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride (3) (94.37 g). To a solution of compound 3 in isopropyl acetate (500 mL), succinic anhydride (35.32 g, 352.95 mmol) and DIPEA (40.67 g, 314.6 mmol) were added at 25 C and stirred for 4 h. After complete consumption of starting material (based on HPLC), reaction was quenched with citric acid (5% aq., 500 mL). The organic layer was washed with water (500 mL). Brine (1% aq., 1250 mL) was added to the organic split followed by a slow addition of NaOH (5% aq., 283 mL) until the pH of the aqueous phase was 7-8. The aqueous layer was separated and washed with isopropyl acetate (400 mL). The aqueous split was then evaporated in vacuum at 50 C until no significant isopropyl acetate fraction outflows, the temperature was raised to 95 C and CaCl2 solution (5% aq, 300 mmol) was added dropwise. The precipitated solid was filtered and washed with water (400 mL). The wet solid was dried under vacuum at 75 C for 24 h to provide 105.5 g (93.5% yield) of the title compound 4c having 99.21% purity by HPLC. HRMS (m/z) calcd for: 412.2124 (M4a + H)+; found 412.2123; 1H NMR (400 MHz, d6-DMSO) δ 7.96 (1H, d, J = 8.2 Hz), 7.62 (2H, d, J = 7.4 Hz), 7.55 (2H, d, J = 8.1 Hz), 7.43 (2H, t, J = 7.6 Hz), 7.33 (1H, t, J = 7.3 Hz), 7.24 (2H, d, J = 8.1 Hz), 4.02-3.86 (3H, m), 2.74 (1H, dd, J = 13.4, 6.3 Hz), 2.64 (1H, dd, J = 13.4, 6.8 Hz), 2.50-2.44 (1H, m), 2.26 (4H, dd, J = 22.4, 7.3 Hz), 1.81-1.68 (1H, m), 1.47-1.36 (1H, m), 1.10 (3H, t, J = 7.1 Hz), 1.04 (3H, s, J = 7.0 Hz). 13C NMR (151 MHz, d6-DMSO) δ 179.77, 175.89, 173.65, 172.82, 140.46, 138.55, 138.23, 130.27, 129.34, 127.62, 126.90, 126.77, 60.13, 48.65, 40.98, 40.48, 37.88, 36.49, 33.96, 33.05, 18.37, 14.45.
53.6 g		Add 15.01g of succinic anhydride to the SAC01 reaction solution at room temperature; cool to 0-10 and stir, add 20.3g of DIPEA dropwise, and take a sample 6h after the addition is complete.Send HPLC to detect the raw material SAC01<0.5%. After the reaction is completed, 250ml of 5% citric acid aqueous solution is added to the reaction solution, the liquids are separated, and the organic phase is taken.The organic phase is washed once with 250 ml of water.Add 625ml of 1% salt water and 142ml of 5% sodium hydroxide solution to the organic phase, adjust the pH to 7.5, separate the liquids, and wash the aqueous phase once with 200ml of isopropyl acetate.After the organic solvent in the water phase was removed by distillation under reduced pressure at 50C, the temperature of the water phase solution was raised to 85-95C, and 150ml of 5% calcium chloride solution was added dropwise.After dripping, it was cooled to room temperature, stirred and filtered with suction, and the filter cake was washed with 250 ml of water to obtain 53.6 g of compound SAC04.The yield was 95.5%, the HPLC purity was 99.21%, and the total content of diastereomers in the isomer HPLC was 1.80%

Reference： [1]Patent: WO2017/97275,2017,A1 .Location in patent: Page/Page column 35; 36
[2]Patent: WO2016/74651,2016,A1
[3]Patent: WO2016/74651,2016,A1
[4]Patent: WO2016/74651,2016,A1
[5]Patent: WO2017/3483,2017,A1
[6]Patent: WO2017/97275,2017,A1
[7]Patent: CN106674206,2017,A .Location in patent: Paragraph 0031; 0057; 0061; 0062
[8]Patent: CN107082746,2017,A .Location in patent: Paragraph 0051; 0064-0069; 0080
[9]Tetrahedron,2020,vol. 76
[10]Patent: CN112574132,2021,A .Location in patent: Paragraph 0082; 0083; 0086; 0087; 0090; 0091; 0094

7
[ 108-30-5 ]
[ 752174-62-2 ]
[ 149709-62-6 ]

Yield	Reaction Conditions	Operation in experiment
77.9%	With pyridine; In dichloromethane; at 40 - 45℃; for 10h;	To a reaction flask was added ethyl (2R,4S)-2-methyl-4-amino-5-(1,1'-biphenyl-4-yl)-pentanoate (VII) (1.55 g, 5 mmol), pyridine (1.2 g, 15 mmol) and dichloromethane 25 mL, stirred and dissolved. Succinic anhydride (1.0 g, 10 mmol) was added, heated to 40-45C, and the reaction was stirred for 6 hours. Succinic anhydride (0.5 g, 5 mmol) was added, and the reaction was continued for 4 hours. TLC detection was carried out. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was washed, and recrystallized with ethyl acetate and n-hexane to give white solid Sacubitril (I) 1.6 g, yield 77.9%.
		In a 500ml of reaction flask added 62.2g of compound C,500ml of isopropyl acetate,22g of succinic anhydride and stirred at evenly atroom temperature for 30min, then cooled to 0 ~ -10 C, drop wise added 26g of triethylamine, after completion of additionwarming to 0 ~ 10 C it was stirred 3-4 hours until the TLC detection of raw materials disappeared, then 20% aqueoussolution of citric acid was added dropwise to the above reaction mixture toadjust the pH to 4 to 5, layers were allowed to stand and the aqueous layer wasextracted twice with isopropyl acetate(2X150ml), in organic layer added with 1M sodium hydroxide to adjust the pH to 7-8 and the aqueous layer was separated,The organic layer was again washed once with 200 ml of deionized water, theaqueous layers were combined, at room temperature into the aqueous layer 100 gof an aqueous solution containing 16 g of calcium chloride was added dropwise, largeamount of solid was precipitated and centrifugalized. The filter cake waswashed twice with 200 ml deionized water and dried to obtain 71.3 g of calcium salt ina yield of 83.2%.
	With pyridine; In dichloromethane;	Example 1: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester from (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid To a suspension of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid (30g) in dichloromethane (450ml), pyridine (210ml) was added and reaction mixture was stirred for 10-15 minutes. Succinic anhydride (14.46g) was added to a reaction mixture under stirring and reaction mixture was stirred for about 8-10 hours. Solvent was distilled out from the reaction mixture and ethyl acetate (150ml) was added in to it. Reaction mixture was stirred for few minutes. Organic layer was separated and washed with dilute hydrochloric acid solution (IN, 100ml X 4times) followed by washing with brine solution (100 ml X 2 times). Organic layer was separated and dried over sodium sulfate. After removal of solvent by distillation oily product 35g (88.28%) having 90% HPLC purity was obtained.

13.9 g	With triethylamine; In dichloromethane; at 40℃; for 1h;Inert atmosphere; Industrial scale;	15.1 g of compound 6 was added to the reaction flask, 150 ml of absolute ethanol was added, and hydrogen chloride gas was introduced into the reaction system under cooling with ice water. After 10 min was added, the reaction was continued for 2 hours.TLC analysis of raw materials reaction is complete, the reaction solution concentrated to no liquid dripping.Add 150mL of dichloromethane to the residue, and then add 4.4g succinic anhydride to the above solution, add 11.1g triethylamine to the reaction solution, the temperature to 40oC to continue stirring for 1 hour, TLC analysis of raw materials reaction is complete,The reaction solution was concentrated to no liquid drop to give a pale yellow viscous liquid AHU-377 13.9 g, ee value of 99.77% (chiral HPLC analysis), and the chiral HPLC profile was shown in Fig. 2
20 g	With N-ethyl-N,N-diisopropylamine; In toluene; at 5 - 10℃; for 1h;	Succinic anhydride (5.0 g) and diisopropyl ethyl amine (4.0 mL) were added to toluene (32 mL) at 5C to 10C. A solution of the compound of Formula II in toluene (64.0 mL; example 7) was added to the reaction mixture at 5C to 10C. The reactionmixture was stirred at 5C to 10C for 1 hour. Water (30 mL) was added to the reactionmixture and the pH of the solution was adjusted to 2.0 by adding N hydrochloric acid (15mL) at 5C to 10C. The reaction mixture was stirred at 5C to 10C for 10 minutes. The layers obtained were separated and the toluene (90 mL) was recovered from the organic layer under 400 mm to 9 mm of Hg pressure for 40 minutes to obtain the title compound.Yield: 20.0 g

Reference： [1]Patent: CN104557600,2016,B .Location in patent: Paragraph 0038; 0039
[2]Patent: CN105924355,2016,A .Location in patent: Paragraph 0025
[3]Patent: WO2017/33212,2017,A1 .Location in patent: Page/Page column 32
[4]Patent: CN106467471,2017,A .Location in patent: Paragraph 0097; 0116; 0117; 0118
[5]Patent: WO2017/141193,2017,A1 .Location in patent: Page/Page column 53

8
[ 31603-77-7 ]
[ 149709-62-6 ]

Reference： [1]Patent: CN105924355,2016,A

9
[ 108-30-5 ]
ethyl (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-azido-2-methylpentanoate [ No CAS ]
[ 149709-62-6 ]

Yield	Reaction Conditions	Operation in experiment
82%		8 g of compound 6 (24 mmol) was dissolved in 120 mL of tetrahydrofuran,25 g of triphenylphosphine (4 eq) was added at room temperature,The mixture was stirred at this temperature for 14 hours,Then, 16 mL of triethylamine (5 eq) and 7.1 g of succinic anhydride (3 eq) were added at room temperature,The mixture was stirred at this temperature for 40 hours,Add water to quench,Dichloromethane dilution,The aqueous phase was extracted with dichloromethane,The organic phase was combined and washed once with saturated brine,Dried over anhydrous sodium sulfate and filtered,The solvent was distilled off under reduced pressure,Column chromatography gave Compound 1 (8 g, yield 82%).

Reference： [1]Patent: CN106380421,2017,A .Location in patent: Paragraph 0112; 0113; 0114; 0115; 0116; 0117-0131

10
[ 149709-62-6 ]
[ 23323-37-7 ]
(2R,4S)-5-biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methylpentanoic acid ethyl ester n-octyl-D-glucamine salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	In acetone; at 10℃;Reflux;	Example 12: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester n-Octyl-D-Glucamine salt. To a solution of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester (25g) in acetone (250ml) was added n-Octyl-D-Glucamine (17.83g) under stirring at 10-15C. Reaction mixture was stirred for 5-10 minutes at 25-30C and then heated to reflux. At reflux temperature added water (5ml) in the reaction mixture. The reaction mixture was cooled to 10-20C and stirred at this temperature for 2-3 hours. Solid product was filtered and washed with acetone (50ml). After drying 35g (82%) product was obtained. The HPLC purity of the product is 99%.

Reference： [1]Patent: WO2017/33212,2017,A1 .Location in patent: Page/Page column 35

11
[ 42882-31-5 ]
[ 149709-62-6 ]
(2R,4S)-5-biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methylpentanoic acid ethyl ester 1-(naphthalen-1-yl)ethan-1-amine salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.6%	In acetone; at 10℃;Reflux;	Example 18: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester naphthyl ethyl amine salt. To a solution of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester (20g) in acetone (200ml) was added naphthyl ethyl amine (8.3g) under stirring at 10-15C. Reaction mixture was stirred for 5-10 minutes at 25-30C and then heated to reflux. The reaction mixture was cooled to 10- 20C and stirred at this temperature for 2-3 hours. Solid product was filtered and washed with acetone (40ml). After drying 20g (70.6%) product was obtained. The HPLC purity of the product is more than 99%.

Reference： [1]Patent: WO2017/33212,2017,A1 .Location in patent: Page/Page column 37-38

12
[ 1012341-50-2 ]
[ 149709-62-6 ]

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

13
[ 247257-48-3 ]
[ 149709-62-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
50 g	With potassium hydroxide In Isopropyl acetate; water; acetone at -5 - 20℃; Autoclave;	1 The 28 g of isopropyl acetate, 440 g of acetone, 27.4 g of Sacubitril and 34.1 g of fimasartan was added sequentially in to a 1 L dry reaction kettle and stirred to dissolve. At a controlled temperature of -5 - 5° C aqueous solution of potassium hydroxide (7.47 g of potassium hydroxide dissolved in 15 g of water) was added dropwise and addition was completed within 0.5-1h. then stirred the reaction at 10 to 20 ° C for 3-4h. Filtration was carried out, leaching filter cake with the suitable amount of acetone, filter cake was dried at 35 ~ 45 ° C, vacuum degree ≤ -0.08MPa for 8 ~ 10h;to obtain 50g of Sacubitril Fimasartan Potassium , chemical purity 99.8%, Optical purity: 99.9%, water content 5.5%, potassium content: 74.8%.

Reference： [1]Current Patent Assignee: Gu Guoming;Xiong Jinwu - CN106674206, 2017, A Location in patent: Paragraph 0031; 0066; 0068

14
[ 149709-62-6 ]
[ 137862-53-4 ]
[3-((1S,3R)-1-biphen-4-ylmethyl-3-ethoxycarbonyl-1-butyloxycarbamoyl)propionic acid-(S)-3'-methyl-2-(pentanoyl{2''-(tetrazol-5-yl)biphen-4'-ylmethyl}amino)butanoic acid]sodium trihydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.4%		The Sacubitril calcium salt (2.80 kg, 3 . 25 µM, 1 . 0eq), for 28L isopropyl acetate (10.0 v/w), and 2N HCl aqueous solution (6.5L, 13 . 00 µM, 4 . 0eq), stirring at the room temperature 30min, separating the organic phase, the organic phase with saturated salt water for washing, salt after washing the concentrated under reduced pressure, acetone for two, to adding valsartan (2.84 kg, 6 . 50 µM, 2 . 0eq), acetone (84L, 30.0 v/w) stirring clarify, adding sodium hydroxide 46% aqueous solution (780.00g, 19 . 50 µM, 6 . 0eq; soluble in 1.7L), room temperature stirring for about 10min after, solids are separated out, continuing to stir 2 hours after the filtering.

Reference： [1]Patent: CN106905253,2017,A .Location in patent: Paragraph 0054-0057

15
[ 1038924-97-8 ]
[ 149709-62-6 ]

Yield	Reaction Conditions	Operation in experiment
97.4%	With ethanol; sodium carbonate; at 60℃;	A round bottom flask (200 mL) was charged with compound formula II (15 g), ethanol (60 mL), and sodium carbonate (8.0 g), heated to 60 C., and stirred for 5-6 hours.After the reaction is completed, add dilute hydrochloric acid solution to adjust the pH to 6-7, reduce to room temperature and concentrate the reaction system, add ethyl acetate and water, extract and separate the liquids, evaporate the organic phase to obtain 20g of Shakubi Qu, purity 99.8%, yield 97.4 %, dr>99.99%.
85%	In tetrahydrofuran; water; for 1.5h;	Dissolve 68.59g of the compound of formula 9 in a mixed solvent (THF:H2O=3:1, volume ratio), add 5g of lithium hydroxide, and react at room temperature for 1.5 hours.The reaction was quenched by adding water, the reaction solution was extracted with ethyl acetate, the aqueous phase was acidified with 5% dilute HCl and then extracted with ethyl acetate, and the organic phases were combined.The organic phase was dried with anhydrous sodium sulfate, filtered, and column chromatography was used to obtain sacubat with a yield of 85%.
70%	With lithium hydroxide; In tetrahydrofuran; water; at 20℃; for 1.5h;	The compound of formula 6 (1.0 eq) was dissolved in a mixed solvent (THF: H 2 O = 3:1, by volume).Adding lithium hydroxide(1.2eq),Reaction at room temperature for 1.5 hours,Add water to quench the reaction,The reaction solution was extracted with ethyl acetate.The aqueous phase was acidified with 5% dilute HCl and then extracted with ethyl acetate.The organic phases were combined and the organic phase was dried over anhydrous sodium sulfate.Filtration, concentration, column chromatography,That is, Sacubitril, the yield is 70%.

44.6 g

With ethanol; potassium carbonate; at 50 - 60℃;

Dissolve the crude compound V in 450 ml of absolute ethanol, Add 38.6 g (0.28 mol, 2.0 eq) of potassium carbonate, The system is heated to 50-60 C, Insulation reaction for 5 to 7 hours, The substrate is basically completely reactive. Add dilute acetic acid solution to adjust the pH to 6-7. Concentrate the reaction system to room temperature, Add ethyl acetate and water, The extract was separated and the organic phase was evaporated to dryness to obtain 44.6 g of Sacubitril. The purity was 99.3%, and the yield was 90.2%.

Reference： [1]Patent: CN113387829,2021,A .Location in patent: Paragraph 0167-0171
[2]Patent: CN111943862,2020,A .Location in patent: Paragraph 0040-0041; 0043
[3]Patent: CN108727213,2018,A .Location in patent: Paragraph 0137-0139
[4]Patent: CN109206419,2019,A .Location in patent: Paragraph 0097-0099

16
[ 621-65-8 ]
[ 149709-62-6 ]
(2R,4S)-2-methyl-4-(4-(2,3-bis(nitrooxy)propoxy)-4-oxobutyryl)-5-[(1,1' -biphenyl)-4-yl]pentanoic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.2%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 0 - 20℃; for 5h;Inert atmosphere;	An oven-dried 500 mL three-necked flask was placed, equipped with a mechanical stirrer, a nitrogen gas shield, and a thermometer device, to which was added <strong>[149709-62-6]sacubitril</strong> acid (a compound of the formula A) (20.5 g, 0.05 mol), chloroform (120 ml), 1,2-dinitroglycerin (compound represented by formula F) (14.5 g, 0.08 mol) and triethylamine (8.1 g, 0.08 mol). The reaction system was cooled to 0 to 5 C, and 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (EDAC hydrochloride) (15.3 g, 0.08 mol) was added. The ice water bath was removed and naturally warmed to room temperature and the reaction was stirred for 5 hours. The reaction was completed by HPLC, and 80 ml of tap water was added to the reaction system. After layering, the organic layer was taken and the organic layer was washed once with saturated brine.The organic layer was dried (MgSO4). The title compound (22.5 g, 78.2%) of the structure of formula H was obtained. The organic layer was dried (MgSO4). The title compound (22.5 g, 78.2%) of the structure of formula H was obtained.

Reference： [1]Patent: CN108892624,2018,A .Location in patent: Paragraph 0048-0052

17
[ 623-87-0 ]
[ 149709-62-6 ]
(2R, 4S)-2-methyl-4-(4-(1,3-bis(nitrooxy)propoxy)-4-oxobutyryl)-5-[(1,1'-biphenyl)-4-yl]pentanoic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68.1%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 0 - 20℃; for 5h;Inert atmosphere;	An oven-dried 500 mL three-necked flask was placed, equipped with a mechanical stirrer, a nitrogen gas shield, and a thermometer device, to which was added <strong>[149709-62-6]sacubitril</strong> acid (a compound of the formula A) (20.5 g, 0.05 mol), chloroform (120 ml). Glycerol 1,3-dinitrate (compound represented by formula G) (14.5 g, 0.08 mol) and triethylamine (8.1 g, 0.08 mol). The reaction system was cooled to 0 to 5 C and EDAC hydrochloride (15.3 g, 0.08 mol) was added. The ice water bath was removed, and the mixture was naturally warmed to room temperature and the reaction was stirred for 5 hours. The reaction was completed by HPLC, and 100 ml of tap water was added to the reaction system. After layering, the organic layer was taken and the organic layer was washed once with saturated brine. The organic layer was dried (MgSO4). The title compound (19.6 g, 68.1%) of the structure of formula J was obtained.

Reference： [1]Patent: CN108892624,2018,A .Location in patent: Paragraph 0055-0060

18
[ 146563-40-8 ]
[ 149709-62-6 ]
(2R,4S)-2-methyl-4-{4-[4-(nitrooxy)butoxy]-4-oxobutanamido}-5-[1,1'-biphenyl]-4-yl}pentanoic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72.5%	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 48 - 50℃;Inert atmosphere;	An oven-dried 250 mL three-necked flask was placed, equipped with a mechanical stirrer, a nitrogen gas shield, and a thermometer device, to which was added <strong>[149709-62-6]sacubitril</strong> acid (a compound of the formula A) (12.3 g, 0.03 mol), anhydrous DMF (60 mL), The mixture was stirred at room temperature, and K2CO3 (8.3 g, 0.06 mol) and potassium iodide (1.0 g) were added thereto, and 4-bromobutyl nitrate (the compound represented by Formula K) (8.0 g, 0.04 mol), prepared in the step (a) was added dropwise at room temperature, stir at room temperature for 3 to 3.5 hours, and heat to 48 to 50 C for 2.5 to 3 hours. After the end of the reaction, the reaction system was poured into cold water (500 g), and 200 mL of ethyl acetate was added to the mixture. The organic layer was separated and the organic layer was washed with tap water (80 ml×3) and saturated. Wash once with 80 ml of saline. The organic layer was dried (MgSO4) The title compound (11.5 g, 72.5%) of the structure of formula L was obtained.

Reference： [1]Patent: CN108892624,2018,A .Location in patent: Paragraph 0064; 0065; 0070-0073

19
[ 149709-62-6 ]
ammonium 4(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With ammonium hydroxide; In acetone; at 0 - 10℃; for 4h;	The crude product of ethyl (2R,4S)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoate (60.0 g, 0.145 mol) obtained by the method of step 1.2 of example 1 and acetone (720 ml) were added to a 1 L three-necked flask equipped with a mechanical stirrer, dissolved by stirring at room temperature; cooled to 0-10 C. for 5-10 min, added dropwise with concentrated ammonia water (24.4 g, 0.358 mol), after the addition, kept stirring for 4 h and filtered. The filter cake was washed with acetone (72 ml), vacuum dried at 10-30 C., -0.09 to -0.1 MPa for 4-6 h to give 46.86 g solid of ammonium 4-((2S, 4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoate, the compound of formula (A), with a yield of 70%-75% and a purity higher than 99.5%. The process repeatability of the procedure is higher than that of step 1.3 and the energy consumption can be reduced under room temperature heating.
	With ammonium hydroxide; In acetone; at 0 - 10℃; for 4h;	Sacubitril was added to acetone, stirred at room temperature, cooled to 0-10 C, added dropwise with a slight excess of concentrated ammonia water, stirred for another 4 hours after completion of addition, and then filtered, washed with acetone, vacuum-dried to give the target compound with purity of more than 99.5%, MS: m/z = 412.3 (M+H)+.

Reference： [1]Patent: US2020/55812,2020,A1 .Location in patent: Paragraph 172-175
[2]Patent: EP3524250,2019,A1 .Location in patent: Paragraph 0066; 0067

20
[ 6066-82-6 ]
[ 149709-62-6 ]
ethyl (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutanamido)-2-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.4%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 20h;	Step 2: Ethyl (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutanamido)-2-methylpentanoate (1-c) To a mixture of 1-b (71 g, 172.5 mmol) and hydroxysuccinamide (39.71, 345 mmol) in DMF (461.5 mL), was added EDC HCl (66.14 g, 345 mmol) at ambient temperature. The resulting clear solution was stirred for 20 h at RT. Once HPLC indicated 5.51% starting material and 81.1% product formation, the reaction was quenched with water (1065 mL) at 5-10 C., and then stirred at ambient temperature for an additional 1 h. The resulting solid was filtered and washed with water (2*210 mL). The crude material was dissolved in EtOAc (560 mL), n-heptane (1120 mL) was then added, and the resulting mixture was stirred at ambient temperature for 1 h. The resulting white solid was collected by filtration and washed with n-heptane, to afford Sac-OSu 1-c (75.8 g, 86.4%) as a white solid. HPLC purity: 95.97% and 1H NMR (δ, ppm, DMSO-d6): 7.9 (1H, d), 7.6-7.7 (4H, m), 7.5 (2H, t), 7.35 (1H, t), 7.25 (2H, d), 3.9-4.0 (3H, m), 2.8-2.9 (8H, m), 2.4-2.5 (3H, m), 1.8 (1H, m), 1.4 (1H, m), 1.1 (3H, t), 1.0 (3H, d). LCMS: 96.73% ([M+1]=508.9).

Reference： [1]Patent: US2019/240177,2019,A1 .Location in patent: Paragraph 0434; 0436

21
calcium 3-[(2S,4R)-1-[1,1'-biphenyl]-4-yl}-5-ethoxy-4-methyl-5-oxopentan-2-yl]carbamoyl}propanoate [ No CAS ]
[ 149709-62-6 ]

Yield	Reaction Conditions	Operation in experiment
98.8%	With hydrogenchloride; In Isopropyl acetate; water; at 10 - 15℃; for 0.666667h;	Step 1: 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid (Sacubitril) (1-b) To a suspension of sacubitril calcium salt (1-a, 90 g, 232.2 mmol) in iPrOAc (900 mL) cooled to 10-15 C. was added aq. 2N HCl solution (218.5 mL); (observed slightly exothermicity) and the resulting reaction mixture was stirred for an additional 40 min. Once HPLC indicated 93.99% product formation and complete consumption of starting material the organic layer was separated and washed with water (2180 mL). The organic layer was then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 50 C. The remaining solution was stripped off with THF (180 mL3), which afforded sacubitril (1-b, 92 g, 98.8%). HPLC purity: 99.65% and 1H NMR (δ, ppm, DMSO-d6): 12.0 (1H, bs), 7.8 (1H, d), 7.7 (2H, d), 7.6 (2H, d), 7.4-7.5 (2H, t), 7.3-7.4 (1H, t), 7.2-7.3 (2H, d), 4.0 (2H, q), 2.6-2.8 (2H, m), 2.2-2.4 (4H, m), 1.7-1.8 (1H, m), 1.3-1.4 (1H, m), 1.0-1.2 (8H, m).

Reference： [1]Patent: US2019/240177,2019,A1 .Location in patent: Paragraph 0434; 0435

22
[ 149709-62-6 ]
[ 74-88-4 ]
ethyl (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(4-methoxy-4-oxobutanamido)-2-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;	Methyl iodide (80 mg, 0,56 mmol) was added slowly to a solution of <strong>[149709-62-6]sacubitril</strong> (1 , 1 10 mg, 0,26 mmol) and potassium carbonate (185 mg, 1 ,3 mmol) in 6 mL of DMF. The reaction was stirred at room temperature for 3 hours then quenched with 20 mL of distilled water and extracted with ethyl acetate (3 times, 25 mL). The organic phase was washed with 2 N HCI (20 mL), MQ water (20 mL), brine (20 mL), dried over MgS04, and concentrated under reduced pressure. The mixture was purified by chromatography on silica gel eluting with hexane:ethyl acetate (6:4) to give 98 mg (0.23 mmol) of the desired compound 2 ( 88% yield). An analytical HPLC was run and the chromatogram is shown in Figure 1. 1H NMR (300 MHz, CDCI3) d 7.58 (d, J = 7.0 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1 H), 7.24 (d, J = 8.2 Hz, 2H), 5.63 (d, J = 8.6 Hz, 1 H), 4.31 - 4.17 (m, J = 10.5, 6.3 Hz, 1 H), 4.13 (q, J = 7.1 Hz, 2H), 3.66 (s, 3H), 2.92 - 2.77 (m, 2H), 2.66 - 2.48 (m, 3H), 2.41 (t, J = 6.7 Hz, 2H), 2.00 - 1.88 (m, J = 13.9, 9.3, 4.3 Hz, 1 H), 1.59 - 1.46 (m, J = 14.2, 9.8, 4.4 Hz, 1 H), 1.24 (t, J = 7.1 Hz, 3H), 1.16 (d, J = 7.1 Hz, 3H). (0138) 13C NMR (75 MHz, CDCI3) d 176.35, 173.47, 170.87, 140.85, 139.38, 136.75, 129.90, 128.76, 127.18, 127.09, 126.99, 77.46, 77.04, 76.61 , 60.55, 51.82, 48.55, 40.46, 37.43, 36.48, 31.20, 29.37, 17.65, 14.20. (0139) HRMS (ESI): Exact mass calculated for C25H32N05[M]+ 426.2275; found: 426.2271.

Reference： [1]Patent: WO2020/210914,2020,A1 .Location in patent: Page/Page column 16-17

23
[ 124750-92-1 ]
[ 149709-62-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
3.5 g	With calcium hydroxide In lithium hydroxide monohydrate; propan-2-one at 20℃; for 18h; Inert atmosphere;	2-3 Preparation of complex: (prepared according to Example 2 of patent WO2017125031A1) At room temperature, add AHU377 free acid 2.36g, EXP3174 2g and 40mL acetone obtained according to the method of Example 1 into a 250mL there-necked flask, and dissolve it; at room temperature, add calcium hydroxide solid and 1mL water relative to AHU377 1.3 equivalents, stir at room temperature 10h, add 40mL of acetone, react for 8h, filter through a Buchner funnel under nitrogen protection, rinse the solid with acetone to obtain a white solid, vacuum dry at 35°C for 8h, and dry to obtain 3.5g of solid (EXP3174·AHU377) 3 -·1.5Ca 2+·2.5H 2O, 99% pure by HPLC.
3.5 g	With calcium hydroxide In lithium hydroxide monohydrate; propan-2-one at 20℃; for 18h; Inert atmosphere;	2-3 Preparation of the complex: (prepared in accordance with Example 2 of Patent WO2017125031A1) At room temperature, the AHU377 free acid 2.36g, EXP3174 2g and 40mL acetone obtained according to Example 1 method was added to a 250mL three-mouth bottle, dissolved; at room temperature, added relative to AHU377 1.3 equivalent calcium hydroxide solids and 1mL of water, stirred at room temperature for 10h, supplemented with 40mL acetone, and then reacted for 8h, nitrogen protection by Brinell funnel extraction, the solid was washed with acetone, to obtain a white solid, vacuum baked at 35 ° C for 8h, dried to obtain a solid 3.5g ( EXP3174· AHU377)3-·1.5Ca2+·2.5H2O, HPLC test purity of 99%. Repeat the test to obtain an adequate dose of pharmacodynamic experiments.

Reference： [1]Current Patent Assignee: SHENZHEN SALUBRIS PHARMACEUTICALS CO., LTD. - WO2021/254409, 2021, A1 Location in patent: Page/Page column 5-6
[2]Current Patent Assignee: SHENZHEN SALUBRIS PHARM CO LTD; SHENZHEN SALUBRIS PHARMACEUTICALS CO., LTD. - WO2022/37512, 2022, A1 Location in patent: Page/Page column 4-6

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	149709-62-6	MDL No. :	MFCD00920862
Formula :	C₂₄H₂₉NO₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PYNXFZCZUAOOQC-UTKZUKDTSA-N
M.W :	411.49	Pubchem ID :	9811834
Synonyms :	AHU-377

Num. heavy atoms :	30
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.38
Num. rotatable bonds :	13
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	115.78
TPSA :	92.7 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.15 cm/s

Log Po/w (iLOGP) :	2.88
Log Po/w (XLOGP3) :	3.74
Log Po/w (WLOGP) :	3.84
Log Po/w (MLOGP) :	3.15
Log Po/w (SILICOS-IT) :	4.73
Consensus Log Po/w :	3.67

[ CAS No. 149709-62-6 ] {[proInfo.proName]}

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[ 149709-62-6 ] Synthesis Path-Upstream 1~1

[ 149709-62-6 ] Synthesis Path-Downstream 1~23

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[ 149709-62-6 ]

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Inquiry

Lipinski :	0.0
Ghose :	None
Veber :	1.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Log S (ESOL) :	-4.19
Solubility :	0.0268 mg/ml ; 0.0000652 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.38
Solubility :	0.00172 mg/ml ; 0.00000418 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-6.79
Solubility :	0.0000675 mg/ml ; 0.000000164 mol/l
Class :	Poorly soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	3.61

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:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
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P103	Read label before use
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Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
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P353	Rinse skin with water/shower.
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P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
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P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed