Name: 137862-53-4|(S)-2-(N-((2'-(1H-Tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoic acid|95%
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SKU: A133780
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1
[ 137863-17-3 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium hydroxide In diethyl ether; lithium hydroxide monohydrate at 20℃;
95%	With lithium hydroxide monohydrate; sodium hydroxide In methanol at 25℃; for 12h;
93%	Stage #1: valsartan methyl ester With sodium hydroxide In lithium hydroxide monohydrate at 20℃; for 20h; Stage #2: With hydrogenchloride; lithium hydroxide monohydrate	4.III Step III: {2S)-3-Methyl-2-[pentanoyl-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl] aminojbutanoic acid (valsartan) (Ic); Compound (Ib) (0.0771 g, 0.0001717 mol), NaOH (0.04 g, 0.0010302 mol) and water (1 mL) were stirred at room temperature for 20 hrs (TLC monitoring: CH2Cl2/Me0H 95:5). HCl 2N was added until pH 2 was reached. The aqueous solution was extracted with AcOEt. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give the compound (Ic) (0.070 g). Yield: 93%1H-NMR (400 MHz, CD3OD, δ) of the two rotamers A and B: 0.80 (d, J=6.8Hz, 3HB, CH5CH), 0.83-0.87 (m, 6HA, CH5CH2 + CH3CH), 0.95 (t, J=7.2Hz, 3HB, CH5CH2), 1.00-1.02 (m, 3HA+3HB, CH5CH), 1.23-1.31 (m, 2HA), 1.35-1.44 (m, IHA), 1.46-1.59 (m,1HA+2HB), 1.62-1.69 (m, 2HB), 2.16-2.38 (m, 3HA+1HB), 2.47-2.55 (m, 1HB, CHHCO),2.61-2.68 (m, 1HB, CHHCO), 4.14 (d, J=10.4ηz, 1HB, NCH)5 4.59 (d, J=IOHz, 1HA,NCH), 4.61 (s, 2HB, NCH2), 4.67 (d, J=17.4Hz, IHA, NCHH), 4.77 (d, J=17.4Hz, 1HA, NCHH), 7.03 (d, J=8ηz, 2HB) 7.11 (d, J=8Hz, 2HA) 7.19 (d, J=8Hz, 2HB) 7.25 (d, J=8Hz,2HA) 7.52-7.58 (m, 2HA+2HB) 7.64-7.69 (m, 2HA+2HB) (aromatic protons) ppm.

92.8%	With lithium hydroxide monohydrate; sodium hydroxide In dichloromethane at 20℃; for 4h;	4-6; 1-3 Step 3. 250 mL of methanol, 20 g of intermediate product b and 2 mL of concentrated hydrochloric acid with a mass fraction of 37% were added to the three-necked flask, and the reaction was stirred at room temperature for 3 h. After the reaction was completed, suction filtration was performed, and sodium hydroxide was added to the filtrate to adjust the pH to 7, and then concentrated to A constant weight was obtained to obtain intermediate product c, 10.1 g of intermediate product c, 200 mL of dichloromethane and 100 mL of sodium hydroxide solution with a concentration of 0.5 mol/L were added to the reaction kettle, and the reaction was stirred at room temperature for 4 hours. layer, the aqueous phase was extracted twice with dichloromethane, the water layer was cooled to below 5°C in an ice-water bath, the pH was adjusted to 3.0 with hydrochloric acid, a solid was precipitated, stirred and crystallized and then cooled to 0°C, suction filtered, the filter cake was washed with water and then added with ethyl acetate , heated to dissolve, decolorized with activated carbon, the filtrate was cooled to 0 °C, filtered with suction after crystallization, washed 3 times, and vacuum-dried to constant weight at 50 °C to obtain crude valsartan; Step 4. Carry out chiral separation of the crude valsartan, dissolve the crude valsartan in methanol to obtain a 0.1 mg/mL valsartan methanol solution, add a chiral stationary phase, the solid-liquid ratio is 1:10, 25°C Shake in a water bath for 2h, take the supernatant and concentrate to constant weight to obtain the target product valsartan.
88%	Stage #1: valsartan methyl ester With sodium hydroxide; lithium hydroxide monohydrate at 20℃; Stage #2: With hydrogenchloride	32 A mixture of methyl N-pentanoyl-N-[2'-(1 H-tetrazol-5-yl)-1 ,1'-biphenyl-4- yl]methyl}-L-valinate (50 mg) in 10% NaOH (1 ml_) was stirred at room temperature overnight. The mixture was acidified with concentrated HCI and extraction was carried with ethyl acetate (4x10 ml_). The organic layer was washed with saturated NaCI solution, followed by drying and evaporating to dryness (42 mg, 88%).
65%	Stage #1: valsartan methyl ester With barium hydroxide; lithium hydroxide monohydrate at 20 - 30℃; for 10h; Stage #2: With hydrogenchloride In lithium hydroxide monohydrate
92 mg	With sodium hydroxide In methanol for 8h; Heating;
	With sodium hydroxide; lithium hydroxide monohydrate at 20℃; for 12h;	2 Preparation of (S)-N- (1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N- [2' (1H-tetrazol-5- yl) biphenyl-4-yl-methyl] amine barium salt (Valsartan Barium) Sodium hydroxide (1N, 92ml) was added to the mass of (S)-N- (1- methoxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'(1H-tetrazol-5-yl) biphenyl-4-yl- methyl] amine as obtained above and was stirred for 12 hours at room temperature till the disappearance of the starting material. The reaction mixture was washed twice with dichloromethane (60 ml each). The aqueous layer was separated, acidified by concentrated hydrochloric acid to pH 2-2.1 and extracted with ethyl acetate (30ml). The organic layer was washed with water (6 ml) and concentrated to obtain crude valsartan (chiral purity: 96.07%, HPLC: purity 98.78%). It was then dissolved in ethanol (36ml) and water (36 ml) was added to it. Barium hydroxide octahydrate (5.28 g) was then added to the above mixture and stirred for 1 hour. The reaction mixture was filtered, concentrated to about 40ml at 50-55°C under reduced pressure, cooled and treated with acetone (36 ml). The reaction mixture was stirred for lhour, filtered and washed with acetone (12 ml). The solid obtained was dried to obtain valsas-tan barium. Yield: 4.0 g; HPLC Purity: 99.7% ; Chiral purity: 99.75% ; XRD, IR spectra and DSC graph were similar to those shown in Fig. I, II and III respectively.
	Stage #1: valsartan methyl ester With sodium hydroxide; lithium hydroxide monohydrate at 20 - 30℃; for 5h; Stage #2: With hydrogenchloride In lithium hydroxide monohydrate	I.D Step D: Preparation of [N-(l-oxopentyI)-N-[[2'-(lH-tetrazol-5-yl)[l,l'- biphenyl]-4-yl]methyl]-L-vaIine] (Valsartan); N-(l-Oxopentyl)-N-[[2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl]-L-valine methyl ester (19 g) was added to DM water (76 ml) at 20-30°C and reacted with 22% w/v aqueous sodium hydroxide solution (38 ml) for 5h at 20-30°C. Aftercompletion of reaction, pH of the reaction mass was adjusted to 6.5 +/- 0.2 withdilute HCl and washed with ethyl acetate (40 ml). The aqueous phase was treated with activated carbon (1 g) at 20-30°C and the clear filtrate obtained after removalof carbon was acidified with dilute hydrochloric acid to pH 2.0+/-0.2 to precipitatethe product.The reaction mixture was cooled to 0-5°C, filtered the product, washed with water and dried under reduced pressure to yield 15.3 g of crude N-(l-oxopentyl)-N-[[2'- (lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl] methyl] -L- valine (Valsartan) as a white solid. The crude Valsartan was recrystallized from ethyl acetate to obtain pure Valsartan.
	Stage #1: valsartan methyl ester With barium dihydroxide; lithium hydroxide monohydrate at 20 - 30℃; for 10h; Stage #2: With hydrogenchloride In lithium hydroxide monohydrate Stage #3: With hydrogenchloride; anhydrous sodium carbonate more than 3 stages;	II Example II:; Preparation of [N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yI)[l,l'-biphenyl]-4- yl]methyl]-L-valine] (Valsartan); N-(l-Oxopentyl)-N-[[2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl]-L-valine methyl ester (45 g) produced as per step (C) of Example I was reacted with 15% w/v aqueous barium hydroxide solution (528 ml) for 10 h at 20-30°C. After completion of reaction, the precipitated solid was filtered, treated with 10 % w/v dilute HCl to pH 0.5 to 1.5 in DM water and isolated crude Valsartan.The crude Valsartan was dissolved in 2.5% w/v aqueous sodium carbonate solution (460 ml) at 20°C-30°C and pH was adjusted to 5-7 with 10% w/v hydrochloric acid and then washed with methylene chloride (90 ml). The aqueous layer was acidified with 10% w/v hydrochloric acid and the product was extracted with ethyl acetate (495 ml). The organic layer was separated and ethyl acetate was distilled completely under reduced pressure at 20-60°C. The resulting solid mass was dissolved in ethyl acetate (225 ml) at 40-500C, cooled to -15 to -2O0C, filtered and dried to yield Valsartan (22 g, 99.7% purity by HPLC).
	Stage #1: valsartan methyl ester With potassium hydroxide; lithium hydroxide monohydrate In toluene at 40℃; for 3h; Stage #2: With hydrogenchloride; lithium hydroxide monohydrate In ethyl acetate	1 The addition of 14% (2.5N) potassium hydroxide (400 mL) to the isolated middle phase is carried out, whereupon stirring is performed for 3.0 h at 40+/-3° C.2 phases form. A lower phase, which is aqueous for the most part, is ((S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine) with a small volume of a toluene upper phase. The upper phase is separated and discarded.5 g activated carbon and 5 g celite are added to the lower phase and stirring is carried out for 1 h at 40-50° C., after which filtration is performed. Then, 720 mL ethyl acetate are added and acidification to pH 2.0+/-0.5 is carried out with 6N HCL. The aqueous lower phase is separated, the organic upper phase is washed with 200 mL water, and the aqueous phases are discarded.Subsequently, heating to 50° C. is carried out and 480 mL methylcyclohexane are added dropwise.Water is completely separated out with a water separator. A complete water separation is indispensable (the prerequisite for the crystallization in the following step). The presence of even small quantities of water leads to a two-phase system, where the product can separate as a second liquid phase and cannot be filtered. Cooling is carried out slowly to 5+/-5° C., followed by stirring for 1 h, filtering, and washing with ethyl acetate-methylcyclohexane 3/2, whereupon drying is performed at 40° C. in a vacuum.
	Stage #1: valsartan methyl ester With potassium hydroxide; lithium hydroxide monohydrate at 40℃; for 3h; Stage #2: With hydrogenchloride; lithium hydroxide monohydrate In ethyl acetate	2 After completion of the reaction, the reaction solution is stirred with water or a saline solution (250 mL), whereupon the solids dissolve and a three-phase liquid system forms. The lower phase is separated; the two upper phases are washed with water or a saline solution (200 mL). The middle phase is isolated and stirred vigorously with aqueous potassium hydroxide (2.5N, 400 mL) for 3 h at 40° C. A two-phase system forms with an aqueous, product-containing lower phase and an organic upper phase. The aqueous phase is isolated, stirred with 5 g activated carbon and 5 g celite for 1 h at 40° C., and then filtered. Ethyl acetate (720 mL) is added to the filtrate and acidification is carried out with hydrochloric acid (5-6N) to pH 2.0, with vigorous stirring and ice cooling. The organic phase is washed with 300 mL water and after separation of the washing phase, an aliphatic hydrocarbon or a mixture of aliphatic hydrocarbons (480 mL) is added dropwise, preferably methylcyclohexane or isooctane. The residual water present in the system is separated out by means of a water separator. Cooling is done slowly to 5° C., at which point crystallization begins. The solids are filtered off, washed with a mixture of ethyl acetate and hydrocarbon and dried at 40° C. in a vacuum.
	Stage #1: valsartan methyl ester With methanol; tetra(n-butyl)ammonium hydroxide; lithium hydroxide monohydrate at 40℃; for 3h; Stage #2: With hydrogenchloride; lithium hydroxide monohydrate In ethyl acetate	4 After completion of the reaction, the reaction solution is stirred with water or a saline solution (250 mL), whereupon the solids are dissolved and a three-phase liquid system forms. The lower phase is separated; the two upper phases are washed with water or a saline solution (200 mL). The middle phase is isolated and stirred with tetrabutylammonium hydroxide 40% in methanol (260 mL, 400 mmol) for 3 h at 40° C. Water (400 mL) is added, and 400 mL liquid are first distilled off under normal pressure and, toward the end, under reduced pressure. With the addition of 5 g activated carbon and 5 g celite, stirring is carried out for 1 h at 40° C. followed by filtration. Ethyl acetate (720 mL) is added to the filtrate, followed by acidification with hydrochloric acid (5-6N) to pH 2.0, while stirring vigorously and with ice cooling. The organic phase is washed twice with 300 mL water and after separation of the washing phase at approx. 50° C., an aliphatic hydrocarbon or a mixture of predominantly aliphatic hydrocarbons (480 mL) is added dropwise, preferably, methylcyclohexane or petroleum spirit 80/110. The residual water present in the system is separated out by means of a water separator. Cooling is carried out slowly to 5° C., at which point crystallization begins. The solids are filtered off, washed with a mixture of ethyl acetate and hydrocarbon and dried at 40° C. in a vacuum. Yield over two stages, each according to the synthesis protocol of II: approx. 70% of the theoretical.
	Stage #1: valsartan methyl ester With barium(II) hydroxide In lithium hydroxide monohydrate at 20 - 30℃; for 10h; Stage #2: With hydrogenchloride In lithium hydroxide monohydrate	II Example IIPreparation of [N-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine] (Valsartan)N-(1-Oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl]-L-valine methyl ester (45 g) produced as per step (C) of Example I was reacted with 15% w/v aqueous barium hydroxide solution (528 ml) for 10 h at 20-30° C. After completion of reaction, the precipitated solid was filtered, treated with 10% w/v dilute HCl to pH 0.5 to 1.5 in DM water and isolated crude Valsartan.The crude Valsartan was dissolved in 2.5% w/v aqueous sodium carbonate solution (460 ml) at 20° C.-30° C. and pH was adjusted to 5-7 with 10% w/v hydrochloric acid and then washed with methylene chloride (90 ml). The aqueous layer was acidified with 10% w/v hydrochloric acid and the product was extracted with ethyl acetate (495 ml). The organic layer was separated and ethyl acetate was distilled completely under reduced pressure at 20-60° C. The resulting solid mass was dissolved in ethyl acetate (225 ml) at 40-50° C., cooled to -15 to -20° C., filtered and dried to yield Valsartan (22 g, 99.7% purity by HPLC).
	Stage #1: valsartan methyl ester With sodium hydroxide In lithium hydroxide monohydrate at 40℃; for 4h; Stage #2: In lithium hydroxide monohydrate Cooling; Acidic conditions;	2 The reaction mixture was cooled and 65 mL of ethyl acetate were added. The organic phase was washed with water (20 mL, 3 x) and evaporated. To the residue 40 mL of 3M NaOH were added and the mixture was heated at 40 °C for 4 hours. Then the mixture was cooled and the pH value of the mixture was adjusted to a value between 1.5 to 2.0. After that 50 mL of ethyl acetate were added and the phases were stirred for 5 min. Then the phases were separated and the aqueous phase was re-extracted with 50 mL of ethyl acetate. The collected organic phases were washed with ethyl acetate (20 mL 3 x) and evaporated. To the concentrate 100 mL of ethyl acetate were added and the mixture was evaporated again. To the residue 40 mL of ethyl acetate were added and the mixture was stirred at room temperature for 24 h. During this time crude valsartan precipitated. The obtained suspension was cooled to a temperature below 0 °C and stirred at this temperature for 1 h and then the product was separated by filtration and dried.Yield: 5.8g (89 %) of crude valsartan.The crude product was re-crystallized from ethyl acetate.Overall yield: 5.1 g (88 %).Content of individual impurities: below 0.10 %.
	Stage #1: valsartan methyl ester With lithium hydroxide monohydrate; sodium hydroxide In o-dimethylbenzene at 10 - 60℃; Stage #2: With hydrogenchloride In lithium hydroxide monohydrate at 15 - 20℃;	3 Taken organic layer from example 2 containing N-Valeryl-N-[(2'-cyanobiphenyl- 4-yl) methyl]-(L)-valine methyl ester, add tri-n-butyl tin chloride (170g: 0.523m) and sod'ium azide (34g:0.523m). Heated to 135-138°C stirred for 24hrs, cooled to 10-15°C, added a solution of aqueous sodium hydroxide solution (54g in 900ml DM water), heated to 55-60°C for 2-2.5hrs. After completion of the reaction, mass was cooled to 25-30°C and separated out aqueous and organic layers. Wash the aqueous layer (pH 13) twice with 100 ml o-xylene. Cooled the aqueous layer to 15-20°C and adjusted pH to 2.5-3.0 by dilute hydrochloric acid and extract the compound with dichloromethane. Organic layer washed with water and brine solution. Organic layer was concentrated and to get 98g crude Valsartan (Tin content - 806 ppm; HPLC purity - 98%; R-isomer=6.1 %) and valsartan crystallized in ethyl acetate (750 ml) followed by washing of wet cake with chilled dichloromethane (200 ml) and dried in FBD at 40-65°C.Pure valsartan (Tin content: 80 ppm; HPLC purity: 99.9%; S-isomer: 99.2; R-isomer: 0.8%; Yield: 48g, 40%)
	With lithium hydroxide monohydrate; sodium hydroxide In methanol at 0 - 65℃; for 4h;	3.4 Example 3-4 Example 3-4 (0362) (0363) MVAL (2 g, 1 equivalent) was dissolved in methanol (5 mL, 2.5 vol). The solution was cooled to 0° C.-5° C., aqueous sodium hydroxide solution (0.53 g sodium hydroxide/2.5 mL deionized water) was added, and the mixture was stirred at 0° C.-5° C. for 5 min. The mixture was stirred at 60° C.-65° C. for 4 hr. The degree of progression of the reaction was checked by TLC (TLC eluent: 5% methanol/methylene chloride, detection method: UV), and complete consumption of MVAL was confirmed. The reaction mixture was concentrated under reduced pressure at 40° C.-45° C. To the concentrated residue were added deionized water (10 mL, 5 vol) and methylene chloride (10 mL, 5 vol), and the mixture was stirred for 5 min and partitioned. Concentrated hydrochloric acid was added at 0-5° C., and the aqueous layer was adjusted from pH 10-12 to 1-2. The obtained mixture was extracted with methylene chloride (2×10 mL, 2×5 vol). To the organic layer was added sodium sulfate, and the mixture was dried. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude VAL (2.1 g, yield 108%). The crude product was recrystallized from ethyl acetate to give the object compound (HPLC purity: 99.72 area %).
	Stage #1: valsartan methyl ester With NaNO₂ at 15℃; for 0.5h; Stage #2: With hydrogenchloride In ethyl acetate at 15 - 55℃; for 3h;	1 219.8 Kg (540.6 mol) was added to the reaction kettleN-[(2'-cyanobiphenyl-4-yl)methyl]-N-(1-oxopentyl)-L-proline methyl ester(II)Concentrate (HPLC:N-[(2'-cyanobiphenyl-4-yl)methyl]-N-(1-oxopentyl)-L-proline methyl ester content ≥97.0%),Add 200.0Kg diethylene glycol dimethyl ether,Control the temperature inside the reactor below 45.0 ° C,Add 132.0Kg (2030.8mol) in batchesSodium azide and 105.0Kg anhydrous zinc chloride,The temperature is raised to 125.0~128.0 °C and the heat preservation reaction is about 35.0 hours.HPLC detectionN-[(2'-Cyanobiphenyl-4-yl)methyl]-N-(1-oxopentyl)-L-valine methyl ester (II) residue ≤ 4.0%,Stop the reaction,Cool down to below 60.0 °C,Then add 8.7% (w/w) of the new configurationNaOH solution of 1800Kg,Stir well,Control the temperature of the reactor at a temperature of 35.0~40.0 °C for about 5~6h.HPLC detection of valsartan methyl ester (III) residue ≤ 2.0%, stop the reaction,Cool down to below 15.0 °C,Add 112.0Kg (1623.2mol) of sodium nitrite,Stir for 30.0min,And control the temperature in the kettle below 15.0 ° C,234.0 kg of purified concentrated hydrochloric acid was slowly added dropwise to the reaction vessel, followed by the addition of ethyl acetate 30.0 kg.Slowly add 290.0Kg of concentrated concentrated hydrochloric acid.Then slowly add the diluted purified hydrochloric acid.Adjust PH=3.5~4.5.The reaction mixture was centrifuged in a centrifuge,Washed,Collect the filter cake,Put it in the reaction kettle,Add 1700.0Kg ethyl acetate and 1140.0Kg drinking water,The purified hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 1.0.After stirring, let stand and layer.Let go of the water layer,Wash the organic layer with diluted purified hydrochloric acid.The ethyl acetate is then distilled under reduced pressure at less than 45.0 ° C.Add 860.0~1050.0Kg ethyl acetate,Control the temperature inside the kettle below 55.0 ° C,Stir until dissolved,Control the temperature in the kettle to 37.0~38.0 °C,Add seed crystals,Stir for 3.0 hours,Then slowly cool down to 0.0~5.0 °C,Stop stirring,Centrifuge the resulting material,Drying crude valsartan solid 194.4Kg,The yield was 80.1%.
	Multi-step reaction with 2 steps 1.1: sodium hydroxide / toluene / 0.17 h / 5 - 20 °C 1.2: 25 °C 2.1: hydrogenchloride / lithium hydroxide monohydrate; ethyl acetate / 1 h / 5 - 50 °C / pH 1 / Large scale
	Multi-step reaction with 2 steps 1.1: potassium hydroxide / 5,5-dimethyl-1,3-cyclohexadiene / 0.5 h / 5 - 60 °C 1.2: 50 °C 2.1: sulfuric acid / lithium hydroxide monohydrate / 8 h / 5 - 20 °C / pH 3 / Large scale

Reference： [1]Goossen, Lukas J.; Melzer, Bettina [Journal of Organic Chemistry, 2007, vol. 72, # 19, p. 7473 - 7476]
[2]Location in patent: experimental part Ghosh, Samir; Kumar, A. Sanjeev; Mehta [Journal of Chemical Research, 2010, # 4, p. 191 - 193]
[3]Current Patent Assignee: S I M S (unclear); S I M S SOC IT MEDICINAL - WO2008/12852, 2008, A1 Location in patent: Page/Page column 20; 31
[4]Current Patent Assignee: NINGBO MENOVO PHARMACEUTICAL COMPANY LIMITED - CN113717118, 2022, B Location in patent: Page/Page column 0048; 0052-0054; 0058-0060; 0064-0074
[5]Current Patent Assignee: ENANTIA SL; ENANTIA - WO2006/67216, 2006, A2 Location in patent: Page/Page column 29
[6]Location in patent: experimental part Kumar N, Senthil; Reddy, Shankar B.; Sinha, Brajesh Kumar; Mukkanti, Kagga; Dandala, Ramesh [Organic Process Research and Development, 2009, vol. 13, # 6, p. 1185 - 1189]
[7]Zhang, Chen; Zheng, Guojun; Fang, Lijing; Li, Yulin [Synlett, 2006, # 3, p. 475 - 477]
[8]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2005/49587, 2005, A1 Location in patent: Page/Page column 10-11
[9]Current Patent Assignee: AUROBINDO PHARMA LIMITED - WO2008/4110, 2008, A2 Location in patent: Page/Page column 11-12
[10]Current Patent Assignee: AUROBINDO PHARMA LIMITED - WO2008/4110, 2008, A2 Location in patent: Page/Page column 12
[11]Current Patent Assignee: Sanochemia Pharmazeutika AG - US2009/203920, 2009, A1 Location in patent: Page/Page column 3
[12]Current Patent Assignee: Sanochemia Pharmazeutika AG - US2009/203920, 2009, A1 Location in patent: Page/Page column 3-4
[13]Current Patent Assignee: Sanochemia Pharmazeutika AG - US2009/203920, 2009, A1 Location in patent: Page/Page column 4-5
[14]Current Patent Assignee: AUROBINDO PHARMA LIMITED - US2009/281326, 2009, A1 Location in patent: Page/Page column 4-5
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[20]Current Patent Assignee: ZHUHAI RUNDU PHARMACEUTICAL CO LTD - CN111072581, 2020, A

2
[ 137863-90-2 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
66.5%	Stage #1: methyl 2-(N-((2'-cyanobiphenyl-4-yl)methyl)pentanamido)-3-methylbutanoate With sodium azide; zinc chloride bis(dimethylformamide) complex In N,N-dimethyl-formamide at 130 - 140℃; for 24h; Large scale; Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide at 25 - 30℃; Large scale; Stage #3: With water; sodium hydroxide In chloroform Large scale;	Example 3: One-pot preparation of valsartan (7) A suitable reactor was charged with 200 Kg (2.73 kmol) of DMF followed by 168 kg (1.239 kmol) of anhydrous zinc chloride at RT. After 1h vigorous stirring at 75°C, bis(dimethyliminio)methoxy)zinc chloride slowly precipitates out as a white crystalline powder. Then, it was added a 406 kg (1 kmol) of methyl-N-(2’-cyano-[1,1’-biphenyl]-4-yl)methyl)-N-pentanoyl-L-valinate (6) followed by sodium azide (115 kg, 1.784 kmol) over the period of 30 min and increased the reaction temperature to 130°C-140°C and maintained for 28-30 h. After completion of the reaction, it was cooled to 30-35°C and pH adjusted to 1.5 with dilute HCL and extracted with 1000 L of chloroform. Then, saturated NaOH (40 kg) was slowly added to chloroform layer in reactor and stirred for another 8-9 h at 30-35°C. Thus, separated organic layer was discarded and the aqueous layer was added 1000 L of ethyl acetate and pH was adjusted to 1.5 with HCL at 0-5°C. Thus, obtained ethyl acetate layerw as collected and distilled off completely to yield a yellow color semi-crystalline material. The obtained, semi-solid was further added with 400 L of cyclohexane at 30°C and stirred for 45 min which results a pale yellow crystalline valsartan (7). Yield: 300 kg (66.5%). HPLC purity: 99.42%.[M+]: 435.5125; 1H-NMR (400 MHz, DMSO-d6): δ 0.762 (m, 3H), 0.856 (m, 3H), 0.912 (m, 3H), 1.524 (m, 6H), 2.255 (m, 1H), 3.34 (m, 1H), 4.40 (m, 1H), 4.59 (m, 1H), 6.951 (m, 1H), 7.16 (m, 2H), 7.237 (m, 1H), 7.727 (m, 4H), 12.62 (brs, 1H); 13C-NMR (100 MHz, DMSO-d6): δ 174.0, 172.4, 171.8, 141.7, 138.2, 131.54, 131.1, 129.3, 128.8, 128.2, 127.4, 126.7, 70.3, 63.4, 49.9, 32.9, 28.05, 27.3, 20.6, 14.2.
	Multi-step reaction with 2 steps 1.1: sodium azide; tri-n-butyltin chloride; tetrabutylammonium bromide / toluene / 72 h / Heating 1.2: 55 percent / acetic acid / toluene; H₂O 2.1: 99 percent / NaOH / diethyl ether; H₂O / 20 °C
	Stage #1: methyl 2-(N-((2'-cyanobiphenyl-4-yl)methyl)pentanamido)-3-methylbutanoate With sodium azide; tributyltin chloride In xylene at 25℃; Heating / reflux; Stage #2: With sodium hydroxide In water; xylene at 25 - 35℃; for 24 - 30h; Stage #3: With acetic acid In water	Preparation of (S)-N- (l-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N- [2'- (1H- tetrazol-5-yl)-biphenyl-4-yl methyl] amine (Valsartan) N-Valeryl-N- [ (2'-cyanobiphenyl-4-yl) methyl]- (L)-valine methyl ester (51. 5 kg), tributyl tin chloride (61.9 kg), sodium azide (16.5 kg) were added to xylene (258 lit) and stirred for 1-2 hours at a temperature of 25-35°C then heated the mass to reflux and stirred till the reaction substantially completes. Cool the mass to 25-35°C and 10% sodium hydroxide solution (250 lit. ) was added and further stirred for 24-30 hours. The aqueous layer was separated from the resulting biphasic solution and washed with toluene (52 X 2 lit. ). The pH of the aqueous layer was adjusted towards neutral with acetic acid (115 lit. ) and washed with chloroform (52 X 2 lit. ). The pH of the aqueous layer was further lowered with acetic acid (20 lit. ) and extracted the compound into dichloromethane (220 x 1 + 110 x 1). The combined organic layer was successively washed with water, 5% sodium chloride solution and dried over anhydrous sodium sulphate. The solvent from the reaction solution was completely distilled off and triturated the resulting oily mass with hexane to yield the crude Valsartan, which was recrystallised in dichloromethane followed by ethyl acetate to afford sufficient pure Valsartan, which is having an amorphous pattern by its X-ray diffractogram (Yield: 8.8 kgs).

	Stage #1: methyl 2-(N-((2'-cyanobiphenyl-4-yl)methyl)pentanamido)-3-methylbutanoate With sodium azide; tributyltin chloride In o-xylene for 40h; Heating / reflux; Stage #2: With lithium hydroxide; water In o-xylene at 30℃; for 13h;	2 example 2; preparation of N-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine (valsartan) A mixture of o-xylene (510 ml), N-[(2'-cyanobiphenyl-4-yl)-methyl]-N-valeryl-(L)-valine methyl ester (169.8 g), tributyl tin chloride (204.2 g) and sodium azide (54.4 g) was charged into a round bottomed flask and heated to reflux. The reaction mixture was maintained at reflux for about 40 hours and then cooled to 30° C. 70.2 g of lithium hydroxide in water (1190 ml) was added to the reaction mass at 30° C. and stirred for 13 hours. The aqueous layer was separated and washed twice with toluene (2×170 ml). To the separated aqueous layer 170 ml of dichloromethane was added and the pH was adjusted to 6.75 using 20% aqueous acetic acid (205 ml). The aqueous layer was separated and washed with dichloromethane (170 ml). To the separated aqueous layer dichloromethane (680 ml) was added and the pH was further adjusted to 5, using acetic acid (48 ml). The aqueous layer was separated and extracted with dichloromethane (680 ml). The combined organic layer was washed with water (680 ml), followed by washing with a solution of sodium chloride (34 g) in water (680 ml). The organic layer was concentrated at atmospheric pressure and about 90% of the solvent was distilled off at 40-48° C. To the residual mass cyclohexane (340 ml) was added and concentrated under reduced pressure at 50-58° C. to obtain a residue. The residue was cooled to 30° C., then 680 ml of cyclohexane was added to the residue and stirred for about 50 minutes at 28-30° C. The resultant solid was filtered and washed with cyclohexane (170 ml). The obtained solid was dried at about 50° C. to give 118.2 g of the solid product. (Purity by HPLC 96.6 area-%).
	Stage #1: methyl 2-(N-((2'-cyanobiphenyl-4-yl)methyl)pentanamido)-3-methylbutanoate With azido tributyltin (IV) In dichloromethane; o-xylene for 6.25h; Heating / reflux; Stage #2: With lithium hydroxide; water In dichloromethane; o-xylene at 28 - 30℃; for 10h;	3 To the resultant tributyl tin azide solution in methylene chloride, N-[(2'-cyanobiphenyl-4-yl)-methyl]-N-valeryl-(L)-valine methyl ester (28.3 g) and o-xylene (85 ml) were added and heated to reflux. The reaction mass was maintained at reflux for about 6 hours, 15 minutes and then cooled to about 30° C. 11.7 g of lithium hydroxide in water (198 ml) was added and stirred for about 10 hours at 28-30° C. Reaction completion was confirmed by thin layer chromatography and the organic and aqueous layers were separated. The aqueous layer was washed twice with toluene (2×28.3 ml). To the aqueous layer was added dichloromethane (28.3 ml) and the pH was adjusted to 6.7 using a 20% aqueous acetic acid (32 ml) solution. The aqueous layer was separated and washed with dichloromethane (28.3 ml). The aqueous layer was separated and 113.2 ml of dichloromethane was added. The pH of the reaction mass was adjusted to 5 using acetic acid (8.2 ml). The reaction mixture was stirred for 15 minutes and the organic and aqueous layers were separated. The aqueous layer was again extracted with dichloromethane (113.2 ml). The combined organic layers were washed with water (113.2 ml) and then with a solution of sodium chloride (5.7 g) in water (113.2 ml) followed by a further wash with water (113.2 ml). The organic layer was concentrated at atmospheric pressure and about 90% of the solvent was distilled off at 42° C. To the residual mass cyclohexane (56.6 ml) was added and concentrated under reduced pressure at about 55° C. to obtain a residue. The residue was cooled to 30° C.; 113.2 ml of cyclohexane was added to the residue and stirred for about 55 minutes at 28-30° C. The resultant solid was filtered and washed with cyclohexane (28.3 ml). The obtained solid was dried at about 50° C. for about 6 hours to give 22.3 g of the crude valsartan. (Purity by HPLC 98.75 area-%)
	Stage #1: methyl 2-(N-((2'-cyanobiphenyl-4-yl)methyl)pentanamido)-3-methylbutanoate With sodium azide; tributyltin chloride In o-xylene for 20 - 25h; Heating / reflux; Stage #2: With sodium hydroxide; water In o-xylene at 20℃; for 20 - 25h; Stage #3: With acetic acid In dichloromethane for 0.5h;	2 100 g oxalate salt obtained in Example 1 and 119 g. of Potassium carbonate are added to 400 ml o-xylene and 400 ml water and cooled to 0-5° C. 44.5 g valeroyl chloride is added to the reaction mixture over a period of 1 to 1.5 hours and stirred for about 1.5 to 2 hours at 0-5° C. After completion of the reaction, the layers are separated and the organic layer is washed with 400 ml 5% sodium bicarbonate solution. 160 g tributyltin chloride and 59 g sodium azide are added to organic layer and heated to reflux for about 20-25 hours. The reaction mixture is cooled to ambient temperature and a 1000 ml of 10% sodium hydroxide solution is added to the reaction mixture and stirred at ambient temperature of 20-25 hours. After the completion of the reaction, layers are separated and 1000 ml dichloromethane is added to the aqueous layer, 200 ml of acetic acid is added to it till pH 3-4 is obtained and stirred for about 30 minutes. The layers are separated and the organic layer is washed with brine solution. 1000 ml 5% sodium bicarbonate solution is added to the organic layer and stirred for 10-12 hours at room temperature. Layers are separated and 1000 ml dichloromethane is added to aqueous layer. 100 ml acetic acid is added to it till pH 3 to 4 and layers are separated. The organic layer is washed with water and distilled out under vacuum at 40-45° C. 200 ml cyclohexane is added to the residue and stripped out. Finally 700 ml cyclohexane is added to the residue to form slurry which is stirred for about half an hour and filtered. The crude Valsartan is dried under vacuum at 40-45° C. (yield: 40-45 g).
	Stage #1: methyl 2-(N-((2'-cyanobiphenyl-4-yl)methyl)pentanamido)-3-methylbutanoate With azido tributyltin (IV) In dichloromethane; xylene at 25 - 30℃; for 24h; Heating / reflux; Stage #2: With potassium hydroxide; water In dichloromethane; xylene at 20℃; Stage #3: With hydrogenchloride; ethylenediaminetetraacetic acid; water	1 Example 1; Compound of formula II (50 gm) was treated with tributyltin azide prepared from reaction of tributyltin chloride (81 gm) and sodium azide (25 gm) in water (62 ml) and extracted in dichloromethane] in xylene at 25-3O0C under N2 atmosphere under refluxed for 24 hrs. After completion of the reaction, mixture was cooled to room temperature and quenched with aqueous potassium hydroxide (53.8 gm in 800 ml water) with stirring. The isopropyl ether (65 ml) was added to the reaction mixture and stirred followed by the layer separation. Aqueous layer was then treated with charcoal (7 gm) and filtered and washed with dichloromethane (3 x 50 ml). The pH of the aqueous layer was adjusted to 6.8-7.2 using hydrochloric acid and then treated with charcoal (7 gm) and filtered. EDTA (5 gm) was added to the aqueous solution and pH was adjusted again to 4.0-4.5 using hydrochloric acid and stirred. The aqueous layer was extracted with dichloromethane (3 x 66.5 ml) and then organic layer was washed with 10% sodium chloride solution. The organic layer was evaporated to dryness to get residue and then residue was taken in ethyl acetate (25 ml) and raised the temperature to 40-450C followed by treatment with charcoal (5 gm) and filtered. The reaction mixture was cooled to 18-220C and filtered the residue under nitrogen atmosphere. The residue was washed with ethyl acetate and dried.
	Multi-step reaction with 2 steps 1.1: diethylaluminium chloride / xylenes / 1 h / 110 °C / Inert atmosphere 2.1: diethylaluminum azide / xylene / 20 - 110 °C 2.2: 1 h / 0 °C
	Stage #1: methyl 2-(N-((2'-cyanobiphenyl-4-yl)methyl)pentanamido)-3-methylbutanoate With diethylaluminium chloride In xylenes at 110℃; for 1h; Inert atmosphere; Stage #2: With sodium azide In xylenes at 110℃; for 44h; Inert atmosphere;	VI In an argon filled three necked flask, 2.4 g (3.00 mmol) of a solution of (S)-2-[(2'-cyanobiphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid methyl ester in xylenes (3.00 mmol) is diluted with 5 ml of dry xylene (40 mmol). The mixture is heated to 110°C and 1.94 ml of diethylaluminium chloride (15 mmol) are added. The mixture is stirred at 110°C. After 60 minutes, 0.59 g of sodium azide are added as a solid in one portion. The mixture is stirred at 110°C. After 44h, the reaction mixture is allowed to cool to room temperature and transferred into a three necked flask containing 20 eq of 10% (w/w) aqueous sodium hydroxide (24.0 g, 60 mmol) while the temperature is maintained below 30°C. The resulting biphasic mixture is transferred into a separation funnel and the upper xylenic phase is discarded. The aqueous phase is washed with 6.8 ml of xylenes (55 mmol). Sodium nitrite (0.45 g, 6.6 mmol) is dissolved in the basic aqueous solution. The mixture is added carefully to an emulsion of 7.99 g of 37% aqueous hydrochloric acid (81 mmol) and 10 ml ethyl acetate (102 mmol) while the temperature is maintained below 5°C in an ice-bath. The phases are separated and the aqueous phase is extracted with 10 ml ethyl acetate (102 mmol). The combined organic phases are washed with 10 ml H2O (555 mmol). The solvent is removed under vacuum and 20 ml of xylenes (160 mmol) are added and the mixture is again concentrated to dryness. The crude oily product is dissolved in 15 ml EtOAc (153 mmol), concentrated to approx. 5 ml and 2 ml cyclohexanes (21 mmol) are added dropwise until a white precipitate does just redissolve at 60 °C. The mixture is placed in a fridge at 8 °C. After 16 h, an off-white precipitate is collected by filtration. The product is washed with cold ethyl acetate /cyclohexane 1:1 and dried under vacuum to give (S)-3-Methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid (Valsartan). 1 H-NMR (CDC13, 400 MHz, ppm): main rotamer δ= (0.94-1.05 (9 H, m), 1.40-1048 (2 H, m), 1.72-1.79 (2 H, m), 2.61-2.65 (2 H, m), 2.69-2.78 (1 H, m), 3.36 (1 H, d, JH,H = 11.1 Hz), 4.21 (1 H, d, JH,H = 14.8 Hz), 5.00 (1 H, d, JH,H = 14.8 Hz), 7.19-7.25 (4 H, m), 7.47-7.50 (1 H, m), 7.52-7.56 (1 H, m), 7.59-7.63 (1 H, m), 8.07-8.09 (1 H, m).
	Multi-step reaction with 2 steps 1.1: sodium azide; zinc(II) chloride / diethylene glycol dimethyl ether / 26 h / 120 °C 2.1: sodium hydroxide / water / 4 h / 40 °C 2.2: pH 1.5 - 2 / Cooling; Acidic conditions
	Stage #1: methyl 2-(N-((2'-cyanobiphenyl-4-yl)methyl)pentanamido)-3-methylbutanoate With sodium azide; tributyltin chloride In o-xylene at 145℃; for 18h; Large scale reaction; Stage #2: With sodium hydroxide In water at 10 - 15℃; for 18h; Large scale reaction; Stage #3: With hydrogenchloride In water at 25 - 35℃; Large scale reaction;
	Multi-step reaction with 2 steps 1: sodium azide / toluene / 50 h / Reflux 2: sodium hydroxide; water / toluene / 12 h / 20 - 30 °C
	Stage #1: methyl 2-(N-((2'-cyanobiphenyl-4-yl)methyl)pentanamido)-3-methylbutanoate With sodium azide; triethylamine hydrochloride In N,N-dimethyl-formamide at 100℃; for 36h; Inert atmosphere; Stage #2: With hydrogenchloride; sodium hypochlorite In water; N,N-dimethyl-formamide; toluene at 20℃; Inert atmosphere;	7.1 the preparation of valsartan Under the protection of the team,Dissolve 19 g of the product in the second step with 70 ml of DMF,Then, 17 g of triethylamine hydrochloride was added,And 17 g of sodium azide (NaN3)The reaction was carried out at 100 ° C for 36 hours,Add 150 ml of toluene.Cooling to 20 ° C,Add 45ml concentration of lmol / 1 sodium hypochlorite aqueous solution,With a mass percentage of 9% hydrochloric acid to adjust ρΗ = 3, static water separation,The upper layer is a toluene layer, the toluene layer is washed with saturated brine,The organic layer was washed with saturated brine, 3 times, 100 ml each,Then add 20 ml of water and add K0H to give ρH = 11 and incubate at 25 ° C for 10 hours. Reaction end, stratification,The water layer to 10 ° C, adjust ρΗ = 1, filter, washed to get valsartan crude. Second, the purification of valsartanThe obtained crude valsartan was added to 100 ml of ethyl acetate,Heated to fully dissolved; cooled to room temperature 25 ° C, continue to cool to 10 ° C for 2 hours, filter, filter cake with a small amount of cold (5 ° C, 20ml) ethyl acetate washing; drying, And then the mixture was cooled to room temperature by 25 ° C. The filter cake was washed with a small amount of ethyl acetate (20 ml) and dried, and the mixture was cooled to room temperature. Dry, get Valsartan secondary crystallization products, that is, refined salad. The purified impurities in valsartan were tested by HPLC, and valsartan impurity T was not detected.Quality is not detected, chiral isomer is not detected.
	Stage #1: methyl 2-(N-((2'-cyanobiphenyl-4-yl)methyl)pentanamido)-3-methylbutanoate With C₆H₁₆N₂Zn⁽¹⁺⁾N₃^(1-) In toluene at 20 - 110℃; for 48h; Stage #2: With sodium hydroxide In water at 35 - 40℃;	2; 3; 4; 1 Example 3 A post-treatment method for an improved valsartan reaction mixture: 30.0 g (73.8 mmol) of N-[(2'-cyanobiphenyl-4-yl) A was added to a 500 mL clean and dry four-neck reaction flask. Methyl]-N-(1-oxopentyl)-L-valine methyl ester (II), 60.0 g of toluene and 19.4 g (69.3 mmol) of zinc azide tetramethylethylenediamine complex salt [TMEDA· Zn(N3)2] (water content 5.0%,Prepared according to Example 1-1 of WO2012148148A2), stir evenly at room temperature, raise the temperature to 105.0-110.0 °C, keep warm for 48 hours, pass the sampling test, cool down to cool less than 60.0 °C, add 45.0g of 30.0% sodium hydroxide aqueous solution and 170.0g water ,The temperature is controlled at 35.0~40.0 °C for hydrolysis reaction.Insulation 3.0~5.0h, sampling and testing,The toluene layer was separated, the aqueous layer was cooled to a temperature less than 20.0 ° C, and 5.8 g (84.1 mmol) of sodium nitrite was added.Stir well, slowly add 36.0% concentrated hydrochloric acid dropwise to adjust the pH to PH=3.5~4.5. After the addition is complete, filter and collect the filter cake. The filter cake was poured into a reaction flask, 300 ml of ethyl acetate and 120.0 ml of water were added, and purified hydrochloric acid was added dropwise to adjust the reaction liquid to pH=1.0. After stirring, the layers were allowed to stand, the aqueous layer was discarded, and the organic layer was washed with diluted purified hydrochloric acid. Add 120.0 mL of water to the ethyl acetate layer, wash twice, and then steam under reduced pressure at 45.0 ° C.Ethyl acetate was distilled to obtain the residue, and then 150.0 g of ethyl acetate was added to the residue, and the mixture was stirred until it was dissolved. The mixture was further cooled to 0 to 5.0 ° C under stirring, filtered and dried to obtain a crude valsartan solid 26.1 g. The rate is 81.1%.

Reference： [1]Reddy, Kesamreddy Ranga; Reddy, Emani Vijayabhaskar; Shanmukha Kumar [Indian Journal of Heterocyclic Chemistry, 2018, vol. 28, # 2, p. 295 - 300]
[2]Goossen, Lukas J.; Melzer, Bettina [Journal of Organic Chemistry, 2007, vol. 72, # 19, p. 7473 - 7476]
[3]Current Patent Assignee: CORD JANET I; DR REDDY'S LABORATORIES LIMITED - WO2003/89417, 2003, A1 Location in patent: Page/Page column 8
[4]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - US2006/149079, 2006, A1 Location in patent: Page/Page column 4-5
[5]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - US2006/149079, 2006, A1 Location in patent: Page/Page column 5
[6]Current Patent Assignee: ALEMBIC LTD - US2006/258878, 2006, A1 Location in patent: Page/Page column 6-7
[7]Current Patent Assignee: VIATRIS INC - WO2009/1375, 2008, A2 Location in patent: Page/Page column 6
[8]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2011/51213, 2011, A1
[9]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - EP2316821, 2011, A1 Location in patent: Page/Page column 27-28
[10]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/124655, 2011, A1
[11]Location in patent: experimental part Aalla, Sampath; Gilla, Goverdhan; Bojja, Yakambram; Anumula, Raghupathi Reddy; Vummenthala, Prabhakar Reddy; Padi, Pratap Reddy [Organic Process Research and Development, 2012, vol. 16, # 4, p. 682 - 686]
[12]Current Patent Assignee: AUROBINDO PHARMA LIMITED - US2013/144067, 2013, A1
[13]Current Patent Assignee: SECOND PHARMA - CN103554049, 2016, B Location in patent: Paragraph 0016; 0084; 0085; 0088-0091
[14]Current Patent Assignee: XUANCHENG MEINUOHUA PHARMACEUTICAL; NINGBO MENOVO PHARMACEUTICAL COMPANY LIMITED - CN109761924, 2019, A Location in patent: Paragraph 0021-0027

3
[ 3839-22-3 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: 50 percent / basic copper(II) carbonate; potassium carbonate; triphenylphosphine / palladium(II) bromide; 1,10-phenanthroline / quinoline / 24 h / 170 °C 2.1: molecular sieves 3 Angstroem / tetrahydrofuran / 60 h / 20 °C 2.2: 90 percent / sodium cyanoborohydride / tetrahydrofuran; ethanol / 24 h / 23 °C 3.1: 98 percent / pyridine / CH₂Cl₂ / 2 h / 40 °C 4.1: sodium azide; tri-n-butyltin chloride; tetrabutylammonium bromide / toluene / 72 h / Heating 4.2: 55 percent / acetic acid / toluene; H₂O 5.1: 99 percent / NaOH / diethyl ether; H₂O / 20 °C
	Multi-step reaction with 6 steps 1.1: copper(II) oxide; potassium carbonate; potassium fluoride / palladium(II) bromide; 1,10-phenanthroline / quinoline / 24 h / 170 °C 2.1: 167.9 mg / aq. HCl / 2 h / 50 °C 3.1: molecular sieves 3 Angstroem / tetrahydrofuran / 60 h / 20 °C 3.2: 90 percent / sodium cyanoborohydride / tetrahydrofuran; ethanol / 24 h / 23 °C 4.1: 98 percent / pyridine / CH₂Cl₂ / 2 h / 40 °C 5.1: sodium azide; tri-n-butyltin chloride; tetrabutylammonium bromide / toluene / 72 h / Heating 5.2: 55 percent / acetic acid / toluene; H₂O 6.1: 99 percent / NaOH / diethyl ether; H₂O / 20 °C
	Multi-step reaction with 6 steps 1.1: copper(II) oxide; potassium carbonate; potassium fluoride / palladium(II) bromide; 1,10-phenanthroline / quinoline / 24 h / 170 °C 2.1: 165.9 mg / aq. HCl / 2 h / 50 °C 3.1: molecular sieves 3 Angstroem / tetrahydrofuran / 60 h / 20 °C 3.2: 90 percent / sodium cyanoborohydride / tetrahydrofuran; ethanol / 24 h / 23 °C 4.1: 98 percent / pyridine / CH₂Cl₂ / 2 h / 40 °C 5.1: sodium azide; tri-n-butyltin chloride; tetrabutylammonium bromide / toluene / 72 h / Heating 5.2: 55 percent / acetic acid / toluene; H₂O 6.1: 99 percent / NaOH / diethyl ether; H₂O / 20 °C

Reference： [1]Goossen, Lukas J.; Melzer, Bettina [Journal of Organic Chemistry, 2007, vol. 72, # 19, p. 7473 - 7476]
[2]Goossen, Lukas J.; Melzer, Bettina [Journal of Organic Chemistry, 2007, vol. 72, # 19, p. 7473 - 7476]
[3]Goossen, Lukas J.; Melzer, Bettina [Journal of Organic Chemistry, 2007, vol. 72, # 19, p. 7473 - 7476]

4
[ 135689-93-9 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: molecular sieves 3 Angstroem / tetrahydrofuran / 60 h / 20 °C 1.2: 90 percent / sodium cyanoborohydride / tetrahydrofuran; ethanol / 24 h / 23 °C 2.1: 98 percent / pyridine / CH₂Cl₂ / 2 h / 40 °C 3.1: sodium azide; tri-n-butyltin chloride; tetrabutylammonium bromide / toluene / 72 h / Heating 3.2: 55 percent / acetic acid / toluene; H₂O 4.1: 99 percent / NaOH / diethyl ether; H₂O / 20 °C

Reference： [1]Goossen, Lukas J.; Melzer, Bettina [Journal of Organic Chemistry, 2007, vol. 72, # 19, p. 7473 - 7476]

5
[ 137863-20-8 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
72.5%	With sodium hydroxide In water at 65℃; for 2.5h; optical yield given as %ee;
70%	With hydrogen In methanol at 20℃;	9; 10; 11; 12 A solution of 50 g (S)-N-(1-benzyloxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 500 mL methanol was hydrogenated at room temperature with 2.5 g (5% loading) of 5% Pd-C until the completion of reaction. After reaction catalyst was filtered out and crude valsartan was obtained by evaporation of the solvent. It was then partitioned between 500 mL of 10% sodium bicarbonate solution and 200 mL MDC [dichloromethane]. The aqueous phase was separated and rendered acidic. Valsartan was isolated by extraction with ethyl acetate,and crystallization from a mixture of ethyl acetate and hexane. The precipitated valsartan was filtered, washed with hexane and dried to give 34 gms (82% yield) of Valsartan. Purity of valsartan obtained was 99.8% and R-isomer 0.07% as measured by HPLC area percent.; Example 10: (S)-N-(1-Carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine (Valsartan) A solution of 50 g (S)-N-(1-benzyloxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 300 mL methanol was hydrogenated at room temperature with 1,25 g (2.5 % loading) of 5% Pd-C and further proceeded analogously to example 9. Valsartan was crystallized from a mixture of ethyl acetate and di-isopropyl ether, filtered, washed with di-isopropyl ether and dried to give 29 gms of Valsartan (Yield-70%). Purity of valsartan was 99.83% and R-isomer 0.03% as measured by HPLC area percent.; Example 11 : Valsartan A solution of 50 g (S)-N-(1-benzyloxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 500 mL methanol was hydrogenated at room temperature with 1.25 g (2.5% loading) of 5% Pd-C until the completion of reaction. The crude valsartan was obtained by filtration and evaporation of the solvent. The residue was partitioned between 500 mL of 10% sodium bicarbonate solution and 200 mL MDC. The aqueous phase was separated and rendered acidic. Valsartan was isolated by extraction with ethyl acetate. The organic phase was distilled under reduced pressure to dryness. The residue was then suspended in a mixture of ethyl acetate and hexane at ambient temperature, filtered, washed with water, and dried to give 34 gms of Valsartan (yield of 82%). Purity of Valsartan obtained was 99.8% and R-isomer 0.05% by HPLC analysis.; Example 12 : Valsartan A solution of 50 g (S)-N-(1-benzyloxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 500 mL methanol was hydrogenated at room temperature with 2.5 gm (5% loading) of 5% Pd-C until the completion of reaction. The crude valsartan was obtained by filtration and evaporation of the solvent, and was partitioned between 500 mL of 10% sodium bicarbonate solution and 200 mL MDC. The aqueous phase was separated and rendered acidic. Valsartan was isolated by extraction with ethyl acetate. The organic phase was distilled under reduced pressure to dryness, slurried in a mixture of ethyl acetate:hexane:water (ratio 2:5:1), filtered, and dried to obain 34 gm (82% yield) of valsartan. Purity of valsartan obatinaed was 99.8% and R-isomer 0.02% as measured by HPLC analysis.
70%	With hydrogen In methanol at 20℃;	9; 10; 11; 12 (S)-N-(1-Carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine (Valsartan) Example 9 (S)-N-(1-Carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine (Valsartan) A solution of 50 g (S)-N-(1-benzyloxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 500 mL methanol was hydrogenated at room temperature with 2.5 g (5% loading) of 5% Pd-C until the completion of reaction. After reaction catalyst was filtered out and crude valsartan was obtained by evaporation of the solvent. It was then partitioned between 500 mL of 10% sodium bicarbonate solution and 200 mL MDC [dichloromethane]. The aqueous phase was separated and rendered acidic. Valsartan was isolated by extraction with ethyl acetate, and crystallization from a mixture of ethyl acetate and hexane. The precipitated valsartan was filtered, washed with hexane and dried to give 34 gms (82% yield) of Valsartan. Purity of valsartan obtained was 99.8% and R-isomer 0.07% as measured by HPLC area percent. Example 10; (S)-N-(1-Carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine (Valsartan) A solution of 50 g (S)-N-(1-benzyloxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 300 mL methanol was hydrogenated at room temperature with 1.25 g (2.5% loading) of 5% Pd-C and further proceeded analogously to example 9. Valsartan was crystallized from a mixture of ethyl acetate and di-isopropyl ether, filtered, washed with di-isopropyl ether and dried to give 29 gms of Valsartan (Yield-70%). Purity of valsartan was 99.83% and R-isomer 0.03% as measured by HPLC area percent. Example 11; Valsartan A solution of 50 g (S)-N-(1-benzyloxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 500 mL methanol was hydrogenated at room temperature with 1.25 g (2.5% loading) of 5% Pd-C until the completion of reaction. The crude valsartan was obtained by filtration and evaporation of the solvent. The residue was partitioned between 500 mL of 10% sodium bicarbonate solution and 200 mL MDC. The aqueous phase was separated and rendered acidic. Valsartan was isolated by extraction with ethyl acetate. The organic phase was distilled under reduced pressure to dryness. The residue was then suspended in a mixture of ethyl acetate and hexane at ambient temperature, filtered, Clashed with water, and dried to give 34 grns of Valsartan (yield of 82%). Purity of Valsartan obtained was 99.8% and R-isomer 0.05% by HPLC analysis. Example 12; Valsartan A solution of 50 g (S)-N-(1-benzyloxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 500 mL methanol was hydrogenated at room temperature with 2.5 gm (5% loading) of 5% Pd-C until the completion of reaction. The crude valsartan was obtained by filtration and evaporation of the solvent, and was partitioned between 500 mL of 10% sodium bicarbonate solution and 200 mL MDC. The aqueous phase was separated and rendered acidic. Valsartan was isolated by extraction with ethyl acetate. The organic phase was distilled under reduced pressure to dryness, slurried in a mixture of ethyl acetate:hexane:water (ratio 2:5:1), filtered, and dried to obain 34 gm (82% yield) of valsartan. Purity of valsartan obatinaed was 99.8% and R-isomer 0.02% as measured by HPLC analysis.

62%	With potassium hydroxide In methanol for 4h; Heating / reflux;	11 Example 11 N-(1-OXOPENTYL)-N-[[2 -(LH-TETRAZOL-5-YL) [1, 1 -BIPHENYL]-4-YL] METHYL]-L-VALINE (valsartan, VIII) A suspension of 10 g (0.013 mol) of the benzyl ester OF N-(1-OXOPENTYL)-N-[[2 -(1-TRITYL-LH- tetrazol-5-yl) [1, 1 -BIPHENYL]-4-YL] methyl]-L-valine (benzyl ester of trityl valsartan, IX) in 75 ml of anhydrous methanol was refluxed for 10 hr. The solution was then cooled to-10 °C and stirred at this temperature overnight; the precipitated crystals were sucked off and washed with a small amount of ice-cold methanol. Thus formed methanolic solution was, after adding potassium hydroxide (0.6 g), refluxed for 4 hr. Methanol was evaporated in vacuo, the mixture was diluted with 10 ml of water, and, after acidification with hydrochloric acid, valsartan was extracted using ethyl acetate (3 x 40 ml). The organic layer was washed with water (2 x 25 ml), concentrated to 30 ml and the product crystallized after adding cyclohexane (50 ml). 3.5 g (62 %) of valsartan (VIII) were obtained after sucking off and drying in vacuo. Mp = 109-113 °C
60%	With hydrogen In methanol at 25℃; for 16h;
55%	With hydrogen In methanol at 20℃; for 5h;	33 A mixture of benzyl N-pentanoyl-N-[2'-(1 H-tetrazol-5-yl)-1 ,1 '-biphenyl-4- yl]methyl}-L-valinate_(200 mg) in MeOH (2 ml_) containing 10% palladium on activated Charcoal (Pd/C, 40 mg) was hydrogenated at room temperature for 5 h. The resulting crude product was filtered through a Celite pad and the solvent was evaporated. The crude was partitioned between diethyl ether and 2M NaOH. The aqueous layer was then acidified with concentrated HCI.Extraction was carried with ethyl acetate followed by drying and evaporating to dryness to furnish the desired product (91 mg, 55%). 1H-NMR (400 MHz, CDCI3): Major rotamer: δ 0.94-1.11 (m, 9 H, 2 CH3 (iPr), CH3 (pentanoyl)), 1.42 (m, 2 H, CH2Me), 1.73 (m, 2 H, CH2Et), 2.43 and 2.64 ( 2 m, 3 H, CH2CO and CH(iPr)), 4.17 (d, 1 H, J = 10.4 Hz, CHN), 4.36 and 4.98 (2 d, 1 H each, J = 15.6 Hz, CH2-Ph), 7.07-7.99 (m, 8 H, H-Ar) ppm. Minor rotamer: δ 0.94-1.11 (m, 9 H, 2 CH3 (iPr), CH3 (pentanoyl)), 1.42 (m, 2 H, CH2Me), 1.73 (m, 2 H, CH2Et), 2.43 and 2.64 ( 2 m, 3 H, CH2CO and CH(iPr)), 3.68 (bs, 1 H, CHN), 4.30 and 5.18 (2 d, 1 H each, J = 15.6 Hz, CH2-Ph), 7.07-7.99 (m, 8 H, H-Ar) ppm. IR (υ): 3000 (broad band, OH), 1782 (CO-acid), 1722 (CO-amide) cm"1. MS-CI (NH3): 436 (M+ +1 , 22)
53%	With hydrogen In methanol	10 Example 10 N-(1-OXOPENTYL)-N-[[2 -(LH-TETRAZOL-5-YL) [1, 1 -BIPHENYL]-4-YL] METHYL]-L-VALINE (valsartan, VIII) A suspension of 10 g (0.013 mol) of the benzyl ester OF N-(1-OXOPENTYL)-N-[[2 -(1-TRITYL-LH- TETRAZOL-5-YL) [1, 1 -BIPHENYL]-4-YL] METHYL] -L-VALINE (BENZYL ESTER OF TRITYL VALSARTAN, IX) IN 75 ml of anhydrous methanol was refluxed for 10 hr. The solution was then cooled to-10 °C and stirred at this temperature overnight; the precipitated crystals were sucked off and washed with a small amount of ice-cold methanol. 3 g (84 %) of methyltriphenylmethyl ether (XIII) were obtained. The crude benzyl ester of valsartan (X) was then dissolved in 20 ml of methanol and hydrogenated on 3% Pd/C. The mother liquor was, after the catalyst was removed, evaporated to dryness and 3g (53 %) of valsartan (VIII) crystallized after crystallization from the mixture ethyl acetate/cyclohexane. Mp = 109 °C-113 °C.
	Stage #1: (S)-N-(1-benzyloxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine With sodium hydroxide; water at 60 - 65℃; for 2.5h; Stage #2: With hydrogenchloride In water at 20 - 25℃;	1 Example Valsartan benzyl ester (100 gm), water (800 ml) and sodium hydroxide (50 gm) are mixed and stirred for dissolution. The solution is heated to 65°C and maintained for 2 hours 30 minutes at 60°C to 65°C. The reaction mass is cooled to 25°C and then washed with n-heptane (800 ml). The pH of the separated aqueous layer is adjusted to 2.0 by adding dilute hydrochloric acid at 20°C to25°C. Then the aqueous layer is extracted with methylene dichloride (1100 ml). Methylene dichloride layer is washed with water (1600 ml) and then with 10% sodium chloride solution (300 ml). Methylene dichloride layer is dried using sodium sulfate and then distilled under vacuum at 60°C to give 90 gm of residue. The residue is added to a mixture of ethyl acetate (235 ml) and diisopropyl ether (235 ml) and heated to reflux. Then the reaction mass is treated with activated charcoal, filtered through hyflobed and washed with diisopropyl ether (80 ml) and ethyl acetate (80 ml) at 50°C. The clear filtrate is cooled to 25°C and stirred for 2 hours at 25°C to 30°C. Then a further quantity of diisopropyl ether (720 ml) is added, maintained for 10 hours at 20°C to 25°C, cooled to 0°C and maintained for 2 hours at 0°C to 5°C. Then filtered the contents, washed with chilled diisopropyl ether (100 ml) and dried to give 50 gm of 99.7 % pure valsartan.
	With hydrogen In methanol at 20℃;	3 Example 3. Preparation of (S)-N-(1-carboxy-2-methylprop-1-yl)N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]amine (Valsartan) Palladium carbon(3gm, 10%) was added to a solution of (S)-N- (1-benzyloxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N- [2' (1H-tetrazol-5-yl) biphenyl-4-yl-methyl] amine obtained above in methanol (100 mL) and hydrogenated at room temperature. The reaction was monitored by TLC and after completion of the reaction, the product was filtered, concentrated and treated with a solution of sodium carbonate (8.25 g in 100 mL water). The aqueous layer was washed with dichloromethane, acidified and extracted with ethyl acetate (85 mL). The ethyl acetate solution was concentrated to 40 mL and stirred at room temperature for 15 minutes. A fraction of the valsartan precipitated out at this stage to form a suspension. n-Pentane (240 mL) was added to the suspension and was stirred at room temperature. The precipitate was filtered and washed with n-pentane followed by drying under reduced pressure at50 C to 55 C to yield about 6.5 g of valsartan.
	With hydrogen In methanol at 20℃;	1 Preparation of (S)-N- .-N-(1-carboxy-2-methyl-prop-1-yl .-N-pentanoyl-N-r2l (lH-tetrazol-5- yl) biphenyl-4-yl-methyl] amine barium salt (Valsartan Barium) Palladium carbon (3g, 10%) was added to the solution of (S)-N- (1- benzyloxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N- [2' (lH-tetrazol-5-yl) biphenyl-4- yl-methyl] amine obtained above in methanol (l 00ml) and hydrogenated at room temperature. The reaction was monitored by TLC. After completion of the reaction, it was filtered, concentrated and treated with a solution of sodium carbonate (8.25 g in 100 ml water). The aqueous layer was washed with dichloromethane, acidified and extracted with ethyl acetate. The organic layer was concentrated (HPLC Purity: 93.5%). It was dissolved in a mixture of ethanol (150 ml) and water (150 ml). This solution was treated with barium hydroxide (18.1 g) and stirred for 1 hour. It was then filtered and concentrated to about 150 ml at 55 to 65°C under reduced pressure. It was treated with acetone (150 ml) and stirred for 2 hours at 0 to 5°C. The solid obtained was filtered, washed with acetone (50 ml) and dried to obtain title salt as white crystalline solid. Yield: 16.5 g; HPLC Purity: 99.3% ; XRD, IR spectra and DSC graph were identical to those shown in Fig. I, II and III respectively.
	With hydrogen In methanol at 20℃; for 24h;	1.a-1.b a. 46 g of N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-vaIine benzyl ester, 108 g of tributyltin chloride, 34g of sodium azide, 0.5g of TBAB and 1 mL of DMF in 200 ml of o-xylene were heated to boiling with stirring for 6 hours, After completion of the reaction, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to remove o-xylene and DMF. 450 mL sl,heτ was added lυ the residue follpwed by treatment with 1 N aqueous sodium hydroxide solution. The reaction mixture was intensively stirred for 2 h. The aqueous phase was separated off and rendered acidic with 1N aqueous hydrochloric acid. The precipitated product was isolated by filtration. The crude was dissolved in ethyl acetate and dried with anhydrous Na2SO4. It was concentrated to render 38g of N-[(2'-(1H4etrazol-5-yl)biphenyl~4-yl)methyl]~N- valeryl-(L)-valine benzyl ester with [ctjo2039,5 and melting interval of 50-54 0C. A solution of 42.2 g of N-[(2'-(1 H-tetrazol~5^yl)biphenyl-4-yl)methyl]-N-valeryl-(L)- valine benzyl ester in 300 ml of methanol was hydrogenated at room temperature with the addition of 8 g Of1PdZC (10% ) until the calculated amount of hydrogen had been absorbed (24 h). The crude acid was obtained by filtration and evaporation of the solution. It was partitioned between 2N sodium bicarbonate solution and ethyl acetate. The aqueous phase was separated off and rendered acidic, and the title compound is isolated by extraction with ethyl acetate. It is obtained from ethyi acetate in crystalline form and has a melting interval of 103- 105 0C and an optical rotation [αfo20 -64.95° (c=1% in methanol), b. Recrystalfisation of (S)-N-(I -Ca rboxy-2~methyl-prop-1-yl)-N-pentanoyl-N-[2'- (1 H-teirazol-5-yl)bi phenyl-4-ylmethylJ-amine55 g of crude valsartan was charged into a round bottomed flask containing ethyl acetate (330 ml) and the contents were heated to reflux under stirring to form a clear solution. To the clear solution, 5.5 g of activated charcoal was added and stirred at reflux for about 35 minutes. The reaction mass was filtered hot through a flux calcined diatomaceouβ earth (Hyflow) bed and the bed was washed with ethyl acetate (27.5 ml). The resultant filtrate was cooled to about 35 0C. and seeded with 2.75 g of pure valsartan. The seeded solution was stirred for 1 hour, 15 minutes at 35 0C. and subsequently cooled stepwise: to 30 0C. for 1 hour, 15 minutes; further to 15 0C. for about 40 minutes; and further to about 5 0C. for about 2 hours, 20 minutes; all accompanied by stirring. The separated solid was filtered and washed with ethyl acetate (27.5 ml) to get solid compound. It was followed by washing with 3OmL of hexane. The dry solid was suspended in 100 ml_ of hexane and was refuxed for 2h. It was then cooled to room temperature and separated by filtration followed by washing with 20 ml_ of hexane to render 41g of the products Purity by HPLC: 99.83%)
	With hydrogen In ethyl acetate	2.c; 7.c C) PREPARATION OF (S)-3-METHYL-2-FPENTANOVL- [2'- (1 H-TETRAZOL-5-YL)-BIPHENYL-4-VL-METHYLL-] [AMINO}-BUTYRIC] acid A solution of (S)-3-Methyl-{2-pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}- butyric acid benzylester (10.6 g; 20.0 [MMOL)] in Ethylacetate (43 ml) is hydrogenated at 4 bar [/50°C] in presence of a wet palladium on charcoal catalyst 5% (1.12 [G,] containing [50] % water). After completion of the reaction (cease of hydrogen consumption) the catalyst is removed by filtration and the filtrate is concentrated at [45°C] in vacuo (water is [AZEOTROPICALLY] removed). The crystallization of the product is initiated at [45°C] and-after addition [OF CYCLO-] hexan (102 ml)-completed by cooling [TO-5°C.] The solid is collected by filtration, and after drying at [50°C,] [(S)-3-METHYL-2- {PENTANOYL- [2'- (1 H-TETRAZOL-5-YL)-BIPHENYL-4-YL-METHYL]-AMINO}-] butyric acid is received as a white powder. Melting point : 108-110°C. Enantiomeric excess (by HPLC) : ee > [99. 5 %] A solution of (S)-3-Methyl-{2-pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino}- butyric acid benzylester (10. 6 g; 20.0 mmol) in [ETHYIACETATE] [(43 ML)] is [HYDROGENATED AT] 4 bar [/50°C] in presence of a wet palladium on ; charcoal catalyst 5% (1. 12 g, containing 50 [%] water). After completion of the reaction (cease-of hydrogen consumption) the catalyst is removed by filtration and the filtrate is concentrated at 45°C in vacuo (water is azeotropically removed). The crystallization of the product is initiated at [45°C] and-after addition [OF CYCLO-] hexan (102 [ML)-COMPLETED] by cooling to -5°C. The solid is collected by filtration ; and after drying at [50°C,] (S)-3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amino} - butyric acid is received as a white powder. Melting point: [108-110°C.] Enantiomeric excess (by HPLC): ee > 99.5 %
	With hydrogen In ethyl acetate at 25 - 30℃; for 8 - 10h;	4.i; 4.ii Example 4(i); Preparation of Valsartan 5.0 gms of 10% dry palladium on carbon was charged to the dried ethyl acetate layer obtained in example 3 (i) and the contents were subjected to hydrogen bubbling over a period of 8-10 hours at 25-300C. After completion of reaction, the catalyst was removed by filtration. The pH of the clear filtrate was adjusted to 6.5 using liquor ammonia. About 500 ml purified water was added to the reaction mass and stirred for 15 minutes. The resulting mixture was transferred to a separating funnel and the phases separated. The aqueous layer was first washed with 150 ml ethyl acetate followed by 150 ml tertiary butyl methyl ether. The pH of aqueous layer was adjusted to 3.0 to 4.0 using dilute sulphuric acid or acetic acid and extracted with 500 ml ethyl acetate. The ethyl acetate layers were combined together and washed with 500 ml 10% sodium chloride solution followed by 100 ml water. The organic phase was dried over anhydrous sodium sulphate and concentrated under vacuum to afford a residue. About 100ml ethyl acetate was added to the residue and the mixture was stirred for 30 minutes at ambient temperature. The suspension was gradually stirred for 6 hours after the addition of 800 ml n-heptane. The crude solid was separated by filtration, washed with 200.0 ml n- heptane and dried under vacuum at 50-550C to give about 45gms of valsartan.(ii) Preparation of Valsartan10 gms of 10% dry palladium on carbon was charged to the dried ethyl acetate layer obtained in example 3 (iii)and the contents were subjected to hydrogen bubbling over a period of 8-10 hours at 25-30°C. After completion of reaction, the catalyst was removed by filtration. The pH of clear filtrate was adjusted to 6.5 using liquor ammonia. About 100 ml purified water was charged to the reaction mass and stirred for 15 minutes. The resulting mixture was transferred to a separating funnel and the phases separated. The aqueous layer was first washed with 300 ml ethyl acetate followed by 300ml tertiary butyl methyl ether. The pH of aqueous layer was adjusted to 3.0 to 4.0 using dilute sulphuric acid or acetic acid and extracted with 500 ml ethyl acetate twice. The ethyl acetate layers were combined together and washed with 1000 ml 10% sodium chloride solution followed by 2 x 100 ml water. The organic phase was dried over anhydrous sodium sulphate and concentrated under vacuum to a residue. About 200ml ethyl acetate was added to the residue and the mixture was stirred for 30 minutes at ambient temperature. The suspension was charged with 1500 ml diisopropyl ether and gradually stirred for 6 hours. The crude solid valsartan was isolated by filtration, washed with 400.0 ml diisopropyl ether and dried under vacuum at 50-55°C. Yield - 90-95gms.
	With hydrogen In ethyl acetate at 30℃;	11 A solution of 100 gm of N-(1-oxopentyl)-N-[[(2'-(1H-tetrazol-5-yl)-1,1'-biphenyl)- 4-yl] methyl]-L-valinebenzylester in 1000 ml ethylacetate is hydrogenated at 30 deg C with 15 gm of 5% Pd - C until the hydrogen uptake is ceased. The mass over celite bed and filtrate is collected. Added 10% sodium bicarbonate solution (500 ml). Stirred for 20 minutes and the layers are separated. Collected the aqueous layer and washed with ethylacetate (500 ml). Added ethylacetate (300 ml) to the aqueous layer and the pH is adjusted to 1.5 - 2 with 2N hydrochloric acid solution. Stirred for 15 minutes and separated the layers. The aqueous layer is extracted with ethylacetate (250 ml), ethylacetate layers are combined and washed with water (500 ml) and then with 10% aqueous sodium chloride solution (500 ml). Ethylacetate layer is dried over sodium sulfate and distilled under vacuum below 50 deg C. Ethylacetate (200 ml) is added to the residue while hot. Stirred for 5 minutes to obtain clear solution. Cyclohexane (200 ml) is added at room temperature, stirred for 15 minutes. Cyclohexane (400 ml) is added to the above mass at room temperature. Stirred the mass at room temperature for 4 hours. Cooled to 5 deg C and then stirred for 1 hour 30 minutes. Filtered the solid, washed with a mixture of ethylacetate (20 ml) and cyclohexane (80 ml) and dried to give 70 gm of 99.9% pure valsartan. Content of N,N-bis-[[(2'-(1H-tetrazol-5-yl)-1,1'-biphenyl)-4-yl]methyl] L-valine impurity is not detected by HPLC.

Reference： [1]Location in patent: experimental part Wang, Guo-Xi; Sun, Bao-Ping; Peng, Cong-Hu [Organic process research and development, 2011, vol. 15, # 5, p. 986 - 988]
[2]Current Patent Assignee: IPCA LABORATORIES LIMITED - EP1714963, 2006, A1 Location in patent: Page/Page column 3; 9-10
[3]Current Patent Assignee: IPCA LABORATORIES LIMITED - US2006/281801, 2006, A1 Location in patent: Page/Page column 7
[4]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2005/21535, 2005, A2 Location in patent: Page/Page column 15-16
[5]Carpentier, Florian; Felpin, François-Xavier; Zammattio, Françoise; Le Grognec, Erwan [Organic Process Research and Development, 2020, vol. 24, # 5, p. 752 - 761]
[6]Current Patent Assignee: ENANTIA SL; ENANTIA - WO2006/67216, 2006, A2 Location in patent: Page/Page column 30
[7]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2005/21535, 2005, A2 Location in patent: Page/Page column 15
[8]Current Patent Assignee: HETERO DRUGS LIMITED - WO2004/111018, 2004, A1 Location in patent: Page 8-9
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[ 137864-44-9 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
67%	Stage #1: N-[(2'-(1-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester In methanol for 8h; Heating / reflux; Stage #2: With hydrogen In methanol at 40℃; for 16h;	5 Example 5; N-(1-OXOPENTYL)-N-[[2 -(LH-TETRAZOL-5-YL) [L, 19-BIPHENYL]-4-YL] METHYL]-(L)-VALINE (valsartan) N- [ (2 - (I-TRIPHENYLMETHYL-TETRAZOL-5-YL) biphenyl-4-yl) METHYL]-N-VALERYL-(L)-VALINE benzyl ester (660 g) was dissolved under boiling in methanol (1400 ml) and the mixture was refluxed still for 8 h. After carrying out the detritylation, a Pd/C catalyst (75 g, 3 %, 50% water) was added, and the mixture was HYDROGENATED (1 atm) at 40 °C for 16 h. After checking by TLC the mixture was filtered and evaporated in vacuo. Isopropanol (200 ml) and demineralized water (800 ml) were added, the pH was adjusted to 8 by addition of 10% KOH (1350 ML). It was extracted with toluene (2 x 750 ml) and after adding ethyl acetate (1250 ml) the aqueous phase was acidified with 36% HC1 (200 ml) to PH=L. After separating the organic layer the aqueous phase was extracted with ethyl acetate (600 ml) once more. The combined organic phases were washed with demineralized water (2 x 250 ml) and evaporated at bath temperature of 50 °C with azeotropic separation of water. The raw product was dissolved in ethyl acetate (1200 ml) at 50 °C and cyclohexane (2500 ml) was added dropwise to the resulting solution during 2 h, while the substance crystallized; after cooling down to 10 °C it was sucked off and drying in vacuo at 50 °C yielded 250 g (67%) of valsartan ; HPLC 98.3%.
110 g	With 10% Pd/C; hydrogen; N-ethyl-N,N-diisopropylamine In methanol for 6h; Autoclave;	3.3 Example 3. STAGE-3-Preparation of (L)-Valsartan. Stage-II (100) was dissolved in 1.01t methanol and charged into the autoclave About 2-3ml DIPEA (Diisopropyl ethyl amine) was added, then 10g 10% Pd/C (50% wet) and pressure of 3-5kg/cm2 maintained for 6.0 hrs and the reaction mixture monitored by HPLC.The side product was isolated by filtration, the filtrate was concentrated completely and dissolved in 5% caustic solution, washed with Toluene(300mlx3), acidified with 5% HC1 solution and pH adjusted to 2-3. The solids were extracted with EtOAc (150mlx2), the solvent stripped completely.Weight: 100-110g % Purity (by HPLC): 97.0% (+)
110 g	With 10% Pd/C; hydrogen; N-ethyl-N,N-diisopropylamine In methanol for 6h; Autoclave;	3 Example 3 Stage-3-Preparation of (L)-Valsartan Example 3 Stage-3-Preparation of (L)-Valsartan [0105] Stage-II (100 g) was dissolved in 1.0 lt methanol and charged into the autoclave About 2-3 ml DIPEA (Diisopropyl ethyl amine) was added, then 10 g 10% Pd/C (50% wet) and pressure of 3-5 kg/cm2 maintained for 6.0 hrs and the reaction mixture monitored by HPLC. The side product was isolated by filtration, the filtrate was concentrated completely and dissolved in 5% caustic solution, washed with Toluene (300 ml×3), acidified with 5% HCl solution and pH adjusted to 2-3. The solids were extracted with EtOAc (150 ml×2), the solvent stripped completely. [0106] Weight: 100-110 g % Purity (by HPLC): 97.0% (+)

Multi-step reaction with 2 steps 1.1: methanol; oxalic acid / 1.5 h / 5 - 65 °C 1.2: pH 7.5 2.1: hydrogen / 10% Pd/C / ethyl acetate / 8 - 10 h / 25 - 30 °C

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2004/101534, 2004, A1 Location in patent: Page 7
[2]Current Patent Assignee: ALKEM LAB - WO2013/72924, 2013, A1 Location in patent: Page/Page column 27
[3]Current Patent Assignee: ALKEM LAB - US2014/316142, 2014, A1 Location in patent: Paragraph 0105-0106
[4]Current Patent Assignee: CIPLA LTD - WO2008/135762, 2008, A1

7
[ 852212-82-9 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: (S)-4-isopropyl-3-pentanoyl-2-[2'-(2-trityl-2H-tetrazol-5-yl)-biphenyl-4-yl]oxazolidin-5-one With ammonium formate In ISOPROPYLAMIDE at 90℃; Stage #2: With sulfuric acid In tert-butyl methyl ether; ISOPROPYLAMIDE	4 Valsartan 1.0 g (1.5 mmoles) of 4-isopropyl-3-pentanoyl-2-[2'-(1 -trityl-1H-tetrazol-5-yl)-biphenyl-4-yl]oxazolidin-5-one are reacted in 50 ml of N,N,-dimethyl-acetamide with 1.2 g of ammonium formate (19.0 mmoles) and 1.2 g of 5% Pd/C catalyst. The temperature is raised to 90° C. and ammonium formate is added in 1.2 g (19.0 mmoles) portions, at 2 hours interval, until disappearance of the starting substrate. The mixture is cooled and the catalyst is filtered off. tert-Butyl methyl ether and 20% sulfuric acid are added to about pH 2, then sodium chloride to saturation of the aqueous phase. The organic phase is separated and washed with water 3 times. The organic phase is alkalinised with a 10% sodium hydroxide solution. The aqueous phase containing the salified product is separated and washed with tert-butyl methyl ether. Ethyl acetate is added and acidified with a 5% hydrochloric acid solution. The organic phase is separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to a residue. Crystallization from isopropyl ether affords 0.44 g of valsartan (1.05 mmoles; yield: 70%), having purity higher than 99.5% and content in azide derivatives lower than 20 ppm. 1H-NMR (CDCl3) (0.80-1.15 (m, 9H); 1.20-1.50 (m, 2H); 1.60-1.80 (m, 2H); 2.60 (t, 2H); 2.65-2.80 (m, 2H), 3.70 (d, 1H), 4.10 (d, 0.3 H), 4.30 (d, 0.7 H), 4.90 (d, 0.7H), 5.2 (d, 0.3H); 7.00 (d, 0.3H); 7.10-7.20 (m, 4H), 7.40-7.60 (m, 3H), 7.85 (d, 0.7 H).
53%	With hydrogen In tetrahydrofuran at 60℃;	5 Valsartan A solution of the 4-isopropyl-3-pentanoyl-2-[2'-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-yl]oxazolidin-5-one (1.0 g, 1.5 mmoles) in 20 ml of THF is hydrogenated under 5 bars, at 60° C., in the presence of Pd(5%)/C (100 mg). After completion of the reaction, the mixture is cooled and the catalyst is filtered off. After working up the reaction mixture as in Example 4, valsartan (0.33 g, molar yield: 53%) is isolated by crystallization from isopropyl ether.

Reference： [1]Current Patent Assignee: DIPHARMA FRANCIS S.R.L. - US2005/131038, 2005, A1 Location in patent: Page/Page column 5
[2]Current Patent Assignee: DIPHARMA FRANCIS S.R.L. - US2005/131038, 2005, A1 Location in patent: Page/Page column 5

8
[ 155884-01-8 ]
[ 867022-57-9 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: 2-(tetrazol-5'-yl)phenylboronic acid; (S)-2-[(4-bromo-benzyl)-pentanoyl-amino]-3-methyl-butyric acid With sodium hydroxide In water at 70℃; for 2h; Stage #2: With acetic acid In water	7.6 (6) A mixture made up of 0.1 g (0.24 mmol) of N-(4- iodobenzyl) -N-valeryl-L-valine, 0.055 g (0.29 mmol) of 2- (lH-tetrazol-5-yl)phenylboronic acid, 0.038 g (0.95 mmol) of NaOH, 0.0102 g of 5% Pd/C in paste (0.0024 mmol of palladium) and 0.0020 g (0.0035 mmol) of the trisodium salt of 3,3',3"-phosphinidinatris (benzenesulphonate) 1 mL of water is heated at 70°C for 2 h. After cooling the mixture to 20-25°C the catalyst is filtered and 0.1 mL of glacial acetic acid is added to provide, once filtered and dried in an air oven at 45°C, 0.086 g of crude Valsartan. Following purification of this crude product by silica gel chromatography (eluent AcOEt/heptane/AcOH 15: 5:0.2) 0.072 g (68%) of Valsartan is obtained.
60.5%	Stage #1: 2-(tetrazol-5'-yl)phenylboronic acid; (S)-2-[(4-bromo-benzyl)-pentanoyl-amino]-3-methyl-butyric acid With sodium hydroxide In 1,2-dimethoxyethane; ethanol; water for 12.0833h; Heating / reflux; Stage #2: With hydrogenchloride In water	7.1 Example 7: Obtaining (S)-N-(1-carboxy-2-methyl-prop-1-yl) -N-pentanoyl-N- [2'-(lH-tetrazol-5-yl-)- biphenyl-4-yl methyl] amine (Valsartan); Homogeneous catalysis; (1) To a mixture made up of 1.35 mL of ethanol, 13.5 mL of 1.2-dimethoxyethane and 4 mL of water are added 0.50 g (1.35 mmol) of N-(4-bromobenzyl)-N-valeryl-L-valine, 0.308 g (1.62 mmol) of 2-(lH-tetrazol-5-yl)phenylboronic acid, 0.156 g (0.135 mmol) of palladium tetrakistriphenylphosphine and 0.324 g (8.1 mmol) of NaOH. The mixture, following scouring with gentle bubbling of nitrogen for 5 min, is heated at reflux for 12 h. The reaction is cooled to 20-25°C and 25 mL of AcOEt and 25 mL of water are added. The decanted aqueous phase is taken to pH 1-2 with HCl 37% and extracted with 25 mL of AcOEt. After evaporating the AcOEt phase to dryness and purifying by silica gel chromatography (eluent AcOEt/heptane/AcOH 15: 5:0.2) 0.356 g (60.5%) of Valsartan is obtained. NMR IH (CDC13) , 8 (ppm): 0.8-1.1 (m, 9H, -CH (CH3) + - CH2CH3), 1.3-1.5 (m, 2H, -CH2CH3), 1.5-1.8 (m, 2H, - CH2CH2CH3), 2.6 (t, 2H, -CH2CO-), 2.7 (m, 1H, -CH(CH3)2),, 3.5 (d, 1H, -CH-COOH), 4.3-5.0 (dd, 2H, Ar-CH2-), 7.0-7.7 (m, 7H, ArH), 8.0-8.1 (d, 1H, ArH in ortho position to the tetrazol ring).
58%	Stage #1: 2-(tetrazol-5'-yl)phenylboronic acid; (S)-2-[(4-bromo-benzyl)-pentanoyl-amino]-3-methyl-butyric acid With sodium methylate In methanol at 70℃; for 10h; Stage #2: With hydrogenchloride In water; ethyl acetate	7.5 Heterogeneous catalysis; (5) A mixture made up of 1 g (2.70 mmol) of N-(4- bromobenzyl) -N-valeryl-L-valine, 0.513 g (2.70 mmol) of 2- (lH-tetrazol-5-yl)phenylboronic acid, 0.120 g of 5% Pd/C in paste (0.028 mmol of palladium) and 0.0084 g (0.032 mmol) of triphenylphosphine in a solution of 4.1 mL (21.5 mmol) of sodium methoxide in 30% methanol and 10 mL of methanol is heated at 70°C for 10 h. The reaction is cooled to 20-25°C, the catalyst is filtered and the methanol distilled in vacuo. The resulting residue is dissolved in 25 mL of water and, following washing with 25 mL of AcOEt, is acidified to pH 3 with HCl 3N and extracted twice with 20 mL of AcOEt. The combined phases of AcOEt are dried with anhydrous Na2S04 and following distillation of the solvent the crude product obtained is purified by silica gel chromatography (eluent AcOEt/heptane/AcOH 15: 5:0.2) to provide 0.683 g (58%) of Valsartan.

55.6%

Stage #1: 2-(tetrazol-5'-yl)phenylboronic acid; (S)-2-[(4-bromo-benzyl)-pentanoyl-amino]-3-methyl-butyric acid With sodium methylate In methanol at 70℃; for 5h; Stage #2: With hydrogenchloride In water; ethyl acetate

7.3 (3) Nitrogen is bubbled for 5 min. To a mixture made up of 0.50 g (1.35 mmol) of N-(4-bromobenzyl)-N-valeryl-L- valine, 0.308 g (1.62 mmol) of 2-(lH-tetrazol-5- yl) phenylboronic acid, 0.0028 g (0.016 mmol) of palladium chloride and 0.0084 g (0.032 mmol) of triphenylphosphine in a solution of 2.06 mL (13.0 mmol) of sodium methoxide in methanol al 30% and 5 mL of methanol are added. It is heated at 70°C under nitrogen atmosphere for 5 h, 0.050 g of activated carbon is added and it is stirred at the same temperature for a further 15 min. After cooling to 20-25°C it is filtered, the methanol is evaporated and it is treated with 25 mL of HCl IN and 25 mL of AcOEt. The AcOEt phase is dried with anhydrous sodium sulphate and after distilling the solvent the crude product obtained is purified by silica gel chromatography (eluent AcOEt/heptane/AcOH 15: 5:0.2) to provide 0.327 g (55.6%) of Valsartan.

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2005/102987, 2005, A1 Location in patent: Page/Page column 28-29
[2]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2005/102987, 2005, A1 Location in patent: Page/Page column 25-26
[3]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2005/102987, 2005, A1 Location in patent: Page/Page column 28
[4]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2005/102987, 2005, A1 Location in patent: Page/Page column 27

9
[ 155884-01-8 ]
[ 867022-58-0 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: 2-(tetrazol-5'-yl)phenylboronic acid; N-(4-iodobenzyl)-N-valeryl-L-valine With sodium hydroxide In methanol; water for 2.08333h; Heating / reflux; Stage #2: With hydrogenchloride In water	7.2 (2) To a mixture made up of 3 mL of methanol, 0.9 mL of water and 0.096 g (2.4 mmol) of NaOH are added 0.250 g (0.60 mmol) of N- (4-iodobenzyl)-N-valeryl-L-valine, g (0.72 mmol) of 2-(lH-tetrazol-5-yl)phenylboronic acid and 0.035 g (0.030 mmol) of palladium tetrakistriphenylphosphine. Following scouring with gentle bubbling of nitrogen for 5 min, the mixture is heated at reflux for 2 h. The reaction is cooled to 20-25°C, the methanol is distilled in vacuo and 25 mL of AcOEt and 25 mL of water are added. The decanted aqueous phase is taken to pH 1-2 with HC1 37% and extracted with 25 mL of AcOEt. After evaporating the AcOEt phase to dryness and purifying by silica gel chromatography (eluent AcOEt/heptane/AcOH 15: 5:0.2) 0.230 g (88%) of Valsartan is obtained.; Purification of the crude Valsartan A solution made up of 20 g of crude Valsartan obtained according to example 7 (2) dissolved in 160 mL of AcOEt is treated with 1 g of neutral activated carbon at 45-50°C for 1 h. The mixture is filtered, and to the clear solution obtained methylcyclohexane is added slowly at 20- 25°C until precipitation is observed (approximately 120 mL). The mixture thickens at first, and later a fluid suspension is obtained, at which time the slow addition of a further 120 mL of methylcyclohexane is continued. The mixture is left stirring at 20-25°C for 3 h, is filtered and dried in a vacuum oven at 45°C to provide 14 g of Valsartan as a white solid. La enantiomeric purity is determined by chiral HPLC, giving e. e. >99.5%
85%	Stage #1: 2-(tetrazol-5'-yl)phenylboronic acid; N-(4-iodobenzyl)-N-valeryl-L-valine With sodium hydroxide In methanol; water at 70℃; for 3h; Stage #2: With hydrogenchloride In water; ethyl acetate	7.4 (4) Nitrogen is bubbled for 5 min. To a mixture made up of 0.20 g (0.48 mmol) of N-(4-iodobenzyl)-N-valeryl-L-valine, 0.115 g (0.61 mmol) of 2-(lH-tetrazol-5-yl)phenylboronic acid, 0.017 g (0.024 mmol) of bis(triphenylphosphine)palladium chloride and 0.115 g (2.87 mmol) of NaOH in 2.4 mL of methanol and 0.7 mL of water are added. The reaction is heated to 70°C under nitrogen atmosphere. Once 3 h has elapsed the reaction is considered to be completed and the methanol is distilled. The crude product is treated with 25 mL of HC1 IN and 25 mL of AcOEt. The AcOEt phase is dried with anhydrous sodium sulphate and after distilling the solvent the crude product obtained is purified by silica gel chromatography (eluent AcOEt/heptane/AcOH 15: 5:0.2) to provide 0.178 g (85%) of Valsartan.
71.4%	Stage #1: 2-(tetrazol-5'-yl)phenylboronic acid; N-(4-iodobenzyl)-N-valeryl-L-valine With sodium methylate In methanol at 70℃; for 10h; Stage #2: With hydrogenchloride In water; ethyl acetate	7.5 Heterogeneous catalysis; (5) A mixture made up of 1 g (2.70 mmol) of N-(4- bromobenzyl) -N-valeryl-L-valine, 0.513 g (2.70 mmol) of 2- (lH-tetrazol-5-yl)phenylboronic acid, 0.120 g of 5% Pd/C in paste (0.028 mmol of palladium) and 0.0084 g (0.032 mmol) of triphenylphosphine in a solution of 4.1 mL (21.5 mmol) of sodium methoxide in 30% methanol and 10 mL of methanol is heated at 70°C for 10 h. The reaction is cooled to 20-25°C, the catalyst is filtered and the methanol distilled in vacuo. The resulting residue is dissolved in 25 mL of water and, following washing with 25 mL of AcOEt, is acidified to pH 3 with HCl 3N and extracted twice with 20 mL of AcOEt. The combined phases of AcOEt are dried with anhydrous Na2S04 and following distillation of the solvent the crude product obtained is purified by silica gel chromatography (eluent AcOEt/heptane/AcOH 15: 5:0.2) to provide 0.683 g (58%) of Valsartan. In an analogous way, 0.745 g (71.4%) of Valsartan is obtained from 1 g (2.4 mmol) of N-(4-iodobenzyl)-N- valeryl-L-valine, 0.546 g (2.88 mmol) of 2-(lH-tetrazol-5- yl) phenylboronic acid, 0.120 g of 5% Pd/C in paste (0.028 mmol of palladium) and 0.0074 g (0.028 mmol) of triphenylphosphine in a solution of 3.7 mL (19.4 mmol) of sodium methoxide in methanol at 30% and 10 mL of methanol.

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2005/102987, 2005, A1 Location in patent: Page/Page column 26; 29
[2]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2005/102987, 2005, A1 Location in patent: Page/Page column 27
[3]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2005/102987, 2005, A1 Location in patent: Page/Page column 28

10
[ 67-56-1 ]
[ 137862-53-4 ]
[ 137863-17-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	With thionyl chloride at 0 - 25℃; for 4.5h;
	With thionyl chloride at 4 - 20℃; for 3h;	6 50 g of valsartan was charged into a round-bottomed flask containing a mixture of 500 ml of methanol and 15 ml of thionyl chloride at 4-5° C. The mixture was allowed to attain room temperature and was stirred for 3 hours. Solvent was distilled from the reaction mass below 40° C. and the residue was cooled to about 20° C. 250 ml of water was added to the residue and extracted with dichloromethane (3×200 ml). The organic layer was washed with 20% sodium chloride solution (250 ml). The organic layer was dried over sodium sulfate and solvent was distilled completely to get 46 g of the title compound as a solid 1H NMR (200 MHz, CDCl3, δ in ppm): 0.8-1.1 (m, 9H), 1.2-1.8 (m, 4H), 2.2-2.7 (m, 3H), 3.4-3.6(s, 3H), 4.0-5.0 (m, 3H), 7.1-8.2 (m, 8H). Mass: m/z 450.

Reference： [1]Location in patent: experimental part Wu, Chun; Hu, Yanpeng; Li, Qianbin; He, Limei; Chen, Jun; Cheng, Zeneng; Li, Yuanjian; Hu, Gaoyun [Archiv der Pharmazie, 2012, vol. 345, # 5, p. 393 - 400]
[2]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - US2006/149079, 2006, A1 Location in patent: Page/Page column 5

11
[ 137862-53-4 ]
[ 137863-17-3 ]

Yield	Reaction Conditions	Operation in experiment
	In hydrogenchloride; methanol	50 (S)-N-(1-Methoxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine EXAMPLE 50 (S)-N-(1-Methoxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine 0.8 g of N-valeryl-N-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-(L)-valine methyl ester is obtained analogously to Example 3 starting from 4.4 g of N-valeryl-N-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-(L)-valine, which are esterified in MeOH/HCl. Flash chromatography (ethyl acetate/hexane 1:3). FAB-MS: m/e=450 (M+H)+.

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US5399578, 1995, A

12
[ 104963-92-0 ]
[ 137862-53-4 ]
[ 924653-85-0 ]

Yield	Reaction Conditions	Operation in experiment
37%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 6h;	10 Pentanamide, N-[(1S)-2-methyl-1-[[4-[(nitrooxy)methyl]-1-piperidinyl] carbonyl]propyl]-N-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl] To a mixture of valsartan (1.0 g, 2.30 mmol, purchased from Onbio, Inc.) and triethylamine (0.90 g, 8.89 mmol) in dichloromethane (25 mL) was added 4-piperidinemethanol, nitrate (ester), nitrate (1:1) (salt) (1.03 g, 4.60 mmol, prepared according to US 2004/0024057; Example 19a) followed by DMAP (0.068 g, 0.56 mmol) and EDAC (0.53 g, 2.76 mmol). The reaction mixture was stirred at room temperature for 6 hours, diluted with dichloromethane and washed with 5% HCl aqueous solution, water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to give the crude mixture which was purified by column chromatography (silica gel, eluding with 600:400:2.5 hexane:ethyl acetate:acetic acid) to give the title compound as a white foam (0.49 g, 37% yield): mp 86-88° C.; 1H NMR (400 Mz, CDCl3) δ 8.02-7.91 (m, 1H), 7.60-7.39 (m, 3H), 7.13-6.89 (m, 4H), 5.42-5.28 (m, 1H), 4.74-4.12 (m, 6H), 3.10-2.53 (m, 2H), 2.37-2.10 (m, 3H), 2.05-1.80 (m, 4H), 1.59 (m, 2H), 1.17 (m, 2H), 1.06-0.75 (m, 9H); Mass spectrum (API-TIS) m/z 578(MH+), 600 (MNa+).

Reference： [1]Current Patent Assignee: NICOX S.A. - US2007/32533, 2007, A1 Location in patent: Page/Page column 43

13
[ 867022-57-9 ]
[ 155884-01-8 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
80%		Example 3 Synthesis of valsartan An aqueous solution (120 ml) of potassium hydroxide (0.568 mol, 31.8 g) is added in succession with 2-[(4-bromo-benzyl)-pentanoyl-amino]-3-methyl-butyric acid (0.811 mol, 30.0 g), tetrahydrofuran (120 ml), triphenylphosphine (0.0121 mol, 3,2 g) and palladium acetate (0.00405 mol, 0.91 g). The reaction mixture is refluxed and added with <strong>[155884-01-8]2-(2H-tetrazol-5-yl)-benzene-boronic acid</strong> (0.142 mol, 27.0 g) in portions in about 6 h. After completion of the addition, the mixture is left to react for 2h, then cooled to room temperature and the phases are separated. The organic phase is diluted with water (120 ml) and tetrahydrofuran is distilled off under reduced pressure. The remaining aqueous solution is acidified to pH 6.5 and washed with isopropyl acetate (60 ml). The aqueous phase is acidified to pH 2 and diluted with isopropyl acetate (60 ml), the diphasic solution is filtered to remove phenyltetrazol. Phases are separated and the organic phase is concentrated under reduced pressure, to obtain a thick oil that is crystallized from isopropyl acetate (90 ml) and heptane (150 ml). The resulting product is filtered, washed twice with a 1:1 isopropyl acetate/heptane mixture (30 ml), and dried in static dryer at 45C to obtain 28.2 g of the title product (yield 80%). Following the same procedure, starting from a compound (II) wherein X is bromine and Z a residue selected from: 2-butyl-4-chloro-5-hydroxymethyl-imidazol-1-yl;2-ethoxy-3H-benzoimidazol-4-carboxylic acid;2-butyl-1,3-diaza-spiro[4,4]non-1-en-4-on-3-yl; and5-carboxy-4-( 1-hydroxy-1-methylethyl)-2-propyl-imidazo-1-yl,losartan, candesartan, irbesartan and olmesartan can be respectively obtained.
80%	With potassium hydroxide;palladium diacetate; triphenylphosphine; In tetrahydrofuran; for 8.0h;Heating / reflux;	EXAMPLE 3 Synthesis of Valsartan An aqueous solution (120 ml) of potassium hydroxide (0.568 mol, 31.8 g) is added in succession with 2-[(4-bromo-benzyl)-pentanoyl-amino]-3-methyl-butyric acid (0.811 mol, 30.0 g), tetrahydrofuran (120 ml), triphenylphosphine (0.0121 mol, 3,2 g) and palladium acetate (0.00405 mol, 0.91 g). The reaction mixture is refluxed and added with <strong>[155884-01-8]2-(2H-tetrazol-5-yl)-benzene-boronic acid</strong> (0.142 mol, 27.0 g) in portions in about 6 h. After completion of the addition, the mixture is left to react for 2 h, then cooled to room temperature and the phases are separated. The organic phase is diluted with water (120 ml) and tetrahydrofuran is distilled off under reduced pressure. The remaining aqueous solution is acidified to pH 6.5 and washed with isopropyl acetate (60 ml). The aqueous phase is acidified to pH 2 and diluted with isopropyl acetate (60 ml), the diphasic solution is filtered to remove phenyltetrazol. Phases are separated and the organic phase is concentrated under reduced pressure, to obtain a thick oil that is crystallized from isopropyl acetate (90 ml) and heptane (150 ml). The resulting product is filtered, washed twice with a 1:1 isopropyl acetate/heptane mixture (30 ml), and dried in static dryer at 45 C. to obtain 28.2 g of the title product (yield 80%).

Reference： [1]Patent: EP1777224,2007,A2 .Location in patent: Page/Page column 7
[2]Patent: US2007/93540,2007,A1 .Location in patent: Page/Page column 5

14
[ 1033772-60-9 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogen In methanol at 20℃; for 24h;	(2S)-3-Methyl-2-{N-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-N'-(thiophene-2-carbonyl)- amino}-butanoic acid (VS.INT7) (0.4 g, 0.87 mmol) dissolved in methanol (5 ml) and Raney Nickel was added. Reaction mixture was stirred in hydrogen atmosphere at normal pressure at room temperature for 24 hours. Reaction mixture was filtered through celite and evaporated on RVE to yield 0.35 g (90%) of Valsartan. HR-MS: 436.2349 (MH+, calc. for C24H30N5O3+: 436.2353).

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/71400, 2008, A1 Location in patent: Page/Page column 12; 19-20

15
[ 137863-17-3 ]
valsartan [ No CAS ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
	With water; sodium hydroxide for 9h;

Reference： [1]Location in patent: scheme or table Kumar N, Senthil; Reddy, Shankar B.; Sinha, Brajesh Kumar; Mukkanti, Kagga; Dandala, Ramesh [Organic Process Research and Development, 2009, vol. 13, # 6, p. 1185 - 1189]

16
[ 137863-90-2 ]
[ 137863-17-3 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium azide; zinc(II) chloride In diethylene glycol dimethyl ether at 120℃; for 24h;	5 To 1 8.3 g (44 mmol) of (S)-methyl 2-(N-((2'-cyano-[1 , 1 '-biphenyl]-4- yl)methyl)pentanamido)-3-methylbutanoate in form of a colorless oil, 17 mL diglyme 1 1 .3 g (174 mmol) of sodium azide and 8.57 g (63 mmol) of ZnCI2 were added. The mixture was heated for 24 hours at 120 °C.Area% HPLC purity of the reaction mixture: content of the product (together methyl valsartan and valsartan) 90.1 %, content of the nitrile starting material: 2.1 %.

Reference： [1]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/124655, 2011, A1 Location in patent: Page/Page column 17

17
[ 638-29-9 ]
[ 137863-17-3 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 5.5 h / 0 - 5 °C 2: sodium azide; zinc(II) chloride / diethylene glycol dimethyl ether / 24 h / 120 °C

Reference： [1]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/124655, 2011, A1

18
methyl 2-(((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)amino)-3-methylbutanoate hydrochloride [ No CAS ]
[ 137863-17-3 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 5.5 h / 0 - 5 °C 2: sodium azide; zinc(II) chloride / diethylene glycol dimethyl ether / 24 h / 120 °C

Reference： [1]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/124655, 2011, A1

19
[ 1341154-89-9 ]
[ 137862-53-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
40%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 16h;	1 Example V. (2/?)-3-Methyl-2-(/V-((2'-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)pentanamido)- butanoyl N-methyl-N-4-nitroxybutyl-amide 25.0 g Valsartan (3) (1 1 .5 mmol), 4.8 g N-methyl-N-(4-nitroxybutyl)ammonium nitrate (22.7 mmol), 4.6 g diisopropylethylamine (35.5 mmol) and 2.4 g hydroxybenzotriazole(17.7 mmol) are dissolved in 44 g dimethyl formamide (DMF). 3.1 g 1 -Ethyl-3-(3-dimethyl- aminopropyl)carbodiimide HCI (EDCI, 16.0 mmol) is added at 0°C, and the mixture stirred for 16 h at room temperature. Water (200 g) and ethyl acetate (120 g) are added, and the organic phase washed with 10% NaHC03 and citric acid (5 g in 50 g water), then dried over Na2S04, and evaporated. The obtained crude oil is purified by chromatography (Si02; CH2CI2 : EtOH 96 : 4), giving 2.60 g (40%) of a waxy solid. 1H-NMR (200 MHz, CDCI3): 0.75-0.88 (m, 9 H); 1 .12-1 .38 (m, 2 H); 1 .47-1.75 (m, 6 H); 2.05-2.35 (m, 4 H); 2.47 (s, 1 .5 H); 2.65-3.05 (m, 1 H); 3.12 (s, 1 .5 H); 3.31 -3.38 (m, 0.5 H); 3.81 -3.91 (m, 0.5 H); 4.35- 4.58 (m, 3 H); 5.19-5.38 (m, 1 H); 6.81 -7.05 (m, 4 H); 7.39-7.82 (m, 4 H).

Reference： [1]Current Patent Assignee: CARDIOLYNX - WO2011/131613, 2011, A1 Location in patent: Page/Page column 13-14

20
[ 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

21
[ 482577-59-3 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium hydrogencarbonate / dichloromethane; water 1.2: 1 h / 0 - 5 °C 2.1: sodium azide; tributyltin chloride / o-xylene / 24 h / 135 - 138 °C 3.1: sodium hydroxide; water / o-xylene / 10 - 60 °C 3.2: 15 - 20 °C / pH 2.5 - 3

Reference： [1]Current Patent Assignee: JUBILANT PHARMOVA LTD - WO2012/56294, 2012, A1

22
[ 88150-42-9 ]
[ 137862-53-4 ]
[ 58-93-5 ]

Yield	Reaction Conditions	Operation in experiment
		(b) Standard working solutions for AML and VAL 80 mug/mL and for HCT 62.5 mug/mL were prepared from stock solutions by appropriate dilutions with methanol.

Reference： [1]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,2014,vol. 122,p. 744 - 750

23
[ 1582778-32-2 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
70.7%	With 5% palladium on barium sulphate; ammonium formate In water; isopropyl alcohol at 65℃; for 11h;	2.3 Example 2-3 Deprotection Example 2-3 Deprotection (0350) (0351) A mixture of BVAL (0.1 g, 0.16 mmol), ammonium formate (0.1 g, 1.58 mmol), 5% Pd-BaSO4 (0.035 g, 10 mol %), isopropyl alcohol (1 mL, 10 vol) and water (0.6 mL, 6 vol) was stirred at 65° C. for 8 hr, the reaction mixture was cooled to 25° C., and 5% Pd-BaSO4 (7.0 mg, 2.0 mol %) was further added. The reaction mixture was stirred at 65° C. for 3 hr. The conversion yield of this reaction was 98.9%. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained concentrated residue was purified by silica gel column chromatography (5% methanol/methylene chloride) to give valsartan (VAL) (0.1 g, yield 70.7%). (0352) melting point: 70° C.-95° C.; (0353) IR (KBr): νmax=1730, 1619 cm-1; (0354) 1H NMR (DMSO-d6): (CM: major rotamer; Cm: minor rotamer): δ=16.3 (brs, 1H), 12.6 (brs, 1H), 7.70-7.63 (m, 2H, CM, Cm), 7.58-7.53 (m, 2H, CM, Cm), 7.20 (d, J=8.2 Hz, 1H, CM), 7.08 (d, J=8.2 Hz, 1H, Cm), 7.07 (d, J=8.2 Hz, 1H, CM), 6.97 (d, J=8.2 Hz, 1H, Cm), 4.62 (s, 2H, CM), 4.48 (d, J=15.2 Hz, 1H, Cm), 4.46 (d, J=10.3 Hz, 1H, CM), 4.43 (d, J=15.2 Hz, 1H, Cm), 4.08 (d, J=10.5 Hz, 1H, Cm), 2.53-2.45 (m, 2H, Cm), 2.22-2.12 (m, 1H, CM, Cm), 2.21 (dt, J=15.8, 7.9 Hz, 1H, CM), 2.03 (dt, J=15.8, 7.9 Hz, 1H, CM), 1.54 (quint, J=6.9 Hz, 2H, Cm), 1.41 (dquint, J=14.1, 7.9 Hz, 1H, CM), 1.37 (dquint, J=14.1, 7.9 Hz, 1H, CM), 1.31 (sext, J=6.9 Hz, 2H, Cm), 1.15 (sext, J=7.9 Hz, 2H, CM), 0.93 (d, J=6.9 Hz, 3H, Cm), 0.93 (d, J=7.9 Hz, 3H, CM), 0.88 (t, J=6.9 Hz, 3H, Cm), 0.76 (t, J=7.9 Hz, 3H, CM), 0.75 (d, J=7.9 Hz, 3H, CM), 0.70 (d, J=6.9 Hz, 3H, Cm); (0355) HRMS: Calcd for C24H29N5O3, 435.2270 [M]+. Found 435.2267 [M

Reference： [1]Current Patent Assignee: UBE CORPORATION - US2015/239854, 2015, A1 Location in patent: Page/Page column 42

24
[ CAS Unavailable ]
[ 137862-53-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydroxide In Isopropyl acetate; water; acetonitrile at 40 - 65℃;	11 Embodiment 11 the two sha Kubi tune LCZ696 cyclohexylamine salt preparation The sha Kubi tune b cyclohexylamine salt (84g, 142mmol) acetic acid isopropyl ester is dissolved in 60 ml and acetonitrile 1800 ml in the mixed solvent, raising the temperature to 60-65 °C added after stirring dissolves clear valsartan (63g, 145mmol), then dropwise 47g36% of sodium hydroxide aqueous solution, to heat the temperature after the end of the 40 ±3 °C, instillment second grade acid isopropyl ester 610 ml, the drop finishes, for thermal insulation 40 ±3 °C 0.5 hours. Insulation end, temperature control 35 ±5 °C decompression prolapsed 760 ml solvent. escapes finishes, heating to 40 ±3 °C, instillment second grade acid isopropyl ester 920 ml, the drop finishes, temperature control 40 ±3 °C insulation 0.5 hours. Insulation end, temperature control 35 ±5 °C decompression prolapsed 1220 ml solvent, then heating to 40 ±3 °C, instillment second grade acid isopropyl ester 1220 ml, the drop finishes, thermal insulation 0.5 hours. Then temperature control 35 ±5 °C, decompression prolapsed 1220 ml solvent. escapes finishes, cooling to 20-25 °C thermal crystallization 3 hours. End insulation devitrify, vacuum filtration, to obtain the wet articles. Control the temperature in oven wet in 35 °C vacuum drying 12 hours to obtain LCZ696 finished 124g, yield 91%, purity 99.93%. The resulting LCZ696 the DSC, the X-ray powder diffraction data of the data with novartis, crystal consistent with novartis reported, the resulting LCZ696 the content of each component data see table below:
6.3 g	Stage #1: N-pentanoyl-N-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]-methyl]-(L)-valine With sodium hydroxide In methanol at 25 - 35℃; for 0.5h; Stage #2: α-ethyl (αR,γS)-γ-<(3-carboxy-1-oxopropyl)amino>-α-methyl<1,1'-biphenyl>-4-pentanoate monosodium salt In acetone at 25 - 35℃; for 0.166667h;	5; 3-10 EXAMPLE 7: (0228) Preparation of amorphous form of sacubitril valsartan trisodium complex: Acetone (100 ml), valsartan disodium (3.3 gms) and sacubitril sodium salt (3.0 gms) were added in to a round bottom flask at 25-35°C. The reaction mass was stirred for 10 min at 25- 35°C for complete dissolution, distilled out the solvent completely under vacuum at 35-40°C and degassed the solid for 1 hr under vacuum at 35-40°C to obtain amorphous form. Yield: 6.3 gms. The PXRD is set forth in Figure 5.

Reference： [1]Current Patent Assignee: ZHEJIANG TIANYU PHARMACEUTICAL - CN105348209, 2016, A Location in patent: Paragraph 0068; 0069; 0070; 0071
[2]Current Patent Assignee: LAURUS LABS LIMITED - WO2018/69833, 2018, A1 Location in patent: Page/Page column 28; 29-32

25
[ CAS Unavailable ]
[ 137862-53-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
91.9%	Stage #1: N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenyl-methyl)-4-amino-(2R)-methylbutanoic acid ethyl ester calcium salt With hydrogenchloride; water In Isopropyl acetate Stage #2: N-pentanoyl-N-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]-methyl]-(L)-valine With sodium hydroxide In n-heptane; water; acetone at 45℃;	2 Example 2Preparation of Compound I The compound of formula (III) 250g isopropyl acetate 2.8L and 0.57L of water and concentrated hydrochloric acid 130.5g dubbed 2N hydrochloric acid, mix until dissolved clear, liquid separation the aqueous phase, the organic phase was concentrated under reduced pressure until no distillate, residual was dissolved in acetone in 4.8L, 0.6L and n-heptane was added valsartan 250g, stirred clear solution; stirring warming up to 45 , solution of sodium hydroxide and 68.5g water 23.8g dubbed the solution, keeping the temperature not to exceed 45 ; after dropping distilled under reduced pressure, the volume was concentrated to about 4L; isopropyl acetate, concentrated under reduced pressure to continue 4L; isopropyl acetate, concentrated under reduced pressure to continue 4L; isopropyl acetate continue Save pressure concentrated to 4L; distillation was stopped, cooling stirred 3h; centrifuged under nitrogen, the cake (wet product) was added isopropyl acetate 4.5L, stirring for about 30min, centrifuged under nitrogen, the cake was dried under reduced pressure until after centrifugation constant weight, to give a compound of formula 501g (the I), 91.9% yield, 99.6% purity. [HPLC method: Column: Cl 8; column temperature 40 ; flow rate 1.0ml / min; mobile phase A: water - acetonitrile (900: 100, v / v), mobile phase B: water - acetonitrile (100: 900, v / v)].

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED; JILIN YATAI (GROUP) CO., LTD. - CN105330609, 2016, A Location in patent: Paragraph 0047; 0048; 0049

26
[ 1883450-88-1 ]
[ 137862-53-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydroxide In Isopropyl acetate; water; acetone at 25 - 55℃; for 4.5h;	11 Example 9 LCZ696 was prepared from a sakicolbicyclohexylamine salt The dicyclohexylamine salt of sakubicin was added(84 g, 142 mmol)Was dissolved in a mixed solvent of 60 mL of isopropyl acetate and 1220 mL of acetone,The solution was heated to 50-55 ° C. After the solution was dissolved, valsartan (63 g, 145 mmol) was added, and 47 g of a 36% aqueous solution of sodium hydroxide was added dropwise thereto. The mixture was incubated at 40-45 ° C for 2 hours and then cooled to room temperature (25-30 ° C) Insulate for 2 hours. After warming, the temperature was raised to 40 ± 3 ° C, and 610 mL of isopropyl acetate was added dropwise. The mixture was incubated at 40 ± 3 ° C for 0.5 hour. Insulation end, temperature 35 ± 5 decompression off 760mL solvent.Off, the temperature to 40 ± 3 ,920 mL of isopropyl acetate was added dropwise,Drop Bi,Temperature control 40 ± 3 heat 0.5 hours.Insulation end,Temperature 35 ± 5 decompression off 1220mL solvent,And then heated to 40 ± 3 ,1220 mL of isopropyl acetate was added dropwise,Drop Bi,Insulation 0.5 hours.And then temperature control 35 ± 5 ° C, 1220mL under pressure reliefSolvent. Off, cooling to 20-25 heat 3 hours. Insulation crystallization end, vacuum filtration, get wet goods.Wet goods in the oven temperature 35 decompression drying 12 hours in LCZ696 finished 116g, yield 85%, purity99.94%. The DSC and X-ray powder diffraction data of the obtained LCZ696 were compared with the data reported by NovartisAnd the crystal form was consistent with that reported by Novartis. The data of LCZ696 were as follows:Saccuquy content valsartan content sodium ion content moisture contentTheoretical value 42.8% 45.3% 7.2% 4.7%Found 42.7% 45.2% 7.3% 4.8%

Reference： [1]Current Patent Assignee: ZHEJIANG TIANYU PHARMACY CO., LTD. - CN105503638, 2016, A Location in patent: Paragraph 0071;0072

27
[ 137862-53-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
91.66%	With sodium hydroxide In water; acetone at 25 - 35℃; for 5h;	8 Example-8: Preparation of valsartan disodium In a 100 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 2 g (4.592 mmol) valsartan, 10 mL acetone and 0.367 g (9.175 mmol) sodium hydroxide solution in 1.6 mL water were stirred for 5 hours at 25-35°C. The reaction mixture was concentrated to dryness at 40°C under vacuum and the residue was degassed for 1 hour at 40°C. 10 mL methyl tert-butyl ether was added and stirred for 2 hours at 25-35°C. The white solid obtained was filtered and washed with methyl tert-butyl ether. The product was dried at 30- 35°C under vacuum for 4 hours to obtain 2.2 g (91.66%) valsartan disodium having 99.07% purity. The compound was characterized as amorphous powder with disodium salt. Sodium content: 9.13% by IC.X-ray powder diffraction (FIG.7)DSC (FIG.8),TGA (FIG.9).
	With sodium carbonate In water; acetone for 3h; Reflux;	22 Example 22: Preparation of Valsartan disodium trihydrate Example 22: Preparation of Valsartan disodium trihydrate In a 3 I jacketed glass reactor, valsartan acid (300 g) was dissolved in acetone (1200 ml) at room temperature. Sodium carbonate (73.5gr) and deionized water (60ml) were added and heated up to reflux temperature. The mixture was agitated at reflux for 3 hours and afterwards cooled to room temperature. Methyl tert-butyl ether (MTBE) (1200ml) was added and the mixture was stirred for 15 hours at 20°C. The suspension was filtered over a Buchner funnel and the wet product was washed with a mixture of acetone:MTBE (1 : 1, 300ml). The wet product was dried at 35 °C under reduced pressure (20 mbars) until constant mass was obtained. Material was analyzed by XRPD (Figure 9).
	With sodium hydroxide In ethanol	5 EXAMPLE 5 Production of the di-sodium salt of (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine EXAMPLE 5 Production of the di-sodium salt of (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine 1 g of (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine is dissolved in 50 ml of ethanol, mixed with 2.3 ml of 2 normal sodium hydroxide solution and concentrated by evaporation, and the residue is evaporated with each of ethanol and ethyl acetate. The white residue is stirred in hot acetonitrile and filtered by suction at room temperature. Drying in a high vacuum at 80° C. over night yields (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine disodium salt as a white powder. Melting point from 260° C., brownish discolouration at 295° C. Elementary analysis: The material obtained (hygroscopic) can be equilibrated in the air (C24H27N5O3Na2, 5.36 mols H2O, molar mass 576.05)

0.88 kg	With sodium hydroxide In methanol for 2h; Reflux;	7 E xample 7: Preparation of crystalline Form B of (S)-N-(1-Carboxy-2-M ethyl-Prop-1-yl)-N-Pentanoyl-N-[2'-(1 H-Tetrazol-5-yl)-Biphenyl-4-yl-M ethyl]-Amine disodium salt To a solution of amorphous (S)-N-(1 -Carboxy-2-Methyl-Prop-1-yl)-N-Pentanoyl-N-[2'-(1 H-Tetrazol-5-yl)-Biphenyl-4-yl-Methyl]-Amine (1.0 Kg) in MIBK (10 V ol.) (Methylisobutyl ketone) was added 30 % Sodium Methoxide solution in methanol solution (0.88 Kg). The temperature of reaction mass was raised to reflux and methanol was removed azeotropi cal ly. T he suspensi on was mai ntai n under reflux for around 2 hr. The suspensi on i was cool ed to around 25 to 30 °C . The suspensi on mass was sti rred at same temperature for 15-30 min. Filtered the reaction mass. The wet cake was dried for 10-12 hr at 65 to 80 °C under vacuum to yield 0.88 Kg of crystal line Form B of (S)-N-(1 -C arboxy-2- Methyl -Prop- 1-yl)-N-Pentanoyl-N-[2'-(1 H-Tetrazol-5-yl)-Biphenyl-4-yl-Methyl]-Amine disodium salt. The PXRD pattern of Form B of (S)-N-(1-Carboxy-2-Methyl-Prop-1-yl)-N-Pentanoyl- N-[2'-(1H-Tetrazol-5-yl)-Biphenyl-4-yl-Methyl]-Amine disodium salt is shown in figure 4. £ IR (cm"1): 561.00, 669.42, 746.37, 760.47, 785.74, 814.68, 861.08, 942.02, 974.87, 1011.05, 1101.83, 1137.16, 1176.23, 1203.48, 1265.48, 1303.84, 1359.14, 1405.62, 1459.74, 1507.88, 1618.07, 2871.76, 2931.82, 2960.36, 3406.61.
404 g	With sodium hydroxide In water; isopropyl alcohol at 35℃; for 0.166667h;	2 Preparation of Valsartan Disodium Form 2 Example 2 Preparation of Valsartan Disodium Form 2 A solution of sodium hydroxide (84.7 g) in water (90.0 g) was added to a solution of valsartan (450.0 g) in propanol (530 g). The resulting solution was stirred for 10 minutes at 35° C. t-Butyl methyl ether (2960 g) was added and the mixture was stirred at about 50° C. After the crystallization started, the mixture was cooled to 10° C. and was kept at this temperature for 15 minutes. The solid was isolated by filtration under vacuum, washed with t-butyl methyl ether and dried under vacuum. Valsartan disodium (404.0 g) was isolated as white to off-white solid. Analysis by X-ray powder diffraction showed that the obtained solid is valsartan disodium form 2. The X-ray powder diffraction pattern of the product is depicted in .
	With sodium hydroxide In water; isopropyl alcohol at 20℃; for 0.5h;	1-7 Example 1: Preparation of Crystalline Form a of Valsartan Disodium Salts 8.71 mg of valsartan was dissolved in 0.87 mL of isopropanol, and 0.2 mL of 2 mmol aqueous sodium hydroxide solution was added dropwise at room temperature. The mixture was stirred for 0.5 hour, and concentrated under reduced pressure to obtain a solid which was then stirred with n-heptane/ethanol (19/1, by volume) overnight, filtered, and vacuum dried at 40° C. to obtain a solid. 3 mg of the solid was added to 0.1 mL of methyl tert-butyl ether. After stirring for 72 hours, the supernatant was discarded after centrifugation, and the obtained solid was dried in an oven at 30° C. to yield a white solid, which is a type A valsartan disodium salt.This valsartan disodium salt crystalline form A was subjected to a solid-state characterization by X-ray powder diffraction and differential scanning calorimetry. The solid-state characterization parameters and spectrums are as described herein.
	With sodium hydroxide In water for 24h;	2.2 Synthesis First, Val was prepared as the sodium salt (Na2Val). The aqueous solution of Na2Val was prepared by adding NaOH 0.2 mol L-1 in the aqueous suspension of Val until reaching a pH value equal to 12. This solution was maintained under magnetic stirring for 24 h and evaporated at 50 °C. The solid material was kept in a desiccator over anhydrous calcium chloride for 24 h in an appropriate bottle for further characterization.
8.5 g	With sodium dithionite In water; ethyl acetate for 0.5h;	1-7 Example-7: Crude Valsartan (10 gm) is dissolved in Ethyl acetate (150 ml) and charged aqueous solution of sodium hydrosulfite (80 ml). Stirred the reaction mass for 30 min. Separated the layers and Ethyl acetate layer containing main product was washed twice with aqueous sodium hydrosulphite solution. Further, the Ethyl acetate layer is washed with water and sodium chloride solution respectively. Collected Ethyl acetate layer and distilled off Ethyl acetate completely. The residue obtained was dissolved in Methanol. To this reaction mass methanolic NaOH solution was added and methanol is distilled off completely. The residue obtained is dissolved in a mixture of Methanol and Ethyl acetate. Cooled to 0°C and white solid was precipitated out. Filtered and dried to obtain disodium salt of Valsartan (8.5 gm) having nitrosoamine impurities well below the limit of quantification. Method of Analysis of Pure Valsartan and disodium salt of Valsartan by HPLC

Reference： [1]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - WO2017/9784, 2017, A1 Location in patent: Page/Page column 27; 28
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2016/201238, 2016, A1 Location in patent: Paragraph 0097
[3]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US9499499, 2016, B2 Location in patent: Page/Page column 29
[4]Current Patent Assignee: BIOCON LIMITED - WO2018/78592, 2018, A1 Location in patent: Page/Page column 16; 17
[5]Current Patent Assignee: BC PARTNERS LLP - US2019/30000, 2019, A1 Location in patent: Paragraph 0071
[6]Current Patent Assignee: NANJING NORATECH PHARMACEUTICALS - US2019/194149, 2019, A1 Location in patent: Paragraph 0090-0103
[7]Siqueira; Ionashiro; Bannach; De Souza; Morgon; Soares; Siqueira; Leles [Thermochimica Acta, 2021, vol. 698]
[8]Current Patent Assignee: HARMAN FINOCHEM LTD - WO2021/111464, 2021, A1 Location in patent: Page/Page column 11-16

28
[ 761373-05-1 ]
[ 137862-53-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
90.83%	With sodium hydroxide In water; acetone at 25 - 35℃; for 1h;	9 Example-9: Preparation of crystalline Form-II of trisodium salt of valsartan sacubitril complex In a 100 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 0.472 g (1.147 mmol) 4-(((2S,4R)-l-([l, l'-biphenyl]-4- yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid in 7 mL acetone, 0.5 g (1.148 mmol) valsartan and 8 mL acetone were added at 25-35°C. 0.138 g (3.444 mmol in 0.4 mL water) aqueous sodium hydroxide solution was added to the reaction mixture and stirred for 1 hour at 25-35°C. The reaction mixture was concentrated at 40°C under vacuum and degassed for 2 hours. 7.5 mL isopropyl acetate was added and the reaction mixture was heated to reflux temperature and stirred for 15 min. The reaction mixture was cooled to 25-35°C and stirred overnight. The white solid obtained was filtered and washed with isopropyl acetate. The wet-cake was dried at 30-35°C under vacuum for 5 hours to obtain 1 g (90.83%) trisodium salt of valsartan sacubitril complex having 99.92%) purity with onset at 114.85°C and melting endotherm at 127.23°C in DSC. The compound was characterized as crystalline trisodium hemipentahydrate.X-ray powder diffraction (FIG.10)DSC (FIG.11)TGA (FIG.12)Sodium content: 7.38% by IC.Moisture content: 6.12%

Reference： [1]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - WO2017/9784, 2017, A1 Location in patent: Page/Page column 25; 26; 28; 29; 30; 31; 32

29
[ 761373-05-1 ]
[ 137862-53-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
94.23%	With sodium hydroxide In methanol; water at 15 - 35℃; for 1h;	16 Example-16: Preparation of amorphous trisodium salt of valsartan sacubitril complex In a 250 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 6.26 g (14.38 mmol) valsartan, 5.91 g (14.38 mmol) sacubitril and 88.8 mL methanol were added at 25-35°C. The reaction mixture was cooled to 15-20°C and 1.725 g aqueous sodium hydroxide solution was added. The reaction mixture was stirred at 25-35°C for 1 hour. Methanol was distilled at 50-55°C under vacuum and the residue was degassed. 88.8 mL methyl tert-butyl ether was added at 40-45°C and stirred for 10 min. The reaction mixture was distilled to remove methyl tert-butyl ether at 50-55°C under vacuum to obtain white solid. The solid was degassed at 40-45°C for 30 min. 29.6 mL cyclohexane was added at 35-40°C and stirred for 1 hour. The product was filtered and washed with cyclohexane. The wet-cake was dried at 35°C under vacuum for 5 hours to obtain 12.38 g (94.23%) trisodium salt of valsartan sacubitril complex having 99.76% purity (Sacubitril= 46.87 %w/w, Valsartan= 52.07%w/w). The compound was confirmed as amorphous form having x-ray powder diffraction as in Fig.18.

Reference： [1]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - WO2017/9784, 2017, A1 Location in patent: Page/Page column 31; 33; 34

30
[ 137862-53-4 ]
[ 577978-22-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With water; magnesium oxide In ethanol at 20 - 40℃;	2 EXAMPLE 2 Production of the magnesium salt as the hexahydrate in situ of (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine EXAMPLE 2 Production of the magnesium salt as the hexahydrate in situ of (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine (0208) 43.55 g of valsartan [(S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine] are dissolved at room temperature in 600 ml of 50% by volume ethanol (from absolute ethanol-see Merck and quarz-bidistilled water). The slightly turbid solution becomes clear after adding a further 50 ml of 50% ethanol. Using a magnetic stirrer, 4.03 g or 0.1 M MgO (Merck p.a.) are slowly added in small portions to this slightly acidic solution with a pH value of 4. The pH value hereby rises to ca. 6. The process is effected with an excess of 10%, i.e. a further 0.40 g of MgO are added. This excess is not fully dissolved, and the pH value rises to ca. 7.5. The small residue is filtered from the solution through a folded filter and washed with 50 ml of 50% ethanol. (0209) The combined clear solution is carefully concentrated at 40° C. whilst stirring with a magnetic stirrer in a large crystallisation dish. Towards the end of this procedure, the solution has a tendency to harden into a glassy gel. Scratching with a glass rod induces the in situ crystallisation in this phase, which may be recognised by the white colour of the crystalline solid thus formed. The product is dried at 50° C. in a recirculating air drier until reaching a constant weight. The yield of magnesium-valsartan-hexahydrate is 53.7 g or 95% based on the valsartan employed as the free acid. (0210) The melting point for the salt hydrate produced according to example 2, namely the magnesium-valsartan-hexahydrate, for a heating rate of 10 K·min-1 in a sealed sample container with a small internal volume, in an amount of 2.24 mg, was measured at 132° C. and the melting enthalpy at 64 kJ·Mol-1. (0211) The density of the crystals of the hexahydrate of the magnesium salt of valsartan produced according to example 2, determined by a helium pycnometer, is 1.273 g·cm-3. This value conforms to the theoretically calculated value of 1.256 g·cm-3 calculated from the single crystal structure. (0212) The optical rotation of the magnesium-valsartan-hexahydrate produced according to example 2 is measured in methanol as a 1% solution [α]20D=-14°. (0213) The enantiomer purity of the salt hydrate produced according to example 2 is determined by a stereo-specific HPLC method. The stereo-specific separation is achieved by a chiral column (Chiral AGP). The enantiomer purity is determined as ee=99.6%. (0214) Calculation of the interlattice plane intervals from the X-ray powder pattern taken with a Guinier camera is as follows for the most important lines for this batch of the magnesium valsartan hexahydrate: (0215) d in []: 19.78, 10.13, 9.84, 7.28, 6.00, 5.81, 5.67, 5.21, 5.04, 4.88, 4.21, 4.18, 4.08, 3.95, 3.46, 3.42. (0216) Elementary analysis gives the following measured values of the elements present in the hexahydrate of the magnesium salt of valsartan and of water. The water evaluation is carried out at 130° C. after expulsion. The findings of the elementary analysis, within the error limits, correspond to the sum formula (C24H27N5O3)2-Mg2+6H2O.

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US9499499, 2016, B2 Location in patent: Page/Page column 25; 26

31
[ 2087891-71-0 ]
[ 137862-53-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: (2R,4S)-5-biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methylpentanoic acid ethyl ester n-octyl-D-glucamine salt; N-pentanoyl-N-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]-methyl]-(L)-valine In water; acetone for 0.166667h; Stage #2: With sodium hydroxide In water; acetone at 10 - 20℃;	14 Example 14: Preparation of trisodium sacubitril- valsartan hemipentahydrate Example 14: Preparation of trisodium sacubitril- valsartan hemipentahydrate. To a suspension of sacubitril n-Octyl-D-Glucamine salt (2g) in acetone (30ml) and water (10ml) was added valsartan (1.23 g) and reaction mixture was stirred for ten minutes. To this reaction mass sodium hydroxide solution (0.34g in 2ml water) was added slowly by maintaining reaction temperature in between 10-20°C and stirred reaction mixture for one hour. Insoluble n-Octyl-D-Glucamine was removed by filteration. Solvent was removed under vacuum and to get a residue. The residue was triturated in acetone (30ml). Product was filtered and washed with acetone (30ml). After drying 2g (75%) solid crystalline product was obtained.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2017/33212, 2017, A1 Location in patent: Page/Page column 36

32
[ 2087891-74-3 ]
[ 137862-53-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: (2R,4S)-5-biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methylpentanoic acid ethyl ester 1-phenylethan-1-amine salt; N-pentanoyl-N-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]-methyl]-(L)-valine In acetone at 10℃; for 1h; Stage #2: With sodium hydroxide In water; acetone at 10 - 20℃;	17 Example 17: Preparation of trisodium sacubitril- valsartan hemipentahydrate Example 17: Preparation of trisodium sacubitril- valsartan hemipentahydrate. To a solution of sacubitril phenyl ethyl amine salt (2g) in acetone (30ml) was added valsartan (1.64g) and reaction mixture was stirred for ten minutes. To this reaction mass sodium hydroxide solution (0.44g in 2ml water) was added slowly by maintaining reaction temperature in between 10-20°C and stirred reaction mixture for one hour. Solvent was removed under vacuum. The obtained residue was triturated in acetone (30ml). Product was filtered and washed with acetone (30ml). After drying 2.5g (72%) solid crystalline product was obtained.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2017/33212, 2017, A1 Location in patent: Page/Page column 37

33
[ 2087891-75-4 ]
[ 137862-53-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: (2R,4S)-5-biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methylpentanoic acid ethyl ester 1-(naphthalen-1-yl)ethan-1-amine salt; N-pentanoyl-N-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]-methyl]-(L)-valine In acetone at 10℃; Stage #2: With sodium hydroxide In water; acetone	20 Example 20: Preparation of trisodium sacubitril- valsartan hemipentahydrate. To a solution of sacubitril naphthyl ethyl amine salt (10g) in acetone (150ml) was added valsartan (7.47g) and reaction mixture was stirred for ten minutes. To this reaction mass sodium hydroxide solution (2.2g in 10ml water) was added slowly by maintaining reaction temperature in between 10-20°C and stirred reaction mixture for one hour. Solvent was removed under vacuum. The obtained residue was triturated in acetone (30ml). Product was filtered and washed with acetone (150ml). After drying 13.2g (80%) solid crystalline product was obtained.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2017/33212, 2017, A1 Location in patent: Page/Page column 38

34
[ 482577-59-3 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / water; toluene / 2 h / -10 - 0 °C 2: triethylamine; sodium azide / toluene / 10 h / 100 - 105 °C 3: sodium hydroxide; water / 2 h / 80 °C

Reference： [1]Current Patent Assignee: QINGDAO XUEJIE CHEMICALS - CN103923028, 2017, B

35
[ 137863-17-3 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
40 g	With water; sodium hydroxide at 80℃; for 2h;	5 Preparation of valsartan: 45 g of Valsartan methyl ester prepared in Example 4, 250 ml of water was added,5 g of sodium hydroxide solid was added under stirring, heated to 80 ° C and stirred for 2 h. Cooling to 35 below,Adjusted to Ph = 2 to 3 with 3% hydrochloric acid, followed by extraction with 200 ml of ethyl acetate,Organic layer cooling, crystallization, filtration, at 60 ~ 70 ,Vacuum degree ≥-0.09Mpa drying, was Valsartan 40g, mp 108 ~ 112 , [α] 20D-68 ° (C1,Methanol), purity 99.3%, related substances 0.7%Chiral isomer 0.14% [literature: mp 105 to 115 ° C, [α] 20D-67.9 ° (C1, methanol)].

Reference： [1]Current Patent Assignee: QINGDAO XUEJIE CHEMICALS - CN103923028, 2017, B Location in patent: Paragraph 0062-0063

36
[ 1245819-90-2 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium azide; dichloro[(-)-sparteine-N,N']copper(II) In ethyl acetate at 70 - 80℃; for 4h; Large scale;	1.4; 1.5 Step S4. To 10 g of Intermediate 3 was added 38 g of ethyl acetate,0.33mol of sodium azide then divided into three batches added,Each batch 0.11mol, stirring heated to 70 ~ 80 ,Add 2% (-) - sparteine-Cu (II) complex to the amount of Intermediate 3 material.Temperature control 70 ~ 80 , stirring reaction 4h, filtered,The filtrate was added 18g ethyl acetate washed once, liquid separation,Add 18g of ethyl acetate to the aqueous phase, cool to 0 ~ 10 ,Dropping glacial acetic acid solution to adjust the pH to 2 ~ 3, liquid separation,The organic phase was stirred at 0 ~ 10 crystallization 2h, suction filtration,Drying gave 8.8 g crude valsartan, which contains 0.5% isomer; Put 40kg of ethyl acetate in the refining tank and heat to 50 ± 5 .Into step S4 obtained valsartan crude 5kg,Control the temperature at 50 ± 5 until the solution is clear.Pressure filter to the crystallization tank, pressure filtration is completed, cooled to 15 ~ 20 ,And maintain the temperature precipitation crystallization. Feed liquid into the centrifuge drying,Discharge from the centrifuge, transfer to double-cone vacuum dryer,Initial drying temperature is 25 , heating interval 3h, amplitude 15 ,Dry for 12h. The material is cooled to 20 ± 5 , the finished product Valsartan 4.6kg,Yield 92%, purity 99.99%, solvent residue (ethyl acetate) 0.28%Enantiomeric impurities were not detected.
61%	With sodium azide; zinc(II) chloride In N,N-dimethyl-formamide at 120 - 130℃;	4; 2 Example 4 Preparation of Compound I-2 In the three-necked bottle, compound III-2 (R4 is ethyl) 51g,33.3 g of zinc chloride, 27.9 g of sodium azide and 62.5 mL of N,N-dimethylformamide were stirred and heated to 120-130 ° C for reaction.Cool down, add toluene, add hydrochloric acid to adjust the pH,The toluene layer was collected by liquid separation and extracted with a 15% aqueous NaOH solution.Hydrolysis, end of hydrolysis, and then adding 50% hydrogen peroxide solution,Slowly add hydrochloric acid to pH=9~10 (the residual ion of the ferric chloride indicator detection system is residual, and hydrogen peroxide can be added when it is insufficient).Add ethyl acetate,Continue to add acid to pH=3~4, dispense, wash,After the concentration was dry, 162 mL of ethyl acetate was added.Cooling and crystallization, washing, to obtain compound I-2,Azide: not detected; detected NDMA: not detected.Yield 61%,The purity is 98%.

Reference： [1]Current Patent Assignee: ZHUZHOU QIANJIN PHARMACEUTICAL CO., LTD. - CN107056720, 2017, A Location in patent: Paragraph 0066; 0067; 0068; 0069; 0081-0083; 0090-0098
[2]Current Patent Assignee: ZHUHAI RUNDU PHARMACEUTICAL CO LTD - CN109748905, 2019, A Location in patent: Paragraph 0102; 0111

37
[ 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

38
[ 2170486-33-4 ]
[ 137862-53-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
87%	With water; sodium hydroxide In acetone at 20℃; for 2h;	1.5 Step (v) 2.07 g (4.03 mol) of the compound (VI) Valsartan 1.75 g (4.03 mol),Acetone 30mL,Stirred at room temperature for 15 minutes,The suspension became clear,A solution of 0.48 g (12.09 mmol) of sodium hydroxide and 3 mL of water was slowly dropped into the reaction solution,Gradual solid precipitation,Continue stirring for two hours,The reaction solution was suction filtered under nitrogen to give 3.4 g of the final product as a white solid (VII)Yield 87%.

Reference： [1]Current Patent Assignee: BEIJING ZHIYUAN TECH; KEBEIYUAN BEIJING BIOMEDICINE SCIENCE TECH - CN107468685, 2017, A Location in patent: Paragraph 0198; 0199; 0208; 0209

39
[ 2170486-34-5 ]
[ 137862-53-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
85.6%	With water; sodium hydroxide In acetone for 2h;	2.5 Step (v) 1.42 g (3.14 mmol) of compound (V)Valsartan 1.36 g (3.14 mmol),20mL acetone was added to the reaction flask,After stirring for 20 minutes, the turbid liquid becomes clear,A mixture of 0.37 g (9.42 mmol) of sodium hydroxide and 1 mL of water was added dropwise,Continue stirring for 2 hours,Gradual precipitation,The reaction solution was suction-filtered under nitrogen to give 2.68 g of the final compound (VI)Yield 85.6%.

Reference： [1]Current Patent Assignee: BEIJING ZHIYUAN TECH; KEBEIYUAN BEIJING BIOMEDICINE SCIENCE TECH - CN107468685, 2017, A Location in patent: Paragraph 0211; 0212; 0221; 0222; 0223

40
[ 100-37-8 ]
[ 137862-53-4 ]
C₃₀H₄₂N₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.5%	With thionyl chloride; In dichloromethane; for 1h;Reflux;	Valsartan 1.75 g (4.25 mmol),Dichloromethane 30mL,0.49 g (4.25 mmol) of 2- (diethylamino) ethanol was added to the reaction flask,After warming to reflux, 0.34 mL (4.25 mmol) of thionyl chloride,Reaction for 1 hour,HPLC detection reaction was complete,After treatment, the reaction mixture was evaporated to dryness under reduced pressure,Cooled to room temperature by adding 5mL of water,With sodium hydroxide solution to adjust pH = 9 ~ 10,Extract with 30 mL of dichloromethane,The combined organic layers were dried over anhydrous sodium sulfate,2.10 g of Compound (II) concentrated by filtration under reduced pressure were filtered off with a desiccant,Yield 92.5%.

Reference： [1]Patent: CN107468685,2017,A .Location in patent: Paragraph 0321; 0322; 0323

41
[ 1012341-50-2 ]
D-lysine [ No CAS ]
[ 137862-53-4 ]
C₂₄H₂₈N₅O₃^(1-)*Ca⁽²⁺⁾*C₆H₁₄N₂O₂*C₂₂H₂₃NO₅^(2-) [ No CAS ]

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

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

42
[ 108-01-0 ]
[ 137862-53-4 ]
[ 2170486-82-3 ]

Yield	Reaction Conditions	Operation in experiment
93.1%	With thionyl chloride In dichloromethane for 1h; Reflux;	12.1 Step (i) Valsartan 1.75 g (4.25 mmol),Dichloromethane 30mL,0.37 g (4.25 mmol) of 2- (dimethylamino) ethanol was added to the reaction flask,After warming to reflux, 0.34 mL (4.25 mmol) of thionyl chloride,Reaction for 1 hour,HPLC detection reaction was complete,After treatment, the reaction mixture was evaporated to dryness under reduced pressure,Cooled to room temperature by adding 5mL of water,With sodium hydroxide solution to adjust pH = 9 ~ 10,Extract with 30 mL of dichloromethane,The combined organic layers were dried over anhydrous sodium sulfate,2.00 g of Compound (II) concentrated by filtration under reduced pressure was removed by filtration,Yield 93.1%.

Reference： [1]Current Patent Assignee: BEIJING ZHIYUAN TECH; KEBEIYUAN BEIJING BIOMEDICINE SCIENCE TECH - CN107468685, 2017, A Location in patent: Paragraph 0313; 0314; 0315

43
[ 2244559-90-6 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate In 5,5-dimethyl-1,3-cyclohexadiene at 100 - 120℃; for 12h;	5 Taking N-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-N-pentanoyl-L-proline 5g In a three-necked flask, add 50 ml of xylene, and then add 7.92 g of potassium carbonate.The reaction was stirred at 100 to 120 ° C for 12 hours, and the pH was adjusted to 3.0 with hydrochloric acid, and washed with water.The impurities were concentrated to give a weight of 4.37 g, a yield of 88%, and a purity of 90.3%.

Reference： [1]Current Patent Assignee: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD. - CN108440434, 2018, A Location in patent: Paragraph 0017-0028

44
[ 73096-42-1 ]
[ 137862-53-4 ]

Reference： [1]Patent: WO2004/26847,2004,A1
[2]Patent: WO2004/26847,2004,A1
[3]Patent: WO2004/26847,2004,A1

45
[ 34421-94-8 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: magnesium; ethylene dibromide / tetrahydrofuran / 4 h / 12 - 25 °C 2.1: zinc(II) chloride / tetrahydrofuran / 0.75 h / 0 - 20 °C 2.2: 17.67 h / 20 °C 3.1: hydrogenchloride / ethanol; water / 3 h / 45 °C 4.1: sodium hydroxide / methanol / 20 °C 4.2: 60 °C / 3750.38 Torr 5.1: pyridine / 1,2-dimethoxyethane; water / 6.32 h / -10 - 23 °C
	Multi-step reaction with 6 steps 1.1: magnesium; ethylene dibromide / tetrahydrofuran / 4 h / 12 - 25 °C 2.1: zinc(II) chloride / tetrahydrofuran / 0.75 h / 0 - 20 °C 2.2: 17.67 h / 20 °C 3.1: hydrogenchloride / ethanol; water / 3 h / 45 °C 4.1: sodium hydroxide / water / 0.25 h / 20 °C / pH 11 5.1: sodium tetrahydroborate / methanol / 0.5 h / 0 - 5 °C / pH 11 6.1: pyridine / 1,2-dimethoxyethane; water / 6.32 h / -10 - 23 °C
	Multi-step reaction with 7 steps 1.1: magnesium; ethylene dibromide / tetrahydrofuran / 4 h / 12 - 25 °C 2.1: zinc(II) chloride / tetrahydrofuran / 0.75 h / 0 - 20 °C 2.2: 17.67 h / 20 °C 3.1: hydrogenchloride / ethanol; water / 3 h / 45 °C 4.1: N-ethyl-N,N-diisopropylamine / toluene / 20 °C 5.1: sodium tetrahydroborate / methanol / 0.67 h / 0 - 5 °C 5.2: pH 6 - 7 6.1: N-ethyl-N,N-diisopropylamine / toluene / 0.5 - 1 h / 0 - 50 °C 7.1: hydrogen / 5%-palladium/activated carbon / ethyl acetate / 3000.3 Torr

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2004/26847, 2004, A1
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2004/26847, 2004, A1
[3]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2004/26847, 2004, A1

46
[ 16652-76-9 ]
[ 137862-53-4 ]

Reference： [1]Patent: WO2004/26847,2004,A1

47
[ CAS Unavailable ]
[ 7732-18-5 ]
[ 137862-53-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium hydroxide In Isopropyl acetate; acetone at 40 - 45℃; for 2h;	2 Example 2: Preparation of LCZ696 from eutectic IV The eutectic IV (64 g, 142 mmol) prepared by the method described in Example 1 was dissolved in a mixed solvent of 60 mL of isopropyl acetate and 1220 mL of acetone. After heating to 50-55 ° C, stir and dissolve, add valsartan (63 g, 145 mmol). Then, 142 g of an aqueous sodium hydroxide solution (10%, 355 mmol) was added dropwise at this temperature. The mixture was incubated at 40 to 45 ° C for 2 hours, and then cooled to room temperature (25 to 30 ° C) for 2 hours. After the end of the heat preservation, the temperature was raised to 40±3° C., and 600 mL of isopropyl acetate was added dropwise. Incubate at 40 ± 3 ° C for 0.5 hours. At the end of the heat preservation, 760 mL of solvent was removed under reduced pressure at a temperature of 35 ± 5 °C. After the completion, the temperature was raised to 40±3° C., 920 mL of isopropyl acetate was added dropwise, and the temperature was maintained at 40±3° C. for 0.5 hour. After the end of the heat preservation, 1200 mL of solvent was decompressed under reduced pressure at 35±5° C., and then the temperature was raised to 40±3° C., 1200 mL of isopropyl acetate was added dropwise, and the mixture was kept for 0.5 hour. Then, the temperature was controlled at 35 ± 5 ° C, and 1200 mL of solvent was removed under reduced pressure. After the release, cool down to 20-25 ° C for 3 hours. After the end of the thermal crystallization, the mixture was filtered under reduced pressure to obtain a wet product. The wet product was dried under reduced pressure at 35 ° C for 12 hours in an oven to obtain 116 g of LCZ696 finished product, the yield was 85%, and the HPLC purity was 99.94%. X-ray powder diffraction of the obtained LCZ696,

Reference： [1]Current Patent Assignee: ZHEJIANG TIANYU PHARMACEUTICAL - CN108530371, 2018, A Location in patent: Paragraph 0073; 0074

48
[ 482577-59-3 ]
[ 638-29-9 ]
[ 137862-53-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N-[2'-cyanobiphenyl-4-yl-methyl] (L)-valine methyl ester hydrochloride With Sodium hydrogenocarbonate In dichloromethane; lithium hydroxide monohydrate at 15℃; for 0.25h; Stage #2: n-valeryl chloride In dichloromethane at 5℃; for 0.25h; Further stages;	7 Reference Example 7: IN 1280/DEL/2009 N-[2′-cyanobiphenyl-4-yl-methyl] (L)-valine methyl ester hydrochloride (50 gm) was taken in water (100 ml) and dichloromethane (200 ml) and cooled to 15° C. Sodium bicarbonate (35 g) was added to the reaction mixture and was stirred for 15 minutes. The two layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined and washed with water. The organic layer was separated, dried over sodium sulfate. Dichloromethane (50 ml) was added to the organic layer and cooled to 5° C. Valeryl chloride (22.5 g) was added and the reaction mass was stirred for 15 minutes at 5° C. A solution of triethylamine (18 g) in dichloromethane (100 ml) was added dropwise to the reaction mass for about 1 h at 5° C. and the reaction mixture was stirred for 1 hour. The two layers were separated and the organic layer was washed with dilute hydrochloric acid and then with aqueous sodium bicarbonate solution and finally with water. The solvent was distilled off atmospherically under vacuum below 70° C. Xylene (150 ml) was added to the reaction mass and cooled to 25° C. The reaction mixture was washed with dilute hydrochloric acid and then with aqueous sodium bicarbonate solution and water. The o-Xylene layer was then filtered and dried over anhydrous sodium sulphate and used for the next step. The o-Xylene layer was heated to 85° C. and then cooled to 20-25° C. under stirring. N,N-dimethylacetamide (50 ml), zinc chloride (27.5 g) and sodium azide (19 gm) were added at 25° C. The temperature of the reaction mass was raised to 150° C. and maintained for 48 hours. The reaction mass was then cooled to 15° C. Dichloromethane (100 ml), water (100 ml) and sodium nitrite (16 gm) were added to the reaction mass. Aqueous hydrochloric acid solution (250 ml; 20%) was added drop wise to the reaction mass and was stirred for 60 minutes. The two layers were separated and the aqueous layer was washed with dichloromethane. Organic layers were combined and cooled to 15° C. Aqueous sodium hydroxide solution (300 ml; 10%) was added and the reaction temperature was raised to 60° C. and stirred for 2 hours. The reaction mass was cooled to 30° C. and the two layers were separated. The aqueous layer was washed with o-xylene. Dichloromethane (150 ml) was added to the aqueous layer and the pH was adjusted to 2.5 with hydrochloric acid at 15° C. The temperature was raised to 25° C. and stirred for 15 minutes. The two layers were separated and the aqueous layer was washed with dichloromethane. The dichloromethane layers were combined washed with 10% NaCl solution. Dichloromethane was then distilled off under vacuum below 30° C. Ethyl acetate (50 ml) was added and was distilled under vacuum below 45° C. Ethyl acetate (200 ml) was further added to the residue and heated to 55° C. to get clear solution, treated with carbon and filtered. The filtrate was cooled to room temperature and maintained for 10 hours. It was then cooled to 15° C. and stirred for 3 hours. The solid obtained was filtered, washed with dichloromethane and dried to get valsartan. NDMA-12.2 ppm, NDEA:0.90 ppm, NDIPA-BDL, NEIPA-BDL, NDBA-BDL, NMBA-BDL (BDL: 0.03 ppm)

Reference： [1]Current Patent Assignee: HETERO DRUGS LIMITED - US2022/127238, 2022, A1 Location in patent: Paragraph 0102-0104

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	137862-53-4	MDL No. :
Formula :	C₂₄H₂₉N₅O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	435.52	Pubchem ID :	-
Synonyms :	CGP 48933	Chemical Name :	(S)-2-(N-((2'-(1H-Tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoic acid

Num. heavy atoms :	32
Num. arom. heavy atoms :	17
Fraction Csp3 :	0.38
Num. rotatable bonds :	11
Num. H-bond acceptors :	6.0
Num. H-bond donors :	2.0
Molar Refractivity :	122.95
TPSA :	112.07 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.79 cm/s

Log Po/w (iLOGP) :	2.09
Log Po/w (XLOGP3) :	4.46
Log Po/w (WLOGP) :	4.01
Log Po/w (MLOGP) :	3.36
Log Po/w (SILICOS-IT) :	4.21
Consensus Log Po/w :	3.63

[ CAS No. 137862-53-4 ] {[proInfo.proName]}

Quality Control of [ 137862-53-4 ]

Related Doc. of [ 137862-53-4 ]

Product Details of [ 137862-53-4 ]

Calculated chemistry of [ 137862-53-4 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 137862-53-4 ]

Application In Synthesis of [ 137862-53-4 ]

[ 137862-53-4 ] Synthesis Path-Upstream 1~4

[ 137862-53-4 ] Synthesis Path-Downstream 1~48

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

Log S (ESOL) :	-5.02
Solubility :	0.00419 mg/ml ; 0.00000961 mol/l
Class :	Moderately soluble
Log S (Ali) :	-6.53
Solubility :	0.000128 mg/ml ; 0.000000293 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-6.95
Solubility :	0.0000488 mg/ml ; 0.000000112 mol/l
Class :	Poorly soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	3.56

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P201-P202-P261-P271-P280-P304+P340+P312-P308+P313-P403+P233-P405-P501	UN#:	N/A
Hazard Statements:	H336-H361	Packing Group:	N/A
GHS Pictogram:

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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.
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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.
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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.
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P401
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