Name: 204255-11-8|(3R,4R,5S)-Ethyl 4-acetamido-5-amino-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate phosphate|98%
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[ 204254-96-6 ]
[ 204255-11-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 1.) sodium azide, ammonium chloride, 2.) trimethylphosphine / 1.) ethanol, water, 70-75 deg C, 18 h, 2.) acetonitrile, <38 deg C, 2 h 2: sodium azide, ammonium chloride / dimethylformamide / 18 h / 70 - 80 °C 3: 0.98 kg / sodium bicarbonate / hexane / 1 h 4: 1.) hydrogen, 2.) phophoric acid / 1.) Raney nickel / 1.) ethanol, 16 h, 2.) ethanol, 55 65 deg C
	Multi-step reaction with 6 steps 1.1: boron trifluoride diethyl etherate / 1.17 h / 0 °C 1.2: 4 h / 0 - 20 °C 1.3: 36 h / 20 °C 2.1: triethylamine; dmap / 1 h / 0 °C 3.1: sodium hydride / dichloromethane; dimethyl sulfoxide; mineral oil / 8 h / 20 °C 4.1: boron trifluoride diethyl etherate / dichloromethane / 0.37 h / -15 °C 5.1: caesium carbonate / dimethyl sulfoxide / 0.25 h / 80 °C 5.2: 0.33 h / 80 °C 6.1: phosphoric acid / ethyl acetate; ethanol / 2 h / 50 °C
	Multi-step reaction with 5 steps 1.1: sodium azide; ammonium chloride / water; ethanol / 8 h / 70 - 75 °C 1.2: 6 h / Reflux 2.1: sodium azide; ammonium chloride / N,N-dimethyl-formamide / 5 h / 8 - 85 °C 3.1: sodium hydrogencarbonate / water; dichloromethane / 1 h / 20 °C 4.1: hydrogen / ethanol / 18 h / 760.05 Torr 5.1: phosphoric acid / acetone; ethanol / Reflux

Multi-step reaction with 6 steps 1.1: magnesium chloride / toluene / 2 h / 20 - 30 °C 1.2: 16 h / 50 - 60 °C 2.1: benzenesulfonyl chloride / toluene / 0.5 h / 0 - 10 °C 2.2: 4.5 h / 0 - 75 °C 3.1: benzoic acid / toluene / 3 h / 115 - 120 °C 4.1: sodium acetate / toluene / 3 h / 110 - 115 °C 5.1: palladium on activated charcoal; hydrogen; acetic acid / ethyl acetate / 16 h / 50 - 60 °C / 2250.23 - 3750.38 Torr 6.1: phosphoric acid / ethanol / 20 h / -19 - 52 °C

Reference： [1]Rohloff, John C.; Kent, Kenneth M.; Postich, Michael J.; Becker, Mark W.; Chapman, Harlan H.; Kelly, Daphne E.; Lew, Willard; Louie, Michael S.; McGee, Lawrence R.; Prisbe, Ernest J.; Schultze, Lisa M.; Yu, Richard H.; Zhang, Lijun [Journal of Organic Chemistry, 1998, vol. 63, # 13, p. 4545 - 4547]
[2]Nie, Liang-Deng; Wang, Fei-Feng; Ding, Wei; Shi, Xiao-Xin; Lu, Xia [Tetrahedron Asymmetry, 2013, vol. 24, # 11, p. 638 - 642]
[3]Current Patent Assignee: TOHO UNIVERSITY - US2014/51756, 2014, A1
[4]Current Patent Assignee: SHANGHAI AOBO PHARMTECH; ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD. - CN113024396, 2021, A

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[ 196618-13-0 ]
[ 204255-11-8 ]

Yield	Reaction Conditions	Operation in experiment
89.9%	With phosphoric acid; In ethanol; at -18.8℃; for 17h;	(g) Preparation of ethyl (3R,4R,5S)-4-N-Acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate [1:1] A 500 ML 3-necked round-bottomed jacketed flask equipped with an overhead (paddle) stirrer, an addition funnel with nitrogen inlet and a septum with thermocouple, is charged with a solution of 9.40 g (0.08153 mol) of 85% phosphoric acid, followed by 120 ML of absolute EtOH. The solution is heated to 52 C. The crude ethyl (3R,4R,5S)-4-N-Acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate solution from (f) is warmed to 25 C., then approximately 2/3 of the solution is rapidly added to the crystallization vessel.The crystallization mixture is seeded with 102 mg of oseltamivir phosphate and crystallization occurs immediately.The slurry is aged 30 minutes before the remainder of the aminoacetamide solution is added over 30 minutes.The slurry is cooled to -18.8 C (-20 C. jacket) over 15 h and aged 2 h.A 600 ML jacketed, fritted funnel with a N2 sweep (set point of -17 C.) is used for the isolation.The slurry is poured into the funnel and as soon as the solvent front reaches the top of the cake, the crystallization vessel is rinsed with acetone (50 ML) and poured on top of the cake.The wet cake is washed with acetone (450 ML) followed by heptane (350 ML).The product is dried in vacuo (45 C. and ~20 mm Hg with a N2 sweep for 18 h) to yield 29.86 g (89.9% yield) of ethyl (3R,4R,5S)-4-N-Acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate [1:1] as a colorless solid.
88.6%	With phosphoric acid; In ethanol; at 50 - 55℃;	EXAMPLE 2; Preparation of Crystalline Form B of the Compound of Formula I16.9 g of phosphoric acid were mixed with 700 mL ethanol in a nitrogen purged 1000 mL glass reactor fitted with a mechanic stirrer and heated to 50 to 55 C. A solution of 45.8 g of (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid ethyl ester in 250 mL of ethanol was added to the phosphoric acid solution within 3 to 5 minutes under stirring. The result clear solution was cooled to -40 C. within 1 hour without seeding. The obtained crystal suspension was slowly stirred at -40 C. over night. The suspension was filtered and washed with 240 mL of acetone and 300 mL of n-heptane. The crystal was then dried in vacuum under maximal temperature of 50 C. 53 g of fine white crystal form B was obtained, correspond to a yield of 88.6%.
85%	With phosphoric acid; In ethanol; at 60℃; for 3h;	A solution of amine 1 (19 mg, 0.061 mmol) in ethanol (1 mL) was added slowly to a hot (60 C) solution of phosphoric acid (85 %, 11.5 mg, 0.061 mmol) in ethanol (0.2 mL). The resulting mixture was stirred for 3h. After cooling to 0 C, the precipitates were collected by filtration and rinsed with cold acetone (2 x 5 mL) to give tamiflu as a white crystal (21 mg, 85 %).1H NMR (CDCl3, 400 MHz): delta 6.86 (s, IH), 4.34 (d, J= 8.9 Hz, IH), 4.25 (dq, J= 1.5 Hz, J = 7.2 Hz, 2H), 4.07 (dd, J= 9.0 Hz, J = 11.7 Hz, IH), 3.74 (t, J = 6.5 Hz, IH), 3.63-3.54 (m, IH), 2.97 (dd, J1)2 = 5.4 Hz, J1)3 = 17.3 Hz, IH) 2.56-2.49 (m, IH), 2.01 (s, IH), 1.58-1.47 (m, 4H), 1.29 (t, J= 7.1 Hz, 3H), 0.87 (dt, Jlj2 = 7.4 Hz, J1)4 = 17.6 Hz, 6H), 13C NMR (D2O, 100 MHz): delta 175.2, 167.4, 137.8, 127.6, 84.3, 75.1, 62.4, 52.6, 49.1, 28.1, 25.4, 25.0, 22.3, 13.3, 8.5, 8.4; 31P NMR (162 MHz, D2O) delta 0.65; HR/MS (ESI) calculated for C16H29N2O4 [M+H+], 313.2127, found 313.2122.

82%	With phosphoric acid; In ethanol; at 0 - 50℃;	20% H3PO4 in EtOH (0.02 mL) was added in the solution of oseltamivir free base (25 mg, 0.08 mmol) in EtOH (0.5 mL). The mixture was stirred and heated to 50 ?C for 30 min and then cooled to 0 ?C. The solvent was removed and the residue was purified by short column chromatography eluted with MeOH to gave oseltamivir phosphate as a white solid (27 mg, 82%).
70%	With phosphoric acid; In ethanol; at 60℃; for 3h;	To a solution of 13 (10 mg) in ethanol (1 mL) and added a hot (60 C) solution of phosphoric acid (3 mg) in ethanol (1 mL). The reaction mixture was heated and stirred at 60 C for 3 h. After cooling to 0 C, the precipitates were collected by filtration and rinsed with cold acetone (2*1 mL) to afford oseltamivir phosphate (1) (9 mg, 70%) as a white crystal.
7.6%	With phosphoric acid; In ethanol;	Example 13; [Show Image] As shown in the chemical equation 20, after the 1-cyclohexene-1-carboxylic acid derivative (26a) (18.9 mg, 60.5 mumol) was dissolved in ethanol (450 ml), phosphoric acid (ethanol 1 M solution, 60.5 ml) was added, and condensation was performed under reduced pressure, so that a crystal was obtained. This crystal was washed with ethyl acetate and was then recrystallized from ethanol. The obtained crystal was washed twice with acetone, so that a phosphate (27a) (3.3 mg, 8.0 mumol, Y. 7.6%) was obtained in the form of a white crystal. The spectrum data of this phosphate (27a) is as shown below and coincided with the spectrum data of an authentic sample of oseltamivir. In addition, the spectrum data of the compounds (25a) and (26a) coincided with that obtained from a compound derived from the authentic sample of oseltamivir. Furthermore, since the optical rotation of the compound (25a) coincided with that of a compound having an allyl carbamate group derived from the amino group at the 5-position of the authentic sample of oseltamivir, the absolute configuration represented by each chemical formula was confirmed. 1H NMR (D2O):delta(ppm) 6.91 (s, 1H), 4.38 (brd, J = 8.3 Hz, 1H), 4.31 (m, 2H), 4.11 (dd, J = 11.9, 9.5 Hz, 1H), 3.62 (m, 2H),3.02(dd, J = 17.2, 5.8 Hz, 1H), 2.58 (m, 1H), 2.14 (s, 3H), 1.70-1.45 (m, 4H), 1.34 (t, J = 7.0 Hz, 3H), 0.94 (t, J = 7.8 Hz, 3H), 0.90 (t, J = 7.8 Hz, 3H).
	With phosphoric acid; In ethanol; at 55℃;Product distribution / selectivity;	A solution of azide 11a (170 mg, 0.5 mmol) in ethanol (20 niL) was treated with Lindlar's catalyst (100 mg) under an atmosphere of hydrogen for 16 h at room temperature. The reaction mixture was filtered through Celite, and rinsed with ethanol. The filtrate was evaporated under reduced pressure to give colorless foam (155 mg), which was dissolved in ethanol (3 mL) and added slowly in portions to a hot (550 C) solution of phosphoric acid (85%, 115 mg, 0.6 mmol) in ethanol (5 mL). Crystallization commenced within minutes. After cooling to o C, the precipitates were collected by filtration and rinsed with cold acetone (2 x) to afford 1 (187 mg, 91% yield). White crystal, mp 189-1910 C [lit. (Fukuta et al., J. Am. Chem. Soc. 2006,128, 6312-6313) mp 184-1860 C]; [alpha]D20 = -35.8 (c = 1, H2O) [lit.(Rohloff et al., . J. Org. Chem. 1998, 63, 4545-4550.) [alpha] = -39.9 (c = 1, H2O); or lit. (Fukuta et al., 2006) [alpha]D22 = -30.5 (c = 0.480, H2O)]; IR (neat) 3501, 1734, 1612, 1150 cm-i; 1H NMR (600 MHz, D2O) delta 6.91 (1 H, s), 4.39 (1 H, d, J =8.0 Hz), 4.32-4.30 (2 H, m), 4.11 (1 H, dd, J = 10.5, 5.7 Hz), 3-67"3-59 (2 H, m),3.01 (1 H, dd, J = 17.4, 5.4 Hz), 2.60-2.56 (1 H, m), 2.14 (3 H, s), 1.61-1.50 (4 H, m), 1.34 (3 H, t, J = 7.1 Hz), 0.94 (3 H, t, J = 7.3 Hz), 0.89 (3 H, t, J = 7.3 Hz); «C NMR (150 MHz, D2O) delta 178.1, 170.3, 140.7, 130.4, 87.2, 77.9, 65.2, 55.4, 52.0, 30.9, 28.3, 27.9, 25.2, 16.1, 11.36, 11.30; 3phi NMR (162 MHz, D2O) delta 0.43; HRMS calcd for CiOH29N2O4 (M+- H3PO4 + H): 313.2127, found: m/z 313.2123. Anal. Calcd for CiH3iN2theta8P: C, 46.83; H, 7.61; N, 6.83. Found: C, 46.70; H, 7.69; N, 6.74.
	With phosphoric acid; In ethyl acetate; acetone; at 20℃; for 4h;Heating / reflux;Product distribution / selectivity;	Ethyl (3R,4R,5S)-4-(Acetylamino)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (8.5 gm) was dissolved in tetrahydrofuran (130 ml) and then triphenyl phosphine (10.5 gm) and water (50 ml) are added. The contents were heated to reflux, refluxed for 5 hours and then distilled off the solvent under vacuum. To the reaction mass added ethyl acetate (80 ml), washed with 30% sodium chloride solution (50 ml) and distilled off the solvent completely under vacuum. Acetone (130 ml) was added to the residue, heated to reflux, under reflux the mixture of H3PO4 (3 gm) and ethyl acetate (50 ml) was slowly added during 1 hour and then refluxed for 1 hour. The reaction mass was cooled to 25 C. and stirred for 2 hours at 20-25 C. Filtered the solid, washed with acetone (10 ml) and dried at 60-65 C. for 4 hours to yield 6.5 gm of oseltamivir phosphate (HPLC Purity: 99.6%).
	With phosphoric acid; In ethanol; acetone; at 20℃; for 5.5h;Heating / reflux;Product distribution / selectivity;	Ethyl (3R,4R,5S)-4-(Acetylamino)-5-azido-3-(1-ethylpropoxy)-1-cyclohex-ene-1-carboxylate (8.5 gm) was added to pyridine (200 ml) and then bubbled H2S gas for 3 hours at 25-35 C. Stopped the bubbling of H2S gas and then the reaction mixture was stirred for 5 hours at 25-35 C. The reaction mass was flushed with N2 gas for 20-30 minutes and distilled off the solvent completely under reduced pressure keeping the bath temperature below 50 C. To the residue added ethyl acetate (100 ml) and washed with 30% sodium chloride solution (50 ml). Distilled off the ethyl acetate completely under reduced pressure. Acetone (100 ml) was added to the residue, heated to reflux, under reflux the mixture of H3PO4 (3.2 gm) and ethanol (25 ml) was slowly added during 1 hour 30 minutes and then refluxed for 2 hours. The reaction mass was cooled to 25 C. and then stirred for 2 hours at 20-25 C. Filtered the solid, washed with acetone (10 ml) and dried at 60-65 C. for 4 hours to give 6.9 gm of oseltamivir phosphate (HPLC purity: 99.8%).
997 mg	With phosphoric acid; In ethanol; water; ethyl acetate; at 20 - 50℃;	Compound 9 (0.90 g, 2.66 mmol) was dissolved in aqueous tetrahydrofuran (20 mL, THF/H2O = 10:1). Triphenylphosphine (0.77 g, 2.94 mmol) was added in portions at room temperature. After the mixture was heated at reflux and stirring was continued for 8 h. Solvents were removed by vacuum distillation, and the residue was cooled down to room temperature. The residue was then dissolved in a mixed solvent of ethyl acetate (3.5 mL) and ethanol (1.5 mL). After aqueous phosphoric acid (368 mg, 85% w/w, 3.19 mmol) was added, the mixture was warmed to 50 C, and stirring was continued for 2 h at 50 C. The reaction mixture was cooled down to room temperature and stirred for a further 8 h. White crystals were formed and precipitated. After suction and twice rinsing with ethyl acetate, the white crystals were dried under vacuum at 50 C overnight to furnish the title compound oseltamivir phosphate 1 (997 mg, 2.43 mmol) in 91% yield. The characterization data of compound 1 were identical with those of the sample obtained in our previous articles.31,32
0.34 g	With phosphoric acid; In ethanol; ethyl acetate; at 50℃; for 2h;	A solution of compound 8 (460.0mg, 1.005mmol) in DMSO (8mL) was heated to 80C. Fine powdered Cs2CO3 (815.0mg, 2.501mmol) was added quickly, and the mixture was stirred at 80C for 15min. An aqueous solution of acetic acid (50% w/w, 3mL) was added, and stirring was continued at 80C for 20min. After the mixture was cooled down to room temperature, ethyl acetate (30mL) and an aqueous solution of K2CO3 (20% w/w, 15mL) were added. After the mixture was vigorously stirred for 10min, the two phases were separated, and the aqueous phase was extracted twice with ethyl acetate (2×20mL). The organic extracts were combined and dried over anhydrous MgSO4. Evaporation of the solvent under vacuum gave a pale yellow oily residue, which was dissolved in a mixed solvent of ethyl acetate (4mL) and ethanol (4mL). Phosphoric acid (85%, 130.0mg, 1.128mmol) was then added, and the resulting suspension was heated and stirred at 50C for 2h. The suspension was cooled down to room temperature, and then allowed to stand overnight. White crystals were collected on a Buchner funnel by suction and washed twice with ethyl acetate (2×1mL). After being dried overnight in warm air, oseltamivir phosphate 1 (0.340g, 0.828mmol) was obtained in 82% yield. The characterization data of compound 1 were identical with those of the sample obtained in our previous report.(a), (b), (c)and(d)
	With phosphoric acid; In ethanol; acetone;Reflux;	[0102] A phosphoric acid salt of the compound expressed by the Structural Formula (I) can be obtained in the following manner. Specifically, a solution of the compound expressed by the Structural Formula (I) in acetone is refluxed and treated with phosphoric acid in absolute ethanol. Crystallization commences immediately and after cooling to 0 C. for 12 hours the precipitate is collected by filtration to afford the phosphoric acid salt of the compound expressed by the Structural Formula (I) as colorless needles.
	With phosphoric acid; In ethanol; at 45 - 50℃; for 0.75h;	The above formula (II) is dissolved in 240 ml of absolute ethanol at room temperature, and the temperature is raised to 45 to 50 C, and the addition is completed over 60 minutes.Dissolve a mixed solution of 13.4 g of 85% phosphoric acid in 150 ml of absolute ethanol, and stir at 45 to 50 C for 45 minutes; slowly cool down,4.0h was lowered to 0 C, stirred at -5 to 0 C for 60 minutes, suction filtered, and the filter cake was rinsed with 60 ml of absolute ethanol and drained. Vacuum drying Drying (45 ~ 50 C) for 6 h, obtained a white solid (I) crude. The crude product of formula (I) is dissolved in 180 ml of absolute ethanol + 30 ml of pure at room temperature. In a mixed solvent of water, the temperature is raised to 45 to 50 C, the temperature is maintained for 60 minutes, and the mixture is rapidly filtered while the mother liquor is at 45. Concentrated to a solid precipitate at C; add 180 ml of absolute ethanol, continue to concentrate at 45 C to a paste; add 180 ml of absolute ethanol, Warm up, maintain 45 ~ 50 C and continue to stir for 60 minutes; adjust the stirring speed to 75 rev / min, slowly cool down, 2.5 h will drop the temperature The mixture was stirred at -0 to 0 C for 120 minutes to 0 C; filtered, and the filter cake was rinsed with 60 ml of anhydrous ethanol and drained. Dry at 45~50C vacuum After drying for 6 hours, the white solid (I) oseltamivir phosphate was obtained.The total yield was 65.8% and the purity was 99.8%.

Reference： [1]Patent: US2004/180933,2004,A1 .Location in patent: Page/Page column 11
[2]Patent: US2009/176886,2009,A1 .Location in patent: Page/Page column 4
[3]Patent: WO2009/78813,2009,A1 .Location in patent: Page/Page column 43
[4]Chemistry - A European Journal,2010,vol. 16,p. 4533 - 4540
[5]Tetrahedron Letters,2012,vol. 53,p. 6209 - 6211,3
[6]Tetrahedron,2015,vol. 71,p. 2393 - 2399
[7]Patent: EP2050752,2009,A1 .Location in patent: Page/Page column 18-19
[8]Angewandte Chemie - International Edition,2008,vol. 47,p. 5788 - 5791
[9]Patent: WO2009/29888,2009,A2 .Location in patent: Page/Page column 56
[10]Patent: US2009/54682,2009,A1 .Location in patent: Page/Page column 3
[11]Patent: US2009/54682,2009,A1 .Location in patent: Page/Page column 3
[12]Angewandte Chemie - International Edition,2009,vol. 48,p. 5760 - 5762
Angew. Chem., Int. Ed.,2009,vol. 121,p. 5871 - 5873
[13]Tetrahedron Letters,2010,vol. 51,p. 3208 - 3210
[14]Tetrahedron Asymmetry,2011,vol. 22,p. 1692 - 1699
[15]Tetrahedron Asymmetry,2013,vol. 24,p. 638 - 642
[16]Organic Process Research and Development,2004,vol. 8,p. 86 - 91
[17]Russian Chemical Bulletin,2013,vol. 62,p. 163 - 170
Izv. Akad. Nauk, Ser. Khim.,2013,vol. 62,p. 165 - 171,7
[18]Patent: US2014/51756,2014,A1 .Location in patent: Paragraph 0102
[19]Patent: CN109627180,2019,A .Location in patent: Paragraph 0020; 0025; 0026; 0030; 0034; 0035 0039; 0043

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[ 367252-68-4 ]
[ 204255-11-8 ]

Yield	Reaction Conditions	Operation in experiment
83%	With phosphoric acid; In ethanol; at 0 - 78℃; for 15h;Inert atmosphere;	To an oven-dried 10 mL round bottom flask equipped with a stir bar was added ethyl (3R,4R,5S)-4-acetamido-5-((tert-butoxycarbonyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate 9 (1.21 g, 2.9 mmol). The flask was evacuated and backfilled with N2 twice and then EtOH (4 mL) was added. Subsequently, H3PO4 (1.08 mL, 17.6 mmol, 6.0 equiv) in EtOH (1.8 mL) was added to the flask at room temperature using a syringe. The mixture was warmed up to 78 C. and stirred for additional 12 h (monitored by TLC until the starting material was consumed). The mixture was then cooled to 0 C. and stirred for 3 h with precipitates generated. The reaction mixture was filtered and the solid was washed with cold acetone (2.0 mL×3). The solid was collected and dried in vacuo to afford the desired product 10 (Tamiflu) as a white solid (1.0 g, 83% yield, m.p. 188-190 C.). Ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(pentan-3-yloxy) cyclohex-1-ene-1-carboxylate (oseltamivir phosphate, 10) [alpha]D20=-30 (c 1.01, H2O). IR numax (neat)/cm-1: 3347 (m), 3169 (br), 2966 (w), 2937 (w), 2874 (w), 1716 (s), 1656 (s), 1549 (s), 1243 (s), 1120 (s), 952 (s), 850 (m); 1H NMR (400 MHz, D2O) delta 6.75 (s, 1H), 4.23 (d, J=9.0 Hz, 1H), 4.15 (dt, J=7.2, 5.3 Hz, 2H), 3.95 (dd, J=11.6, 9.0 Hz, 1H), 3.55-3.39 (m, 2H), 2.86 (dd, J=17.0, 5.6 Hz, 1H), 2.50-2.35 (m, 1H), 1.98 (s, 3H), 1.41 (ddt, J=41.6, 14.2, 7.2 Hz, 4H), 1.18 (t, J=7.1 Hz, 3H), 0.76 (dt, J=17.7, 7.4 Hz, 6H); 13C NMR (100 MHz, D2O) delta 175.2, 167.3, 137.9, 127.5, 84.2, 75.0, 62.3, 52.6, 49.0, 28.1, 25.4, 25.0, 22.3, 13.2, 8.5, 8.4; LRMS (ESI, m/z): calcd for C16H29N2O4+, [M-H3PO4+H+], 313.2, found 313.2.
75%		To an ice-cooled solution of 17 (100 mg, 0.24 mmol) in CH2Cl2 (1 mL) was added TFA (0.24 mL, 3.23 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled and diluted with CH2Cl2 (5 mL), H2O (3 mL) and toluene (10 mL). The mixture was evaporated and the residue was partitioned between water (30 mL) and EtOAc (25 mL). The aqueous layer was extracted with EtOAc (3×25 mL) and the combined organic layers were washed with satd aq NaHCO3 (25 mL). The separated organic phase was dried (Na2SO4), filtered, and evaporated to dryness. The residue was dissolved in EtOH (1.5 mL) and 1.0 M H3PO4 in EtOH (0.29 mL, 0.29 mmol) was added to the stirred solution. The mixture was warmed to 55 C until white crystals were formed. The mixture was slowly cooled down to 0 C. The crystals were collected and washed with acetone and hexane to yield 1 (0.08 g, 75%) as white crystals, mp 200-201 C (dec). -31.59 (c 0.31, H2O) (reported -31.7 (c 1.0, H2O));16 FTIR (KBr), numax, cm-1: 3508, 1735, 1607, 1142; 1H NMR (400 MHz, CDCl3) delta 0.71 (t, J=7.4, 3H), 0.76 (t, J=7.4, 3H), 1.14-1.17 (m, 3H), 1.38-1.29 (m, 1H), 1.46-1.39 (m, 3H), 2.40 (m, 1H), 1.96 (s, 3H), 2.84 (dd, J=17.4, 5.5 Hz, 1H), 3.41 (quint, J=5.7 Hz, 1H), 3.46-3.48 (m, 1H), 4.15-4.09 (m, 2H), 3.91-3.93 (m, 1H), 4.22-4.19 (m, 1H), 6.71-6.72 (m, 1H); 8.6. 8.7, 13.5, 22.6, 25.2, 25.6, 28.3, 49.3, 52.8, 62.6, 75.3, 84.4, 127.8, 138.1, 167.6, 175.4,
71%		To a stirred solution of 19 (62 mg, 0.15 mmol) in CH2Cl2 (1 mL), TFA (0.22 mL) was added at rt. The resulting solution was stirred for 1 h at the same temperature. After removing solvent under reduced pressure, the residue was dissolved in CH2Cl2 (3 mL), and saturated NaHCO3 aq solution was added at 4 C. The aq layer was extracted with CH2Cl2 (10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. To a stirred solution of crude product in EtOH (2.4 mL), a solution of H3PO4 in EtOH (1 M, 0.3 mL, 0.3 mmol) was added at room temperature. After the resulting solution was warmed to 50 C, crystallization commenced. The mixture was slowly cooled down to 4 C. The crystals were collected and washed with acetone and hexane to afford 1 (32 mg, 71% yield) as white crystals. Mp 205-206 C; [alpha]D25 -26.4 (c 1, H2O); (Reported [alpha]D29 -27.1 (c 0.97, H2O));4q numax (KBr) 3422, 2362, 2342, 1715, 1658, 1248 cm-1; deltaH (400 MHz, CDCl3) 6.81 (m, 1H), 4.33-4.26 (m, 1H), 4.26-4.17 (m, 1H), 4.06-3.98 (m, 1H), 3.60-3.47 (m, 2H), 2.97-2.88 (m, 1H), 2.54-2.42 (m, 1H), 2.04 (s, 3H), 1.58-1.46 (m, 3H), 1.45-1.36 (m, 1H), 1.24 (t, J=7.3 Hz, 3H), 0.84 (t, J=7.7 Hz, 3H), 0.80 (t, J=7.7 Hz, 3H); deltaC (75 MHz, CDCl3) 175.9, 168.0, 138.5, 128.2, 84.9, 75.7, 63.0, 53.2, 49.7, 28.8, 26.1, 25.6, 23.0, 13.9, 9.1, 9.0; m/z (MS-ESI) 313 [M+H]+; HRMS(ESI) calcd for C16H29N2O4 [M+H]+ 313.2132, found 325.2127.

	In ethyl acetate;	EXAMPLE 13a Preparation of (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid ethyl ester phosphoric acid salt To a solution of 10.31 g (3R,4R,5S)-4-acetylamino-5-tert.-butoxy-carbonyl-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid ethyl ester (25 mmol) in 100 ml ethyl acetate were added at room temperature. 25 ml 5N HC1 in ethyl acetate. After 20 min. a white precipitate was formed and the thick suspension was stirred at room temperature for 24 h.
	With phosphoric acid; In ethanol; at 50℃; for 6h;Product distribution / selectivity;	Compound 31a (1.24 g, 3 mmol) was dissolved in ethanol (20 niL) and added slowly in portions to a hot (50 0C) solution of phosphoric acid (10 niL of 1 M solution in ethanol, 10 mmol). The solution was stirred for 6 h at 50 0C. After cooling to 0 0C, the precipitates were collected by filtration and rinsed with cold acetone (3 x 5 mL) to afford Tamiflu (998 mg, 81%) as white crystals; m.p. 187-190 0C [lit. m.p. 184-186 0C]; [alpha]D20 = -36.7 (c = 1, H2O) [lit. [alpha]D = -39.9 (c = 1, H2O); or lit. [alpha]D22 = -30.5 (c = 0.480, H2O)]; IR (film) 3501, 1734, 1612, 1150 cm-1; 1H NMR (600 MHz, D2O) delta 6.91 (1 H, s), 4-39 (1 H, d, J = 8.0 Hz), 4.32-4.30 (2 H, m), 4.11 (1 H, dd, J = 10.5, 5.7 Hz), 3-67"3-59 (2 H, m), 3.01 (1 H, dd, J = 17.4, 5.4 Hz), 2.60-2.56 (1 H, m), 2.14 (3 H, s), 1.61-1.50 (4 H, m), 1.34 (3 H, t, J = 7.1 Hz), 0.94 (3 H, t, J = 7.3 Hz), 0.89 (3 H, t, J = 7.3 Hz); «C NMR (150 MHz, D2O) delta 178.1, 170.3, 140.7, 130.4, 87.2, 77.9, 65.2, 55.4, 52.0, 30.9, 28.3, 27.9, 25.2, 16.1, 11.36, 11.30; 3ip NMR (162 MHz, D2O) delta 0.43; HRMS calcd for CiH29N2O4 (M+ - H3PO4 + H): 313.2127, found: m/z 313.2132. Anal. Calcd for C16H31N2O8P: C, 46.83; H, 7.61; N, 6.83. Found: C, 46.72; H, 7.68; N, 6.75-

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 10619 - 10626
[2]Patent: US10385010,2019,B1 .Location in patent: Page/Page column 20; 24
[3]Angewandte Chemie - International Edition,2008,vol. 47,p. 5788 - 5791
[4]Tetrahedron,2012,vol. 68,p. 6803 - 6809
[5]Tetrahedron,2011,vol. 67,p. 2044 - 2050
[6]Patent: US2001/36653,2001,A1
[7]Patent: WO2009/29888,2009,A2 .Location in patent: Page/Page column 80

4
[ 204255-11-8 ]
[ 196618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium hydrogencarbonate In water at 20℃; for 0.0833333h; Inert atmosphere;	3 4.1.3 Ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (3) To a solution of oseltamivir phosphate (1.0 g, 2.43 mmol) in water (30 mL) was added a saturated solution of sodium bicarbonate (10 mL). The reaction mixture was stirred for 5 min at room temperature. The mixture was extracted with DCM/MeOH mixture (3:1; 4 * 10 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to furnish the free base of oseltamivir (0.75 g, 98% yield). The product was used without further purification. 1H NMR (300 MHz, CDCl3) δ 6.78 (t, J = 2.1 Hz, 1H), 6.26 (d, J = 8.3 Hz, 1H), 4.34-4.10 (m, 3H), 3.55 (dt, J = 10.3, 8.4 Hz, 1H), 3.37 (dd, J = 17.7, 12.0 Hz, 1H), 3.26-3.08 (m, 1H), 2.76 (dd, J = 17.7, 5.1 Hz, 1H), 2.26-2.08 (m, 1H), 2.04 (s, 3H), 1.58 (s, 2H), 1.55-1.44 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H), 0.90 (td, J = 7.4, 3.8 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 171.1, 166.4, 137.8, 129.5, 81.7, 77.6, 77.2, 76.7, 75.0, 60.8, 58.9, 49.3, 33.7, 26.2, 25.7, 23.6, 14.2, 9.6, 9.3. HR-ESI-MS calculated for C16H29O4N2 (M + H)+ 313.2122, found 313.2122.
	Stage #1: oseltamivir phosphate In dichloromethane; water at 25 - 30℃; for 0.166667h; Stage #2: With ammonia In dichloromethane; water Stage #3: In n-heptane at 25 - 30℃; for 1h;	1.a; 1.b Example 1; Step-(a); :Oseltamivir phosphate (20 gm, HPLC purity: 97%) is stirred with water (100 ml) and methylene chloride (100 ml) for 10 minutes at 25 - 300C and then pH of the mass is adjusted to 9 - 10 with liquor ammonia. Separated the layers, the organic layer is subjected to carbon treatment and filtered on hiflo bed. Washed the hiflo bed with methylene chloride (20 ml) and then distilled the organic layer under vacuum at 400C to give 16.5 gm of oseltamivir free base as a residue. Step-(b):To the residue obtained in step-(a) is added n-heptane (100 ml) and stirred for 1 hour at 25 - 300C. Filtered the solid and dried to give 13 gm of pure oseltamivir free base (HPLC Purity: 99.2%, Melting Range: 102.5 - 103.90C).
	Stage #1: oseltamivir phosphate In dichloromethane; water at 25 - 30℃; for 0.166667h; Stage #2: With ammonia In dichloromethane; water Stage #3: In n-heptane; toluene at 20 - 30℃; for 3.5h;	2 Example 2; The residue (5 gm, obtained as per the process described in step-(a) of example 1) is dissolved in toluene (10 ml), n-heptane (70 ml) is slowly added to the solution for 30 minutes to 1 hour at 20 - 300C and then stirred for 2 hours at 20 - 300C. Filtered the solid, washed with n-heptane (20 ml) and dried to yield pure oseltamivir free base (HPLC Purity: 99.3%).

In dichloromethane; water at 20℃; for 0.75h;

9 A stirred solution of oseltamivir phosphonate 100 mg, in 50 mL DCM was treated with 50 mL water, Na2CO3 (60 mg). The white solution was stirred over a period of 45 minutes at room temperature. The combined aqueous and organic layers were extracted with dichloro methane (100 mL) and the organic phase was dried over Na2SO4 and the combined organic phase was evaporated in a rotary evaporator to yield the product oseltamivir as a liquid. This oseltamivir was used without further purification in the next step. Oseltamivir amine was coupled with Fmoc-PEG-acid (16 atoms) in the presence of EDC, HOBt and DIPEA in DCM. The solution was stirred over a period of 16 h at room temperature. The crude product was purified by silica column chromatography using a 8:2 mixture of DCM and hexane. The combined fractions were evaporated and dried on a rotary evaporator to obtain the product as a yellow oil. A solution of 20% piperidine in dichloromethane was added to the above a yellow oil and stirred for 30 min. The crude product was purified by preparative RP-HPLC using aqueous CH3CN, then freeze-dried to yield the desired compound as a pale yellow resin.

Reference： [1]Albinaña, Carlos Berenguer; MacHara, Aleš; Rezacov, Pavlína; Pachl, Petr; Konvalinka, Jan; Kozísek, Milan [European Journal of Medicinal Chemistry, 2016, vol. 121, p. 100 - 109]
[2]Current Patent Assignee: HETERO DRUGS LIMITED - WO2007/77570, 2007, A1 Location in patent: Page/Page column 4
[3]Current Patent Assignee: HETERO DRUGS LIMITED - WO2007/77570, 2007, A1 Location in patent: Page/Page column 4
[4]Current Patent Assignee: PURDUE UNIVERSITY SYSTEM - US9250238, 2016, B2 Location in patent: Page/Page column 84; 85; 86

5
[ 24424-99-5 ]
[ 204255-11-8 ]
[ 367252-68-4 ]

Yield	Reaction Conditions	Operation in experiment
96.3%	With triethylamine; In methanol; at 20℃; for 12h;	<strong>[204255-11-8]Oseltamivir phosphate</strong> (5 g, 1.22 mmol) was added to a 100 ml round-bottomed flask, dissolved in 25 ml of methanol solution, and Boc anhydride (5 g, 2.4 mmol) and 5 ml of triethylamine were added dropwise with stirring.Reaction at room temperature for 12 hours;The methanol was evaporated to dryness under reduced pressure, and the reaction liquid was filtered. The solid was washed with distilled water and dried in a vacuum oven to obtain a white powdery solid A-1. The calculated yield was 96.3%.
91%	With triethylamine; In methanol; at 20℃; for 12h;	To a solution of commercially available 11 <strong>[204255-11-8]oseltamivir phosphate</strong> (1) (10g, 24.4mmol) in 100mL 13 methanol was added 47 diter-butoxycarbonyl anhydride ((Boc)2O, 10g) and 14 triethylamine (TEA, 4mL) at room temperature, and the mixture was stirred for 12h. Subsequently, the solution was evaporated under reduced pressure to remove methanol and was transferred to a separators funnel, and the residue was washed with water to afford 15 2 as a white solid, yield 91%. 1H NMR (400MHz, DMSO-d6) delta 7.80 (d, J=9.1Hz, 1H), 6.61 (d, J=6.9Hz, 2H), 4.21-3.99 (m, 3H), 3.75-3.61 (m, 1H), 3.57 (td, J=15.6, 10.1Hz, 1H), 3.38 (dd, J=10.9, 5.5Hz, 1H), 2.46 (d, J=4.7Hz, 1H), 2.25 (dd, J=17.5, 10.3Hz, 1H), 1.78 (s, 3H), 1.52-1.28 (m, 13H), 1.22 (t, J=7.1Hz, 3H), 0.80 (dt, J=26.5, 7.3Hz, 6H); 13C NMR (100MHz, DMSO-d6) delta 169.66 (s), 165.99 (s), 155.78 (s), 138.66 (s), 129.08 (s), 81.49 (s), 78.04 (s), 75.44 (s), 60.88 (s), 54.61 (s), 49.31 (s), 30.61 (s), 28.65 (s), 26.17 (s), 25.65 (s), 23.31 (s), 14.52 (s), 9.88 (s), 9.43 (s). HRMS (ESI): calcd for C21H36N2O6 [M+H]+ 413.2651; found m/z: 413.2644.
87.2%	With dmap; triethylamine; In dichloromethane; at 20℃; for 2h;	To a solution of commercially available <strong>[204255-11-8]oseltamivir phosphate</strong> 1(8.2 g, 0.02 mol, 1 equiv) in 50 mL dichloromethane was added ditert-butyl dicarbonate ((Boc)2O, 8.72 g, 2 equiv), DMAP (0.2 g) andtriethylamine (TEA, 30 mL) at room temperature, and the mixturewas stirred for 2 h. Subsequently, the solution was evaporated underreduced pressure to remove dichloromethane and TEA andthen saturated citric acid solution was added. After that, themixture was extracted with ethyl acetate, and the organic phasewas dried over anhydrous MgSO4, and concentrated under reducedpressure to give the crude product, which was purified by recrystallizationform isopropyl ether to afford 2 as a white powder, yield87.2%. mp: 149.1-150.2 C. 1H NMR (400 MHz, CD3OD) delta: 6.76 (s,1H, CH), 4.20 (q, J 7.1 Hz, 2H, CH2), 4.10 (d, J 8.3 Hz, 1H, CH), 3.85(dd, J 11.0, 8.7 Hz, 1H, CH), 3.76e3.66 (m, 1H, CH), 3.40 (p,J 5.6 Hz, 1H, CH), 2.68 (dd, J 17.7, 5.1 Hz, 1H, CH), 2.30e2.18 (m,1H, CH), 1.95 (s, 3H, CH3), 1.56e1.41 (m, 13H, 2CH2, 3CH3), 1.29 (t,J 7.1 Hz, 3H, CH3), 0.95e0.83 (m, 6H, 2CH3). 13C NMR (100 MHz,CD3OD) delta: 172.34, 166.13, 156.67, 137.67, 129.05, 82.33, 78.85, 75.71,60.68, 54.77, 48.95, 30.48, 27.33, 25.87, 25.40, 21.60, 13.09, 8.46,8.26. ESI-MS: m/z 413.5 [M H], C21H36N2O6 (412.52).

56%	With triethylamine; In methanol; at 20℃; for 12h;	At room temperature, di-tert-butyl dicarbonate (7.84 mL, 34.1 mmol) and triethylamine (6.80 mL, 48.8 mmol) were added dropwise to a solution of <strong>[204255-11-8]oseltamivir phosphate</strong> salt (3) (10.0 g, 24.4 mmol) in MeOH (50 mL) while the solution was stirred. The reaction mixture was stirred at room temperature for 12 hours. Distilled water (100 mL) was added to the mixture which was then stirred for 1 hour. Next, the produced white solid was filtered and washed with distilled water. The filtrate was dried in a vacuum oven to obtain compound 4 (5.71 g, 56%) as a white solid.
0.82 g	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃; for 2h;	To a mixture of oseltamivir (as the phosphate salt, 0.75 g,1.83 mmol) and NaHCO3 (0.77 g, 9.14 mmol) in THF/H2O (10 mL/10 mL) was added di-tert-butyl dicarbonate [(Boc)2O] (0.52 g,2.38 mmol). The mixture was stirred for 2 h at room temperature,and concentrated under reduced pressure. The residue was dilutedwith CH2Cl2, and washed with water. The aqueous phase wasextracted with CH2Cl2 (3 ). The combined organic phasewas driedover MgSO4, filtered, and concentrated under reduced pressure togive 14 (0.82 g), the Boc derivative of oseltamivir, whichwas used inthe next step without further purification.

Reference： [1]Biochemical Journal,2018,vol. 475,p. 3847 - 3860
[2]Carbohydrate Research,2019,vol. 477,p. 32 - 38
[3]Patent: CN107827830,2018,A .Location in patent: Paragraph 0035; 0036
[4]Chemical Communications,2019,vol. 55,p. 6353 - 6356
[5]European Journal of Medicinal Chemistry,2018,vol. 146,p. 220 - 231
[6]European Journal of Medicinal Chemistry,2019,vol. 178,p. 64 - 80
[7]Patent: US2018/346417,2018,A1 .Location in patent: Paragraph 0057; 0059
[8]Journal of Organic Chemistry,2008,vol. 73,p. 4895 - 4902
[9]Journal of Medicinal Chemistry,2014,vol. 57,p. 8445 - 8458
[10]European Journal of Medicinal Chemistry,2019,vol. 163,p. 710 - 721

6
phosphoric acid [ No CAS ]
[ 196618-13-0 ]
[ 204255-11-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	In ethanol; water at 50 - 55℃; for 1.5 - 2h;	Preparation of (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethyl-propoxy)cyclohex-1-enecarboxylic acid ethyl ester (I) phosphate (1:1)To a solution of 17.0 g of ortho phosphoric acid (85% in water) and 400 mL of EtOH was warmed to 50-55 C. in a dry and nitrogen purged 1000 mL glass reactor fitted with a mechanical stirrer, a condenser, and a 500 mL dropping funnel was added a solution 0.147 mol of ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (I) and 250 mL of EtOH with stirring. After fast addition (10-15 min) of two thirds (ca. 160 mL) of the total volume of this solution, the addition was stopped and the supersaturated clear solution was seeded with 0.2 g of previously obtained ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (1:1). Immediately crystallization commenced. The resulting thick suspension was stirred for 45-60 min at 5-55 C. The remaining amine solution was slowly added (45-60 min) to the suspension at 50-55 C. The feeder was rinsed with 20 mL of EtOH. Subsequently the thick suspension was continuously cooled to 12-20 C. in about 4 h (cooling speed=10 C./h). To complete the crystallization stirring was continued at 12-20 C. for additional 2+-1 h. Ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (1:1) was isolated by pressure filtration (0.3 bar nitrogen overpressure, Dacron filter cloth). The crystalline product was washed twice with 240 mL of acetone and twice with 300 mL of n-heptane at RT. Ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (1:1) was dried in vacuo (ca. 20 mbar) at a maximum temperature of 50 C. until constant weight. Yield: 54-55 g (88-91%) of the title product in the form of colorless needles with an assay of=99 wt. % (sum of impurities <0.5 wt. %, single impurities ?0.1 wt. %). IR (NJL) 3352, 3164, 2923, 2854, 1724, 1663, 1551, 1463, 1263, 1132 cm-1. MS (ion spray) MH+ 313.1, MNa+ 335.3

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2009/76296, 2009, A1 Location in patent: Page/Page column 9

7
[ 5709-98-8 ]
[ 204255-11-8 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 2044 - 2050
[2]Tetrahedron,2011,vol. 67,p. 2044 - 2050
[3]Tetrahedron,2011,vol. 67,p. 2044 - 2050
[4]Tetrahedron,2011,vol. 67,p. 2044 - 2050

8
[ 204255-11-8 ]
[ 63-42-3 ]
[ 1296084-57-5 ]

Reference： [1]ARKIVOC,2011,vol. 2011,p. 260 - 271

9
[ 152120-54-2 ]
[ 204255-11-8 ]
ethyl (3R,4R,5S)-4-acetamido-5-[N²,N³-bis(tert-butoxycarbonyl)guanidino]-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine; In acetonitrile; at 20℃; for 18h;	[0076] Compound 2: 1.13g (3.65mmole) N,N'-bis-Boc-1-Guanylpyrazole was added to a suspension of 1.5g (3.65mmole) oseltamivir monophosphate (1) in 20 ml anhydrous acetonitrile. After addition of 1.2 ml (8.7mmole) of triethyl amine, the suspension was stirred at room temperature for 18 hours. All volatile components were removed by vacuum. The residue was purified by 100g silica gel flash chromatography. 2g of purified compound (2) was obtained with yield of 98%.[0077] 1 H NMR (DMSO-d6) delta 0.787-0.864 (6H, m), 1.216-1.251 (3H, t), 1 .355-1.396 (22H, m),1.799 (3H, s), 2.318-2.344 (1 H, m), 2.659-2.672 (1 H,m),3.400-3.428 (1 H, m),3.959-4.057(2H, m), 4.134- 4.232 (3H, m), 6.661 (1 H, s), 7.893-7.913 (1 H, d), 8.541-8.561 (1 H, d), 1 1.523 (1 H, s).[0078] Mass spectrum: calculated for C27H4eN408: 554.68. MS: m/z 550.20 (M+1 ).
	With amine; In tetrahydrofuran;	N,N?-Di-Boc-1H-pyrazole-1-carboxamidine and proper amine are added to oseltamivir monophosphate (A) in THF. The reaction mixture is stirred until no more starting material is observed. The volatile components are removed by rotary evaporator. The residue is re-dissolved in EtOAc and subjected to flash chromatography for purification.

Reference： [1]Patent: WO2011/123856,2011,A1 .Location in patent: Page/Page column 26
[2]Patent: US9181281,2015,B2 .Location in patent: Page/Page column 25; 27

10
[ 204255-11-8 ]
oseltamivir acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide; In methanol; at 20℃; for 0.5h;	Deprotection of <strong>[204255-11-8]oseltamivir phosphate</strong> to form 4 followed the previously described protocol. Briefly, <strong>[204255-11-8]oseltamivir phosphate</strong> 30 mg was dissolved in 1 mL methanol and 500 muL 1 M NaOH was added. The mixture was stirred at room temperature for 30 min. After completion, Amberlite IR-120 (H+) was added to adjust the pH to 2. Solvents were then removed under vacuum to provide 4 as a white solid. 27 mg (quant.) The spectral data corresponds with literature. 1H NMR (500 MHz, CD3OD) delta 6.55 (s, 1H), 4.12 (d, J = 8.3 Hz, 1H), 3.90 (dd, J = 11.1, 8.3 Hz, 1H), 3.39 (dd, J = 11.1, 5.6 Hz, 1H), 2.84 (dd, J = 17.4, 5.4 Hz, 1H), 2.42 - 2.33 (m, 1H), 2.01 (s, 3H), 1.57 - 1.43 (m, 4H), 0.99 - 0.77 (m, 6H, 2 × CH3). 13C NMR (126 MHz, CD3OD) delta 174.59, 173.95, 134.92, 133.19, 83.32, 76.59, 55.28, 51.33, 31.63, 27.27, 26.63, 23.20, 9.84, 9.61.
96%	With sodium hydroxide; In water; at 20℃; for 4h;	A 25% NaOH solution (25mL) was added to oseltamivir-H3PO4 (750mg, 1.83mmol)(A) in H2O (10mL) and the reaction mixture was stirred for 4hat room temperature. The reaction mixture was consecutively neutralized with concentrated and 1.5N aqueous HCl solutions to reach a pH between 4.25 and 4.27. After the water was removed by distillation under reduced pressure, the solid residue was dissolved in EtOH (3×50mL) and stirred for 2h before being filtered. The organic phase was treated with 10mg of activated charcoal and then filtered and evaporated to dryness to afford B (499mg, 96% yield) as a white powder, m. p. 218±1C. IR neat nu (cm-1): 1654, 1551, 1548, 1462, 1375, 1290, 1128, 1101.1H NMR (CD3OD): delta 6.83 (s, 1H, H-2), 4.25 (d, 1H, J=9Hz, H-3), 3.97 (dd, 1H, J=9, 9Hz, H-4), 3.52 (dt, 1H, J=6Hz, H-5), 3.44 (tt, 1H, J=6Hz, H-7), 2.93 (dd, 1H, J=17, 6Hz, H-6b), 2.42 (m, 1H, H-6a), 2.05 (s, 3H, H-11), 1.53 (dq, 4H, J=8Hz, H-8 and 8?), 0.91 (dt, 6H, J=8Hz, H-9 and 9?). 13C NMR (CD3OD): delta 173.4 (C-10), 167.6 (COO-), 137.3 (C-1), 127.7 (C-2), 82.3 (C-7), 74.4 (C-3), 52.9 (C-4), 49.5 (C-5), 28.3 (C-6), 25.8 and 25.2 (C-8 and 8?), 23.2 (C-11), 8.4 and 8.2 (C-9 and 9?).
88%		An aqueous solution of NaOH (0.5M; 1.9mL) was added dropwise to a stirred solution of <strong>[204255-11-8]oseltamivir phosphate</strong> (0.2g, 0.48mmol) in 1,4-dioxane (1.9mL). The reaction was stirred for 24hat room temperature. The pH was adjusted to neutral by addition of Amberlite IR 120 hydrogen form. After removal of Amberlite the filtrate was concentrated under reduced pressure and the formed residue was purified by preparative HPLC to furnish the free amine derivative 1 (0.12g, 88% yield). 1H NMR (400MHz, MeOD) delta 6.64 (s, 1H), 4.11 (d, J=8.5Hz, 1H), 3.83 (dd, J=11.4, 8.7Hz, 1H), 3.40 (td, J=10.8, 5.5Hz, 1H), 3.34-3.22 (m, 1H), 3.16 (dt, J=3.3, 1.6Hz, 1H), 2.80 (dd, J=17.3, 5.1Hz, 1H), 2.38-2.18 (m, 1H), 1.91 (s, 3H), 1.47-1.28 (m, 4H), 0.75 (dt, J=12.6, 7.4Hz, 6H). 13C NMR (101MHz, MeOD) delta 174.9, 169.6, 138.4, 129.8, 83.7, 76.0, 54.5, 50.5, 30.0, 27.2, 26.6, 23.4, 9.8, 9.6. HR-ESI-MS calculated for C14H23O4N2 (M-H+) 283.1663, found 283.1656.

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 5349 - 5358
[2]European Journal of Medicinal Chemistry,2017,vol. 128,p. 154 - 167
[3]European Journal of Medicinal Chemistry,2016,vol. 121,p. 100 - 109
[4]Synlett,2012,p. 573 - 576
[5]RSC Advances,2015,vol. 5,p. 27735 - 27742
[6]Drug Metabolism and Disposition,2019,vol. 47,p. 465 - 472

11
[ 138-59-0 ]
[ 204255-11-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1.1: benzenesulfonic acid 2.1: orthoformic acid triethyl ester 3.1: dmap; N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 40 °C 4.1: triethylsilane; titanium tetrachloride / dichloromethane / -78 - -10 °C 5.1: hydrogen azide; triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran; benzene / 10 - 20 °C 6.1: 2,6-dimethylpyridine / chloroform / 6 h / 20 - 55 °C 7.1: zirconium(IV) chloride; isopropyl alcohol / 4 h / 50 °C 8.1: triethylamine 9.1: sodium azide 10.1: hydrogen / ethanol 10.2: 50 °C
	Multi-step reaction with 9 steps 1.1: benzenesulfonic acid 2.1: orthoformic acid triethyl ester 3.1: dmap; N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 40 °C 4.1: triethylsilane; titanium tetrachloride / dichloromethane / -78 - -10 °C 5.1: hydrogen azide; triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran; benzene / 10 - 20 °C 6.1: 2,6-dimethylpyridine / chloroform / 6 h / 20 - 55 °C 7.1: zirconium(IV) chloride; isopropyl alcohol / 4 h / 50 °C 8.1: hydrogen azide; triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran; benzene / 10 - 20 °C 9.1: hydrogen / ethanol 9.2: 50 °C
	Multi-step reaction with 11 steps 1: KU-2-8 cationite / 15 h / Reflux 2: triethylamine / ethyl acetate / 4 h / 0 - 3 °C 3: sodium azide; ammonium chloride / methanol / 6.5 h / 10 - 20 °C 4: toluene / 1 h / 20 °C 5: toluene / 7 h / Reflux 6: boron trifluoride diethyl etherate / 17 h / 0 - 20 °C 7: sulfuric acid / ethanol / 16 h / 78 °C 8: sodium carbonate / 0.5 h / 20 °C / pH 6.5 - 7 9: sodium azide / water; ethanol / 24 h / Reflux 10: triphenylphosphine; acetic acid / water; tetrahydrofuran / 16 h / 45 °C 11: phosphoric acid / water; ethyl acetate; ethanol / 50 - 55 °C

	Multi-step reaction with 11 steps 1: KU-2-8 cationite / 15 h / Reflux 2: triethylamine / ethyl acetate / 4 h / 0 - 3 °C 3: sodium azide; ammonium chloride / methanol / 6.5 h / 10 - 20 °C 4: toluene / 1 h / 20 °C 5: toluene / 7 h / Reflux 6: boron trifluoride diethyl etherate / 17 h / 0 - 20 °C 7: sulfuric acid / ethanol / 16 h / 78 °C 8: sodium carbonate / 0.5 h / 20 °C / pH 6.5 - 7 9: sodium azide / water; ethanol / 24 h / Reflux 10: triphenylphosphine; acetic acid / water; tetrahydrofuran / 16 h / 45 °C 11: phosphoric acid / water; ethyl acetate; ethanol / 50 - 55 °C
	Multi-step reaction with 11 steps 1: KU-2-8 cationite / 15 h / Reflux 2: triethylamine / ethyl acetate / 4 h / 0 - 3 °C 3: sodium azide; ammonium chloride / methanol / 6.5 h / 10 - 20 °C 4: toluene / 1 h / 20 °C 5: toluene / 7 h / Reflux 6: boron trifluoride diethyl etherate / 17 h / 0 - 20 °C 7: sulfuric acid / ethanol / 16 h / 78 °C 8: sodium carbonate / 0.5 h / 20 °C / pH 6.5 - 7 9: sodium azide / water; ethanol / 24 h / Reflux 10: triphenylphosphine; acetic acid / water; tetrahydrofuran / 16 h / 45 °C 11: phosphoric acid / water; ethyl acetate; ethanol / 50 - 55 °C
	Multi-step reaction with 8 steps 1.1: thionyl chloride / Reflux 2.1: dmap; triethylamine / 0 - 20 °C 3.1: sodium azide / acetone; water / 20 °C 4.1: triphenylphosphine / tetrahydrofuran / 20 °C / Inert atmosphere 4.2: 8 h / 0 - 5 °C 5.1: dmap; triethylamine 5.2: 0 - 5 °C 6.1: boron trifluoride diethyl etherate / 8 h / 0 - 20 °C / Inert atmosphere 7.1: sodium azide / water; ethanol / 8 h / 80 °C 8.1: hydrogen / ethanol / 16 h / 20 °C 8.2: 0.5 h / 50 °C
	Multi-step reaction with 10 steps 1: thionyl chloride / 0.13 h / 140 °C / 7500.75 Torr 2: triethylamine / ethyl acetate / 0 h / 20 °C / Sonication 3: sodium azide / acetonitrile; water / 0 h / 50 °C 4: acetonitrile / 0 h / 190 °C / 7500.75 Torr 5: boron trifluoride diethyl etherate / acetonitrile / 0 h / 100 °C / 7500.75 Torr 6: sulfuric acid / acetonitrile / 0 h / 170 °C / 7500.75 Torr 7: sodium hydroxide / acetonitrile / 0.01 h / 20 °C 8: sodium azide / water; N,N-dimethyl-formamide / 0.01 h / 190 °C / 7500.75 Torr 9: sodium tetrahydroborate; cobalt(II) chloride; ethanol / water / 0 h / 20 °C / pH 8 / Sonication 10: phosphoric acid / ethanol / 0.02 h / 50 °C / Sonication
	Multi-step reaction with 10 steps 1: thionyl chloride / 0.13 h / 140 °C / 7500.75 Torr 2: triethylamine / ethyl acetate / 0 h / 20 °C / Sonication 3: sodium azide / acetonitrile 4: acetonitrile / 0 h / 190 °C / 7500.75 Torr 5: boron trifluoride diethyl etherate / acetonitrile / 0 h / 100 °C / 7500.75 Torr 6: sulfuric acid / acetonitrile / 0 h / 170 °C / 7500.75 Torr 7: sodium hydroxide / acetonitrile / 0.01 h / 20 °C 8: sodium azide / water; N,N-dimethyl-formamide / 0.01 h / 190 °C / 7500.75 Torr 9: sodium tetrahydroborate; cobalt(II) chloride; ethanol / water / 0 h / 20 °C / pH 8 / Sonication 10: phosphoric acid / ethanol / 0.02 h / 50 °C / Sonication

Reference： [1]Kim, Hee-Kwon; Park, Kyoung-Joo Jenny [Tetrahedron Letters, 2012, vol. 53, # 13, p. 1561 - 1563]
[2]Kim, Hee-Kwon; Park, Kyoung-Joo Jenny [Tetrahedron Letters, 2012, vol. 53, # 13, p. 1561 - 1563]
[3]Kalashnikov; Sysolyatin; Sakovich; Sonina; Shchurova [Russian Chemical Bulletin, 2013, vol. 62, # 1, p. 163 - 170][Izv. Akad. Nauk, Ser. Khim., 2013, vol. 62, # 1, p. 165 - 171,7]
[4]Kalashnikov; Sysolyatin; Sakovich; Sonina; Shchurova [Russian Chemical Bulletin, 2013, vol. 62, # 1, p. 163 - 170][Izv. Akad. Nauk, Ser. Khim., 2013, vol. 62, # 1, p. 165 - 171,7]
[5]Kalashnikov; Sysolyatin; Sakovich; Sonina; Shchurova [Russian Chemical Bulletin, 2013, vol. 62, # 1, p. 163 - 170][Izv. Akad. Nauk, Ser. Khim., 2013, vol. 62, # 1, p. 165 - 171,7]
[6]Lin, Xiong; Qin-Hua, Chen; Peng, Li; Chun-Lei, Li; Guang-De, Yang [Chemical Biology and Drug Design, 2018, vol. 91, # 1, p. 105 - 115]
[7]Current Patent Assignee: NELSON MANDELA UNIVERSITY - WO2020/183281, 2020, A1
[8]Current Patent Assignee: NELSON MANDELA UNIVERSITY - WO2020/183281, 2020, A1

12
[ 107834-03-7 ]
[ 204255-11-8 ]
ethyl (3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-((4-(thiophen-2-yl)benzyl)amino)cyclohex-1-ene-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8445 - 8458
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 6379 - 6397

13
[ 498-62-4 ]
[ 204255-11-8 ]
ethyl (3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-((thiophen-3-ylmethyl)amino)cyclohex-1-ene-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With sodium cyanoborohydride; In methanol; ethanol; at 20℃; for 6h;	Thiophene-3-formaldehyde (1.6 mmol, 0.8 equiv.) was added tothe solution of 30 mL methanol and ethanol (V : V 2 : 1) of<strong>[204255-11-8]oseltamivir phosphate</strong> (0.82 g, 2.0 mmol, 0.8 equiv.). The reactionsolution was stirred for 0.5 h at room temperature, and thenNaBH3CN (0.31 g, 5.0 mmol, 2.5 equiv.) was added and tirred for 6 hat room temperature. The solvent was removed under reducedpressure, and the residue was dissolved in water (30 mL) andextracted with ethyl acetate (3 30 mL). The combined organicphase was washed with saturated sodium chloride (2 30 mL) anddried with anhydrous MgSO4. The MgSO4 was removed by filtrationand concentrated under reduced pressure. The crude product waspurified by flash column chromatography to obtain the correspondingintermediate 3.Ethyl(3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-((thiophen-3-ylmethyl)amino)cyclohex-1-ene-1-carboxylate (3). 77%yield, 1H NMR (400 MHz, DMSO-d6): d 7.80 (d, J 9.1 Hz, 1H), 7.46(dd, J 4.8, 3.0 Hz, 1H), 7.28e7.20 (m, 1H), 7.04 (d, J 4.8 Hz, 1H),6.64 (s, 1H), 4.14 (q, J 7.0 Hz, 2H), 4.00 (d, J 7.8 Hz, 1H), 3.81e3.61 (m, 3H), 3.40e3.35 (m, 1H), 2.73 (td, J 9.7, 5.3 Hz, 1H), 2.65 (dd,J 17.6, 4.6 Hz, 1H), 2.14e1.98 (m, 1H), 1.97e1.73 (m, 4H), 1.41 (th,J 14.2, 7.0 Hz, 4H), 1.22 (t, J 7.1 Hz, 3H), 0.81 (dt, J 15.2, 7.3 Hz,6H). 13C NMR (100 MHz, DMSO-d6): d 170.04,166.30, 142.65, 138.44,129.13, 128.23, 126.30, 121.62, 81.32, 75.69, 60.80, 54.69, 54.56,45.49, 30.87, 26.07, 25.63, 23.48, 14.56, 9.92, 9.41.

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 191
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 8445 - 8458

14
[ 3218-36-8 ]
[ 204255-11-8 ]
(3R,4R,5S)-4-acetylamino-5-(([1,1'-biphenyl]-4-ylmethyl)amino)-3-(1-ethylpropyloxy)-1-cyclohexene-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		In a 50 ml round-bottom flask by adding <strong>[204255-11-8]Oseltamivir phosphate</strong> (0.82g, 2 . 0mmol), anhydrous ethanol 25.0 ml, under the stirring condition to phenyl benzaldehyde (0.4g, 2 . 2mmol), stirring the mixture at room temperature for 5 minutes, by adding sodium cyanoborohydride (0.25g, 4 . 0mmol) to the reaction at room temperature. After four hours, diatomaceous earth filter silica gel column chromatography to obtain white solid 0.64g, yield 67%. 1 HNMR (CDCl 3, 300MHz) delta 7.53-7.60 (m, 4H), 7.30-7.46 (m, 5H), 6.80 (s, 1H), 5.50 (d, 1H, J = 7.2Hz), 4.18-4.26 (m, 3H), 3.93-3.98 (m, 1H), 3.72-3.82 (m, 2H), 3.33-3.41 (m, 1H), 3.15-3.24 (m, 1H), 2.80 (dd, 1H, J = 17.7,5 . 1Hz), 2.22-2.35 (m, 1H), 2.01 (s, 3H), 1.46-1.56 (m, 4H), 1.30 (t, 3H, J = 7.2Hz), 0.90 (t, 6H, J = 7.5Hz). 13 CNMR (CDCl 3, 75MHz) delta 170.65,166 . 52,140.92,139.95,139 . 29,137.19,129.38,128 . 75,128.57,127.35,127 . 17,127.03,81.77,74 . 53,60.88,55.81,53 . 60,50.25,30.41,26 . 15,25.77,23.76,14 . 24,9.52,9.42. HRMScalculatedforcalcdforC 29 H 39 N 2 O 4 [M+H] +: 479.2910, found: m/z479.2904.
	With sodium cyanoborohydride; In ethanol; at 20℃; for 6h;	General procedure: To a solution of compound 5 or 8 (2.0 mmol, 1 equiv) and aldehydes(2.4 mmol, 1.2 equiv) in 30 mL ethanol, NaBH3CN(4.0 mmol, 2 equiv) was slowly added. The mixture was stirred atroom temperature for 6 h and then concentrated. To the residue,20 mL saturated NaCl and 10 mL saturated Na2CO3 solution wasadded, and the mixture was extracted with EtOAc. The combinedextracts were dried over anhydrous MgSO4 and concentrated togive the crude product, which was purified by column chromatographyto produce the corresponding target compounds 6a-band intermediates 9a-b.

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8445 - 8458
[2]Patent: CN103923060,2016,B .Location in patent: Paragraph 0073-0075
[3]European Journal of Medicinal Chemistry,2019,vol. 178,p. 64 - 80

15
[ 145013-05-4 ]
[ 204255-11-8 ]
[ 208720-81-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine; mercury dichloride; In N,N-dimethyl-formamide; at 20℃;	To 50-mL3 neck round bottom flask was added (3R,4R,5S)-5-amino-4-acetylamino-3-(3-pentyloxy)cyclohex-1-ene-1-carboxylic acid ethyl ester phosphate (680mg, 1.66mmol, 1.00 eq.) In N, N- dimethyl Formamide (20 mL) was added dropwise, tert-butyl N-([(tert-butoxy)carbonyl]amino}methanethioyl)carbamate (500mg, 1.81mmol, 1.10 eq), triethylamine (700mg, 6.92mmol, 4.16 when Volume), at room temperature for several minutes then added in HgCl 2 (0.54g, 1.20 eq). The mixture was stirred at room temperature Resulting solution overnight. The solid was filtered off. Diluted with 50mL H 2 O The filtrate was then treated with 2x100mL ethyl Ester acetate. The organic layer was dried over anhydrous sodium sulfate, combined and concentrated under vacuum. Silica gel column The residue was purified using ethyl acetate: petroleum ether (1:3) to give 0.9g (98%) (3R,4R,5S)-5-[[(1Z)-[[(tert-butoxy)carbonyl]amino]([[(tert-butoxy)carbonyl]imino])methyl]amino]-4-acetylamino-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid ethyl esteras a white solid.

Reference： [1]Patent: CN103848762,2016,B .Location in patent: Paragraph 0054; 0060-0062

16
[ 204255-11-8 ]
[ 170304-76-4 ]
C₂₂H₃₇ClN₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 12h;	1.1-1 Synthesis of Oseltamivir-EGamide-chloride (4) Room temperature in the acid 2 (1.60 g, 8.78 mmol) in CH2Cl2 (30mL) was treated with stirring, oseltamivir Phosphate (3) (3.00 g, 7.31 mmol), 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride (2.80 g, 14.6 mmol), 1-hydroxybenzotriazole (1.97 g, 14.6 mmol) and triethylamine (2.03 ml, 14.6 mmol) was added to. After stirring for 12 hours at room temperature, by applying distilled water to the reaction mixture and the reaction was terminated. The mixture was extracted with CH2Cl2 (3x30 mL), and concentrated after combining the base layer dried over anhydrous Na2SO4, filtered. The concentrated liquid column chromatography (EtOAc: MeOH = 20: 1) to give the isolated using the chloride 4 (2.16 g, 62%) of a yellow liquid.

Reference： [1]Current Patent Assignee: KOREA RESEARCH INSTITUTE OF BIOSCIENCE AND BIOTECHNOLOGY - KR101575747, 2015, B1 Location in patent: Paragraph 0033-0037; 0041; 0042

17
[ 400744-83-4 ]
[ 204255-11-8 ]
C₃₀H₄₀N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(1) First, 0.5582g raw material oseltamivir phosphate with 0.3203gBiphenylaldehyde is mixed with 25 ml BIn an alcoholic solution, 0.1212 g of anhydrous acetic acid was added as a catalyst at 25 C for 15 hours. After that, 0.1229 g of sodium cyanoborohydride was slowly added and reacted at 25 C for 15 hours. The TLC was monitored completely. Post-treatment to obtain intermediates

Reference： [1]Patent: CN106117077,2016,A .Location in patent: Paragraph 0021; 0022; 0025; 0026; 0027; 0028-0034

18
[ 555-16-8 ]
[ 204255-11-8 ]
(3R,4R,5S)-4-acetamido-5-((4-nitrobenzyl)amino)-3-((pentan-3-yl)oxy)cyclohexene-1-ene-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With sodium cyanoborohydride; In methanol; ethanol; at 20℃; for 6h;	General procedure: The solution of <strong>[204255-11-8]oseltamivir phosphate</strong> (0.82 g, 2.0 mmol) and akind of aldehyde (2.4 mmol, 1.2 equiv) in 30 mL methanol andethanol (V : V 2 : 1) was stirred at room temperature for half anhour. And then, NaBH3CN (0.31 g, 5.0 mmol, 2.5 equiv) was addedslowly to the solution. After that, the mixture was stirred for 6 h atroom temperature. The solvent was removed under reduced pressure,water (30 mL) was added to the residue and extracted withethyl acetate (3 30 mL). The combined organic phasewas washedwith saturated sodium chloride (2 30 mL) and dried with anhydrousMgSO4 and concentrated under reduced pressure. Theconcentrated crude was purified by flash column chromatographyto obtain the corresponding pure intermediates 1a-1g.
76.3%	With sodium cyanoborohydride; In ethanol; at 30℃; for 5h;	Weigh ostivastine phosphate (0.41 g, 1 mmol)4-nitrobenzaldehyde (0.15 g, 1.2 mmol)Sodium cyanoborohydride (0.12 g, 2 mmol) in 20 mL of ethanol,30 C for 5 h(TLC detection reaction is completed, developing agent: ethyl acetate). The solvent was evaporated, 20 mL of water was added, extracted three times with 20 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated and subjected to flash column chromatography to give a white solid which was the compound (3R, 4R, 5S) -4- (Ethyl 4-nitrobenzyl) amino) -3- (pentan-3-yloxy) cyclohexene-1-ene-1-carboxylate in a yield of 76.3%.

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 191
[2]Patent: CN107056636,2017,A .Location in patent: Paragraph 0099; 0100; 0101; 0102

19
[ 498-62-4 ]
[ 204255-11-8 ]
(3R,4R,5S)-4-acetamido-5-((bis(thiophen-3-yl)ethyl)amino)-3-((pentan-3-yl)oxy)cyclohexene-1-ene-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With sodium cyanoborohydride; In ethanol; at 30℃; for 5h;	Weigh ostivastine phosphate (0.41 g, 1 mmol)Thiophene-3-carbaldehyde (0.269 g, 2.4 mmol)Sodium cyanoborohydride (0.24 g, 4 mmol)20 mL of ethanol solution,30 stirring 5h (TLC detection reaction is completed, developing agent: ethyl acetate).The solvent was evaporated, 20 mL of water was added, extracted three times with 20 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated(3R, 4R, 5S) -4-acetamido-5- (bis (thiophen-3-ylidene)Yl) amino) -3- (pentan-3-yloxy) cyclohexene-1-ene-1-carboxylate (10) in 74% yield.
72%	With sodium cyanoborohydride; In methanol; ethanol; at 20℃; for 8h;	To a solution of <strong>[204255-11-8]oseltamivir phosphate</strong> (0.82 g, 2.0 mmol) in30 mL of methanol and ethanol (V : V 2 : 1), thiophene-3-carbaldehyde (4.4 mmol, 2.2 equiv.) was added at room temperature.The reaction solutionwas stirred for 0.5 h at this temperature,and then NaBH3CN (0.62 g, 10 mmol, 5 equiv.) was added stirred for8 h at room temperature. The solvent was removed under reducedpressure, and the residue was dissolved in water (30 mL) andextracted with ethyl acetate (3 30 mL). The combined organicphase was washed with saturated sodium chloride (2 30 mL),dried with anhydrous MgSO4, filtered and concentrated afterremoving MgSO4. The concentrated product was purified by flashcolumn chromatography, and the corresponding intermediate 5was obtained.Ethyl(3R,4R,5S)-4-acetamido-5-(bis(thiophen-3-ylmethyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate (5).72% yield. 1H NMR (400 MHz, DMSO-d6): d 7.78 (d, J 8.8 Hz, 1H),7.43 (dd, J 4.8, 3.0 Hz, 2H), 7.31e7.25 (m, 2H), 7.01 (d, J 4.7 Hz,2H), 6.58 (s, 1H), 4.14 (q, J 7.1 Hz, 2H), 3.98 (t, J 7.7 Hz, 2H), 3.69(d, J 14.1 Hz, 2H), 3.53 (d, J 14.1 Hz, 2H), 2.86 (td, J 10.5, 4.6 Hz,1H), 2.50 (s, 2H), 2.31e2.17 (m, 1H), 1.91 (s, 3H), 1.44 (dq, J 18.9,6.4 Hz, 4H), 1.22 (t, J 7.1 Hz, 3H), 0.81 (dt, J 14.3, 7.3 Hz, 6H). 13CNMR (100 MHz, DMSO-d6): d 169.18, 166.25, 141.81, 138.77, 129.54,128.53, 126.11, 122.37, 81.51, 77.04, 60.82, 56.72, 52.53, 48.63, 26.03,25.57, 24.45, 23.64, 14.58, 9.92, 9.39.

Reference： [1]Patent: CN107056636,2017,A .Location in patent: Paragraph 0199; 0200; 0201; 0202; 0203
[2]European Journal of Medicinal Chemistry,2020,vol. 191

20
[ 5728-52-9 ]
[ 204255-11-8 ]
(3R,4R,5S)-5-(2-([1,1'-biphenyl]-4-yl)acetamido)-4-acetamido-3-((pentan-3-yl)oxy)cyclohexene-1-ene-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.6%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 30℃; for 8h;	12 (3R, 4R, 5S) -5-(2 - ([1,1'-biphenyl] -4-yl) acetamide)-4-acetamido-3- (pentan-3-yloxy)Cyclohexene-1-ene-1- carboxylic acid ethyl ester(12) Weigh ostivastine phosphate (0.41 g, 1 mmol)2 - ([1,1'-biphenyl] -4-yl) acetic acid(0.22 g, 1.2 mmol),HATU (0.45 g, 1.2 mmol) in 20 mLDichloromethane and 5 mL of triethylamine,30 stirring 8h (TLC detection reaction finished agent: ethyl acetate).The solvent was evaporated, 30 mL of water was added, extracted three times with 30 mL of ethyl acetate, and anhydrous sulfur(3R, 4R, 5S) -5- (3R, 4R, 5S) -5-methyl-1H-imidazolidinate was isolated from the product by flash column chromatography.(2 - ([1,1'-biphenyl] -4-yl) acetamide) -4-acetamido-3- (pentan-3-oxyl) cyclohexene- Acid ethyl ester(12), yield: 82.6%.

Reference： [1]Current Patent Assignee: SHANDONG UNIVERSITY - CN107056636, 2017, A Location in patent: Paragraph 0219; 0220; 0221; 0222

21
[ 1623-93-4 ]
[ 204255-11-8 ]
(3R,4R,5S)-5-(([1,1'-biphenyl]-4-sulfonamide))-4-acetamido-3-((pentan-3-yl)oxy)cyclohexene-1-ene-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine; In dichloromethane; at 20℃; for 6h;	General procedure: To a solution of <strong>[204255-11-8]oseltamivir phosphate</strong> (0.82 g, 2.0 mmol), 10 mLof triethylamine and 30 mL of acetonitrile or dichloromethane,arylsulfonyl chloridewas added (1.2 equiv.) The mixturewas stirredat room temperature for 6 h. After confirming the completion of thereaction by TLC, the solvent was evaporated under reduced pressure.Sodium chloride solution (30 mL) was added to the residueand extracted with ethyl acetate (3 40 mL). The combined organiclayer was washed twice with saturated sodium chloride (30 mL).And dried with anhydrous MgSO4, Then, filtered and the solventwas removed, the crude product was obtained, and purified bycolumn chromatography to obtain the corresponding intermediates16a-16g.
84.7%	With triethylamine; In dichloromethane; at 25 - 30℃; for 8h;	Weigh ostivastine phosphate (0.41 g, 1 mmol)[1,1'-biphenyl] -4-sulfonyl chloride (0.25 g, 1 mmol)In 20 mL of dichloromethane and5 mL of triethylamine solution,25-30 C for 8 h(TLC detection reaction finished developing agent: ethyl acetate). The solvent was evaporated, 30 mL of water was added, extracted three times with 30 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated and subjected to flash column chromatography to give a white solid which was compound (3R, 4R, 5S) -5- (Pentane-3-yloxy) cyclohexene-1-ene-1-carboxylate (12) ),Yield: 84.7%.

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 191
[2]Patent: CN107056636,2017,A .Location in patent: Paragraph 0238; 0239; 0240; 0241

22
[ 400744-83-4 ]
[ 204255-11-8 ]
C₃₀H₄₀N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of compound1 (oseltamivir phosphate) (0.41 g, 1.0 mmol) and biphenyl aldehyde(1.2 mmol, 1.2 equiv) in 25 mL ethanol, added 6 mg (0.1 mmol, 0.1 equiv)anhydrous acetic acid as catalyst, the reaction mixture was stirred at roomtemperature for 20 hrs . The process was monitored by TLC. After the completionof reaction, 0.125 g NaBH3CN (2.0 mmol, 2 equiv) was slowly added.The mixture was stirred at 30 oCfor 20 hrs, then concentrated. To the residual, added 20 mL saturated NaHCO3solution, the reaction mixture was extracted with EtOAc. The combined organiclayer was dried over anhydrous MgSO4and concentrated to give the crude compound 2.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 5429 - 5435

23
[ 65-85-0 ]
[ 204255-11-8 ]
[ 1191921-02-4 ]

Yield	Reaction Conditions	Operation in experiment
73%	With triethylamine; In dichloromethane; at 20℃; for 5h;	General procedure: 1.2 equiv. of acid (benzoic acid or bibenzoic acid) was added to the solution of 10 mL triethylamine and 30 mL acetonitrile ordichloromethane of <strong>[204255-11-8]oseltamivir phosphate</strong> (0.82 g, 2.0 equiv),HBTU or TBTU (2.4 mmol). The mixture was stirred at room temperaturefor 5 h. After TLC detection, the solvent was removedunder reduced pressure. Sodium chloride solution (30 mL) wasadded to the residue and extracted with ethyl acetate (3 40 mL).The combined organic layer was washed twice with saturated sodiumchloride (30 mL). And dried by anhydrous MgSO4, the solventwas removed under reduced pressure after filtering and removingMgSO4, and the crude product was purified by column chromatographyto obtain the corresponding intermediates 12a and 12b. Ethyl(3R,4R,5S)-4-acetamido-5-benzamido-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate (12a). 73% yield, 1H NMR(400 MHz, Methanol-d4): d 7.77 (d, J 7.3 Hz, 2H), 7.53 (t, J 7.3 Hz,1H), 7.45 (t, J 7.5 Hz, 2H), 6.83 (s, 1H), 4.31 (td, J 10.7, 5.5 Hz, 1H),4.27e4.15 (m, 3H), 4.07 (dd, J 11.2, 8.7 Hz, 1H), 3.45 (p, J 5.6 Hz,1H), 2.81e2.73 (m, 1H), 2.46 (ddt, J 17.4, 10.4, 2.9 Hz, 1H), 1.86 (s,3H), 1.62e1.45 (m, 4H), 1.29 (t, J 7.1 Hz, 3H), 0.91 (dt, J 21.3,7.4 Hz, 6H). 13C NMR (100 MHz, CD3OD): d 172.61, 168.81, 166.11,137.69, 134.20, 131.39, 129.05, 128.20, 126.92, 82.52, 75.60, 60.73,54.47, 48.61, 29.85, 25.98, 25.47, 21.43, 13.08, 8.47, 8.28.

Reference： [1]Chemical Biology and Drug Design,2018,vol. 91,p. 105 - 115
[2]European Journal of Medicinal Chemistry,2020,vol. 191

24
[ 451-69-4 ]
[ 204255-11-8 ]
C₂₅H₃₃FN₂O₅ [ No CAS ]

Reference： [1]Chemical Biology and Drug Design,2018,vol. 91,p. 105 - 115

25
[ 204255-11-8 ]
[ 27913-94-6 ]
ethyl (3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-((4-thiomorpholinobenzyl)amino)cyclohex-1-ene-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium cyanoborohydride In methanol; ethanol at 20℃; for 6h;

Reference： [1]Zhang, Jian; Poongavanam, Vasanthanathan; Kang, Dongwei; Bertagnin, Chiara; Lu, Huamei; Kong, Xiujie; Ju, Han; Lu, Xueyi; Gao, Ping; Tian, Ye; Jia, Haiyong; Desta, Samuel; Ding, Xiao; Sun, Lin; Fang, Zengjun; Huang, Boshi; Liang, Xuewu; Jia, Ruifang; Ma, Xiuli; Xu, Wenfang; Murugan, Natarajan Arul; Loregian, Arianna; Huang, Bing; Zhan, Peng; Liu, Xinyong [Journal of Medicinal Chemistry, 2018, vol. 61, # 14, p. 6379 - 6397]

26
[ 204255-11-8 ]
[ 27913-94-6 ]
(3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-((4-thiomorpholinobenzyl)amino)cyclohex-1-ene-1-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium cyanoborohydride / methanol; ethanol / 6 h / 20 °C 2: sodium hydroxide / methanol; water / 20 °C

Reference： [1]Zhang, Jian; Poongavanam, Vasanthanathan; Kang, Dongwei; Bertagnin, Chiara; Lu, Huamei; Kong, Xiujie; Ju, Han; Lu, Xueyi; Gao, Ping; Tian, Ye; Jia, Haiyong; Desta, Samuel; Ding, Xiao; Sun, Lin; Fang, Zengjun; Huang, Boshi; Liang, Xuewu; Jia, Ruifang; Ma, Xiuli; Xu, Wenfang; Murugan, Natarajan Arul; Loregian, Arianna; Huang, Bing; Zhan, Peng; Liu, Xinyong [Journal of Medicinal Chemistry, 2018, vol. 61, # 14, p. 6379 - 6397]

27
[ 100727-07-9 ]
[ 204255-11-8 ]
ethyl (3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-((4-(phenylamino)benzy)amino)cyclohex-1-ene-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium cyanoborohydride In methanol; ethanol at 20℃; for 6h;

Reference： [1]Zhang, Jian; Poongavanam, Vasanthanathan; Kang, Dongwei; Bertagnin, Chiara; Lu, Huamei; Kong, Xiujie; Ju, Han; Lu, Xueyi; Gao, Ping; Tian, Ye; Jia, Haiyong; Desta, Samuel; Ding, Xiao; Sun, Lin; Fang, Zengjun; Huang, Boshi; Liang, Xuewu; Jia, Ruifang; Ma, Xiuli; Xu, Wenfang; Murugan, Natarajan Arul; Loregian, Arianna; Huang, Bing; Zhan, Peng; Liu, Xinyong [Journal of Medicinal Chemistry, 2018, vol. 61, # 14, p. 6379 - 6397]

28
[ 100727-07-9 ]
[ 204255-11-8 ]
(3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-((4-(phenylamino)benzyl)amino)cyclohex-1-ene-1-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium cyanoborohydride / methanol; ethanol / 6 h / 20 °C 2: sodium hydroxide / methanol; water / 20 °C

Reference： [1]Zhang, Jian; Poongavanam, Vasanthanathan; Kang, Dongwei; Bertagnin, Chiara; Lu, Huamei; Kong, Xiujie; Ju, Han; Lu, Xueyi; Gao, Ping; Tian, Ye; Jia, Haiyong; Desta, Samuel; Ding, Xiao; Sun, Lin; Fang, Zengjun; Huang, Boshi; Liang, Xuewu; Jia, Ruifang; Ma, Xiuli; Xu, Wenfang; Murugan, Natarajan Arul; Loregian, Arianna; Huang, Bing; Zhan, Peng; Liu, Xinyong [Journal of Medicinal Chemistry, 2018, vol. 61, # 14, p. 6379 - 6397]

29
[ 86872-96-0 ]
[ 204255-11-8 ]
(3R,4R,5S)-4-acetamido-5-((4-(ethyl(phenyl)amino)benzyl)amino)-3-((pentan-3-yl)oxy)cyclohexene-1-ene-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium cyanoborohydride In methanol; ethanol at 20℃; for 6h;

Reference： [1]Zhang, Jian; Poongavanam, Vasanthanathan; Kang, Dongwei; Bertagnin, Chiara; Lu, Huamei; Kong, Xiujie; Ju, Han; Lu, Xueyi; Gao, Ping; Tian, Ye; Jia, Haiyong; Desta, Samuel; Ding, Xiao; Sun, Lin; Fang, Zengjun; Huang, Boshi; Liang, Xuewu; Jia, Ruifang; Ma, Xiuli; Xu, Wenfang; Murugan, Natarajan Arul; Loregian, Arianna; Huang, Bing; Zhan, Peng; Liu, Xinyong [Journal of Medicinal Chemistry, 2018, vol. 61, # 14, p. 6379 - 6397]

30
[ 86872-96-0 ]
[ 204255-11-8 ]
(3R,4R,5S)-4-acetamido-5-((4-(ethyl(phenyl)amino)benzyl)amino)-3-((pentan-3-yl)oxy)cyclohexene-1-ene-1-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium cyanoborohydride / methanol; ethanol / 6 h / 20 °C 2: sodium hydroxide / methanol; water / 20 °C

Reference： [1]Zhang, Jian; Poongavanam, Vasanthanathan; Kang, Dongwei; Bertagnin, Chiara; Lu, Huamei; Kong, Xiujie; Ju, Han; Lu, Xueyi; Gao, Ping; Tian, Ye; Jia, Haiyong; Desta, Samuel; Ding, Xiao; Sun, Lin; Fang, Zengjun; Huang, Boshi; Liang, Xuewu; Jia, Ruifang; Ma, Xiuli; Xu, Wenfang; Murugan, Natarajan Arul; Loregian, Arianna; Huang, Bing; Zhan, Peng; Liu, Xinyong [Journal of Medicinal Chemistry, 2018, vol. 61, # 14, p. 6379 - 6397]

31
[ 23351-05-5 ]
[ 204255-11-8 ]
(3R,4R,5S)-4-acetamido-5-((4-(1H-pyrrol-1-yl)benzyl)amino)-3-((pentan-3-yl)oxy)cyclohexene-1-ene-1-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 6379 - 6397

32
[ 23351-05-5 ]
[ 204255-11-8 ]
(3R,4R,5S)-4-acetamido-5-((4-(1H-pyrrol-1-yl)benzyl)amino)-3-((pentan-3-yl)oxy)cyclohexene-1-ene-1-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 6379 - 6397

33
[ 107834-03-7 ]
[ 204255-11-8 ]
(3R,4R,5S)-4-acetylamino-5-((4-(thiophen-2-yl)benzyl)amino)-3-(1-ethylpropyloxy)-1-cyclohexene-1-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 6379 - 6397

34
ethyl (3R,4R,5S)-4-N-acetylamino-5-N,N-diallylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate [ No CAS ]
[ 204255-11-8 ]

Yield	Reaction Conditions	Operation in experiment
96.31%		Add 85.0 g (0.217 mol, HPLC purity 99.53%) of compound 3 to 850 mL of ethanol, add 27.34 g (0.260 mmol) of diethanolamine and 8.5 g of 10% palladium on carbon (wet basis 50%) to heat the black suspension. The reaction was carried out at 68 to 78 C for 8 hours; the reaction solution was cooled to 20 to 30 C and filtered.The filter cake was rinsed with 100 mL of ethanol, and the combined filtrate was concentrated under reduced pressure in a hot water bath at 45-55 C until no liquid flowed out, dissolved in 450 mL of 2 mol/l HCl aqueous solution, and the brown solution was concentrated under reduced pressure for 10 minutes to generate a large amount of gas. Cool to 20-30 C; extract with 100 mL of methyl tert-butyl ether and let stand.The temperature was lowered to 20 C, and the pH was adjusted to 9 to 10 with a 25% aqueous ammonia solution to form a brown emulsion.The emulsion was extracted 4 times with 200 mL of ethyl acetate each time, and the organic layer was combined, washed with 200 mL of brine,The filter cake was rinsed with 50 mL of ethyl acetate, and the combined filtrate was concentrated under reduced pressure in a hot water bath at 45-55 C until no liquid flowed out; the concentrate was dissolved in 650 mL of ethanol to obtain a brown solution, and the temperature was raised to 45-55 C, slowly dropping. Add 14g (0.143mol) of a solution of phosphoric acid in ethanol (250mL). After the addition is completed, the obtained reaction solution is cooled to below -10 C, filtered, and the filter cake is dried under vacuum at 50-60 C to obtain 87.5 g of white solid phosphoric acid. Hewei crude product, HPLC purity 99.895%, single maximum impurity 0.056%; 87.5g crude oseltamivir phosphate was added to 3500mL volume concentration of 99.2% ethanol aqueous solution, heated to reflux dissolution, cooling to 65 ~ 70 C, added 4.4g activated carbon, heated to reflux, stirred for 30 minutes, filtered, the filtrate was cooled to 45 ~ 55 C, there is solid precipitation, continue to stir and cool down to -10 C, stirred for 2 hours, filtered, filter cake dried at 50 ~ 60 C vacuum , 85.6gA crystal form of oseltamivir phosphate was obtained, the yield was 96.31%, the HPLC purity was 99.924%, and the single maximum impurity was 0.051%.
89%	With 1,3-dimethylbarbituric acid; phosphoric acid; palladium 10% on activated carbon; triphenylphosphine; In ethanol; at 55 - 78℃;Large scale;	(1) Disposition solution: Dispose solution A and solution B separately;Solution A was composed of 1074.00 kg of Intermediate 11, 3023.65 kg of absolute ethanol, and 0.20 kg of triphenylphosphorus, a 35.52% anhydrous ethanol solution of Intermediate 11;Solution B was composed of 427.54 kg of 1.3-dimethylbarbituric acid, 3023.65 kg of absolute ethanol, and 0.20 kg of triphenylphosphonium. ;Add the solution A and the solution B into the mixing module at the same time for mixing, and then obtain the mixture C;A and solution B are transported with a metering diaphragm pump with a flow rate of 1.00L / min;(2) Reaction: Transfer the mixture C to the reaction module. The reaction module is loaded with a high-performance 10% Pd carbon support. The temperature of the reaction module is always controlled at 78 C. After the reaction, reactant D is obtained;(3) Mixing: 2028.75 kg of ethanolic phosphoric acid solution (wherein the weight percentage of the ethanolic phosphoric acid solution is 15.65%) and the reactant D are transferred to the cooling module 1 for cooling, and the temperature of the cooling module 1 is 8 C. to obtain reactant E; The adding speed is 0.33L / min. The meter used is a metering diaphragm pump;(4) Centrifugation: transfer the reactant E to a centrifugation module for centrifugation at a centrifugation rate of 1000 rpm, discard the supernatant, and collect solid materials;(5) Stirring: Transfer the solid material to the stirring module, and add 4051.69 kg of acetone for stirring and mixing, in which the metering diaphragm pump is used to transport the acetone, the transportation speed is 0.67L / min, and the stirring speed is 45 revolutions / minute to obtain reactant F. ;(6) Heating: transfer reactant F to heating module, heating temperature is 55 C, and obtain reactant G after heating; (7) decolorization: transfer reactant G to decolorization module for decolorization by activated carbon rod, decolorization temperature is 55 C Reactant H is obtained after decolorization;(8) Temperature reduction: transfer the reactant H to the temperature reduction module 2 for the temperature of the temperature reduction module 2 at 3 C, and the reaction product I is obtained after the temperature reduction;(9) Centrifugal drying: The reactant I is transferred to a centrifugal drying module for centrifugation and drying. The centrifugation temperature is 3 C and the drying temperature is 42 C. The obtained solid is oseltamivir phosphate.
85%		Compound IV (415.7 g, 1.06 mol, 1.0 eq.) Was dissolved in 500 mL of dichloromethane, Adding 1,3-dimethylbarbituric acid (NDMBA; 198.2g, 1.27mol, 1.2eq.), After the system was purged with nitrogen 3 times, Under the protection of nitrogen, the catalyst tetratriphenylphosphine palladium (5.8g, 5mmol, 0.5% eq.) Was added, The reaction was heated to 35 C for 7 hours. The reaction was monitored by TLC for completion. filter. The filtrate was washed with a 1M sodium oxide solution and a 1% EDTA aqueous solution in this order, the methylene chloride phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an orange oil. Then dissolve it with 2L of absolute ethanol, add activated carbon (20.8g, 5% W / W), stir and decolorize for 30min, and filter. The filtrate was heated to 48-52 C, and 1 L of 85% ethanolic phosphoric acid solution (85% H3PO4, 122.2 g, 1.06 mol, 1.0 eq.) Was added dropwise with stirring, Add 1.2g (0.3% W / W) of oseltamivir seed crystals, heat and grow for 2 hours, The temperature was lowered to -20 to -15 C with stirring for 20 hours. Filtration and vacuum drying gave oseltamivir V white crystalline powder 369.7 g (theoretical value 435.0 g) with a yield of 85%.

Under nitrogen protection,In a 2000ml reaction bottle,The compound of the formula (V) obtained above is added in that order,Anhydrous ethanol 800g,N,N-dimethylbarbituric acid (85.0 g, 0.54 mol),Palladium acetate (1.01 g, 0.0045 mol),Triphenylphosphine (4.73 g, 0.018 mol),Plus,The temperature was controlled at 20-25 C, and the reaction was stirred for 2 h.Cool down to 10-15 C,Insulation for 30 min, suction filtration, filtrationThe liquid was concentrated to obtain a crude oseltamivir free base of the formula (II) in a yield of 88% and a purity of 96.9%.The above crude oseltamivir free base was dissolved in 1000 ml of absolute ethanol at room temperature.Warming up to 45 to 50 C,After 60 minutes or more, 700 ml of absolute ethanol was added dropwise to dissolve a mixed solution of 60 g of 85% phosphoric acid.Stir at 45-50 C for 45 minutes;Slowly cool down, 4.0h down to 0C,Stirring at a temperature of -5 to 0 C for 60 minutes.Filtering,The filter cake was rinsed with 300 ml of absolute ethanol and drained.Drying in vacuo (45-50 C) for 6 h gave a white solid (I) crude.Room temperature,The crude product of formula (I) is dissolved in a mixed solvent of 800 ml of absolute ethanol and 140 ml of purified water.Warming up to 45 to 50 C,Maintain the temperature and continue to stir for 60 minutes.Hot and fast filtration,The mother liquor was concentrated at 45 C until a solid precipitated;Add 800ml of absolute ethanol,Continue to concentrate at 45 C to a paste;Add 800ml of absolute ethanol,Warming up,Stirring at 45-50 C for 60 minutes;Adjust the stirring speed to 75 rpm,Slowly cool down,2.5h will reduce the temperature to 0 C,Stirring at -5 to 0 C for 120 minutes;Filtering,Rinse the filter cake with 300 ml of absolute ethanol.Drain. Dry at 4550C for 6 hours under vacuum.A white solid (I) oseltamivir phosphate is obtained.The total yield was 63.5% and the purity was 99.5%.

Reference： [1]Patent: CN109438276,2019,A .Location in patent: Paragraph 0023; 0025; 0026-0029
[2]Patent: CN110698358,2020,A .Location in patent: Paragraph 0058-0169
[3]Patent: CN110563600,2019,A .Location in patent: Paragraph 0062-
[4]Patent: CN111153818,2020,A .Location in patent: Paragraph 0034-0035
[5]Patent: CN109627180,2019,A
[6]Patent: CN109574869,2019,A .Location in patent: Paragraph 0020; 0022; 0024-0029
[7]Patent: CN111253276,2020,A .Location in patent: Paragraph 0013; 0037-0039; 0045-0047

35
[ 1208-88-4 ]
[ 204255-11-8 ]
(3R,4R,5S)-4-acetamido-5-((4-(phenylthio)benzyl)amino)-3-((pentan-3-yl)oxy)cyclohexene-1-ene-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium cyanoborohydride; In ethanol; at 20℃; for 6h;	General procedure: To a solution of compound 5 or 8 (2.0 mmol, 1 equiv) and aldehydes(2.4 mmol, 1.2 equiv) in 30 mL ethanol, NaBH3CN(4.0 mmol, 2 equiv) was slowly added. The mixture was stirred atroom temperature for 6 h and then concentrated. To the residue,20 mL saturated NaCl and 10 mL saturated Na2CO3 solution wasadded, and the mixture was extracted with EtOAc. The combinedextracts were dried over anhydrous MgSO4 and concentrated togive the crude product, which was purified by column chromatographyto produce the corresponding target compounds 6a-band intermediates 9a-b.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 64 - 80

36
[ 630067-06-0 ]
[ 204255-11-8 ]
C₂₉H₃₄N₄O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride

Reference： [1]Wu, Chun; Wu, Ke-Jia; Liu, Jin-Biao; Zhou, Xiao-Ming; Leung, Chung-Hang; Ma, Dik-Lung [Chemical Communications, 2019, vol. 55, # 45, p. 6353 - 6356]

37
[ 862500-32-1 ]
[ 204255-11-8 ]
C₂₈H₄₀N₂O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; ethanol at 20℃; for 0.5h; Inert atmosphere;

Reference： [1]Zhang, Jian; Murugan, Natarajan Arul; Tian, Ye; Bertagnin, Chiara; Fang, Zengjun; Kang, Dongwei; Kong, Xiujie; Jia, Haiyong; Sun, Zhuosen; Jia, Ruifang; Gao, Ping; Poongavanam, Vasanthanathan; Loregian, Arianna; Xu, Wenfang; Ma, Xiuli; Ding, Xiao; Huang, Bing; Zhan, Peng; Liu, Xinyong [Journal of Medicinal Chemistry, 2018, vol. 61, # 22, p. 9976 - 9999]

38
[ 1208-88-4 ]
[ 204255-11-8 ]
C₂₉H₃₆N₂O₄S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 9976 - 9999

39
[ 110360-09-3 ]
[ 204255-11-8 ]
ethyl (3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-(((5-(o-tolyl)furan-2-yl)methyl)amino)cyclohex-1-ene-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium tris(acetoxy)borohydride In ethanol at 20℃;	4.2.20. General procedure for the synthesis of compound 9a - h General procedure: To a solution of oseltamivir phosphate (123 mg, 0.3 mmol) andaldehyde (0.36 mmol, 1.2 equiv) in 10 ml ethanol, NaBH(OAc)3(318 mg, 1.5 mmol) was slowly added. The mixture was stirred atroom temperature overnight and then concentrated. To the residue,20 ml saturated NaHCO3 solution was added, and the mixture wasextracted with EtOAc. The combined extracts were dried overanhydrous

Reference： [1]Ye, Jiqing; Yang, Xiao; Xu, Min; Chan, Paul Kay-sheung; Ma, Cong [European Journal of Medicinal Chemistry, 2019, vol. 182]

40
5-(3,5-difluorophenyl)furan-2-carbaldehyde [ No CAS ]
[ 204255-11-8 ]
ethyl (3R,4R,5S)-4-acetamido-5-(((5-(3,5-difluorophenyl)furan-2-yl)methyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium tris(acetoxy)borohydride; In ethanol; at 20℃;	General procedure: To a solution of <strong>[204255-11-8]oseltamivir phosphate</strong> (123 mg, 0.3 mmol) andaldehyde (0.36 mmol, 1.2 equiv) in 10 ml ethanol, NaBH(OAc)3(318 mg, 1.5 mmol) was slowly added. The mixture was stirred atroom temperature overnight and then concentrated. To the residue,20 ml saturated NaHCO3 solution was added, and the mixture wasextracted with EtOAc. The combined extracts were dried overanhydrous

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 182

41
[ 22078-59-7 ]
[ 204255-11-8 ]
ethyl (3R,4R,5S)-4-acetamido-5-(((5-(3-chlorophenyl)furan-2-yl)methyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium tris(acetoxy)borohydride In ethanol at 20℃;	4.2.20. General procedure for the synthesis of compound 9a - h General procedure: To a solution of oseltamivir phosphate (123 mg, 0.3 mmol) andaldehyde (0.36 mmol, 1.2 equiv) in 10 ml ethanol, NaBH(OAc)3(318 mg, 1.5 mmol) was slowly added. The mixture was stirred atroom temperature overnight and then concentrated. To the residue,20 ml saturated NaHCO3 solution was added, and the mixture wasextracted with EtOAc. The combined extracts were dried overanhydrous

Reference： [1]Ye, Jiqing; Yang, Xiao; Xu, Min; Chan, Paul Kay-sheung; Ma, Cong [European Journal of Medicinal Chemistry, 2019, vol. 182]

42
[ 886361-73-5 ]
[ 204255-11-8 ]
ethyl (3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-(((5-(thiophen-3-yl)furan-2-yl)methyl)amino)cyclohex-1-ene-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With sodium tris(acetoxy)borohydride In ethanol at 20℃;	4.2.20. General procedure for the synthesis of compound 9a - h General procedure: To a solution of oseltamivir phosphate (123 mg, 0.3 mmol) andaldehyde (0.36 mmol, 1.2 equiv) in 10 ml ethanol, NaBH(OAc)3(318 mg, 1.5 mmol) was slowly added. The mixture was stirred atroom temperature overnight and then concentrated. To the residue,20 ml saturated NaHCO3 solution was added, and the mixture wasextracted with EtOAc. The combined extracts were dried overanhydrous

Reference： [1]Ye, Jiqing; Yang, Xiao; Xu, Min; Chan, Paul Kay-sheung; Ma, Cong [European Journal of Medicinal Chemistry, 2019, vol. 182]

43
[ 34619-03-9 ]
[ 204255-11-8 ]
[ 367252-68-4 ]

Yield	Reaction Conditions	Operation in experiment
96.3%	With triethylamine; In methanol; at 20℃; for 12h;	To a solution of commercially available <strong>[204255-11-8]oseltamivir phosphate</strong>(1) (5 g, 12.2 mmol) in MeOH (50 mL) was added di-tert-butoxycarbonylanhydride ((Boc)2O, 5 g, 22.3 mmol) and triethylamine(TEA, 2 mL), and the mixture was stirred at room temperature for12 h. Subsequently, the reaction mixture was transferred to aseparator funnel, and the residue was washed with water to afford2 as a white solid, yield 96.3%, mp: 149-150 C.1H NMR (400 MHz, DMSO) delta 7.80 (d, J = 9.1 Hz, 1H), 6.61 (d,J = 6.9 Hz, 2H), 4.21-3.99 (m, 3H), 3.75-3.61 (m, 1H), 3.57 (td,J = 15.6, 10.1 Hz, 1H), 3.38 (dd, J = 10.9, 5.5 Hz, 1H), 2.46 (d,J = 4.7 Hz, 1H), 2.25 (dd, J = 17.5, 10.3 Hz, 1H), 1.78 (s, 3H), 1.52-1.28(m, 13H), 1.22 (t, J = 7.1 Hz, 3H), 0.80 (dt, J = 26.5, 7.3 Hz, 6H); 13CNMR (100 MHz, DMSO) delta 169.66 (s),165.99 (s),155.78 (s),138.66 (s),129.08 (s), 81.49 (s), 78.04 (s), 75.44 (s), 60.88 (s), 54.61 (s), 49.31(s), 30.61 (s), 28.65 (s), 26.17 (s), 25.65 (s), 23.31 (s), 14.52 (s), 9.88(s), 9.43 (s). HRMS: m/z 413.2644 [M + H]+, C21H36N2O6 (412.2573).

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 187

44
[ 1122-91-4 ]
[ 204255-11-8 ]
ethyl (3R,4R,5S)-4-acetamido-5-((4-bromobenzyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate [ No CAS ]