Name: 5104-49-4|2-(2-Fluoro-[1,1'-biphenyl]-4-yl)propanoic acid|98%
Brand: Ambeed
SKU: A481951
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1
[ 5104-49-4 ]
[ 51166-71-3 ]
complex of flurbiprofen with heptakis(2,6-di-O-methyl)-β-cyclodextrin (1:1) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 55℃; for 24h;

Reference： [1]Uekama; Imai; Maeda; Irie; Hirayama; Otagiri [Journal of Pharmaceutical Sciences, 1985, vol. 74, # 8, p. 841 - 845]

2
[ 5104-49-4 ]
[ 137361-33-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride; In DMF (N,N-dimethyl-formamide); 1,2-dichloro-ethane;Heating / reflux;	Flurbiprophen (Compound A, 50 g, 204 mmol) was heated overnight under reflux with SOCl2 (44.8 mL, 614 mmol) in 1,2-dichloroethane (300 mL) and DMF (1 mL) to obtain Compound B (yield was quantitative). Compound B was reacted with p-hydroxy benzaldehyde (Compound C, 24.27 g, 199 mmol) in CH2Cl2 (400 mL) and pyridine (49 mL) to obtain Compound D (yield was quantitative). Compound D was reduced using NaCNBH3 in acetic acid to obtain compound E (yield was quantitative). Compound E (43 g, 123 mmol) was heated over night under reflux with SOCl2 (44.8 mL, 614 mmol) in 1,2-dichloroethane (300 mL) and DMF (1 mL) to obtain Compound F (yield was quantitative). In a separate preparation, compound F was isolated and tested as a final product. In another preparation, Compound F was refluxed for 3 hr in the dark with silver nitrate (187 mmol) in acetonitrile (350 mL) to obtain the final product, Compound G. Compounds F and G were purified by silica gel chromatography and crystallized from ethyl acetate/n-hexane (yield was 39.5 g, 81%). Purity of compound G was >98% by TLC and 1H NMR (FIG. 3). Compounds F and G correspond to Compounds 9 and 5 described above, respectively.
	With oxalyl dichloride;N,N-dimethyl-formamide; In benzene; at 0 - 20℃; for 20h;	This prodrug was synthesized as shown in Scheme 11, Method I. Thus, to a solution of flurbiprofen (5.0 g, 20.46 mmol) in benzene (50 mL), was added oxalyl chloride (3.11 g, 24.55 mmol) at 0 C. and 2 drops of DMF and stirred at RT for 20 hrs. Benzene was removed under vacuum and the residue was diluted with DCM (50 mL). The reaction mixture was cooled to 0 C. and dry ammonia was passed for 30 min. The reaction mixture was concentrated and, after usual aqueous work-up, 4.5 g of flurbiprofen amide was obtained as a white solid.
	With thionyl chloride; In chloroform; at 60℃; for 2h;	A solution of (+/-) -flurbiprofen (0.87 g, 3.56 mmol) in chloroform (15 ml) was treated with thionyl chloride (1.27 g, 10.7 mmol) and stirred at 60 0C for 2h. Elimination of the solvents afforded a residue which was dissolved in chloroform (20 ml) and treated with triethyl amine (0.5 ml, 3.56 mmol) and 6 (0.74 g, 3.56 mmol). After stirring at room temperature overnight, the reaction mixture was washed with water (30 ml), K2CO3 20% (30 ml) and HCl 1 N (30 ml). Evaporation of the dried organic phase afforded a residue which was purified by flash chromatography. Eluting with ethyl acetate/petroleum ether (7:3) afforded 0.21 g of 37(14% yield) as a white solid: 1H-NMR (CDCl3, 200 MHz) delta1.57-1.65 (m, 5H), delta 3.20 (q , 2H), delta 3.31 (q, 2H), delta 3.60 (q, IH), delta 5.11 (s, 2H), delta 5.23 (br s exch, IH), delta 6.12 (br s exch, IH), delta 7.13-7.59 (m,13H).

	With thionyl chloride; In benzene;Reflux;	General procedure: A solution of NSAIDs having carboxylic acid group (1a-h) (1 mmol) in dry benzene (5-8 mL) was refluxed with freshly distilled thionyl chloride (1.2 mmol) for 2-3 h. After the completion of reaction, excess of thionyl chloride was removed under reduce pressure to afford the acid chlorides (2a-h) which were dissolved in anhydrous acetone for further use. The acid chlorides (2a-h) were then treated with a solution of (+)-6-aminopenicillanic acid (6-APA, 1 mmol) in 2% NaHCO3 (40 mL) diluted with acetone (30 mL). The reaction mixture was stirred for 2-4 h at room temperature and then concentrated under reduced pressure and washed with ethyl acetate (25 mL). The aqueous layer was then acidified with HCl (0.1 M), extracted with ethyl acetate and then washed with distilled water dried over anhydrous Na2SO4. The ethyl acetate was rotary evaporated and triturated with n-hexane to afford the title compounds (4a-h).
	With thionyl chloride; In dichloromethane; at 0 - 20℃; for 4h;	take flurbiprofen 53.7g (0.22mol) was added 500mL dried three-necked flask,150mL of dichloromethane was added, followed by stirring in an ice bath to control the temperature at 0-5 deg.] C, preferably 3 , thionyl chloride was slowly added dropwise 49.3mL,After the completion of dropwise slowly warmed to room temperature, the reaction was stirred for 4h, the reaction by TLC. After completion of the reaction under reduced pressure recycle of excess thionyl chlorideTo give a pale yellow oil;

Reference： [1]Patent: US2005/182134,2005,A1 .Location in patent: Page/Page column 22
[2]Collection of Czechoslovak Chemical Communications,1987,vol. 52,p. 766 - 774
[3]Tetrahedron Asymmetry,1995,vol. 6,p. 991 - 1000
[4]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 667 - 671
[5]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 8701 - 8706
[6]Patent: US2006/46967,2006,A1 .Location in patent: Page/Page column 114-115; 145
[7]Journal of Organic Chemistry,2008,vol. 73,p. 9473 - 9475
[8]Patent: WO2009/34457,2009,A1 .Location in patent: Page/Page column 41-42
[9]Journal of Medicinal Chemistry,2011,vol. 54,p. 2293 - 2306
[10]Chemical and Pharmaceutical Bulletin,2012,vol. 60,p. 465 - 481
[11]RSC Advances,2014,vol. 4,p. 53842 - 53853
[12]PLoS ONE,2015,vol. 10
[13]Chemical Communications,2015,vol. 51,p. 14929 - 14932
[14]Patent: CN105753701,2016,A .Location in patent: Paragraph 0037
[15]Journal of Heterocyclic Chemistry,2016,vol. 53,p. 1395 - 1401
[16]Journal of Enzyme Inhibition and Medicinal Chemistry,2016,vol. 31,p. 1018 - 1028
[17]Patent: CN109096191,2018,A .Location in patent: Paragraph 0038; 0039; 0046; 0047
[18]Angewandte Chemie - International Edition,2020,vol. 59,p. 5242 - 5247
Angew. Chem.,2020,vol. 132,p. 5280 - 5285,6

3
[ 5104-49-4 ]
[ 55216-11-0 ]
complex of flurbiprofen with heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (1:1) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 55℃; for 24h;
	In water at 45℃; for 0.583333h;

Reference： [1]Uekama; Imai; Maeda; Irie; Hirayama; Otagiri [Journal of Pharmaceutical Sciences, 1985, vol. 74, # 8, p. 841 - 845]
[2]Rudrangi, Shashi Ravi Suman; Kaialy, Waseem; Ghori, Muhammad U.; Trivedi, Vivek; Snowden, Martin J.; Alexander, Bruce David [European Journal of Pharmaceutics and Biopharmaceutics, 2016, vol. 104, p. 164 - 170]

4
[ 113544-38-0 ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sulfuric acid; water; In 1,4-dioxane; at 120℃; for 4h;Inert atmosphere;	A solution of compound 14 (72.3 mg, 0.28 mmol) in dioxane (3 mL) was added to 5%vol/vol aqueous H2SO4 (1.9 mL) and the mixture refluxed for 4 hours. After additionof water (2 mL) the reaction mixture was extracted three times with ethyl acetate (3 x4 mL) and the combined organics dried over anhydrous Na2SO4, filtered andconcentrated to give desired product 15, 67.7 mg, 99%, white solid, m.p. 103-105 oC;1H NMR (500 MHz, CDCl3) delta 7.56 - 7.50 (m, 2H), 7.46 - 7.34 (m, 4H), 7.20 - 7.12 (m,2H), 3.79 (q, J = 10.0 Hz, 1H), 1.56 (d, J = 10.0 Hz, 3H). 19F NMR (471 MHz, CDCl3)delta -117.42. 13C NMR (125 MHz, CDCl3) delta 179.9, 159.7 (d, J = 246.3 Hz), 140.9 (d, J =7.5 Hz), 135.4, 130.9 (d, J = 3.8 Hz), 129.0 (d, J = 2.5 Hz), 128.5, 128.2 (d, J = 13.8Hz), 127.7, 123.7 (d, J = 2.5 Hz), 115.4 (d, J = 23.8 Hz), 44.8, 18.0. MS calcd forC15H14FO2 (M+H)+: 245.10, found: 245.05. These data are in agreement with thosereported previously in the literature40

Reference： [1]Chem,2019,vol. 5,p. 2718 - 2730
[2]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1998,vol. 37,p. 239 - 246
[3]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 307 - 312

5
[ 5001-96-7 ]
[ 74-88-4 ]
[ 5104-49-4 ]

Reference： [1]Chemistry - A European Journal,1998,vol. 4,p. 1969 - 1973
[2]Journal of the American Chemical Society,2011,vol. 133,p. 11936 - 11939

6
[ 621-76-1 ]
[ 5104-49-4 ]
(S)-(+)-flurbiprofen [ No CAS ]
(S)-2-(2-fluoro-4-biphenylyl)propanoic acid propyl ester [ No CAS ]
(R)-2-(2-fluoro-4-biphenylyl)propanoic acid propyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	In propan-1-ol; acetonitrile at 45℃; for 144h; Enzymatic reaction;
	In propan-1-ol; acetonitrile at 45℃; for 144h; Enzymatic reaction;
390 mg	With Candida antartica lipase In acetonitrile at 45℃;

Reference： [1]Morrone, Raffaele; Piattelli, Mario; Nicolosi, Giovanni [European Journal of Organic Chemistry, 2001, # 8, p. 1441 - 1443]
[2]Morrone, Raffaele; Piattelli, Mario; Nicolosi, Giovanni [European Journal of Organic Chemistry, 2001, # 8, p. 1441 - 1443]
[3]Panico; Cardile; Vittorio; Ronsisvalle; Scoto; Parenti; Gentile; Morrone; Nicolosi [Il Farmaco, 2003, vol. 58, # 12, p. 1339 - 1344]

7
[ 67-56-1 ]
[ 5104-49-4 ]
[ 113544-38-0 ]

Yield	Reaction Conditions	Operation in experiment
98.8%	With sulfuric acid; for 0.25h;Reflux; Microwave irradiation;	Prepared using amodified literature procedure.13 A mixture of 2-(2-fluorobiphenyl-4-yl)propanoic acid (1) (4.50 g; 18.423 mmol), methanol (100 mL) andconcentrated sulfuric acid (2-3 drops) was irradiated under microwaves(300 W) to reflux. After completion of the reaction (as indicated byTLC), excess methanol was distilled off and the resultant mixture waspoured over ice cooled aqueous sodium bicarbonate solution (4%) to getthe required product in the form of off-white hard flakes. Off white solid;m.p. 40C (lit.13 39 C). IR (KBr): 2984, 1733, 1623 cm-1; 1H NMR (CDCl3) delta1.52(d, J = 6.8 Hz, 3H, CH3), 3.71(s, 3H, OCH3), 3.78 (q, J = 6.8, 1.0 Hz,1H, CH), 7.39-7.54 (m, 8H, ArH). MS m/z [M+H]+ 259.28.
95%	With sulfuric acid; for 3h;Reflux;	A solution of flurbiprofem (2-(2-fluorobiphenyl-4-yl)propanoic acid) (3.00 g, 12.3 mmol) in methanol (20 mL) containing a catalytic amount of conc. H2SO4 was refluxed for 3 h using a Dean-Stark trap. After cooled to room temperature, the reaction mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (3×15 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by column chromatography (ethyl acetate/petrol ether=1/3, v/v) to furnish intermediate 5 as a white solid (3.01 g, 95%); mp 45-46 C. 1H NMR (CDCl3): delta 7.56-7.53 (d, 2H, arom), 7.48-7.34 (m, 4H, arom), 7.17-7,11 (m, 2H, arom), 3.82-3.71 (m, 4H, CHCH3, COOCH3), 1.57-1.54 (d, 3H, CHCH3).
95%	With sulfuric acid; for 3h;Reflux; Dean-Stark;	A solution of flurbiprofem (2-(2-fluorobiphenyl-4-yl)propanoic acid) (3.00 g, 12.3 mmol) in methanol (20 mL) containing a catalytic amount of conc. H2SO4 was refluxed for 3 h using a Dean-Stark trap. After cooled to room temperature, the reaction mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (3×15 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by column chromatography (ethyl acetate/petrol ether=1/3, v/v) to furnish intermediate 6 as a white solid (3.01 g, 95%); mp 45-46 C. 1H NMR (CDCl3): delta 7.56-7.53 (d, 2H, arom), 7.48-7.34 (m, 4H, arom), 7.17-7,11 (m, 2H, arom), 3.82-3.71 (m, 4H, CHCH3, COOCH3), 1.57-1.54 (d, 3H, J = 7.0 Hz, CHCH3).

65%

The synthesis of methyl ester of flurbiprofen: Methyl 2-(2-fluorobiphenyl-4-yl)propanoate [3a] About 30 mmol flurbiprofen was dissolved in methanol. After heating under reflux for half an hour in a water bath, 1 ml of concentrated sulfuric acid was added dropwise. The reaction medium which was heated at 80-90C in a water bath and the reaction is terminated by checking with TLC and the reaction mixture is neutralized with 5% sodium bicarbonate solution by controlling the pH. After it was neutralized, it was kept in the fridge together with the medium in which it was neutralized. The precipitated solid compound is collected by filtration. The obtained crude product was purified by crystallization with a suitable solvent. If it has an enough purity, it is used in the next step.

Reference： [1]Bulletin of the Chemical Society of Japan,2003,vol. 76,p. 2395 - 2397
[2]Journal of Chemical Research,2015,vol. 39,p. 668 - 673
[3]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3162 - 3165
[4]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 2462 - 2470
[5]Angewandte Chemie - International Edition,2018,vol. 57,p. 10697 - 10701
Angew. Chem.,2018,vol. 130,p. 10857 - 10861,5
[6]Journal of the American Chemical Society,2018,vol. 140,p. 16026 - 16031
[7]Patent: EP2878592,2015,A1 .Location in patent: Paragraph 0018; 0041; 0043
[8]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2007,vol. 46,p. 1164 - 1168
[9]Chemical and Pharmaceutical Bulletin,2005,vol. 53,p. 524 - 528
[10]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2219 - 2223
[11]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 759 - 763
[12]Medicinal Chemistry Research,2013,vol. 22,p. 5685 - 5699
[13]Letters in drug design and discovery,2014,vol. 11,p. 121 - 131
[14]Angewandte Chemie - International Edition,2018,vol. 57,p. 10357 - 10361
Angew. Chem.,2018,vol. 130,p. 10514 - 10518,5

8
[ 5104-49-4 ]
[ 122151-38-6 ]
(S)-2-(2-Fluoro-biphenyl-4-yl)-propionic acid (S)-1-methyl-2-oxo-2-pyrrolidin-1-yl-ethyl ester [ No CAS ]
(R)-2-(2-Fluoro-biphenyl-4-yl)-propionic acid (S)-1-methyl-2-oxo-2-pyrrolidin-1-yl-ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide In toluene for 1.5h; Title compound not separated from byproducts;

Reference： [1]Ammazzalorso, Alessandra; Amoroso, Rosa; Bettoni, Giancarlo; De Filippis, Barbara; Fantacuzzi, Marialuigia; Giampietro, Letizia; Maccallini, Cristina; Tricca, Maria L. [European Journal of Organic Chemistry, 2006, # 18, p. 4088 - 4091]

9
[ 5104-49-4 ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
85.2%		At room temperature, racemic flurbiprofen (61.0 g, 0.26 mol 1) was dissolved in a mixed solution of methanol (40 mL) and toluene (160 mL) To the mixture was slowly added dropwise 16.9 mL of S - (-) - phenethylamine (15.9 g, 0.13 mol 1) at 60 C, (+) - flurbiprofen-s - (-) - benzene was added to the system in order to induce the crystallization. After completion of the dropwise addition, Ethylamine salt seed ( 0.5g), And then cooled to 0-5 C and keep this temperature lh, The resulting S- (+) - flurbiprofen-S - (-) - phenethylamine salt solid was collected by filtration, Recrystallization from methanol (48 mL) and toluene (192 Ml) gave 26 g of S- (+) - flurbiprofen, a white solid in a yield of 85.2% and ee> 99.5%.

Reference： [1]Patent: CN105777544,2016,A .Location in patent: Paragraph 0033
[2]Bulletin of the Chemical Society of Japan,2003,vol. 76,p. 2395 - 2397
[3]Collection of Czechoslovak Chemical Communications,1987,vol. 52,p. 766 - 774
[4]Patent: WO2015/145163,2015,A1
[5]ChemCatChem,2016,vol. 8,p. 916 - 921
[6]Angewandte Chemie - International Edition,2019,vol. 58,p. 11479 - 11482
Angew. Chem.,2019,vol. 131,p. 11603 - 11606,4

10
[ 5104-49-4 ]
[ 64858-91-9 ]

Yield	Reaction Conditions	Operation in experiment
95%		Example 24 Preparation of Compound AX [3-(2-Fluoro-biphenyl-4-yl)butyramide] To a chilled (0 C.) solution of 2-(2-fluoro-biphenyl-4-yl)propionic acid in THF was added isobutyl chloroformate followed by dropwise addition of TEA. The resulting white slurry was allowed to stir for 1 hour and then diluted with THF (50 mL) and filtered. The filter cake was washed with additional THF (50 mL) and the filtrate was concentrated to approximately 50 mL using a rotary evaporator. The concentrated filtrate was then stirred at -20 C. and a solution of NaBH4 in H2O (20 mL) was dropwise added over a period of 15 minutes. The resulting suspension was stirred for 2 hours at 0 C., diluted with water (200 mL), and extracted with ethyl acetate (2*100 mL). The ethyl acetate layers were combined and washed with 1.0 N HCl solution (100 mL) followed by a 5% bicarbonate solution wash (100 mL). The ethyl acetate solution was then concentrated to an oily residue of 2-(2-fluoro-biphenyl-4-yl)propanol (4.47 g, 95% yield).

Reference： [1]Patent: US9206143,2015,B2 .Location in patent: Page/Page column 30
[2]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1998,vol. 37,p. 1221 - 1227
[3]ChemSusChem,2014,vol. 7,p. 2684 - 2689

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 6 Preparation of a collyrium containing flurbiprofen and tetrahydrozoline hydrochloride (Composition 6)
		Example 6 Preparation of a collyrium containing flurbiprofen and tetrahydrozoline hydrochloride (Composition 6)

12
[ 69097-20-7 ]
[ 5104-49-4 ]
3-(2-fluoro-4-biphenylyl)-2-oxo-1-butanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogenchloride; thionyl chloride; In 1,4-dioxane;	REFERENCE EXAMPLE 2 STR48 To thionyl chloride (40 ml) was added 2-(2-fluoro-4-biphenylyl) propionic acid (10.0 g, 40.9 mmol) by portions with stirring at room temperature. After the addition, the mixture was stirred over night at room temperature, and the solution was evaporated under reduced pressure to afford the acid chloride. After tris(trimethylsilyloxy)ethylene (35.9 g, 123 mmol) was added to the acid chloride at room temperature, the mixture was stirred at 95 C. for 4 h, then cooled to room temperature. After the addition of dioxane (53.3 ml) and then 0.6N hydrochloric acid (21.5 ml) dropwise to the mixture, the solution was stirred at 85 C. for 30 min, then cooled to room temperature, saturated with sodium chloride, and extracted with ether. The ether extracts were washed with water, dried with anhydrous sodium sulfate, and evaporated under reduced pressure to a residue, which was chromatographed to afford 3-(2-fluoro-4-biphenylyl)-2-oxo-1-butanol (10.0 g, 95% yield) as crystalline material: mp 63-64.5 C. NMR(CDCl3)delta 1.48(d, 3H), 2.97(t, 1H), 3.80(q, 1H), 4.25(d, 2H), 6.93-7.62(m, 8H) ppm; IR(neat) 3450, 1725, 1610, 1480, 1420, 1270 cm31 1.

Reference： [1]Patent: US4914112,1990,A

13
[ 5104-49-4 ]
flurbiprofen ester [ No CAS ]
acetoxymethyl 2-(2-fluoro-4-biphenylyl)propionate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.9%; 69.1%	With potassium carbonate; In N-methyl-acetamide; diethyl ether; Chloromethyl acetate;	Reference Example 1 Method of preparing a flurbiprofen ester Into a solution of 7.32 g (30 mmol) of 2-(2-fluoro-4-biphenylyl)propionic acid in 100 ml of anhydrous dimethylformamide, was added with ice-cooling 2.1 g (15 mmol) of anhydrous potassium carbonate, and the mixture was stirred for 1 hour. To the above mixture was added dropwise in the course of 10 minutes at 0 to 5 C. 3.3 g (30 mmol) of acetoxymethyl chloride which had been purified by distillation. After completion of the addition, the mixture was stirred for 2 hours at room temperature. The reaction mixture was cooled with ice, filtered to remove the inorganic materials, and then the solvent was distilled off under reduced pressure. The residue was mixed with 150 ml of diethyl ether, washed successively with water, 10% aqueous sodium carbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 8.24 g of an oily crude product in 86.9% crude yield. The product was further subjected to vacuum distillation under a nitrogen atmosphere to give 6.55 g of oily acetoxymethyl 2-(2-fluoro-4-biphenylyl)propionate. Yield: 69.1%, b.p.: 196-197 C./0.4 mmHg

Reference： [1]Patent: US4613505,1986,A

14
[ 81937-33-9 ]
[ 325477-93-8 ]
[ 149-73-5 ]
2(3'-fluoro-4'-phenyl)-phenyl-propionic acid [ No CAS ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
82.6%	With hydrogenchloride; sodium nitrite; trichloroacetic acid;copper(I) chloride; In benzene;	EXAMPLE 5 2(3'-fluoro-4'-phenyl)-phenyl-propionic acid A mixture of 2-[(3'-fluoro-4'-amino)-phenyl]-propionic acid (5 g; 0.0273 mole), trichloroacetic acid (6 g; 0.0367 mole), cuprous chloride (0.14 g; 0.0014 mole) and of trimethylorthoformate (5.8 g; 0.0548 mole) in benzene (140.6 g; 1.8 moles) was heated to 60 C. under nitrogen. To this mixture aliquots of sodium nitrite (2.1 g; 0.0304 mole) were added. The reaction mixture was maintained under stirring for 26 hours and then hydrolyzed with water and diluted hydrochloric acid. The organic layer was separated and concentrated by evaporation of the solvent; the residue was treated with a 1:1 hydroalcoholic solution (200 ml) of 10% potassium hydrate and heated to reflux for two hours. After distillation of the solvent, the residue was taken up with water and the aqueous layer, after extraction with ethyl ether, was made acid with 10% hydrochloric acid. The organic compound was then extracted with ethyl ether and the organic layer washed with water till neutralization and dried over sodium sulfate. After removal of the solvent, the residue was chromatographed on silica gel 60 (Merck 70-230 mesh) column eluding with 9:1 benzene-acetone. 5.5 g of 2-[(3'-fluoro-4'-phenyl)-phenyl]-propionic acid were obtained; m.p. 111-113 C. Yield, 82.6%.

Reference： [1]Patent: US4542233,1985,A

15
[ 41604-19-7 ]
[ 56985-74-1 ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sulfuric acid; magnesium; In tetrahydrofuran; water;	EXAMPLE 1 A solution of <strong>[41604-19-7]4-bromo-2-fluorobiphenyl</strong> (2.51g;0.01 mole) in dry tetrahydrofuran (15ml) was aded dropwise, with stirring, to magnesium turnings (0.25g;0.0103g. atom) under a nitrogen atomosphere. When the addition was complete, the mixture was stirred and boiled under reflux for 30 minutes. The mixture was then cooled and a suspension of sodium 2-bromopropionate (1.75g;0.01 mole) in dry tetrahydrofuran (20ml) was added. Frothing occurred and when this had subsided the mixture was boiled under reflux with stirring, for one hour. The mixture was then cooled in an ice-bath and water (15ml) was added, followed by sulphuric acid (20%;5ml). The mixture was stirred for 10-15 minutes, and extracted with ether. The extract was washed with water and then extracted with aqueous potassium carbonate (1N). This extract was washed with ether and then added to a mixture of concentrated hydrochloric acid (10ml) and water (20ml). The mixture was cooled overnight and the precipitate filtered, washed with water and dried in vacuo to give 2 -(2-fluoro-4-biphenylyl)propionic acid.

Reference： [1]Patent: US3959364,1976,A

16
[ 5104-49-4 ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1.2Variation of solvent quantitiesS-Flurbiprofen (2Og) was charged to a 500ml jacketed glass reactor. Toluene (200 ml) was added and the solution was heated to 600C. Sodium hydroxide solution (46 ml of 28% w/w solution, 5.1 molar equivalents) and methanol (70 ml) were added. The mixture was heated to reflux for 4 hours. Solvent was removed by distillation until the distillate temperature reached 1000C and the volume removed was replaced with toluene. The reaction mixture was neutralised by addition of hydrochloric acid (60 ml of 36% w/w) at 6O0C and the lower aqueous layer was separated off. The organic layer containing the flurbiprofen was analysed and found to have an enantiomeric excess of 5.6%.The above procedure was repeated at half the scale using different solvent proportions. S-flurbiprofen (1Og) was mixed with toluene (100 ml) and methanol (20 ml). Sodium hydroxide solution (25 ml of 28% w/w solution, 5.6 molar equivalents) was added and the mixture heated to reflux for 3 hours. After distillation of solvent and neutralisation by addition of hydrochloric acid (35 ml of 36% w/w solution), the organic layer was found to contain flurbiprofen with enantiomeric excess of 3.4%.

Reference： [1]Chirality,2019,vol. 31,p. 410 - 417
[2]Patent: WO2010/1103,2010,A1 .Location in patent: Page/Page column 17

17
[ 1201594-47-9 ]
[ 98-80-6 ]
[ 5104-49-4 ]

Reference： [1]Journal of the American Chemical Society,2009,vol. 131,p. 17748 - 17749

18
[ 5104-49-4 ]
[ 71-36-3 ]
[ 5104-49-4 ]
[ 5104-49-4 ]
(R)-flurbiprofen n-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Candida antarctica lipase B immobilised on acrylic resin; In toluene; at 60℃; under 5171.62 Torr;Molecular sieve; Flow reactor; Enzymatic reaction;	General procedure: Experiments reported in Table 1 were carried out as follows: 10 mg of racemic flurbiprofen 1 (0.04 mmol), 10.8 muL of n-butanol (0.12 mmol, 3 equiv) were dissolved in toluene (2 mL) and the solution was flowed through a glass column (10 mm i.d. × 100 mm length) filled with Novozym 435 (250 mg) and molecular sieves (250 mg). A 100 psi back-pressure regulator was applied to the system. Temperature and flow rate were varied and their values are reported in Table 1. After collecting a total volume of 4 mL, the reaction outcome was analyzed by chiral HPLC. To this aim, a sample of 100 muL was withdrawn, evaporated and re-dissolved in acetonitrile (100 muL). Experiments reported in Tables 2 and 3 were carried using the same reactor set-up and following the procedure described above, varying the concentration of reagents and the amount of catalyst and molecular sieves, according to the data reported in the tables. Due to the use of a large excess of molecular sieves, which are expected to trap the produced water, this reaction can be considered quasi-irreversible; therefore, the enantiomeric ratio (E) was calculated from two of the following three properties: the conversion (c), the enantiomeric excess of the product (eep) and enantiomeric excess of the remaining substrate (ees) [20]. The specific reaction rate (rflow) was calculated from the concentration of the product ([P] (mumol/mL)), flow rate (f (mL/min)), and the mass of biocatalyst employed (mE (g)) according to Eq. (2) [21].

Reference： [1]Chirality,2010,vol. 22,p. 597 - 603
[2]Journal of Molecular Catalysis B: Enzymatic,2012,vol. 84,p. 78 - 82

19
[ 64858-91-9 ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium hydrogensulfate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper(II) nitrate trihydrate; oxygen In 1,2-dichloro-ethane at 20℃; for 40h;	49 Step I: General procedure: A balloon was inserted into the Shrek tube, the oxygen was pumped for 3 times, and Cu(NO 3 ) 2.3H 2O (24.6 mg, 0.1 mmol), TEMPO (16.1 mg, 0.1 mmol), KHSO 4 (14.1 mg, 0.1 mmol) were added in sequence ), 1a (243.0 mg, 1.0 mmol) and DCE (4 mL).The reaction was stirred at room temperature for 36 hours until completion by TLC monitoring.The reaction solution was passed through a short silica gel column (3 cm), eluted with ether (3 x 25 mL),Rotary evaporation to remove the solvent,The crude product was isolated and purified by silica gel column chromatography(eluent: petroleum ether/ethyl acetate = 10/1 to 1/1) to give the product 2a as a pale yellow solid (252.3 mg, 98%).
88%	With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hypochlorite; sodium chlorite In water; acetonitrile at 20℃; for 24h; aq. phosphate buffer;
40%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; laccase from Trametes versicolor; oxygen In aq. acetate buffer at 20℃; for 144h; Enzymatic reaction;

	With alcohol dehydrogenase-9V₁; dimethyl sulfoxide In aq. buffer at 30℃; for 21h; Enzymatic reaction;
98%	With potassium hydrogensulfate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper(II) nitrate trihydrate; oxygen In 1,2-dichloro-ethane at 20℃; Schlenk technique;
98 %	With potassium hydrogensulfate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper(II) nitrate trihydrate; oxygen In 1,2-dichloro-ethane at 20℃;	49 Step I: General procedure: A balloon was inserted into the Shrek tube, the oxygen was pumped for 3 times, and Cu(NO 3 ) 2.3H 2O (24.6 mg, 0.1 mmol), TEMPO (16.1 mg, 0.1 mmol), KHSO 4 (14.1 mg, 0.1 mmol) were added in sequence ), 1a (243.0 mg, 1.0 mmol) and DCE (4 mL).The reaction was stirred at room temperature for 36 hours until completion by TLC monitoring.The reaction solution was passed through a short silica gel column (3 cm), eluted with ether (3 x 25 mL),Rotary evaporation to remove the solvent,The crude product was isolated and purified by silica gel column chromatography(eluent: petroleum ether/ethyl acetate = 10/1 to 1/1) to give the product 2a as a pale yellow solid (252.3 mg, 98%).

Reference： [1]Current Patent Assignee: FUDAN UNIVERSITY - WO2022/206399, 2022, A1 Location in patent: Page/Page column 6; 31-32
[2]Location in patent: experimental part Galletti, Paola; Pori, Matteo; Giacomini, Daria [Synlett, 2010, # 17, p. 2644 - 2648]
[3]Galletti, Paola; Pori, Matteo; Funiciello, Federica; Soldati, Roberto; Ballardini, Alberto; Giacomini, Daria [ChemSusChem, 2014, vol. 7, # 9, p. 2684 - 2689]
[4]Könst, Paul; Merkens, Hedda; Kara, Selin; Kochius, Svenja; Vogel, Andreas; Zuhse, Ralf; Holtmann, Dirk; Arends, Isabel W. C. E.; Hollmann, Frank [Angewandte Chemie - International Edition, 2012, vol. 51, # 39, p. 9914 - 9917]
[5]Yu, Yibo; Zhai, Di; Zhou, Zhengnan; Jiang, Sheng; Qian, Hui; Ma, Shengming [Chemical Communications, 2023, vol. 59, # 35, p. 5281 - 5284]
[6]Current Patent Assignee: FUDAN UNIVERSITY - WO2022/206399, 2022, A1 Location in patent: Page/Page column 6; 31-32

20
[ 41604-19-7 ]
[ 5104-49-4 ]

Reference： [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 4470 - 4474
[2]Chemistry - A European Journal,2012,vol. 18,p. 9391 - 9396
[3]Patent: CN108558651,2018,A
[4]Patent: CN108558651,2018,A
[5]Journal of the American Chemical Society,2019,vol. 141,p. 11393 - 11397

21
[ 74648-00-3 ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium hydroxide; In ethanol; water; at 110℃; for 7h;Inert atmosphere;	2-fluoro-4-biphenylacetonitrile (5 mmol), pyridine borane complex (3 equivalents), sodium hydroxide (1.5 equivalents) was added to a 25 ml Schlenk reaction tube under a nitrogen atmosphere, N, N-dimethylformamide (5 ml) as a solvent, and a rubber stopper was added to the reaction tube and placed in an oil bath and stirred at 100 C for 3 hours. After completion of the reaction, ethyl acetate was extracted and chromatographed, and the eluent was petroleum ether / ethyl acetate (v: v = 30: 1) to give 2-fluoro-4-biphenylpropionitrile. 2-fluoro-4-biphenylpropionitrile (4 mmol), sodium hydroxide (3 equiv.), Water (8 ml) and ethanol (2 ml) were added to a 25 ml two-necked round- Add rubber stopper into the oil bath pot, 110 reflux reaction 7h. After completion of the reaction, the ethyl acetate was extracted and chromatographed, and the eluent was petroleum ether / ethyl acetate (v: v = 5: 1) to give 2-fluoro-4-biphenylpropionic acid, The

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 11770 - 11775
Angew. Chem.,2018,vol. 130,p. 11944 - 11949,6
[2]Patent: CN107137387,2017,A .Location in patent: Paragraph 0032-0035
[3]Angewandte Chemie - International Edition,2011,vol. 50,p. 4470 - 4474
[4]Patent: CN108558651,2018,A .Location in patent: Paragraph 0004; 0056

22
[ 5001-96-7 ]
[ 74-88-4 ]
[ 5104-49-4 ]
[ 5104-49-4 ]

Reference： [1]Journal of the American Chemical Society,2011,vol. 133,p. 11936 - 11939

23
[ 5104-49-4 ]
[ 4064-06-6 ]
[ 1207167-00-7 ]

Yield	Reaction Conditions	Operation in experiment
61%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In dichloromethane; at 20℃; for 12h;	Synthesis of Diacetone 6'-O-<strong>[5104-49-4]Flurbiprofen</strong>-D-galactopyranoside (2a) 1 g of flurbiprofen 2 (4.1 mmol), 1.067 g of 1,2,3,4-di-O-isopropylidene-D-alpha-galactopyranose (4.1 mmol), 786 mg of N-ethyl-N'-(3-dimethyl aminopropyl)carbodiimide (EDC) HCl (4.1 mmol), and 25.2 mg of 4-(dimethyl amino)pyridine (DMAP) (0.205 mmol) were dissolved in anhydrous dichloromethane (10 mL). The reaction mixture was kept under electromagnetic stirring at room temperature for 12 hours. The organic phase was extracted several times with water and dehydrated with anhydrous sodium sulphate, filtered and dried in vacuo. The reaction crude was purified on a chromatography column with silica gel using CH2Cl2 as eluent, to obtain 1.21 g of 2a as a white solid (yield 61%) m/z: 487 (M+H)+.

Reference： [1]Patent: US2011/212904,2011,A1 .Location in patent: Page/Page column 5

24
[ 5104-49-4 ]
[ 71-36-3 ]
[ 5104-49-4 ]
(S)-flurbiprofen n-butyl ester [ No CAS ]
(R)-flurbiprofen n-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Candida antarctica lipase B immobilised on acrylic resin; In toluene; at 60℃; under 5171.62 Torr;Molecular sieve; Flow reactor; Enzymatic reaction;	General procedure: Experiments reported in Table 1 were carried out as follows: 10 mg of racemic flurbiprofen 1 (0.04 mmol), 10.8 muL of n-butanol (0.12 mmol, 3 equiv) were dissolved in toluene (2 mL) and the solution was flowed through a glass column (10 mm i.d. × 100 mm length) filled with Novozym 435 (250 mg) and molecular sieves (250 mg). A 100 psi back-pressure regulator was applied to the system. Temperature and flow rate were varied and their values are reported in Table 1. After collecting a total volume of 4 mL, the reaction outcome was analyzed by chiral HPLC. To this aim, a sample of 100 muL was withdrawn, evaporated and re-dissolved in acetonitrile (100 muL). Experiments reported in Tables 2 and 3 were carried using the same reactor set-up and following the procedure described above, varying the concentration of reagents and the amount of catalyst and molecular sieves, according to the data reported in the tables. Due to the use of a large excess of molecular sieves, which are expected to trap the produced water, this reaction can be considered quasi-irreversible; therefore, the enantiomeric ratio (E) was calculated from two of the following three properties: the conversion (c), the enantiomeric excess of the product (eep) and enantiomeric excess of the remaining substrate (ees) [20]. The specific reaction rate (rflow) was calculated from the concentration of the product ([P] (mumol/mL)), flow rate (f (mL/min)), and the mass of biocatalyst employed (mE (g)) according to Eq. (2) [21].

Reference： [1]Journal of Molecular Catalysis B: Enzymatic,2012,vol. 84,p. 78 - 82

25
[ 5104-49-4 ]
[ 190124-72-2 ]

Yield	Reaction Conditions	Operation in experiment
89%		<strong>[5104-49-4]Flurbiprofen</strong> (10 mmol) and CDI (12 mmol) were taken into a100 mL round-bottommed flask and dissolved in minimum volume ofTHF (?10 mL). Stirred the reaction mixture for 10 min to activate thecarboxylic functional group of flurbiprofen. Then, hydrazine hydrate(5 mL) was added into the reaction mixture and refluxed for 4 h withconstant stirring. Progress of the reaction was checked by the TLC(6:4=EtOAc:Hexane) analysis. Reaction mixture was poured ontocrushed ice (100 mL). Precipitates were appeared immediately whichwere filtered, washed with distilled water, and dried in vacuum. Thesolid product was crystallized from ethanol. Structure of the product (1)was characterized by the spectroscopic techniques such as EI-MS, 1Hand 13C NMR. 4.3. 2-(2-Fluoro-[1,1?-biphenyl]-4-yl)propanehydrazide (1)Solid; Yield: 89%; M.P.: 119-121 C; 1H NMR (300 MHz, DMSO-d6):delta 9.22 (s, 1H, NHa), 7.52 (m, 6H, H-5, H-8, H-9, H-10, H-11, H-12), 7.24(dd, J6,2=1.6 Hz, J6,5=4.4 Hz, 1H, H-6), 7.21 (s, 1H, H-2), 4.22 (s,2H, NH2), 3.61 (q, JCH,CH3=7.2 Hz, 1H, CH), 1.36 (d, JCH3,CH=7.2 Hz,3H, CH3); 13C NMR (100 MHz, DMSO-d6): delta 173.2, 158.5, 136.4, 135.9,130.2, 129.0, 129.0, 128.1, 127.5, 127.5, 127.3, 125.5, 118.2, 42.7,18.0; EI-MS m/z (% rel. abund.): 258 (M+, 41), 226 (27), 199 (1 0 0),183 (16); Anal. Calcd for C15H15FN2O: C=69.75; H=5.85;N=10.85; Found: C=69.77; H=5.84; N=10.87.

Reference： [1]Bioorganic Chemistry,2018,vol. 81,p. 157 - 167
[2]Medicinal Chemistry Research,2013,vol. 22,p. 5685 - 5699
[3]Journal of Chemical Research,2015,vol. 39,p. 668 - 673

26
[ 1603-40-3 ]
[ 5104-49-4 ]
2-(2-fluoro-(1,1'-biphenyl)-4-yl)-N-(3-methylpyridin-2-yl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 24h;	General procedure: A mixtureoftheappropriateacid(flurbiprofen, naproxenor 2-(2-(2-fluorobiphenyl-4-yl)propanamido)aceticacid,1mmol),EDC (0.19g,1.1mmol),andHOBt(0.13g,1mmol)indryacetoni-trile (10mL)wasstirredatroomtemperaturefor30minandthentreatedwith2-amino-3-methylpyridine(0.11g,1mmol).Themixture wasstirredatroomtemperatureforanadditional24hand thesolutionwasthenevaporatedtodrynessinvacuo.Theresiduewasdissolvedinethylacetate(20mL)andwashed sequentiallywithbrine(25 mL),10%aqueoussodiumcarbonate(25 mL),10%aqueouscitricacid(25 mL),andwater(25 mL).Theorganiclayerwasdriedoveranhydrousmagne-sium sulphateand filtered.Concentrationofthedriedextractsyielded thetitleamidesinanalyticallypureformwithoutaddi-tional purification.

Reference： [1]European Journal of Pharmacology,2013,vol. 720,p. 383 - 390

27
[ 5104-49-4 ]
[ 2567-29-5 ]
(±)-3-(biphenyl-4-yl)-2-(2-fluorobiphenyl-4-yl)-2-methylpropanoic acid [ No CAS ]

Reference： [1]Archiv der Pharmazie,2015,vol. 348,p. 55 - 61

28
[ 5104-49-4 ]
tert-butyl (2,2-difluoro-3-hydroxypropyl)carbamate [ No CAS ]
C₂₃H₂₆F₃NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 5h;	100 mg (1.0 eq., 0.47 mmol) of the compound 1 was dissolved in 10 mL of DCM, and added with 122 mg (1.05 eq., 0.50 mmol) of flurbiprofen and 17 mg (0.3 eq., 0.14 mmol) of DMAP. Then, under ice cooling, 182 mg (2.0 eq., 0.95 mmol) of WSC was added followed by stirring overnight at room temperature. After confirming by TLC the disappearance of the reacting materials, the reaction solution was quenched with a saturated aqueous solution of NH4Cl under ice cooling and liquid fractionation extraction was performed 3 times by using DCM and water. The collected organic layer was washed in order with a saturated aqueous solution of NH4Cl, a saturated aqueous solution of NaHCO3, and a saturated aqueous solution of NaCl. After drying over magnesium sulfate, it was concentrated under reduced pressure by using an evaporator in water bath at 40 C., and the desired compound 8 was obtained in an amount of 211 mg (yield: quant.).

Reference： [1]Patent: US2016/151506,2016,A1 .Location in patent: Paragraph 0379-0381

29
[ 5104-49-4 ]
flurbiprofen acid bromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With phosphorus tribromide; In tetrahydrofuran; at 0 - 20℃; for 3h;	Take flurbiprofen 34.2g (0.14mol) was added dry 250mL three flask, 120mL of tetrahydrofuran was added, followed by stirring; ice-bath controlled at a temperature of 0-5 deg.] C, preferably 3 , phosphorus tribromide was slowly added dropwise 20mL , slowly warming to room temperature after completion of dropwise, the reaction stirred for 3h, the reaction by TLC. after completion of the reaction under reduced pressure recycle of excess phosphorus tribromide , to give a pale yellow oil, the above-described light yellow oil obtained was dissolved in 100mL dichloromethane methylene chloride solution containing bromide;
	With phosphorus(V) oxybromide; In dichloromethane; for 7h;Cooling with ice; Reflux;	36.8 g of flurbiprofen was added to the three-necked bottle.Add 150 mL of dichloromethane and stir to dissolve the flurbiprofen.Under ice bath, slowly add 30 mL of phosphorus oxybromide. After the addition is completed, stir at room temperature for 3 hours.After heating and refluxing for 4 hours, the thin layer plate was monitored. After the reaction was completed, the solvent was distilled off under pressure to obtain a pale yellow solid;No need to purify, directly dissolved in 180mL of dichloromethane for use;

Reference： [1]Patent: CN105753701,2016,A .Location in patent: Paragraph 0040
[2]Patent: CN109096191,2018,A .Location in patent: Paragraph 0049; 0050; 0059; 0060

30
[ 64858-90-8 ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
72.2%		In the above-mentioned 2 - (2-fluoro-4-biphenyl) propionic acid ethyl ester by adding 9.44kg10% NaOH, heating to 95 C hydrolysis, TLC detection reaction is complete (about 3h) the rear, lower the temperature to 25 C the following, filtration, filtrate with 30% sulfuric acid solution to adjust the pH value to less than 4, is filtered, then, to obtain 2 - (2-fluoro-4-biphenyl) propionic acid crude product;In the 2 - (2-fluoro-4-biphenyl) propionic acid crude product with ethyl acetate is added in the mixed solvent of petroleum ether 8.5L (by volume ratio, ethyl acetate: petroleum ether = 1:7), heating to 65 C dissolved, through the activated carbon after the decoloring the heat filters, crystalline (cooling), filtering, drying (60 C), to obtain 2 - (2-fluoro-4-biphenyl) propionic acid pure product 601g (yield 72.2%, purity 99.65%).
	With sodium hydroxide;Reflux;	6) The obtained yellow-brown oil was added to 120 mL of ethanol and stirred to dissolve.100 mL of a 5% by mass sodium hydroxide solution was added and refluxed for 6-7 hours.7) After completion of the reaction, the mixture was concentrated under reduced pressure, and ethanol was recovered in a yield of 95% or more. The mixture was washed twice with 100 mL of ethyl acetate. The aqueous layer was adjusted to pH <3 with hydrochloric acid and extracted twice with 100 mL of ethyl acetate. Two times, dried over anhydrous sodium sulfate.8) After filtration, the filtrate was concentrated under reduced pressure, and the residue was added with 50 mL of petroleum ether. The mixture was heated and dissolved, and then added with a solution of 1.0 g of activated carbon, refluxed for 20 min, filtered while hot, and the filtrate was cooled to give a white solid.The yield was 90% and the purity was 99.5%.

Reference： [1]Patent: CN105601504,2016,A .Location in patent: Paragraph 0034; 0068; 0069
[2]Patent: CN108558651,2018,A .Location in patent: Paragraph 0007; 0029; 0030-0032; 0044
[3]Journal of the American Chemical Society,2019,vol. 141,p. 10978 - 10983

31
[ 5104-49-4 ]
methyl 2-(4-(3-aminophenyl)-1H-1,2,3-triazol-1-yl)acetate [ No CAS ]
methyl 2-(4-(3-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propanamido)phenyl)-1H-1,2,3-triazol-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 40℃;Inert atmosphere; Sealed tube;	General procedure: In a typical run, a 15 mL screw cap tube was charged with the selected carboxylic acid (0.5 mmol), HATU (2 equiv/mol), DMF(1 ml) and DIPEA (2 equiv/mol.). A solution of 1 or 2 (0.5 mmol) in DMF (1 ml) was then added dropwise. The tube was flushed with argon, sealed, and the mixture was stirred overnight at 40 C. After cooling down to rt, the crude reaction mixture was diluted with water (10 mL) and extracted with EtOAc(3 15 mL). The combined organic layers were washed with brine(3 15 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a residue, which was purified as indicated for each compound (see Supporting material).

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 4381 - 4389

32
[ 5707-04-0 ]
[ 5104-49-4 ]
C₂₁H₁₇FOSe [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With tributylphosphine; In dichloromethane; at -15℃; for 3h;Inert atmosphere;	In a 50 ml flask were added benzene selenium chloride (0.23 g, 1.23 mmol) and anhydrous dichloromethane (30 ml)Ice-salt bath cooling to -15 C stirring, Tributylphosphine (0.33 g, 1.64 mmol) was added sequentially,2-(2-fluoro-[1,1'-biphenyl]-4yl)propanoic acid (0.20 g, 0.82 mmol),Access to high purity argon gas protection,The reaction was stirred at -15 C for 3.0 hours,TLC monitoring reaction was complete,The solvent was removed by distillation under reduced pressure,Silica gel column chromatography separation,The mobile phase consisted of ethyl acetate (V): petroleum ether (V) = 1: 8,To give a white solid VIII0.23 g, 73% yield.
73%	With tributylphosphine; In dichloromethane; at -15℃; for 3h;Inert atmosphere;	Benzene selenium chloride was added to a 50 ml flask(0.23 g, 1.23 mmol)And anhydrous dichloromethane (30 ml)Ice-salt bath cooling to -15 C stirring, followed by addingTributyl phosphorus (0.33 g, 1.64 mmol),2- (2-fluoro-4-biphenyl) propionic acid(0.20 g, 0.82 mmol), protected by high purity argon, maintained at -15 C for 3.0 hours. TLC was monitored and the reaction was complete. Solvent, silica gel column chromatography, using ethyl acetate (V): petroleum ether (V) = 1: 8 as the mobile phase, white solid VIII 0.23 g, yield 73%.

Reference： [1]Patent: CN106176721,2016,A .Location in patent: Paragraph 0074; 0075
[2]Patent: CN106146372,2016,A .Location in patent: Paragraph 0074; 0075

33
2-(1-bromoethyl)-2-(2-fluoro-(1,1'-biphen-4-yl)-5,5-dimethyl)-1,3-dioxocyclohexane [ No CAS ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
91.2%		Embodiment 9 Synthesis of 2-(3-fluoro-4-phenyl)phenylpropionic acid (flurbiprofen) under catalysis of zinc 2-(3-fluoro-4-phenyl)propionate 7.84 g (0.02 mol) of 2-(1 -bromoethyl)-2-(2-fluoro-(1,1'-biphen-4-yl)-5,5-dimethyl-1,3-dioxocyclohexan e, 0.276 g (0.0005 mol) of zinc 2-(6-methoxylnaphthyl)propionate and 30 mL of toluene are added into a 500 mL round-bottom flask and undergo a reflux reaction for 3.5 h, a 30% sodium hydroxide solution (50 mL) is added, after refluxing under stirring for 3.5 h and cooling to 50 C., water (15 mL) and a small amount of activated carbon are added, and the stirring refluxing is continued for 0.5 h. After cooling, filtration and standing, an aqueous layer is separated, a toluene layer is washed with water (30 mL*3), the aqueous layers are combined and adjusted with concentrated hydrochloric acid to a pH of 1-2 to separate a white solid, and the white solid is filtered, the crude product is washed with water and dried. Recrystallization is performed using ethanol-water to obtain 4.45 g of a white powder with a yield of 91.2%. The m.p. is 110-112 C.

Reference： [1]Patent: US2016/326085,2016,A1 .Location in patent: Paragraph 0024

34
[ 1576-43-8 ]
[ 5104-49-4 ]
2-(2-fluorobiphen-4-yl)-N-(4-hydroxyphenylsulfonyl)propionamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%		A solution of 2- (2-fluoro-4-biphenyl) propionic acid (0. 61 g, 2.52 mmol) in dry dichloromethane was added to a 50 ml round bottom flask and CDI (0. 41 g, 2.52 mmol) The mixed solution was stirred at 0-5 C for 2 hours. After addition of 4-hydroxyphenylsulfonamide (0.44 g, 2.52 mmol) and DBU (0.3 ml), the mixture was stirred at room temperature for about 6 hours. The TLC was followed by the reaction. The organic phase was washed with NaH2P04 (2 * 5 ml), saturated brine (2 * 5 ml). Dried over anhydrous sodium sulfate, The solvent is removed. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give the title compound (0.62 g yield 79%)

Reference： [1]Patent: CN103159650,2016,B .Location in patent: Paragraph 0051-0053

35
[ 49773-20-8 ]
[ 5104-49-4 ]
2-(2-fluorobiphen-4-yl)-N-(2-methylsulfonylethyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%		A solution of 2- (2-fluoro-4-biphenyl) propionic acid (0. 61 g, 2.52 mmol) in dry dichloromethane was added to a 50 ml round bottom flask and CDI (0. 41 g, 2.52 mmol) inside, The mixed solution was stirred at 0-5 C for 2 hours. Methanesulfonamide ethylamine (0.31 g, 2.52 mmol) was added, Silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) gave the title compound (0.788) in 77% yield.

Reference： [1]Patent: CN103159650,2016,B .Location in patent: Paragraph 0055-0057

36
[ 98-10-2 ]
[ 5104-49-4 ]
2-(2-fluorobiphen-4-yl)-N-(phenylsulfonyl)propionamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%		Take 50ml round bottom flask, CDI (0. 41 g, 2.52 mmol) was added to a dry dichloromethane solution of 2- (2-fluoro-4-biphenyl) propionic acid (0. 61 g, 2.52 mmol) Mixed solution at Stir at 0-5 C for 2 hours. (0.39 g, 2.52 mmol) and DBU (0.3 ml) were added and the mixture was stirred at room temperature for about 6 hours. The TLC was followed by the reaction. The organic phase was washed with NaH2P04 (2 * 5 ml), saturated brine (2 * 5 ml). Dried over anhydrous sodium sulfate and the solvent was removed. The target compound (0.62 g) was isolated by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) in a yield of 79%.

Reference： [1]Patent: CN103159650,2016,B .Location in patent: Paragraph 0047-0049

37
[ 40258-78-4 ]
[ 5104-49-4 ]
S-(+)-flurbiprofen axetil [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.5%	With N-ethyl-N,N-diisopropylamine; In acetone; at 0 - 25℃; for 12h;	Accurately weigh 3L three bottles S- (+) - flurbiprofen (50 g, 0. mol), 1-bromoacetate (50.18, 0.3 mol), Add 800mL of acetone stirring to make it all dissolved, The reaction temperature was reduced to 0 ° C, To the above solution was slowly added dropwise DIPEA (12.9 g, 0 lmo 1) In acetone (50 mL) And stirred at 25 ° C for 12 hours, 0 ° C by adding 100 mL of water to quench the reaction, followed by extraction with ethyl acetate 4 times, Each time 200mL, the combined organic phase washed with saturated sodium chloride solution 2 times, each time 300mL, with anhydrous sodium sulfate to dry, vacuum evaporation by rapid chromatography (filler for the neutral aluminum oxide RhoEpsilon: EpsilonAlpha = 10: 1). After removal of the organic solvent, the solvent was removed by evaporation under reduced pressure and repeated three times and then vacuum dried at 50 ° C for 12 hours to obtain 27.9 g of the title compound as a pale yellow oil in a yield of 84.5 percent, Dr = 99.44percent Recovery of S- (+) - flurbiprofen 18.6 g, ee = 99.61percent.

Reference： [1]Patent: CN105777544,2016,A .Location in patent: Paragraph 0037-0041

38
[ 40258-78-4 ]
[ 5104-49-4 ]
S-(+)-flurbiprofen axetil [ No CAS ]
C₁₉H₁₉FO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63.4%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In toluene; at 0 - 25℃; for 4h;	S-(+) -flupiflofen (2.0 g, 8.19 mmol) was accurately weighed into a 100 mL three-necked flask, Add 50mL of acetone stirring to make it all dissolved, The reaction temperature was reduced to 0 ° C, Slowly add KHC03 solid (410 m g, 4 lOmmo 1) Then (2. lg, 12.29 mmol) 1- Bromide B Ethyl acetate solution of acetone 10 mL at 0 ° C Was added dropwise to the above acetone solution of S- (+) - fluorobiloprofen, And stirred at 25 ° C for 4 hours, then 25 ° C was added to 100 mL of water to quench the reaction, followed by extraction with ethyl acetate 3 times, 50 mL each time. The combined organic phases were washed twice with saturated sodium chloride solution, 30 mL each time, Dried over anhydrous sodium sulfate and evaporated in vacuo to give 860 mg of the title compound as a pale yellow oil in a yield of 63.5 by flash chromatography (padding of neutral aluminum oxide, PE: EpsilonAlpha = 10: 1) percent, Dr = 93.2percent.

Reference： [1]Patent: CN105777544,2016,A .Location in patent: Paragraph 0037-0041

39
[ 2579-22-8 ]
[ 5104-49-4 ]
C₂₄H₁₉FO₃ [ No CAS ]

Reference： [1]ACS Catalysis,2016,vol. 6,p. 8030 - 8035

40
[ 5104-49-4 ]
(S)-4-(3-minopiperidin-1-yl)coumarin [ No CAS ]
C₂₉H₂₇FN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 0.5h;	General procedure: Method A: CDA (1, 4, or 7) and carboxylic acid dissolved in DCM were stirred for 15 min at roomtemperature. N,N?-Dicyclohexylcarbodiimide (DCC) was then added, and the mixture was stirred for 30min at room temperature

Reference： [1]Heterocycles,2017,vol. 94,p. 964 - 978

41
[ 5104-49-4 ]
(S)-4-(3-aminoazepan-1-yl)coumarin [ No CAS ]
C₃₀H₂₉FN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 0.5h;	General procedure: Method B: CDA, carboxylic acid, and DMAP dissolved in DCM were stirred for 15 min at roomtemperature. DCC was added, and the mixture was stirred for 30 min at room temperature

Reference： [1]Heterocycles,2017,vol. 94,p. 964 - 978

42
[ 5104-49-4 ]
(S)-4-(3-aminopyrrolidin-1-yl)coumarin [ No CAS ]
C₂₈H₂₅FN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 0.5h;	General procedure: Method A: CDA (1, 4, or 7) and carboxylic acid dissolved in DCM were stirred for 15 min at roomtemperature. N,N?-Dicyclohexylcarbodiimide (DCC) was then added, and the mixture was stirred for 30min at room temperature

Reference： [1]Heterocycles,2017,vol. 94,p. 964 - 978

43
[ 25984-63-8 ]
[ 5104-49-4 ]
4-thiocarbamoylphenyl 2-(3-fluoro-4-phenylphenyl) propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34.5%		General procedure: To the solution of (naproxen, 230mg 1.0mmol) in 8mL of acetonitrile, DMAP (18mg, 0.15mmol) and EDCI (190mg, 1.0mmol) were added with stirring at room temperature for 0.5h. To the reaction mixture <strong>[25984-63-8]4-hydroxythiobenzamide</strong> (153mg, 1.0mmol) was added and stirred for 4hat room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in trichloromethane; the organic layer was washed with brine, with NaCl 5%, and then dried on anhydrous Na2SO4, filtered and the solvent evaporated. The crude product was chromatographed on a silica gel (CHCl3/CH3OH 30:1), and 148.8mg pale yellow solid was obtained.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 138,p. 51 - 65

44
[ 41604-19-7 ]
[ 5104-49-4 ]

Reference： [1]European Journal of Organic Chemistry,2017,vol. 2017,p. 4859 - 4863
[2]European Journal of Organic Chemistry,2017,vol. 2017,p. 4859 - 4863
[3]European Journal of Organic Chemistry,2017,vol. 2017,p. 4859 - 4863
[4]European Journal of Organic Chemistry,2017,vol. 2017,p. 4859 - 4863
[5]Patent: US2018/282252,2018,A1
[6]Patent: US2018/282252,2018,A1

45
[ 41604-19-7 ]
3-(2-fluoro-[1,1'-biphenyl]-4-yl)propanoic acid [ No CAS ]
[ 5104-49-4 ]
[ 5104-49-4 ]

Reference： [1]European Journal of Organic Chemistry,2017,vol. 2017,p. 4859 - 4863
[2]European Journal of Organic Chemistry,2017,vol. 2017,p. 4859 - 4863

46
[ 24388-23-6 ]
2-(3-fluoro-4-chlorophenyl)propionic acid [ No CAS ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); potassium carbonate; In ethanol; water; toluene; for 4h;Inert atmosphere; Reflux;	In a 1000ml three-necked flask, 85 g (0.42 mol) of the product 2- (3-fluoro-4-chlorophenyl) propionic acid (4) from Step A was added 89.7 g (0.44 mol) of phenylboronic acid pinacol ester (5), ethanol 200ml, toluene 300ml, a solution of potassium carbonate 121 g (0.88 mol) in 200 ml of water was added. Stir well and add under nitrogen PdCl2(Amphos)2 155 mg (0.05 mol%). Heated to reflux for 4h, TLC showed no raw material remaining, the reaction is over. The solvent is evaporated, cooled to 0 C, suction filtered. The resulting solid was washed with 200 ml of cold water. Then the solid was dissolved in hot water, hydrochloric acid was added dropwise to a pH value of less than 3, precipitated a large amount of solid, filtered and dried at room temperature to give a white flurbiprofen product 95.5g, yield 89%, HPLC purity 99.58% .

Reference： [1]Patent: CN106496015,2017,A .Location in patent: Paragraph 0041; 0042; 0043; 0044; 0052-0054

47
[ 60811-18-9 ]
[ 5104-49-4 ]

Reference： [1]Patent: CN106496015,2017,A

48
2-(3-fluoro-4-chlorophenyl)propionic acid [ No CAS ]
[ 98-80-6 ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With bis(tri-t-butylphosphine)palladium(0); potassium carbonate; In ethanol; water; toluene; for 4h;Inert atmosphere; Reflux;	In a 1000ml three-necked flask, 85 g (0.42 mol) of the product 2- (3-fluoro-4-chlorophenyl) propionic acid (4) 53.7 g (0.44 mol) of phenylboronic acid (5), ethanol 200ml, toluene 300ml, a solution of potassium carbonate 121 g (0.88 mol) in 200 ml of water was added. Stir well and add under nitrogen Pd(Pt-Bu3)2 90mg (amount 0.04mol%). Heated to reflux for 4h, TLC showed no raw material remaining, the reaction is over. The solvent is evaporated, cooled to 0 C, suction filtered. The resulting solid was washed with 200 ml of cold water. Then the solid was dissolved in hot water, hydrochloric acid was added dropwise to a pH value of less than 3, precipitated a large amount of solid, filtered and dried at room temperature to give a white flurbiprofen product 96.6g, yield 90%, HPLC purity 99.6% .

Reference： [1]Patent: CN106496015,2017,A .Location in patent: Paragraph 0037; 0038; 0039; 0062; 0063; 0064

49
[ 38780-40-4 ]
[ 5104-49-4 ]
C₂₁H₂₆ClFN₂O₂Pt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With sodium carbonate; silver nitrate; In N,N-dimethyl-formamide; at 20℃; for 24h;Darkness;	Cis-dichloro-, 2-cyclohexanediamine platinum (190 mg), AgNO3 (43 mg), flurbiprofen (122 mg) andNa2C03 (35.3mg) added to the round bottom flask, and then add 10ml DMF, dark at room temperature 24h. The precipitate was centrifuged to remove AgCl. After the filtrate was concentrated, 50 ml of ethyl acetate was added and the mixture was washed three times with 50 ml of 0.1 M Na2CO3 and washed with water three times. The ethyl acetate layer was collected and dried over anhydrous sodium sulfate overnight. Filtration, the filtrate with methanol: chloroform = 1: 9 eluent, silica gel column chromatography to obtain flurbiprofen - cyclohexanediamine platinum complexes,Yield 56%, the structural formula shown in Figure 36

Reference： [1]Patent: CN107296794,2017,A .Location in patent: Paragraph 0140-0142

50
[ 34904-92-2 ]
[ 5104-49-4 ]
(1-(3,5-dimethoxyphenyl)-2-oxo-2-phenyl-ethyl)2-(3-fluoro-4-phenyl-phenyl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67.7%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;	Compound 2 was synthesized via DCC mediated esterification. <strong>[5104-49-4]Flurbiprofen</strong> (0.82 g, 3.35 mmol), DMB (1.01 g,3.7 mmol), and DMAP (45 mg, 0.37 mmol) were dissolved in anhydrous DCM (50 ml) with stirring prior to the addition of DCC. The mixture was stirred at room temperature overnight during which time dicyclohexylurea precipitated from solution. The filtrate was washed with 0.2 M HCl, saturated sodium bicarbonate solution and brine prior to drying over magnesium sulfate. The filtrate was concentrated using rotary evaporation and the product purified by flash chromatography on a silica gel column using DCM as the eluent. The product was isolated as a white solid (1.13 g, 67.7%). delta(CDCl3): 7.94 & 7.88 (d, 2H, J = 8.16 & 8.08, 2 x O = CC-CH); 7.597-7.316 (m, 9H, aromatic H); 7.234-7.101 (m,2H, aromatic H); 6.74 & 6.72 (s, 1H, O = C-CH-O-); 6.56 &6.53 (s, 2H, 2 x -CH-C-O-CH3); 4.016-3.872 (m, 1H, -CHCH3);1.61 (dd, 3H, -CH3). m/z (%): 499.19 (M + 1, 100),255.10 (20).

Reference： [1]Pharmaceutical Research,2017,vol. 34,p. 1469 - 1476

51
[ 5104-49-4 ]
dichlorodihydroxydiamineplatinum [ No CAS ]
cisplatin flurbiprofen [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.3%		Example 1This example prepares a cisplatin-flurbiprofen prodrug by a method that includes the following steps.(1)In a three-necked flask, 1005.94 mg (4.12 mmol) of flurbiprofen was added,N2 for half an hour.(2)Oxalyl chloride (such that the mole ratio of flurbiprofen to oxalyl chloride was 1: 10) was added to a three-necked flask,The temperature was raised to 70 C,Heating, stirring, reflux 1h,Cool to room temperature,A yellow transparent liquid was obtained.(3)The yellow transparent liquid obtained in the step (2) was transferred to an eggplant flask,Rotate to remove oxalyl chloride,Get a yellow oily liquid;Add 6 mL of anhydrous tetrahydrofuran (THF),Remove by rotary evaporation; repeat this procedure twice.(4)69.3 mg (0.207 mmol) of dichlorodihydroxydiamineplatinum (Pt (NH3) 2 (OH) 2Cl2) was added to the eggplant-shaped flask in the step (3)6 mL of tetrahydrofuran (THF),In the dark conditions,The temperature was raised to 70 C,Heated, stirred, reflux 2h,The bottle to get a light yellow precipitate;Cool to room temperature,Tetrahydrofuran (THF) was removed by rotary evaporation.(5)To the eggplant bottle in step (4) was added 5ml of acetone,25ml ultrapure water,Into the refrigerator at 4 dark overnight.(6)Rotate to remove acetone,Pour out the upper suspension,Rotate to remove the remaining water,A dry, pale yellow product was obtained.(7)To the step (6) eggplant flask was added about 8ml of cold diethyl ether to re-suspend the product,Suction filtration,Wash twice with cold ether,Drained to give the final light yellow product (product protected from light).The final yield was: 92.3%.

Reference： [1]Patent: CN107445818,2017,A .Location in patent: Paragraph 0034; 0035; 0036; 0037; 0038; 0039; 0040-0073

52
[ 5104-49-4 ]
sodium 2-(2-fluoro-4-biphenylyl)propionate dihydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.7%		1.221 kg flurbiprofen, 3.7 g ascorbic acid, 1.832 kg water, 1.447 kg ethanol were added to the reaction vessel.Heating with stirring to warm up to 70 ~ 75 C dissolved; then began to add 30% aqueous NaOH solution (containing 0.200 kg NaOH); after the completion of the dropwise, the reaction temperature was maintained stirring 1.5h;Stop the reaction, slowly cooled to room temperature, and then cooled to 0 ~ 5 C under stirring crystallization 2h;After filtration, the resulting solid is maintained at a vacuum degree of more than 0.08 MPa, and dried at a temperature of 30-35C for 5 hours.A white powdery solid 1.446 kg was obtained, which is fluniprofen sodium form I. After testing,In this embodiment, the yield of crystalline form I of flurbiprofen sodium is 95.7%, and the liquid phase purity is 99.89%.The moisture content is 11.89%, and the resulting flurbiprofen sodium form I is pure and contains only impurity A.The impurity A content is 0.06%.

Reference： [1]Patent: CN106905143,2017,A .Location in patent: Paragraph 0053; 0054; 0055

53
[ 5104-49-4 ]
flurbiprofen sodium [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.8%	With sodium methylate; In methanol; at 65℃; for 1.5h;Large scale;	Add 1.221 kg of flurbiprofen, 2.894 kg of methanol to the reaction kettle, and heat to 65 C. with stirring to dissolve.Then began to drop 28% methanol solution of sodium methoxide 0.965kg; after dripping, keep the temperature and stir the reaction for 1.5h; stop the reaction, slowly cool to room temperature, then cool to 0 ~ 5 C under stirring crystallization 2h, filtration, the resulting solid The vacuum degree is maintained at more than 0.08 MPa, and the temperature is dried at 30-35 C. for 5 hours to obtain 1.262 kg of a white powdery solid, ie, Fluben-Profen sodium form II.After testing, the yield of crystalline form II of flurbiprofen sodium is 94.8% and the liquid purity is 99.55%.The moisture content is 0.15%, and the obtained flurbiprofen sodium crystal form II is of high purity, which contains only impurity A and impurity B, impurity A content is 0.31%, impurity B content is 0.14%.

Reference： [1]Patent: CN106905143,2017,A .Location in patent: Paragraph 0067; 0067; 0068

54
[ 5104-49-4 ]
[ 2618-96-4 ]
N-{1-[2-fluoro-(1,1'-biphenyl)-4-yl]ethyl}-N-phenylsulfonylbenzenesulfonamide [ No CAS ]

Reference： [1]Chemistry - A European Journal,2018,vol. 24,p. 9254 - 9258

55
[ 582-22-9 ]
[ 5104-49-4 ]
C₁₅H₁₃FO₂*C₉H₁₃N [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 9150 - 9153
Angew. Chem.,2018,vol. 130,p. 9289 - 9293,5

56
[ 582-22-9 ]
[ 5104-49-4 ]
C₁₅H₁₃FO₂*C₉H₁₃N [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 9150 - 9153
Angew. Chem.,2018,vol. 130,p. 9289 - 9293,5

57
[ 5104-49-4 ]
1-selenocyano-2-ethylamine hydrobromide [ No CAS ]
2-(2-fluorobiphenyl-4-yl)-N-(2-selenocyanatoethyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%		General procedure: To a solution of patent NSAIDs (1.0 eq) in DCM (5 mL)and DMF (5 mL) was added EDCI (1.2 eq.), HOBT (1.2eq.), and TEA (3.0 eq.). The mixture was stirred at 25 C for30 min. Then 2-selenocyanatoethanamine hydrobromide(1.2 eq) or 2-selenocyanatopropanamine hydrobromide (1.2eq.) was added into the mixture. The mixture was stirred at25 C for 16 h. TLC showed the reaction was complete. Themixture was diluted with H2O (20 mL), the aqueous layer was extracted with DCM (15 mL × 2), the combined organiclayer was washed with brine (20 mL × 2), dried overNa2SO4, filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by columnchromatography on silica gel, eluting with dichloromethane/methanol solution to obtain the desire compound.

Reference： [1]Medicinal Chemistry Research,2018,vol. 27,p. 2071 - 2078

58
[ 5104-49-4 ]
2-selenocyanatopropanamine hydrobromide [ No CAS ]
2-(2-fluorobiphenyl-4-yl)-N-(3-selenocyanatopropyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		General procedure: To a solution of patent NSAIDs (1.0 eq) in DCM (5 mL)and DMF (5 mL) was added EDCI (1.2 eq.), HOBT (1.2eq.), and TEA (3.0 eq.). The mixture was stirred at 25 C for30 min. Then 2-selenocyanatoethanamine hydrobromide(1.2 eq) or 2-selenocyanatopropanamine hydrobromide (1.2eq.) was added into the mixture. The mixture was stirred at25 C for 16 h. TLC showed the reaction was complete. Themixture was diluted with H2O (20 mL), the aqueous layer was extracted with DCM (15 mL × 2), the combined organiclayer was washed with brine (20 mL × 2), dried overNa2SO4, filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by columnchromatography on silica gel, eluting with dichloromethane/methanol solution to obtain the desire compound.

Reference： [1]Medicinal Chemistry Research,2018,vol. 27,p. 2071 - 2078

59
[ 5104-49-4 ]
[ 107-19-7 ]
C₁₈H₁₅FO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48.94%		To the solution of (indomethacin, 357mg 1.0 mmol) in 8mL ofacetonitrile, DMAP (18 mg, 0.15 mmol) and EDCI (190 mg,1.0 mmol)were added with stirring at room temperature for 0.5h. Then,propargyl alcohol (0.07 mL, 1.0 mmol) was added to the mixturesolution and stirred for 4h. After filtration, the filtrate was evaporatedunder reduced pressure to remove the solvent. The oily residuewas dissolved in trichloromethane; the organic layer waswashed with brine and dried with anhydrous Na2SO4, then filtered;the solvent was removed. The crude product was chromatographedon a silica gel, and 260 mg white solid was obtained.

Reference： [1]Journal of Organometallic Chemistry,2018,vol. 874,p. 49 - 62

60
[ 5104-49-4 ]
[ 42771-79-9 ]

Reference： [1]Israel Journal of Chemistry,2019
[2]Chemistry - An Asian Journal,2018,vol. 13,p. 2410 - 2413

61
[ 58885-58-8 ]
[ 5104-49-4 ]
Boc-aminopropanol-flurbiprofen [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;Cooling with ice;	In 2 ml of dichloromethane, 352 mg (2 mmol) of Boc-aminopropanol and 489 g (2 mmol) of flurbiprofen (manufacturedby Wako Pure Chemical Industries) were dissolved, and 48 mg (0.4 mmol) of DMAP and 423 g (2.2 mmol) ofWSCI·HCl/2 ml dichloromethane were added thereto in this order under ice-cooling. After returning to room temperatureand stirring overnight, ethyl acetate was added thereto, followed by separation by washing with 5% citric acid twice,water, 5% sodium hydrogen carbonate twice, water and saturated brine consecutively. After dehydration drying withsodium sulfate, ethyl acetate was evaporated under reduced pressure to give 753 mg of the titled compound (yield 94%).The structure was identified by 1H-NMR (CDCl3).1H-NMR (500 MHz, CDCl3) delta (ppm) = 1.26 (9H, s, Boc), 1.54 (3H, d, -OCOCH(CH3)-), 1.80 (2H, quant,-NHCH2CH2CH2O-), 3.13 (2H, m, -NHCH2CH2CH2O-), 3.76 (1H, q, - OCOCH(CH3)-), 4.15 (2H, m, -NHCH2CH2CH2O-),4.66 (1H, br, -NHCH2-), 7.10-7.55 (9H, m, Aromatic H)

Reference： [1]Patent: EP3363463,2018,A2 .Location in patent: Paragraph 0125

62
[ 5104-49-4 ]
[ 91503-79-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / tetrahydrofuran / 0.5 h / 25 °C 2: tetrahydrofuran / 15 - 70 °C

Reference： [1]Current Patent Assignee: SHANGHAI MAPLE BIOLOGICAL TECH - CN108558651, 2018, A

63
2-Fluoro-4-((E)-1-methyl-but-2-enyl)-biphenyl [ No CAS ]
[ 5104-49-4 ]

Reference： [1]ACS Catalysis,2019,vol. 9,p. 1253 - 1257

64
[ 5104-49-4 ]
meptazin sodium [ No CAS ]
2-(2-fluoro-4-biphenyl)-propionic acid 3-(3-ethyl-1-methyl-1H-hexahydroazepin-3-yl)phenyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	In dichloromethane; at 20℃; for 11h;Reflux;	Step two, dissolving the above meptrol sodium salt in 160 mL of dichloromethane,Add a three-necked bottle, add 32.6 g of flurbiprofen, and stir the reaction for 3 hours at room temperature.After refluxing for 8 hours at elevated temperature, the reaction mixture was transferred to a round bottom flask, and the solvent was evaporated under reduced pressure.Wash three times with an equal volume of 1 mol/L dilute hydrochloric acid, and wash three times with an equal volume of saturated saline.The organic phase was dried over anhydrous sodium sulfate.The volume ratio of methylene chloride is 1:1, and the target product is collected and purified.Concentration gave 45.8 g of product as colorless oil, yield 76%.

Reference： [1]Patent: CN109096191,2018,A .Location in patent: Paragraph 0027; 0028; 0031; 0034; 0035; 0037

65
[ 202982-67-0 ]
[ 5104-49-4 ]

Reference： [1]Journal of the American Chemical Society,2019,vol. 141,p. 10978 - 10983

66
[ 124-38-9 ]
[ 55258-76-9 ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
76%	With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; triisopropylsilanethiol In N,N-dimethyl-formamide at 0℃; for 24h; Irradiation; Sealed tube;

Reference： [1]Meng, Qing-Yuan; Schirmer, Tobias E.; Berger, Anna Lucia; Donabauer, Karsten; König, Burkhard [Journal of the American Chemical Society, 2019, vol. 141, # 29, p. 11393 - 11397]

67
[ 31469-22-4 ]
[ 41604-19-7 ]
[ 5104-49-4 ]

Reference： [1]Journal of the American Chemical Society,2019,vol. 141,p. 11749 - 11753

68
[ 5104-49-4 ]
[ 75-36-5 ]
2-(4′-acetyl-2-fluoro-[1,1′-biphenyl]-4-yl)propanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64.1%		To a suspension of AlCl3 (7.6 g, 57.316 mmol) in CH2Cl2 (30 mL)was added dropwise the solution of acetyl chloride (1.74 mL,24.564 mmol) in CH2Cl2 (10 mL) at 0 C. The mixture was maintained at this temperature for 0.5 h, and then flurbiprofen (4.0 g,16.376 mmol) in CH2Cl2 (20 mL) was dropped. The obtained mixture was stired for 3 h at room temperature. After complete reaction, the mixture was poured into cold 18% aqueous HCl (32 mL) and stired violently for 1 h. Then the organic phase was separated and washed with 10% aqueous HCl (30 mL) and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was recrystallized from C2H5OH/H2O (2:1, v/v) to give pure compound 2. Light yellow oil in 64.1% yield.

Reference： [1]Bioorganic Chemistry,2019

69
[ 186581-53-3 ]
[ 124-38-9 ]
[ 63444-55-3 ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
55%		General procedure: A solution of diethylzinc (1 M in toluene, 0.75 ml, 0.75 mmol, 3 eq) was added to a mixture of 6c(69.0 mg, 0.252 mmol) and SANi in DMA (1.0 ml) in an argon atmosphere. The vessel was immersed ina liquid nitrogen bath. After the mixture had been frozen, the tube was evacuated to 0.05 mmHg. The tubewas backfilled with CO2 in a plastic balloon and the frozen mixture was thawed at room temperature.Then, the reaction mixture was stirred at 80 C for 24 hours. The mixture was poured into 1 M HCl (ca.10ml) at 0 C, and the aqueous layer was extracted with ether (ca. 10 ml) for three times. The organic layerwas dried over Na2SO4 and concentrated. The residue was diluted with ether (ca. 2 ml) followed bytreatment of CH2N2, which was prepared from 1-methyl-3-nitro-1-nitrosoguanidine and 40% aq. KOH.After the mixture had been concentrated, the crude product was purified by preparative thin-layer chromatography on silica gel (hexane/AcOEt = 10:1) to afford 7c (64.5 mg, 77%) as a colorless oil.Spectral data of 7c: IR (neat) 1738 cm-1; 1H NMR (500 MHz, CDCl3) d 7.68 (d, J = 8.3 Hz, 2H), 7.30 (d,J = 8.3 Hz, 2H), 7.26-6.91 (m, 3H), 6.85 (s, 1H), 3.65-3.61 (m, 4H), 2.44 (s, 3H), 1.37 (d, J = 7.0 Hz,3H); 13C NMR .(125 MHz, CDCl3) d 174.1, 149.7, 145.3, 142.3, 132.3, 129.7, 129.6, 128.5, 126.2, 121.5,121.1, 52.0, 44.9, 21.6, 18.3. EI-LRMS m/z 334 (M+), 275, 179; EI-HRMS calcd for C17H18O5S334.08749, found 334.08822.

Reference： [1]Chemistry Letters,2019,vol. 48,p. 1406 - 1409

70
[ 5104-49-4 ]
[ 1477-44-7 ]
C₄₆H₅₉FO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	General procedure: Glycyrrhetinic acid (1g, 2.13mmol) was dissolved in methanol (20mL) and concentrated sulfuric acid (1mL) was added. The reaction was refluxed for 48h at 70C and monitored by TLC. The crude product was separated by column chromatography (CHCl3:CH3OH=30:1), obtained methyl glycyrrhetinate (0.94g, 1.94mmol), Yield: 91%. A1 and methyl glycyrrhetinate were dissolved in anhydrous CHCl2, DMAP and EDCI was added, and the mixture was stirred at room temperature for 24h. The reaction was monitored by TLC. The crude product was isolated by column chromatography to get a white solid.

Reference： [1]Bioorganic Chemistry,2020,vol. 99

71
[ 5104-49-4 ]
[ 55258-76-9 ]

Yield	Reaction Conditions	Operation in experiment
17%	With potassium phosphate; PrPPTNO; water; 1,4-dimethyl but-2-enedioate In acetonitrile at 25 - 30℃; for 16h; Inert atmosphere; Schlenk technique; Darkness; UV-irradiation;

Reference： [1]El-Hage, Firas; Schöll, Christopher; Pospech, Jola [Journal of Organic Chemistry, 2020, vol. 85, # 21, p. 13853 - 13867]

72
[ 768-59-2 ]
[ 5104-49-4 ]
4-ethylbenzyl 2-(2-fluoro[1,1'-biphenyl]-4-yl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 12h;

Reference： [1]Zhou, Min-Jie; Zhang, Lei; Liu, Guixia; Xu, Chen; Huang, Zheng [Journal of the American Chemical Society, 2021, vol. 143, # 40, p. 16470 - 16485]

73
[ 40258-78-4 ]
[ 5104-49-4 ]
[ 91503-79-6 ]

Yield	Reaction Conditions	Operation in experiment
94.9%	With potassium carbonate In tetrahydrofuran at 50℃; for 12h;	1 Example 1: Synthesis of compound fluoroprofen esters .Flulbeprofen (200.00g), ethyl 1-bromoacetate (177.75g) and anhydrous potassium carbonate (124.48g) were added to tetrahydrofuran 800ml, stirred and heated, the reaction system temperature was maintained at 50 °C for 12 hours (TLC monitoring reaction) was complete, the reaction system was cooled to room temperature, filtration was pumped, the filter cake was washed with 200ml tetrahydrofuran, the filtrate was combined, and the 60 °C vacuum was rotated to give flubiprofen ester crude product as a colorless liquid of 256.60 g and a yield of 94.9%. HPLC tested: purity 99.449% (Figure 1); High-resolution mass spectrometry: 353.1163 [M+Na]+(Figure 2), the theoretical calculation value of the ion peak of the flurbiprofen ester molecule is: 353.1160 [M+H]+, which is in line with the error range of high-resolution mass spectrometry, and the measured value is consistent with the theoretical value
93.2%	With potassium carbonate In tetrahydrofuran at 50℃; for 12h;	1-5 Example 1: Synthesis of flurbiprofen axetil Add flurbiprofen (200.00g), 1-bromoethyl acetate (177.75g) and anhydrous potassium carbonate (124.48g) into 800ml tetrahydrofuran, stir and raise the temperature, keep the reaction system temperature at 50 and react for 12 hours (TLC monitors the reaction) ) To the completion of the reaction, the reaction system was cooled to room temperature, filtered with suction, washed the filter cake with 200ml of tetrahydrofuran, combined the filtrate, and evaporated under reduced pressure at 60°C to obtain the crude flurbiprofen axetil as colorless liquid 256.60g, the yield was 94.9% .
	With potassium carbonate In propan-2-one at 50 - 60℃; for 2h;	1 take by weighing flurbiprofen 600g and add it to the reactor, add 6L of acetone and stir to dissolve, weigh 350g of anhydrous potassium carbonate and 1 -550 g of bromoethyl acetate, refluxed for 2 hours at 50-60 °C, filtered, washed with 1 L of acetone, and concentrated to dryness to obtain the crude product.

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - CN114075109, 2022, A Location in patent: Paragraph 0090-0093
[2]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - CN113636933, 2021, A Location in patent: Paragraph 0019-0025
[3]Current Patent Assignee: HUMANWELL HEALTHCARE (GROUP) CO., LTD. - CN113912492, 2022, A Location in patent: Paragraph 0075

74
[ 5104-49-4 ]
[ 15398-96-6 ]
(1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl)(trifluoromethyl)sulfane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With copper acetylacetonate; 1,10-Phenanthroline; N-(tert-butyl)-N-fluoro-3,5-bis(trifluoromethyl)benzamide In 1,2-dichloro-ethane at 20℃; for 48h; Inert atmosphere; Glovebox; Sealed tube; Irradiation;

Reference： [1]Mao, Runze; Bera, Srikrishna; Turla, Aurélya Christelle; Hu, Xile [Journal of the American Chemical Society, 2021, vol. 143, # 36, p. 14667 - 14675] Bera, Srikrishna; Hu, Xile; Mao, Runze; Turla, Aurélya Christelle [Journal of the American Chemical Society, 2021, vol. 143, # 41, p. 17302 - 17302]

75
[ 56430-45-6 ]
[ CAS Unavailable ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
90.6%	With lithium hydroxide monohydrate; magnesium; triphenylphosphine; palladium (II) chloride In toluene at 130℃; Autoclave;	14; 20-26; 1-5 Example 14 In the autoclave, put 10.5 mg of palladium chloride, 1.4 mg of magnesium, 31.3 mg of triphenylphosphine, 14.01 g (59.7 mmol) of 2-(2-fluoro-4-biphenyl) chloroethane, 3.22 g of water and toluene 15mL, after capping, the air in the autoclave was replaced with carbon monoxide (CO), so that the atmosphere in the autoclave was a carbon monoxide atmosphere.Then use a booster pump to fill the autoclave with carbon monoxide gas to stabilize the internal pressure at about 10.0MPa, then place the autoclave in an oil bath, stir and heat to raise the temperature to 130°C, and the reaction process automatically controls the internal pressure at 14.0MPa- 15.0MPa, after the reaction is completed, the temperature is lowered to below 30°C,After the pressure is released, the reactor lid is opened to obtain the reaction product. After the reaction product is filtered and concentrated, dichloromethane (CH2Cl2) is added to dissolve it. After washing with water, the dichloromethane is removed in vacuo.Then, n-hexane was added for crystallization and slurrying, filtered and dried to obtain flurbiprofen, which was a white solid with a molar yield of 90.6% and a purity of 97.9%.

Reference： [1]Current Patent Assignee: ZHEJIANG XINJIANG - CN114644559, 2022, A Location in patent: Paragraph 0091-0093; 0109-0144

76
[ CAS Unavailable ]
[ 2795153-72-7 ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
94.7%	With tris(4-methoxyphenyl)phosphane; lithium hydroxide monohydrate; magnesium; palladium (II) chloride In toluene at 130℃; Autoclave;	19 Example 19 In the autoclave, drop into palladium chloride 10.5mg, magnesium 1.4mg,Tris(4-methoxyphenyl)phosphine 42.1mg, 2-(2-fluoro-4-biphenyl)iodoethane 19.45g (59.7mol), water 3.22g and toluene 15mL, capped with carbon monoxide ( CO) replaced the air in the autoclave so that the atmosphere in the autoclave was a carbon monoxide atmosphere. Then use a booster pump to fill the autoclave with carbon monoxide gas to stabilize the internal pressure at about 10.0MPa, then place the autoclave in an oil bath, stir and heat to raise the temperature to 130°C, and the reaction process automatically controls the internal pressure at 14.0MPa-15.0MPa,After the reaction is completed, the temperature is lowered to below 30 ° C, and the reaction kettle cover is opened after the pressure is released to obtain the reaction product. After the reaction product is filtered and concentrated, dichloromethane (CH2Cl2) is added to dissolve,After washing with water, dichloromethane was removed in vacuo, then n-hexane was added for crystallization and slurrying, filtered and dried to obtain flurbiprofen as a white solid with a molar yield of 94.7% and a purity of 98.7%.

Reference： [1]Current Patent Assignee: ZHEJIANG XINJIANG - CN114644559, 2022, A Location in patent: Paragraph 0106-0108

77
[ CAS Unavailable ]
[ 56430-44-5 ]
[ 5104-49-4 ]

Yield	Reaction Conditions	Operation in experiment
95.4%	With lithium hydroxide monohydrate; magnesium; triphenylphosphine; palladium (II) chloride In toluene at 130℃; Autoclave;	1-8; 20-26; 1-5 Example 2 In the autoclave, put into palladium chloride 10.5mg, magnesium 1.4mg, triphenylphosphine 31.3mg, 2-(2-fluoro-4-biphenyl)bromoethane 16.65g (59.7mol), water 3.22g and toluene 15mL, after capping, the air in the autoclave was replaced with carbon monoxide (CO), so that the atmosphere in the autoclave was a carbon monoxide atmosphere. Then use a booster pump to fill the autoclave with carbon monoxide gas to stabilize the internal pressure at about 10.0MPa, then place the autoclave in an oil bath, stir and heat to raise the temperature to 130C, and the reaction process automatically controls the internal pressure at 14.0MPa-15.0 MPa, after the reaction is completed, the temperature is lowered to below 30°C, and the reactor lid is opened after the pressure is released to obtain the reaction product. The reaction product is filtered and concentrated, and then added.Dissolve in dichloromethane (CH2Cl2), wash with water, remove dichloromethane in vacuo, then add n-hexane for crystallization and beating, filter and dry to obtain flurbiprofen, which is a white solid with a molar yield of 95.4% and a purity of 99.5%.

Reference： [1]Current Patent Assignee: ZHEJIANG XINJIANG - CN114644559, 2022, A Location in patent: Paragraph 0052-0075

78
[ 881681-00-1 ]
[ 5104-49-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
86.8 %	In tert-butyl methyl ether at 15 - 45℃;	1.1-1.2 test 1 Flurbiprofen (1.00 g, 4.1 mmol, 1.0 eq) and vonoprazan (1.49 g, 4.3 mmol, 1.05 eq) were added to 20 mL of methyl tert-butyl ether, stir and dissolve at 45°C, and slowly precipitate a white solid after dissolution, then cool down to 15°C, stir for 5 hours, filter with suction, rinse the filter cake with 5 mL of methyl tert-butyl ether, dry the filter cake in vacuum at 45°C, and obtain 2.10 g of a white solid , yield 86.8%.

Reference： [1]Current Patent Assignee: TIANDI HENGYI PHARMACEUTICAL - CN114989138, 2022, A Location in patent: Paragraph 0033-0043

79
[ 1187594-09-7 ]
[ 5104-49-4 ]
[ 2893771-80-5 ]

Yield	Reaction Conditions	Operation in experiment
25.1 %	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	20 Synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(2-fluoro-[1,1′-biphenyl]-4-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile 2-[1-(ethanesulfonyl)-3-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile(baricitinib, 742 mg, 2 mmol), 4-dimethylaminopyridine (DMAP, 610 mg, 5 mmol), 2-(2-fluoro-4-biphenyl)propionic acid (flurbiprofen, 537 mg, 2.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( EDCI, 576 mg, 3 mmol) dissolved in dichloromethane (20 mL) with stirring for 20 h at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. Then separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to 1:2), the target compound was obtained, white solid, 0.3 g, yield 25.1%.

Reference： [1]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2023/1045, 2023, A1 Location in patent: Page/Page column 114-115

80
[ 941678-49-5 ]
[ 5104-49-4 ]
[ 2893771-93-0 ]

Yield	Reaction Conditions	Operation in experiment
63.9 %	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	33 (3R)-3-cyclopentyl-3-(4-(7-(2-(2-fluoro-[1,1′-biphenyl]-4-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile Combine (R)-3-(4-(7H-pyrrole[2,3-d]pyridine-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane (ruxotinib, 153 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 6 mg, 0.05 mmol), 2-(2-fluoro-4-biphenyl)propionic acid (flurbiprofen, 146 mg, 0.6 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) dissolved in dichloromethane (10 mL) and stirred for 16 hours at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. After silica gel column chromatography (petroleum ether/ethyl acetate = 11 to 12), the target compound was obtained, white solid, 0.17 g, yield 63.9%.

Reference： [1]Current Patent Assignee: COVAL BIOPHARMA SHANGHAI - WO2023/1045, 2023, A1 Location in patent: Page/Page column 135-136

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	5104-49-4	MDL No. :
Formula :	C₁₅H₁₃FO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	244.26	Pubchem ID :	-
Synonyms :	dl-Flurbiprofen;Ansaid;Flurbiprofen, Ansaid, Froben, Cebutid, Antadys;(±)-Flurbiprofen	Chemical Name :	2-(2-Fluoro-[1,1'-biphenyl]-4-yl)propanoic acid

Num. heavy atoms :	18
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.13
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	68.19
TPSA :	37.3 Å²

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-4.84 cm/s

[ CAS No. 5104-49-4 ] {[proInfo.proName]}

Quality Control of [ 5104-49-4 ]

Related Doc. of [ 5104-49-4 ]

Product Details of [ 5104-49-4 ]

Calculated chemistry of [ 5104-49-4 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 5104-49-4 ]

Application In Synthesis of [ 5104-49-4 ]

[ 5104-49-4 ] Synthesis Path-Upstream 1~1

[ 5104-49-4 ] Synthesis Path-Downstream 1~80

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Log Po/w (iLOGP) :	2.12
Log Po/w (XLOGP3) :	4.16
Log Po/w (WLOGP) :	4.1
Log Po/w (MLOGP) :	3.79
Log Po/w (SILICOS-IT) :	3.87
Consensus Log Po/w :	3.61

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

Log S (ESOL) :	-4.27
Solubility :	0.0131 mg/ml ; 0.0000536 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.65
Solubility :	0.00545 mg/ml ; 0.0000223 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.01
Solubility :	0.00239 mg/ml ; 0.00000979 mol/l
Class :	Moderately soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	2.45

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P201-P202-P264-P270-P280-P301+P310+P330-P308+P313-P405-P501	UN#:	2811
Hazard Statements:	H301-H361	Packing Group:	Ⅲ
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
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P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
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P270	Do not eat, drink or smoke when using this product.
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P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
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P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
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P313	Get medical advice/attention.
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P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
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P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling