3-CHLORO-4-FLUOROCINNAMIC ACID

General procedure: The suitable aldehyde (10 mmol), malonic acid (30 mmol, 3.12 g) and piperidine (0.5 mL) were dissolved in pyridine (20 mL) and the mixture was heated under reflux for 4 h. The solution was cooled to room temperature and poured in ice-cold aqueous HCl (100 mL, 3 M). The white solid precipitate was filtered, washed with water (350 mL), aqueous NaHCO3 (20 mL, 5percent w/v), then again with water (250 mL) and dried in an oven (60 C). If required, the crude solid was recrystallysed from EtOH/H2O.General procedure: The suitable aldehyde (10 mmol), malonic acid (30 mmol, 3.12 g) and piperidine (0.5 mL) were dissolved in pyridine (20 mL) and the mixture was heated under reflux for 4 h. The solution was cooled to room temperature and poured in ice-cold aqueous HCl (100 mL, 3 M). The white solid precipitate was filtered, washed with water (350 mL), aqueous NaHCO3 (20 mL, 5% w/v), then again with water (250 mL) and dried in an oven (60 C). If required, the crude solid was recrystallysed from EtOH/H2O.General procedure: Step 1: to a solution of cinnamic acid 59 (1.0 eq.) in THF (~0.3 M) was added Et3N (1.3 eq.) and then trimethylacetyl chloride (1.2 eq.) dropwise at 0 C. The mixture was stirred at 0 C for 30 min and then filtered. The filtrate was used for the next step without further purification. Step 2: to a solution of lactam 61 (1.0 eq.) in THF (~0.3 M) was added n-BuLi (1.6 M in THF, 1.2 eq.) dropwise at -78 C. After stirring at -78 C for 45 min, the filtrate from last step (1.0 eq.) was added. The resulting mixture was allowed to stir at -78 C until completion, monitored by TLC. The reaction was then quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (3 ×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography. Compounds 6, 1, 2 73, 10, 2 12, 2 14, 1 18, 4 20, 4 26, 5 30, 4 31, 1 32, 1 37, 1 and 385 were reported previously.General procedure: The suitable aldehyde 1j-l, 1n or 1o (0.5 mmol), malonic acid (1.0 mmol) and piperidine (0.01 mmol) were dissolved in DMSO (500 mL) and the mixture was heated in a microwave reactor (30 min, 60 C). After cooling, ammonia solution (9.5 mL, 13% w/v, approx. 7 M, adjusted to pH 10.0 by slow addition of dry ice chunks) was added, followed by E. coli BL21(DE3) cells overproducing the required PAL (400 mg wet cell paste). The suspension was stirred at 37 C for several hours, monitoring the conversion by HPLC. For product isolation, the reaction mixture was acidified to pH <2.0 using aqueous H2SO4 (20% w/v) and centrifuged (8000 rpm, 5 min) to remove cells and precipitated unconverted substrate. Dowex 50WX8 hydrogen form resin (5.0 g), packed in a disposable plastic column, was washed with deionised water (20 mL) and aqueous H2SO4 (20 mL, 5% w/v). The supernatant from the biotransformation was loaded onto the resin (1 mL min1). The resin bed was washed with deionised water until the flow-through tested neutral, then the product was eluted with aqueous NH4OH (20 mL, 5% w/v). Fractions containing the product were pooled and dried overnight in a centrifugal evaporator, to afford the corresponding L-phenylalanine L-3j-l, L-3n or L-3o as a white solid.To a solution of crude 1-[3-((3S, 4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (example 41; 0.03 mg, 0.1 mmol) in N, N-dimethylformamide (0.8 ml) was added To a solution of crude 1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (example 38; 0.03 g, 0.1 mmol) in N, N-dimethylformamide (0.8 ml) was added A solution of D. 1-(3-Chloro-4-fluorocinnamamido)hydantoin To 44 g (0.22 mole) of

Molecular Weight:200.59
XLogP3:2.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:200.0040353
Monoisotopic Mass:200.0040353
Topological Polar Surface Area:37.3
Heavy Atom Count:13
Complexity:218
Defined Bond Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes