* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
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.
Reference:
[1] Tetrahedron, 2016, vol. 72, # 46, p. 7256 - 7262
[2] Journal of Medicinal Chemistry, 2003, vol. 46, # 3, p. 409 - 416
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.
4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one dihydrochloride[ No CAS ]
[ 155814-22-5 ]
1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With triethylamine; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;
Example 11; 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one; 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one; A suspension of 0.099 g (0.32 mmol) 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B) and 0.077 g (0.38 mmol) of <strong>[155814-22-5](E)-<strong>[155814-22-5]3-chloro-4-fluorocinnamic acid</strong></strong> in 3 ml of CH2Cl2 was treated with 0.09 ml (0.64 mmol) of Et3N at RT, cooled (0 C.) and treated with a 0.085 g (0.41 mmol) of N,N'-dicyclohexylcarbodiimide. The reaction was warmed up over night to RT, then partitioned between EtOAc (×3)/saturated NaHCO3. The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to give after purification on catridges, Si-Amine, 70 ml, 20 g (EtOAc/n-heptane 9:1) 0.075 g (64%) of the title compound as a white solid. MS: 422.1 (MH+, Cl).
C. 3-Chloro-4-fluorocinnamic acid A stirred mixture of 3-chloro-4-fluorobenzaldehyde (55 g, 0.35 mole), malonic acid (47 g, 0.45 mole) and 3.5 ml of piperidine in 138 ml of pyridine was heated on a steam bath for 2 hours. The reaction solution was poured into a mixture of 200 ml of concentrated hydrochloric acid and 320 g of ice to give after filtration and water wash 44 g (63%). The crude intermediate was used without further purification in part D.
With pyridine; hydrogenchloride; thionyl chloride;
D. 1-(3-Chloro-4-fluorocinnamamido)hydantoin To 44 g (0.22 mole) of <strong>[155814-22-5]3-chloro-4-fluorocinnamic acid</strong> was added dropwise thionyl chloride (250 ml) followed by heating at reflux for 2 hours. The excess thionyl chloride was removed in vacuo and the residue remaining flushed with dry benzene. The reaction residue was chilled on an ice bath followed by the rapid addition of 1 -aminohydantoin hydrochloride (33 g, 0.22 mole). To the cold reaction mixture was added dropwise pyridine (250 ml). After the addition was complete the cold reaction mixture was heated on a steam btah for 3 hours then poured into 3.5 l. of HCl/ice. Upon standing at room temperature overnight the acidic reaction mixture was filtered and washed with water to give 54 g (82%). The analytical sample was prepared by one recrystallization from CH3 NO2 (DARCO) m.p. 258-260. Anal. Calcd. for C12 H9 ClFN3 O3: C, 48.42; H, 3.05; N, 14.12. Found: C, 48.45; H, 3.18; N, 14.04.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18.0h;
A solution of <strong>[155814-22-5]3-chloro-4-fluorocinnamic acid</strong> (4.52 g, 21.9 mmol), (S)-1-(3-hydroxy-propyl)-3-methyl-piperazin-2-one (3.76 g, 21.9 mmol), N,N-diisopropylethylamine (8.46 g, 65.5 mmol), 1-hydroxybenzotriazole (3.25 g, 24.0 mmol), and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.60 g, 24.0 mmol) in N,N-dimethylformamide (80 ml) was stirred at room temperature for 18 h, then partitioned between 1 M aq. hydrochloric acid solution and ethyl acetate. The organic layer was washed with 1 M aq. hydrochloric acid solution, sat. aq. sodium hydrogencarbonate solution, and brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; CH2Cl2/MeOH/NH4OH 90:10:0.25) produced the title compound (6.54 g, 84%). Colorless gum, MS (ISP)=355.2 (M+H)+.
1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride[ No CAS ]
[ 155814-22-5 ]
[ 1101841-79-5 ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; HATU; In N,N-dimethyl-formamide; for 1.0h;
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 <strong>[155814-22-5]3-chloro-4-fluorocinnamic acid</strong> (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.11 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum MS (ISP)=464.3 (M+H)+.
1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride[ No CAS ]
[ 155814-22-5 ]
[ 1101841-84-2 ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; HATU; In N,N-dimethyl-formamide; for 1.0h;
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 <strong>[155814-22-5]3-chloro-4-fluorocinnamic acid</strong> (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=452.2 (M+H)+.
(S)-2-amino-3-(3-chloro-4-fluorophenyl)propanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonium hydroxide; carbon dioxide; In dimethyl sulfoxide; at 37℃; for 12.0h;pH 10.0;Enzymatic reaction;
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.
With triethylamine; In tetrahydrofuran; at 0℃; for 0.5h;
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.