L-phenylglycine derivative and application thereof
A technology of phenylglycine and its derivatives, which is applied in the chemical field, can solve the problems of high therapeutic dose, etc., and achieve the effect of increasing utilization and improving insulin sensitivity
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Embodiment 1
[0024] Embodiment 1, the preparation of target compound 1
[0025]
[0026] 1. Preparation of Intermediate M1
[0027] M1-a(R 1 =Fmoc) and M1-b(R 1 For the preparation of =Z), see Chinese patent application CN 101633626A.
[0028] M1-c(R 1 =Ts) preparation: in 250mL round bottom flask, add SM 50.0mmol and mass fraction be 10% Na 2 CO 3 solution, stirred to dissolve, cooled in an ice bath, slowly added dropwise 50 mL of Ts-Cl 75 mmol acetone solution, after the addition was completed, the temperature was raised to 18°C and the reaction was stirred, and the pH was maintained at 9-11 during the reaction, and monitored by thin-layer chromatography (TLC). Reaction process, after 4 hours, the reaction was completed, cooled in an ice bath, adjusted to pH 5-6 with 2mol / L HCl, distilled off the organic solvent under reduced pressure, then added 120 mL of EtOAc, cooled in an ice bath, adjusted to pH 3 with 2mol / L HCl ~4, separate the EtOAc layer, extract the aqueous phase wit...
Embodiment 2
[0054] Embodiment two, the preparation of target compound 2
[0055]
[0056] In a 250 mL round bottom flask add R 5 x 1 H or DMF 2-10mL and anhydrous K 2 CO 3 , stirred, added 1b, stirred at 25-40°C, TLC monitored the reaction progress, A 5 After 1 hour, the reaction was completed. Add 100 mL of ice NaCl solution and 50-80 mL of EtOAc, cool in an ice bath, adjust the pH to 5-6 with 2 mol / L HCl, extract with EtOAc (3×30 mL), combine the organic layers, and wash with saturated NaCl solution to medium sex, anhydrous Na 2 SO 4 Dry, filter with suction, concentrate the filtrate under reduced pressure, and separate and purify by column chromatography to obtain 2. The specific preparation conditions and results are shown in Table 4.
[0057] Preparation conditions and results of Table 42
[0058]
[0059]
[0060]
[0061] 2a: m.p.92.7~99.1℃; (c 1.0 mg / mL, EtOAc); 1 H NMR (CDCl 3 , 300MHz) δ: 3.65(s, 3H, -COO CH 3 ), 3.92 (s, 2H, CO CH 2 ), 5.01~5.13 (m...
Embodiment 3
[0080] Embodiment three, the preparation of target compound 3
[0081]
[0082] Add 2 and THF 10-25mL into a 100mL round bottom flask, stir, cool in an ice bath, add 1mol / L LiOH solution to adjust the pH to 10-12, B 2 ℃ stirring reaction, TLC monitoring reaction progress, A 6 Hours later, the reaction was completed, cooled in an ice bath, adjusted to pH 5-6 with 2mol / L HCl, removed the solvent by rotary evaporation under reduced pressure, cooled in an ice bath, adjusted to pH 3-4 with 2mol / L HCl, and extracted the aqueous phase with EtOAc for 3 times, the combined organic layers were washed with saturated NaCl solution, anhydrous NaCl 2 SO 4 After drying and suction filtration, the filtrate was distilled off under reduced pressure to remove EtOAc to obtain 3. The specific preparation conditions and results are shown in Table 5.
[0083] Preparation conditions and results of Table 53
[0084]
[0085]
[0086] 3a: m.p.145.3~154.2℃; (c 1.0mg / mL, DMF); 1 H NMR (D...
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