The synthetic method of bimatoprost
The technology of a kind of bimatoprost, synthetic method, is applied in the synthetic field of bimatoprost, can solve the problems such as the total yield of bimatoprost is not high, the stability of synthetic intermediate is poor, side reaction easily occurs, and avoids column Chromatographic process, easy operation, less side effects
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Embodiment 1
[0053] Embodiment 1: the synthesis of bimatoprost
[0054] Taking coli lactone (1) as raw material to synthesize bimatoprost, the reaction scheme is as follows:
[0055]
[0056] (1) Synthesis of compound 2a
[0057]
[0058] Add TBSCl (52.6g, 350mmol, 3.0eq) and imidazole (25.0g, 360mmol, 3.0eq) to a solution of coli lactone (20g, 116.2mmol) in dichloromethane (200ml), react at room temperature for 8h, and filter with suction 10% hydrochloric acid solution (80mL) was added to the organic phase, then reacted at room temperature for 5h, quenched the reaction with saturated ammonium chloride solution (150ml), concentrated, added dichloromethane (200ml) and water (200ml), and stood to separate layers , the aqueous phase was extracted with dichloromethane (150ml*3), washed with saturated brine (100ml), dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized with ethyl acetate (180ml) to obtain white solid compound 2 (27.4g, 83%). 1 H NMR (400MHz, C...
Embodiment 2
[0077] Embodiment 2: the synthesis of bimatoprost
[0078] (1) Synthesis of compound 2a
[0079]
[0080] Add TBSCl (52.6g, 350mmol, 3.0eq) and potassium carbonate (49.6g, 360mmol, 3.0eq) to a solution of coli lactone (20g, 116.2mmol) in dichloromethane (200ml), react at room temperature for 8h, and filter with suction 10% hydrochloric acid solution (80mL) was added to the organic phase, then reacted at room temperature for 5h, quenched the reaction with saturated ammonium chloride solution (150ml), concentrated, added dichloromethane (200ml) and water (200ml), and stood to separate layers , the aqueous phase was extracted with dichloromethane (150ml*3), washed with saturated brine (100ml), dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized with ethyl acetate (180ml) to obtain white solid compound 2 (24.7g, 75%).
[0081] (2) Synthesis of Compound 3a
[0082]
[0083] At a temperature of 0°C, add PCC oxidant (31.1g, 90mmol, 1.5eq) to a sol...
Embodiment 3
[0099] The synthesis of embodiment 3 bimatoprost
[0100] (1) Synthesis of compound 2b
[0101]
[0102] For the synthesis method, refer to the synthesis of 2a in Example 1. (white solid) 1 H NMR (400MHz, CDCl 3 ):δ4.25(brs,OH),4.13(dd,J=9.2Hz,J=2.3Hz,1H),3.56-3.33(m,3H),2.37-2.08(m,3H),1.80-1.83( m,2H),1.42(m,1H),0.95(t,J=6.6Hz,9H),0.66(q,J=6.6Hz,6H)ppm.MS(m / z):287(M + +1).
[0103] (2) Synthesis of compound 3b
[0104]
[0105] For the synthesis method, refer to the synthesis of 3a in Example 1. 1 H NMR (400MHz, CDCl 3 ):δ9.71(s,1H),4.15(dd,J=9.2Hz,J=2.5Hz,1H),3.58(m,1H),2.37-2.12(m,4H),2.05-1.83(m, 2H), 0.96(t, J=6.6Hz, 9H), 0.67(q, J=6.6Hz, 6H)ppm.MS(m / z): 285(M + +1).
[0106] (3) Synthesis of compound 4b
[0107]
[0108] For the synthesis method, refer to the synthesis of 4a in Example 1. 1 H NMR (400MHz, CDCl 3 ):δ7.29-7.16(m,5H),5.68-5.55(m,2H),3.25-3.17(m,2H),2.62(t,J=6.8Hz,2H),2.11-1.75(m,8H ),0.96(t,J=6.6Hz,18H),0.66(q,J=6.6Hz,6H)ppm.MS(m / z):...
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