A new method for synthesizing olaparib crude drug
A synthesis method and intermediate technology are applied in the field of preparation of high-purity olaparib raw materials, and can solve the problems of reducing dimer content and low yield, etc.
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Embodiment 1
[0028] Example 1: Synthesis of IM1
[0029]
[0030] Add 11.0 g of dimethyl phosphite, 6.5 g of sodium methoxide, and 100 mL of methanol into a 250 mL three-necked flask in sequence, cool down in an ice bath to 0-5 degrees Celsius, add 7.5 g of SM1 in batches, and control the internal temperature to not exceed 10 degrees Celsius. Add 12.5 g of methanesulfonic acid dropwise and continue to stir for 0.5 hour after adding the solution at room temperature. After the dropping, the methanol is distilled off under reduced pressure, 150 mL of water is added, and extracted twice with 100 mL of dichloromethane. The organic layers are combined and washed with Dry over anhydrous magnesium sulfate for 0.5 hour, filter, and distill the filtrate under reduced pressure to obtain 10.2 g of white solid, with a yield of 84%. Using the area normalization method to analyze, the purity was 99.03%.
Embodiment 2
[0031] Example 2: Synthesis of IM2
[0032]
[0033] Add 10 g of IM1, 6.2 g of SM2, and 200 mL of tetrahydrofuran into a 500 mL three-necked flask in sequence, cool to 0-5 degrees Celsius in an ice bath, stir to dissolve, add 4.6 g of triethylamine dropwise, control the internal temperature to not exceed 10 degrees Celsius, and After stirring at room temperature for 12 hours, a light yellow solid precipitated out, distilled off THF under reduced pressure, added 100 mL of water and stirred for 1 hour, filtered, and the filter cake was dried under vacuum at 60°C for 4 hours to obtain 10.4 g of a yellow-green solid with a yield of 95%. There are two large peaks in the HPLC spectrum, and the ratio of the peak areas is about 1:3. This is because the intermediate IM2 is a mixture of cis and trans isomers. The area normalization method was used to analyze, and the purity of the two peaks added was 99.83%. The cis-trans isomer mixture does not need to be separated, and directly en...
Embodiment 3
[0034] Embodiment 3: the synthesis of IM3
[0035]
[0036] Add 10 g of IM2, 100 mL of water, and 7 g of sodium hydroxide into a 250 mL three-necked flask in turn, heat to 90°C and stir for 1 hour, then cool down to 70°C, add 28.9 g of 80% hydrazine hydrate dropwise, and control the internal temperature not to exceed 75 degrees Celsius, continue to stir at 70 degrees Celsius for 12 hours after dropping, drop to room temperature, adjust the pH to 2-3 with 2M hydrochloric acid, precipitate a light yellow solid, filter, and vacuum dry the filter cake at 70 degrees Celsius for 5 hours to obtain 11.1 g of a yellow solid. 99%. Using the area normalization method to analyze, the purity was 96.10%.
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