Novel side chain of 25-hydroxyitamin D2 series medicines and preparation method thereof
A technology of hydrocarbon group and amino group, applied in the field of preparation of common side chains, can solve the problems of low yield, limitation, difficult synthesis and purification, etc., and achieve the effects of high yield, easy product and short route.
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Its synthetic route is as follows:
Dissolve (R)-methyl 3-hydroxy-2-methylpropanoate (11.8 g, 100 mmol) in diethyl ether, and add MeMgBr (3M, 100 mL, 300 mmol) dropwise to it in an argon atmosphere at zero degrees Celsius. Then, continue stirring for 6 hours, slowly drop 1M hydrochloric acid into it to quench the reaction, extract with ethyl acetate (300 mL each time) three times, combine the organic phases, dry over anhydrous magnesium sulfate, filter and concentrate to obtain a colorless oily substance 11 (10.7 g ) with a yield of 90%. 1 H NMR (300MHz, δ, ppm) 0.81 (3H, d, J=6.9 Hz), 1.14 (3H, s), 1.22 (3H, s), 1.77 (1H, m), 3.58 (1H, b), 3.66 (2H, m), 3.84 (1H, b). 13 C NMR (75MHz, δ, ppm) 12.9, 23.9, 29.6, 43.9, 66.1, 74.5. ESI-HRMS (m / z) [M + ]118.0, 100.0, 85.0, 59.0.
The colorless oil obtained above was dissolved in dichloromethane (100 mL) and pyridine (10 mL), to which were added 4-(N,N-dimethylamino)pyridine (1 g) and p-toluenesulfonyl chloride (20 g, 105mmol)...
Example Embodiment
Its synthetic route is as follows:
Dissolve (R)-ethyl 3-hydroxy-2-methylpropanoate (11.8 g, 100 mmol) in ether, add MeLi (1 M, 300 mL, 300 mmol) dropwise to it at zero degrees Celsius under argon atmosphere, and finish dropping Then, continue to stir for 6 hours, slowly drop 1M hydrochloric acid into it to quench the reaction, extract with ethyl acetate (300 mL each time) three times, combine the organic phases, dry over anhydrous magnesium sulfate, filter and concentrate to obtain a colorless oily substance 11 (10.1 g ), the yield is 85%.
The colorless oil obtained above was dissolved in dichloromethane (100 mL) and triethylamine (10 mL), and methanesulfonyl chloride (11.4 g, 100 mmol) was added to it under cooling in an ice-salt bath, and stirring was continued for 2 hours until the raw materials disappeared. , water was added to quench the reaction, the solution was separated, the aqueous phase was extracted with dichloromethane (200 mL) three times, dried over anhydrou...
Example Embodiment
Example 1: Compound 1a, its molecular structure is as follows, wherein R1=R2=OCH2CH3, R=CH2OCH3.
Its synthetic route is as follows:
Dissolve the above p-toluenesulfonate 12 (13.6g, 50mmol) in dry CH2C12 (100mL), add pyridine (10g) and 4-(N,N-dimethylamino)pyridine to it under ice-water bath cooling , and then slowly dropwise added benzoyl chloride (10 g). After reacting at room temperature for 12 hours, the mixture was washed with water, and the aqueous phase was extracted with CH2Cl2. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography to obtain the product 18 (13 g) in a yield of 78%.
The above mesylate 18 (11.3 g) was dissolved in dry CH3CN (100 mL), anhydrous NaI (5 g) was added to it, heated under reflux for 5 hours, concentrated to remove CH3CN, added with ether (100 mL), filtered, and filtered with ether (200 mL) to wash the filter cake, the combined filtr...
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