Halogenated pivaloyl glucopyranose and its preparation method for sglt2 inhibitor
A technology of valeryl glucopyranose and halogenated glucopyranose, which is applied in the field of drug synthesis, can solve problems such as poor redox economy, lack of stereospecificity, and large-scale operation hazards, and achieve high stereoselectivity and conversion efficiency, reduce energy consumption, and reduce the effects of isomer impurities
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Embodiment 1
[0090] Example 1, the preparation method of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene (compound XII) ;
[0091] The reaction formula is as follows:
[0092]
[0093] Follow the steps in order:
[0094] 1), Preparation of 1,2,3,4,6-O-pentachloropivaloyl-D-glucopyranose (intermediate XII-3):
[0095] D-glucose (XII-1, 5 g, 27.8 mmol) was suspended in anhydrous dichloromethane (80 mL) under nitrogen and the resulting mixture was stirred at room temperature for 5 minutes, then cooled to 0° C. and stirred for 10 minutes. Then, with stirring, pyridine (30 mL) was added dropwise to the resulting mixture over about 10-15 minutes, and N,N-dimethylaminopyridine (0.25 g, 2.04 mmol) was added. The temperature was lowered to 0°C, and a dichloromethane solution of monochloropivaloyl chloride was slowly added dropwise to the reaction solution (monochloropivaloyl chloride (XII-2, 23.6g, 152.9mmol) was dissolved in 15mL of dichloromethane), The dropwi...
Embodiment 2
[0113] Example 2, (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol (compound XIII) Preparation
[0114] The reaction formula is as follows:
[0115]
[0116] Change 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene (XII-5) in step 3) of Example 1 to 2-chloro-5-bromo- 1-(2,3,4,6‐O‐tetrachloropivaloyl‐β‐D‐halogenated glucopyranose in 4′-ethoxydiphenylmethane (XIII-1), step 5) base)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene (XII-6) to 1-(2,3,4,6‐O‐tetra Monochloropivaloyl‐β‐D‐haloglucopyranosyl)-4-chloro-3-[(4-ethoxyphenyl)methyl]benzene (XIII-2), molar mass unchanged; the rest Identical to Example 1. Among them, the intermediate XIII-2 is equivalent to the product XII-6 obtained in step 4) of Example 1.
[0117] That is, in this case, intermediate XII-4 and 2-chloro-5-bromo-4'-ethoxydiphenylmethane (intermediate XIII-1) were used as starting materials for the preparation.
[0118] Intermediate XIII-2, yield 75.2%. 1 H NMR (50...
Embodiment 3
[0120] Example 3, (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furyl]oxy]phenyl]methanol Base] phenyl] -D-glucitol (compound XIV)) preparation method,
[0121] The reaction formula is as follows:
[0122]
[0123] Change 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene (XII-5) in step 3) of Example 1 to (S)-4-iodo- 1-(2,3,4,6‐O‐tetrachloropivaloyl in 1-chloro-2-(4-tetrahydrofuran-3-yloxybenzyl)benzene (XIV-1), step 5) ‐β‐D‐haloglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene (XII-6) was changed to 1-(2 ,3,4,6‐O‐tetrachloropivaloyl‐β‐D‐halogenoglucopyranosyl)-4-chloro-3-[[4-[[(3S)-tetrahydro-3- Furyl] oxygen group] benzene (XIV-2), molar weight is constant; All the other are identical to embodiment 1. Among them, the intermediate XIV-2 is equivalent to the product XII-6 obtained in step 4) of Example 1.
[0124] That is, it is prepared from intermediate XII-4 and (S)-4-iodo-1-chloro-2-(4-tetrahydrofuran-3-yloxybenzyl)benzene (inter...
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