A preparing method of a miglitol intermediate

Abstract

The invention belongs to the field of medicine synthesis, and relates to a preparing method of a miglitol intermediate. The method includes performing Swern oxidation by adopting tetrabenzyl glucose diol as a raw material to obtain a tetrabenzyl glucose dicarbonyl derivative, and directly subjecting the oxidation product without separation to a double reductive amination reaction with ethanolamine and sodium cyanoborohydride under the existence of a dehydrant to prepare tetrabenzyl miglitol that is an important intermediate for preparation of miglitol. The method is mainly advantageous in that: the tetrabenzyl glucose dicarbonyl derivative which is instable is directly used for the reaction in the next step without separation; proper reaction conditions are selected in the double reductive amination reaction step to directly obtain an optically pure target product 2-position of which is in an R configuration; steps of separation and purification for an enantiomer mixture are omitted, and loss caused by the steps is omitted; and the method is short in reaction time and high in yield.

Description

technical field

[0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of a highly stereoselective miglitol intermediate. Background technique

[0002] Miglitol, chemical name (2R,3R,4R,5S)-2-hydroxymethyl-1-(2-hydroxyethyl)-3,4,5-piperidinetriol, molecular formula: C 8 h 17 NO 5 , molecular weight 207.2, structural formula as shown in formula 1:

[0003]

[0004] Miglitol is a strong α-glucosidase inhibitor, which can competitively inhibit the activity of α-glucosidase on the villi of the small intestine, slow down the hydrolysis of polysaccharides, and effectively inhibit the rise of postprandial blood glucose concentration in diabetic patients.

[0005] The tetrabenzyl miglitol of formula 4 is an important intermediate for the synthesis of miglitol, and the optical purity of the intermediate directly determines the difficulty and cost of the synthesis of miglitol.

[0006]

[0007] Zhen-Xing Zhang et al. re...

Examples

Embodiment 1

[0035] Example 1: Preparation of (2,3,4,6)-O-tetrabenzylglucodiol (2)

[0036] Add 54.00g (100mmol) of tetrabenzylglucose, 10.10g (260mmol) of sodium borohydride, and 500mL of absolute ethanol into a 1L reaction flask, react for 24h under room temperature stirring, and concentrate the reaction solution under reduced pressure. After adding 100 mL of ethyl acetate to the residue, wash with water, and wash the organic phase with anhydrous Mg 2 SO 4 After drying, filtering and concentrating, 53.10 g of a colorless, transparent viscous object was obtained. The purity as determined by HPLC was 96.0%, and the yield was 98.0%.

[0037] 1 H NMR (400MHz, CDCl 3 )δ7.41–7.19(m,20H),4.74–4.47(m,8H),4.08–3.99(m,1H),3.88(dt,J=7.0,3.6Hz,1H),3.82–3.69(m, 3H),3.67–3.60(m,2H),3.57(dd,J=11.8,4.4Hz,1H),2.89(dd,J=24.5,3.4Hz,1H),2.17–1.88(br,1H).

Embodiment 2

[0038] Example 2: Preparation of Tetrabenzyl Miglitol (4)

[0039] (1) Preparation of Tetrabenzyl Glucose Dicarbonyl Derivatives (3)

[0040] Add 8.0mL (93mmol) oxalyl chloride and 80mL dichloromethane into a 250mL reaction flask, and cool down to -78°C. A mixture of 7.1 mL (100 mmol) of dimethyl sulfoxide and 50 mL of dichloromethane was added dropwise with stirring, and stirred at -78°C for 40 min. Dissolve 10.8g (20mmol) of tetrabenzyl glucodiol in 40mL of dichloromethane and slowly drop into the above system, react at -65°C for 2.5h. Add 33.2 mL of triethylamine dropwise to the reaction system, slowly raise the temperature to 0°C and stir for 20 min, and the oxidation reaction solution obtained after the reaction is directly put into the next reaction without treatment.

[0041] (2) Preparation of Tetrabenzyl Miglitol (4)

[0042] Add 4.80 g (80 mmol) of ethanolamine, 5.00 g (80 mmol) of sodium cyanoborohydride, and 500 mL of methanol into a 1000 mL reaction flask, and ...

Embodiment 3

[0045] Example 3: Preparation of Tetrabenzyl Miglitol (4)

[0046] (1) Preparation of Tetrabenzyl Glucose Dicarbonyl Derivatives (3)

[0047] Add 8.0mL (93mmol) oxalyl chloride and 80mL dichloromethane into a 250mL reaction flask, cool down to -70°C, slowly add a mixture of 7.1mL (100mmol) dimethyl sulfoxide and 50mL dichloromethane dropwise under stirring, at -70°C Stir for 40min. Dissolve 10.80g (20mmol) of tetrabenzyl glucodiol in 40mL of dichloromethane and add dropwise to the above system, and react at -70°C for 2.5h. Add 33.2 mL of triethylamine dropwise to the reaction system, slowly raise the temperature to 10°C and stir for 20 min, and the oxidation reaction solution obtained after the reaction is directly put into the next reaction without treatment.

[0048] (2) Preparation of Tetrabenzyl Miglitol (4)

[0049] Add 2.40 g (40 mmol) of ethanolamine, 2.50 g (40 mmol) of sodium cyanoborohydride, and 500 mL of methanol into a 1000 mL reaction flask, and stir at room t...

technical field

[0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of a highly stereoselective miglitol intermediate. Background technique

[0002] Miglitol, chemical name (2R,3R,4R,5S)-2-hydroxymethyl-1-(2-hydroxyethyl)-3,4,5-piperidinetriol, molecular formula: C 8 h 17 NO 5 , molecular weight 207.2, structural formula as shown in formula 1:

[0003]

[0004] Miglitol is a strong α-glucosidase inhibitor, which can competitively inhibit the activity of α-glucosidase on the villi of the small intestine, slow down the hydrolysis of polysaccharides, and effectively inhibit the rise of postprandial blood glucose concentration in diabetic patients.

[0005] The tetrabenzyl miglitol of formula 4 is an important intermediate for the synthesis of miglitol, and the optical purity of the intermediate directly determines the difficulty and cost of the synthesis of miglitol.

[0006]

[0007] Zhen-Xing Zhang et al. re...

Examples

Embodiment 1

[0035] Example 1: Preparation of (2,3,4,6)-O-tetrabenzylglucodiol (2)

[0036] Add 54.00g (100mmol) of tetrabenzylglucose, 10.10g (260mmol) of sodium borohydride, and 500mL of absolute ethanol into a 1L reaction flask, react for 24h under room temperature stirring, and concentrate the reaction solution under reduced pressure. After adding 100 mL of ethyl acetate to the residue, wash with water, and wash the organic phase with anhydrous Mg 2 SO 4 After drying, filtering and concentrating, 53.10 g of a colorless, transparent viscous object was obtained. The purity as determined by HPLC was 96.0%, and the yield was 98.0%.

[0037] 1 H NMR (400MHz, CDCl 3 )δ7.41–7.19(m,20H),4.74–4.47(m,8H),4.08–3.99(m,1H),3.88(dt,J=7.0,3.6Hz,1H),3.82–3.69(m, 3H),3.67–3.60(m,2H),3.57(dd,J=11.8,4.4Hz,1H),2.89(dd,J=24.5,3.4Hz,1H),2.17–1.88(br,1H).

Embodiment 2

[0038] Example 2: Preparation of Tetrabenzyl Miglitol (4)

[0039] (1) Preparation of Tetrabenzyl Glucose Dicarbonyl Derivatives (3)

[0040] Add 8.0mL (93mmol) oxalyl chloride and 80mL dichloromethane into a 250mL reaction flask, and cool down to -78°C. A mixture of 7.1 mL (100 mmol) of dimethyl sulfoxide and 50 mL of dichloromethane was added dropwise with stirring, and stirred at -78°C for 40 min. Dissolve 10.8g (20mmol) of tetrabenzyl glucodiol in 40mL of dichloromethane and slowly drop into the above system, react at -65°C for 2.5h. Add 33.2 mL of triethylamine dropwise to the reaction system, slowly raise the temperature to 0°C and stir for 20 min, and the oxidation reaction solution obtained after the reaction is directly put into the next reaction without treatment.

[0041] (2) Preparation of Tetrabenzyl Miglitol (4)

[0042] Add 4.80 g (80 mmol) of ethanolamine, 5.00 g (80 mmol) of sodium cyanoborohydride, and 500 mL of methanol into a 1000 mL reaction flask, and ...

Embodiment 3

[0045] Example 3: Preparation of Tetrabenzyl Miglitol (4)

[0046] (1) Preparation of Tetrabenzyl Glucose Dicarbonyl Derivatives (3)

[0047] Add 8.0mL (93mmol) oxalyl chloride and 80mL dichloromethane into a 250mL reaction flask, cool down to -70°C, slowly add a mixture of 7.1mL (100mmol) dimethyl sulfoxide and 50mL dichloromethane dropwise under stirring, at -70°C Stir for 40min. Dissolve 10.80g (20mmol) of tetrabenzyl glucodiol in 40mL of dichloromethane and add dropwise to the above system, and react at -70°C for 2.5h. Add 33.2 mL of triethylamine dropwise to the reaction system, slowly raise the temperature to 10°C and stir for 20 min, and the oxidation reaction solution obtained after the reaction is directly put into the next reaction without treatment.

[0048] (2) Preparation of Tetrabenzyl Miglitol (4)

[0049] Add 2.40 g (40 mmol) of ethanolamine, 2.50 g (40 mmol) of sodium cyanoborohydride, and 500 mL of methanol into a 1000 mL reaction flask, and stir at room t...

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