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Method for preparing 1,2-ketal protected-1,2,4-butanetriol

A technology of ketal protection and butanetriol, which is applied in the production of bulk chemicals and organic chemistry, can solve problems such as poor operability, increased cost, and unsuitability for large-scale production, and achieve high utilization rates

Inactive Publication Date: 2013-04-10
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with the first synthetic method, the advantage of this method is that it avoids the generation of 2,4-ketal isomer III, but the disadvantage is that it uses expensive LiAlH 4 As a reducing agent, it can only be used for small-scale preparation in the laboratory
[0006] Another patent [WO00 / 55155 (2000)] reports that with respect to the raw material 3,4-ketal protecting group-3,4-dihydroxybutyrate (II) 6 times the molar amount of NaBH 4 I was prepared by reducing in methanol. The utilization rate of the reducing agent in this method is too low, which will inevitably lead to increased cost and poor operability, and is not suitable for large-scale production.

Method used

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  • Method for preparing 1,2-ketal protected-1,2,4-butanetriol
  • Method for preparing 1,2-ketal protected-1,2,4-butanetriol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Add 100ml tetrahydrofuran and 3.27g KBH successively into a 250ml three-necked flask equipped with electromagnetic stirring, a thermometer and a reflux condenser 4 , 5.46g magnesium chloride, heated to reflux in an oil bath under the protection of nitrogen for 2 hours, then added 10.0g II dropwise, and the drop was completed in about 2 minutes. reaction, filter the reaction solution, wash the filter cake with a mixed solution of 40ml tetrahydrofuran and methanol (10:1), concentrate the filtrate to dryness, add 200ml methanol to dissolve the resulting residue and concentrate to dryness again, and dissolve the resulting residue with 200ml ethyl acetate , washed with saturated brine, anhydrous MgSO 4 Drying, solvent removal under reduced pressure obtains 7.58g colorless transparent oil product (S)-I[R 1 = R 2 =Me; GC: 97.8%; bp: 75-76°C / 2mmHg; 1 H-NMR (CDCl 3 , 400MH Z ): 1.35(3H,s), 1.42(3H,s), 1.82(2H,m), 2.39(1H,s), 3.58(1H,dd), 3.78(2H,t), 4.08(1H,dd) , 4.25(1H, ...

Embodiment 2

[0024] Add 80ml tetrahydrofuran, 2.61gKBH successively into a 250ml three-necked flask equipped with electromagnetic stirring, a thermometer and a reflux condenser 4 , 4.37g magnesium chloride, 10.0g (R)-II (R 1 = R 2 = Me,R 3 =Et), drop it in about 2 minutes, continue to reflux for 2 hours, then change to an ice-water bath to cool to an internal temperature of 5-10°C, and carefully add 10ml of methanol to quench the reaction. Filter the reaction solution, wash the filter cake with a mixed solution of 60ml tetrahydrofuran and methanol (10:1), concentrate the filtrate to dryness, add 50ml methanol to dissolve the residue and concentrate again to dryness, and dissolve the residue with 200ml ethyl acetate , washed with saturated brine, anhydrous MgSO 4 Drying, solvent removal under reduced pressure obtains 7.31g colorless transparent oil product (S)-I(R 1 = R 2 =Me).

Embodiment 3

[0026] Add 150ml tetrahydrofuran, 5.88g KBH successively into a 500ml four-necked bottle equipped with electromagnetic stirring, a thermometer and a reflux condenser 4 , 4.40g lithium chloride, 15.0g (S)-II (R 1 = R 2 = R 3 =Me), heated to reflux in an oil bath under the protection of nitrogen for 3 hours, then changed to an ice-water bath to cool to an internal temperature of 5-10°C, carefully added 50ml of saturated brine to quench the reaction, extracted with 3×200ml of ethyl acetate, combined the organic layers and Anhydrous MgSO 4 Drying, solvent removal under reduced pressure obtains 11.33g colorless and transparent oil product (S)-I(R 1 = R 2 = Me).

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Abstract

The invention provides a preparation method for 1,2-ketal protection group-1,2,4- tromethamine and is characterized in that 3,4-ketal protection group-3,4-dihydroxy hydroxybutyrate (II) is deoxidized with NaBH4 or KBH4 in the presence of Lewis acid to prepare the 1,2-ketal protection group-1,2,4- tromethamine (I). The method of the invention has high yield and easy operation with cheap and available reducing agent, and is suitable for large-scale production.

Description

technical field [0001] The invention relates to a preparation method of a drug synthesis intermediate 1,2-ketal protecting group-1,2,4-butanetriol. Background technique [0002] 1,2-ketal protecting group-1,2,4-butanetriol (I) is an important synthon in the total synthesis of many natural products, such as the antibiotics Griseoviridin and Madumycin (Griseoviridin and Madumycin; J.Org.Chem., 1986, 51(26):5111-5123), macrolide antineoplastic drug spongistatin (Spongistatin; Org.Lett., 2003, 5(25):4819-4822), etc., According to literature reports, its synthetic method mainly contains the following two types according to the raw materials: [0003] One is direct reduction of borane-dimethyl sulfide complex [Tetrahedron Lett., 1982, 23 (47): 4883-4886 with malic acid as raw material; J.Org.Chem., 1983, 48: 4427-4430 ; Can.J.Chem.1984,62(11):2146-2147; J.Org.Chem., 1984,49:2834-2837] or by boron trifluoride-ether and NaBH 4 Pre-reaction to prepare diborane for reduction [Heter...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D317/20C07C31/22
CPCY02P20/55
Inventor 张福利邱友春张椿年
Owner SHANGHAI INST OF PHARMA IND CO LTD
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