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Process for preparing 4-[9-(6-aminopurine)]-2(S)-hydroxybutyrate methyl ester

A technology based on methyl hydroxybutyrate and aminopurine, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of high price, low production efficiency, and cumbersome post-processing, and achieve the effects of easy scale-up production, high production efficiency, and cost reduction

Active Publication Date: 2009-06-17
NINGBO ZIYUAN PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this preparation method, (S)-(-)-α-hydroxybutyrolactone is expensive, the yield of tetraisopropyl titanate ring-opening reaction is very low, the aftertreatment is loaded down with trivial details, and the chiral center is prone to occur in the reaction process racemization; in addition, adopting the method of column chromatography to purify DZ2002 is time-consuming and laborious, and the production efficiency is low

Method used

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  • Process for preparing 4-[9-(6-aminopurine)]-2(S)-hydroxybutyrate methyl ester
  • Process for preparing 4-[9-(6-aminopurine)]-2(S)-hydroxybutyrate methyl ester
  • Process for preparing 4-[9-(6-aminopurine)]-2(S)-hydroxybutyrate methyl ester

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Experimental program
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Effect test

Embodiment 2

[0032]

[0033] L-malic acid (4.0g, 30.0mmol) was suspended in dry benzene (80ml), added fresh benzaldehyde (3.2g, 30mmol), pyridine p-toluenesulfonate (151.0mg, 0.6mmol), and the mixture was heated to reflux After about 3 hours, the system becomes clear. The solvent was removed by concentration, and the resulting residue was diluted with water (100ml), and extracted well with dichloromethane. The obtained organic phases were combined, washed with saturated brine, dried, and concentrated to obtain a nearly colorless transparent oil I-2, 4.3 g, yield: 65.3%, which was used directly in the next step without purification.

Embodiment 3

[0035]

[0036] L-malic acid (10.0g, 74.6mmol) was suspended in fresh 2,2-dimethoxypropane (100ml), p-toluenesulfonic acid (0.20g, 1.04mmol) was added and reacted at room temperature for 6h, the system became clear . The solvent was removed by concentration, and the resulting residue was diluted with water (150ml), and extracted well with dichloromethane. The obtained organic phases were combined, washed with saturated brine, dried, and concentrated to obtain a nearly colorless transparent oil, which slowly solidified to obtain a white crystal I-1, 4.8 g, yield: 37.0%.

Embodiment 4

[0038]

[0039] L-malic acid (6.7g, 50.0mmol) was suspended in fresh diethyl ether (100ml), and redistilled propionaldehyde (3.2g, 55.0mmol) was added under ice cooling. Then, distilled boron trifluoride ether solution (19.0ml, 150.0mmol) was added dropwise within 30min. After the addition was completed, the reaction was kept for 3h. After the system was diluted with water (100ml), it was fully extracted with ether, the organic phases were combined, washed with saturated brine, dried and concentrated to obtain a transparent oil I-3, 6.8g, yield: 78.1%, without purification, the next step Use directly.

[0040] (2) Selective reduction of the protected L-malic acid intermediate I to alcohol II (with R 1 = R 2 =Methyl is an example to illustrate that is I-1 compound, but does not make any limitation)

[0041]

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Abstract

The invention discloses a novel method for preparing and purifying 4-[9-(6-amino purine group)]-2 (S)-hydroxyl methyl butyrate. The method comprises: based on cheap and easily obtained L-malic acid, through functional group protection of one carboxyl and two carboxyls at the same time, an intermediate compound I is obtained; the intermediate compound I is selectively reduced into an intermediate ethanol II; the hydroxyl in the intermediate ethanol II is converted into an easily removed group, so as to obtain an intermediate compound III; the intermediate compound III is subjected to nucleophilic substitution reaction to obtain an intermediate compound IV; and the intermediate compound IV is subjected to protective group removal and methyl esterification simultaneously under the action of acid or alkali in the methanol to obtain a crude product of the 4-[9-(6- amino purine group)]-2 (S)-hydroxyl methyl butyrate, and a pure product is obtained after the crude product is recrystallized and purified. Compared with the prior preparation method, the method has the characteristics of low cost, mild conditions, difficult racemization of a chiral center during reaction, high production efficiency and the like, improves the quality and yield of products greatly, lowers the cost greatly, and is suitable for large-scale preparation.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and relates to a 4-[9-(6-aminopurinyl)]-2(S)-hydroxybutyric acid methyl ester [4-(6-Amino-purin-9-yl)- 2(S)-hydroxy-butyric acid methylester, referred to as DZ2002] new preparation and purification method. Background technique [0002] DZ2002 is a reversible inhibitor of S-adenosyl-L-homocysteine ​​hydrolase (SAHH). Studies have confirmed that: DZ2002 selectively inhibits the function of macrophages and activated B cells, inhibits cellular immunity and humoral immune response, DZ2002 has a wide distance between toxic dose and therapeutic dose, and has a high therapeutic index (Choneg- Sheng Yuan, USP: 2005 / 0182075, 2005; Yun-Feng Fu, Jun-Xia Wang, Jian-Ping Zuo etc., The Journal of Pharmacology and Experimental Therapeutics, 118, 1229-1237; Brian R. Lawson, Yulia Manenkova, Chong Yuan etc., The Journal of Immunology, 178, 5366-5374, 2007). [0003] The known synthetic method of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/34
CPCC07D473/34C07D317/34Y02P20/55
Inventor 南发俊左建平张仰明顾民唐炜
Owner NINGBO ZIYUAN PHARMA INC
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