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Preparation method of GalNAc intermediate

A technology of intermediates and compounds, which is applied in the field of improving the process and preparing GalNAc intermediates, can solve the problems of long reaction time, low yield, complicated operation, etc., and achieve the effect of convenient purification, high yield, and high reaction yield

Pending Publication Date: 2021-11-23
SHANGHAI JINGXIN BIOLOGICAL MEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in this route, the compound of formula 17A is a key intermediate, which is not commercially available in China. The above-mentioned original research route and the reported literature all use tert-butyl acrylate to prepare the compound of formula 17A. The yield is low, the reaction time is long, and the operation is very complicated.

Method used

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  • Preparation method of GalNAc intermediate
  • Preparation method of GalNAc intermediate
  • Preparation method of GalNAc intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Synthesis of I (R1=Ac, R2=Boc)

[0042]

[0043] A (38.0g, 1.0eq) was dissolved in dichloromethane (DCM), CDI (16.3g, 1.1eq) and triethylamine (12.9g, 1.5eq) were added with stirring, and stirred at room temperature for three hours. Then B (16.3g, 1.1eq) was added and reacted overnight at room temperature. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium bicarbonate solution (100 mL), extracted and separated, and the organic phase was collected. Wash the organic phase again with water (100mL), separate the organic phase, add 2N dilute hydrochloric acid to the organic phase, extract and separate layers, wash the organic phase with water (100mL), and finally wash the organic phase with saturated brine (100mL) , collected the organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated to give beige solid I (38.7 g, yield 75.5%).

Embodiment 2

[0044] Embodiment 2: the synthesis of I (R1=Bz, R2=Cbz)

[0045] Dissolve A (63.3g, 0.1mol) in THF1.3L, add 23.0g of EDCI.HCl, 16.2g of HOBt, 50.5g of triethylamine under stirring, stir at room temperature for three hours, then add 2.4g of B6, and heat up to React overnight at 40°C. After the reaction is complete, spin off the solvent, add 500 mL of water and 500 mL of dichloromethane, extract and separate, and collect the organic phase. Wash the organic phase with 500mL of clear water again, separate the organic phase, add 300mL of 2N dilute hydrochloric acid to the organic phase, extract and separate layers, wash the organic phase with 500mL of clear water, and finally wash with 500mL of saturated saline, and dry over anhydrous sodium sulfate. Filtration and concentration gave light yellow solid I (61.4 g, yield: 74.6%).

Embodiment 3

[0046] Embodiment 3: the synthesis of I (R1=Bz, R2=Boc)

[0047]Dissolve A (6.33g, 0.01mol) in 80mL of 2-methyltetrahydrofuran, add 5.69g of HBTU and 1.93g of DIPEA under stirring, and stir at room temperature for three hours. Subsequently, 2.09 g of B was added, and the temperature was raised to 40 to react overnight. After the reaction is complete, add 50 mL of water, extract and separate the liquid, add 30 mL of 2N dilute hydrochloric acid to the organic phase, extract and separate layers, wash the organic phase with 50 mL of water, and finally wash with 50 mL of saturated saline, dry over anhydrous sodium sulfate, filter, and concentrate , to obtain light yellow solid I (5.63g, yield: 71.3%).

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Abstract

The invention relates to a preparation method of a GalNAc intermediate (a compound as shown in a formula III). The preparation method comprises the following steps: 1) carrying out deprotection reaction on a compound as shown in a formula I to obtain a compound as shown in a formula II; and 2) carrying out condensation reaction on the compound shown in the formula II and a compound shown in a formula X or reacting the compound shown in the formula II and the activated compound shown in the formula X under organic alkali to generate a compound shown in a formula III. The synthesis method is simple in process route, low in cost and suitable for industrial production.

Description

technical field [0001] The present invention relates to an improved process for the preparation of GalNAc intermediates. Background technique [0002] GalNAc-siRNA is a single conjugate formed by carbohydrate compounds and siRNA, and N-acetylated galactosamine (GalNAc) is covalently conjugated to the 3' end of the sense strand of siRNA with different sequences in a trivalent state. Formation of polysaccharide-siRNA monoconjugates. GalNAc is the targeting ligand of sialic acid receptor (ASGPR), which has high affinity and rapid internalization ability with liver surface cells, so that this type of siRNA conjugate can specifically bind membrane proteins and enter cells. siRNA-like conjugates have good application potential in the treatment of liver-related diseases involving gene overexpression. It was found in the study that when the single dose of GalNAc-siRNA single conjugate was 1ug / g, subcutaneous injection could Achieve effective silencing of liver-specific target gene...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/04C07H1/00
Inventor 徐苗焕祝小平郭四根
Owner SHANGHAI JINGXIN BIOLOGICAL MEDICAL
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