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Preparation method of N-acetyl-D-galactosamine

A galactosamine and acetyl technology, which is applied in the field of preparation of N-acetyl-D-galactosamine, can solve the problem of affecting the yield of N-acetyl-D-galactosamine and difficult to effectively separate peracetylated products , long reaction time of overacetylation, etc., to achieve the effect of easy production, mild conditions, and enlarged production

Pending Publication Date: 2021-07-23
ANHUI YINFENG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] There are following technical problems in peroxidized D-galactosamine: the first, adopt inorganic base such as sodium hydroxide, sodium carbonate, sodium bicarbonate and sodium alkoxide as acid-binding agent such as sodium methylate, almost do not take place acetylation reaction; 1. The molecular structure of D-galactosamine contains multiple hydroxyl groups and one amino group. The introduction of acetyl groups has a steric hindrance effect on the further substitution of hydrogen in the remaining hydroxyl groups in the molecular structure. The specific performance is that the reaction time of peracetylation is long and the yield Low; third, the peracetylation reaction is easy to generate oily products, and it is difficult to effectively separate the peracetylated products by the method of carrying water with toluene, which will affect the recrystallization of N-acetyl-D-galactosamine, and finally affect the N-acetyl - Yield of D-galactosamine

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] S1: In the 100L reactor, add 10kg D-galactosamine hydrochloride (in terms of purity 100%, 46.4mol, 1eq of S1, CAS No. 1772-03-8), temperature control 0 ℃, add 30kg acetic anhydride ( About 6eq), 30kg of pyridine (about 8eq), stirred for 1-2 hours, then added 200g of 4-dimethylaminopyridine (substrate mass 2%), warmed up to room temperature, stirred for 10h, and the reaction ended;

[0030] S1 Post-treatment: After removing the solvent under reduced pressure, add 10 kg of toluene with distilled solvent until no further distillation is carried out, and cool down to room temperature. Add 30 kg of anhydrous methanol for beating for 2 hours, filter with suction, and dry to obtain 16.13 kg of a white solid (98% content of D-galactosamine pentaacetate, detected by a calcium-type cation exchange column).

[0031] S2: Add 10kg of D-galactosamine pentaacetate intermediate (CAS No. 76375-60-5, 1eq of S2) into a 100L reactor, add 70kg of methanol, add about 3.5kg of sodium methoxid...

Embodiment 2

[0035] S1: In a 100L reactor, add 10kg D-galactosamine hydrochloride (in terms of 100% purity, 46.4mol, 1eq of S1), control the temperature at 0°C, add 30kg acetic anhydride (about 6eq), 30kg pyridine (about 8eq), stirred for 1-2 hours, then added 200g of 4-dimethylaminopyridine (substrate mass 2%), tris (2-chloroethyl) phosphate 132g (0.01eq), warmed up to room temperature, stirred for 12h, and reacted Finish;

[0036] S1 Post-treatment: After removing the solvent under reduced pressure, add 10 kg of toluene with distilled solvent until no further distillation is carried out, and cool down to room temperature. Add 30 kg of anhydrous methanol for beating for 2 hours, filter with suction, and dry to obtain 16.72 kg of white solid (the content of D-galactosamine pentaacetate is 97.8%, detected by calcium-type cation exchange column).

[0037] S2: 10kg of D-galactosamine pentaacetate intermediate (1eq of S2), 70kg of methanol, and about 3.5kg of sodium methoxide were added to ad...

Embodiment 3

[0041] Embodiment 3 is based on embodiment 1, and the difference is that phosphate tris (2-chloroethyl) ester 265g (0.02eq) is added in the S1 reaction system, and after the same post-treatment as in embodiment 1, a white solid (D-galactose Amine pentaacetate content 98.2%) 16.91kg.

[0042] The S1 yield of Example 2 was 93.6%.

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Abstract

The invention discloses a preparation method of N-acetyl-D-galactosamine. The preparation method comprises the following steps that S1, acetylation is carried out on D-galactosamine hydrochloride to prepare D-galactosamine pentaacetate; and S2, O-acetylation is carried out on the glycosamine pentaacetate to generate N-acetyl-D-galactosamine. A reaction system in the S1 contains D-galactosamine hydrochloride, a solvent, an acylating agent and an acid-binding agent, the acylating agent is acetic anhydride, the acid-binding agent is prepared from 4-dimethylaminopyridine, and the reaction temperature is -5 DEG C to 5 DEG C; and the solvent is prepared from organic bases with pKa of 5-12 at 25 DEG C. According to the preparation method of the N-acetyl-D-galactosamine, the alkaline solvent firstly reacts with HCl in the D-galactosamine hydrochloride, then the alkaline solvent and the 4-dimethylaminopyridine jointly promote acetylation, the yield of the peracetylation reaction of the D-galactosamine hydrochloride is increased, the reaction rate is increased, the peracetylation reaction conditions are mild, and production is easy to expand.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a preparation method of N-acetyl-D-galactosamine. Background technique [0002] Targeted drug delivery is an effective way to increase drug utilization, improve efficacy, reduce costs, and reduce side effects. N-acetyl-D-galactosamine-modified liposomes are used as carriers for fluorescent marker coumarin-6, siRNA drugs, etc., which can promote the targeted absorption of drugs. [0003] In the prior art, the synthesis steps of sugar amines retaining N-acetyl groups are as described in CN103476782A, using sugar amine hydrochloride as raw material, including two preparation methods: one is prepared through selective aminoacetylation, and selective The acetylation reaction conditions are harsh; the other is peracetylated D-galactosamine, and then hydrolyzes the ester group to retain the amide group. [0004] There are following technical problems in peroxidized D-galactosam...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H5/06C07H1/00
CPCC07H5/06C07H1/00
Inventor 常松
Owner ANHUI YINFENG PHARMA
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