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A kind of preparation method of 3-o-carbamoylmannose donor derivative, bleomycin disaccharide and its precursor

A technology for carbamoyl mannose and derivatives, which is applied in the field of medicine and chemical industry, can solve the problems of difficult purification, poor sorbitol selectivity, slow progress and the like, and achieves the effects of strong operability, cheap raw materials and high selectivity

Active Publication Date: 2021-08-10
GUANGZHOU UNIVERSITY OF CHINESE MEDICINE
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

Although Lu Wei's research group recently reported that sorbitol can be prepared in gram-scale by head-to-tail flipping, the selectivity of acetaldehyde-protected sorbitol in the route is poor, and the optimal yield is only 17%, and the purification is difficult, which affects its larger scale. Preparation (Synthesis of Two Antibiotic Antitumor Bleomycin Disaccharides, Tetrahedron, 2017, 73, 6172-6180)
[0005] To sum up, in the past 30 years, many research groups have reported the improvement of bleomycin disaccharide synthesis methods, but the progress is slow, and the synthesis scale is almost at the milligram level, and these methods have long routes and low yields. Low, poor operability and repeatability of the reaction, not suitable for industrialization, etc.

Method used

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  • A kind of preparation method of 3-o-carbamoylmannose donor derivative, bleomycin disaccharide and its precursor
  • A kind of preparation method of 3-o-carbamoylmannose donor derivative, bleomycin disaccharide and its precursor
  • A kind of preparation method of 3-o-carbamoylmannose donor derivative, bleomycin disaccharide and its precursor

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Experimental program
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Effect test

Embodiment 1

[0052] An embodiment of the preparation method of the 3-O-carbamoylmannose donor derivative (M-8) of the present invention comprises the following steps:

[0053] (1) Preparation of methyl α-D-mannopyranoside (M-2)

[0054] The structural formula of the M-2 is:

[0055] Under the protection of nitrogen, 100 grams of mannose (M-1) (257.7mmoL) was dissolved in dry 250mL of methanol, 1.0mL of acetyl chloride was added, and after reflux for 6 hours, when the mannose was completely dissolved, the methanol was distilled off under reduced pressure to obtain The crude product was washed and filtered with absolute ethanol to obtain 188.2 g of methyl α-D-mannopyranoside as a white solid, with a yield of 97%.

[0056] 1 H NMR (400MHz, CDCl 3 )δ7.39-7.27(m,5H),4.72(s,1H),4.68-4.65(d,J=12.0Hz,1H),4.59-4.56(dd,J=12.0Hz,1H),4.03(t ,J=9.6Hz,1H),3.91(s,1H),3.81(d,J=8.0Hz,1H),3.72(d,J=12.8Hz,1H),3.66(d,J=9.2Hz,1H ), 3.53 (d, J=8.0Hz, 1H), 3.30 (s, 3H).

[0057] (2) Preparation of methyl...

Embodiment 2

[0082] An embodiment of the preparation method of the 3-O-carbamoylmannose donor derivative (M-8) of the present invention comprises the following steps:

[0083] (1) Preparation of methyl α-D-mannopyranoside (M-2)

[0084] Under the protection of nitrogen, 100 grams of mannose (M-1) (257.7mmoL) was dissolved in dry 250mL of methanol, 1.0mL of acetyl chloride was added, and after reflux for 6 hours, when the mannose was completely dissolved, the methanol was distilled off under reduced pressure to obtain The crude product was washed and filtered with absolute ethanol to obtain 188.2 g of methyl α-D-mannopyranoside as a white solid, with a yield of 97%.

[0085] (2) Preparation of methyl-3-O-benzyl-α-D-mannopyranoside (M-3)

[0086] Under the protection of nitrogen, 50 grams of M-2 (257.7mmoL) and 32 grams of dibutyltin oxide (129mmoL) were dissolved in 250mL of dry toluene, and after reflux for 1 hour, the toluene was evaporated under reduced pressure to obtain the crude prod...

Embodiment 3

[0098] An embodiment of the preparation method of 3-O-carbamoylmannose (M-8) of the present invention comprises the following steps:

[0099] (1) Preparation of methyl α-D-mannopyranoside (M-2)

[0100] Under the protection of nitrogen, 100 grams of mannose (M-1) (257.7mmoL) was dissolved in dry 250mL of methanol, 1.0mL of acetyl chloride was added, and after reflux for 6 hours, when the mannose was completely dissolved, the methanol was distilled off under reduced pressure to obtain The crude product was washed and filtered with absolute ethanol to obtain 188.2 g of methyl α-D-mannopyranoside as a white solid, with a yield of 97%.

[0101] (2) Preparation of methyl-3-O-benzyl-α-D-mannopyranoside (M-3)

[0102] Under the protection of nitrogen, 50 grams of M-2 (257.7mmoL) and 12.8 grams of dibutyltin oxide (51.6mmoL) were dissolved in 250mL of dry toluene, and after reflux for 1 hour, the toluene was evaporated under reduced pressure to obtain the crude product, which was dri...

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Abstract

The invention discloses a preparation method of 3-O-carbamoylmannose donor derivatives, which comprises selective benzylation, acetylation, debenzylation and aminomethylation of the 3-hydroxyl group of methyl-α-mannoside Acylation series reaction. At the same time, the invention also discloses a method for preparing bleomycin disaccharide and its precursor by using the 3-O-carbamoylmannose donor derivative prepared by the method as a donor. The preparation method of the 3‑O‑carbamoylmannose donor derivative of the present invention has the advantages of high protection and deprotection selectivity, short route and high yield, and simultaneously solves the problem of the production of bleomycin disaccharide and its precursor. Low efficiency, poor operability and repeatability of the reaction, unsuitable for industrialization and other problems, has the advantages of cheap and easy-to-obtain raw materials, high yield, strong operability, easy control of conditions, industrial scale-up, high efficiency and low cost.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a preparation method of a 3-O-carbamoylmannose donor derivative, bleomycin disaccharide and its precursor. Background technique [0002] Bleomycin (BLM) is a glycopeptide antitumor antibiotic drug used in the first-line clinical treatment of tumors. It is mainly used to treat squamous cell carcinoma, Hodgkin's malignant lymphoma, cervical cancer and testicular cancer. Streptomyces verticillus. The BLM structure consists of three parts: 1) 5 amino acids composed of pyrimidine-imidazole structure; 2) 1 side chain containing bithiazole amino group; 3) 1 unique disaccharide structure. A large number of studies have shown that the pyrimidine-imidazole structure is the key part of the anti-tumor effect of BLM, which can selectively oxidize and cleave the 5'-GC-3' and 5'-GT-3' sequences in DNA, thereby exerting anti-tumor activity; The structure can ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H1/02C07H13/12
CPCC07H1/02C07H13/12
Inventor 周文李茂林袁思思
Owner GUANGZHOU UNIVERSITY OF CHINESE MEDICINE
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