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A kind of preparation method of nelarabine

A technology of nelarabine and amino, which is applied in the field of chemical preparation of nelarabine, can solve the problems of high raw material price, low total yield, long route, etc., and achieve the effect of easy control of reaction, short reaction route and safe reaction

Active Publication Date: 2020-05-01
ZHEJIANG CHENGYI PAHRMACEUTICAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The steps of this method have been shortened compared with the previous method, but there are still many steps, and the total yield is still low
[0017] The main problems in the prior art are: long route, high raw material price, low total yield

Method used

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  • A kind of preparation method of nelarabine
  • A kind of preparation method of nelarabine
  • A kind of preparation method of nelarabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Preparation of 2-amino-6-methoxypurine (2)

[0046] Add 51.0g of 2-amino 6-chloropurine (1) and 34.0g of sodium methoxide into 500ml of methanol, stir to dissolve, heat in an oil bath at 67°C, reflux for 10h, and monitor the progress of the reaction by TLC. After the reaction was completed, the solvent was evaporated to produce a large amount of white solid, which was dissolved by adding 500ml of water, then adjusted to pH 7.5 with dilute hydrochloric acid solution, and a large amount of white solid was precipitated, left to stand for 30min and then filtered to obtain 44.4g of filter cake with a yield of 98.0%.

Embodiment 2

[0048]Preparation of silylated product (3) of 2-amino6-methoxypurine

[0049] Add 45.3g of 2amino-6-methoxypurine (2) into 500ml of 1,2-dichloroethane, stir for 10min, but it does not dissolve. Then 66.0 g of trimethylchlorosilane and 61.0 g of triethylamine were added, and the reaction was stirred at 60° C. for 6 to 7 hours, and the reaction progress was monitored by TLC. After the reaction, the insoluble matter was filtered out, and the filtrate was spin-dried to obtain 72.4 g of a reddish-brown oily substance 6-methoxy-N,9-bis(trimethylsilyl)-9H-purin-2-amine, with a yield of 78.0% .

[0050] Change the ratio of 6-methoxyguanine (2):trimethylchlorosilane:triethylamine to 1:5:5, and other conditions are the same as in Example 2. 69.5 g of reddish-brown syrupy substance 6-methoxy-N,9-bis(trimethylsilyl)-9H-purin-2-amine was obtained, with a yield of 71.1%.

[0051] The organic solvent was changed to dichloromethane, the reaction temperature was changed to 38° C., the react...

Embodiment 3

[0053] Preparation of cytarabine (4)

[0054] Add 52.9g of cyclocitidine hydrochloride into 500ml of water, stir to dissolve, then adjust the pH value of the solution to 12.0-14.0 with sodium hydroxide solution, stir and react at 25°C for 10h, and monitor the reaction progress by TLC. After the reaction, the water was evaporated to obtain a large amount of white solid, which was then dissolved in 500ml of methanol, filtered, and the filtrate was evaporated to dryness to obtain 43.8g of white powdery solid cytarabine, m.p.: 212-214°C. Yield 90.1%.

[0055] Change the reaction temperature to 60°C and the reaction time to 4h. Other conditions are the same as embodiment three. 44.8 g of white powdery solid cytarabine was obtained, m.p.: 213-214°C. Yield 92.2%.

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Abstract

The invention discloses a preparation method of nelarabine. The preparation method comprises the following steps: by taking cyclocytidine hydroc and 2-amino-6-chloropurine as a raw material, protecting amino and hydroxyl with acetyl after cyclocytidine hydroc is hydrolyzed to form tetraacetyl cytarabine; and then carrying out a base conversion reaction with silanized 2-amino-6-chloropurine under the action of trimethylsilyl trifluoromethanesulfonate to obtain the target product nelarabine. The raw materials are relatively low in price and easy to purchase, and the preparation method is relatively short in reaction route, mild in condition, low in equipment demand, low in production cost and safe to react and easy to control, and provides probability for reducing the production and manufacturing costs of nelarabine.

Description

[0001] (1) Technical field [0002] The invention relates to a chemical preparation method of nelarabine, which belongs to the field of medicine and chemical industry. [0003] (2) Background technology [0004] Nelarabine is a prodrug of the guanosine analogue 9-β-D-arabinofuranosylguanine (Ara-G). Chemical name: 9-β-D-arabinofuranosyl-6-methoxy-9H-purin-2-amine. As a therapeutic drug for treating hematological tumors and T lymphocytic leukemia, it has remarkable curative effect. [0005] Its structural formula is as follows: [0006] [0007] Before the present invention was made, it was reported in the literature that the synthetic route of nelarabine mainly contained: [0008] 1. Biological enzyme catalysis method [0009] European Patent EP0294114; Tetrahedron Letters, 2005, 46, 2961-2964 reported that the arabinoside of 2-amino-6-methoxypurine and uracil was used as raw material in purine nucleoside phosphorylase and uridine phosphorylase Under the action, the nel...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/19C07H1/00
CPCC07H1/00C07H19/19
Inventor 颜贻意吕志东
Owner ZHEJIANG CHENGYI PAHRMACEUTICAL
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