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Preparation method of 2,4-diamino-6-bromomethyl pteridine

A technology of bromomethylpteridine and hydroxymethylpteridine, applied in the field of compound preparation, can solve the problems of low yield, cumbersome route, difficult to enlarge, etc., and achieves the effects of high product purity, simple post-processing, and avoiding deterioration

Inactive Publication Date: 2013-03-06
TIANJIN SCIPHARMACN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The route is cumbersome and the yield is low
And the raw material diketene is highly toxic, and the related reactions need to use a large amount of dichloromethane as a solvent at low temperature, which is difficult to scale up, and the purity of the final product is only about 65%.

Method used

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  • Preparation method of 2,4-diamino-6-bromomethyl pteridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Add 28.6g of 2,4,5,6-tetraaminopyrimidine hydrochloride, 500mL methanol and water mixed solution (v:v=1:1) into a 1L four-neck flask, stir to dissolve. Add 50 g of acidic 4A molecular sieves, pass air under vigorous stirring, and react for 12 hours. Molecular sieves were removed by filtration, the filtrate was adjusted to pH=8 with sodium bicarbonate, a brown solid was precipitated, filtered, and dried to obtain 14 g of 2,4-diamino-6-hydroxymethylpteridine, yield: 73%. MS m / z 192(M+H) +

Embodiment 2

[0018] Add 28.6g of 2,4,5,6-tetraaminopyrimidine hydrochloride, 500mL methanol and water mixed solution (v:v=1:1) into a 1L four-neck flask, stir to dissolve. Add 50 g of acidic 4A molecular sieves, feed oxygen under vigorous stirring, and react for 12 hours. Molecular sieves were removed by filtration, and the filtrate was adjusted to pH=8 with sodium bicarbonate, and a brown solid was precipitated, filtered, and dried to obtain 17.5 g of 2,4-diamino-6-hydroxymethylpteridine, yield: 91%. MS m / z 192(M+H) +

Embodiment 3

[0020] Add 26g of triphenylphosphine, 18g of NBS, and 200mL of carbon tetrachloride into a 500mL four-necked flask, stir vigorously and cool down to 0°C. Add 10 g of 2,4-diamino-6-hydroxymethylpteridine in batches, and then stir the reaction overnight. Filter to obtain the crude product. 12.8 g of 2,4-diamino-6-bromomethylpteridine was recrystallized from a mixed solvent of 100 mL of water and DMF to obtain 12.8 g of brown needle crystals, with a yield of 96%. MS m / z254(M+H) +1 H NMR (400MHz, d6-DMSO) δ: 9.10(s, 1H), 8.65(s, 2H), 8.01(s, 2H), 4.94(s, 2H).

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Abstract

The invention discloses a preparation method of 2,4-diamino-6-bromomethyl pteridine, wherein the preparation method comprises: on the basis of utilizing 2,4,5,6-tetraaminopyrimidine hydrochloride as a raw material and acidic 4A molecular sieve as a catalyst, reacting the raw material with 1,3-dioxyacetone in the presence of oxygen to generate 2,4-diamino-6-bromomethyl pteridine, and performing bromination under the action of NBS (N-bromosuccinimide) and triphenylphosphine to obtain the product 2,4-diamino-6-bromomethyl pteridine. The technique is simple to operate, the yield is high, and large scale industrial production is easier to realize.

Description

technical field [0001] The invention relates to the preparation of a compound, in particular to the preparation of 2,4-diamino-6-bromomethylpteridine. Background technique [0002] Methotrexate (MTX) is an anti-folate metabolism drug, which can inhibit the humoral immune response. Because it can affect folate reductase, it will hinder the biosynthesis of purine and pyrimidine nucleotides, resulting in DNA deficiency, so that immune blast cells cannot produce small Lymphocytes and plasma cells, thus inhibiting delayed hypersensitivity and humoral antibody production, no significant anti-inflammatory effect at doses required for immunosuppression. It is mainly applicable to acute leukemia, breast cancer, choriocarcinoma and malignant mole, head and neck tumors, bone tumors, leukemic meningospinal infiltration, lung cancer, reproductive system tumors, liver cancer, refractory common psoriasis, and autoimmune diseases. [0003] 2,4-diamino-6-bromomethylpteridine is a key interm...

Claims

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Application Information

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IPC IPC(8): C07D475/08
Inventor 何磊
Owner TIANJIN SCIPHARMACN
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