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5-cyclohexyl uracil arabinoside, preparation method and application thereof

A technology of triacetyl arabinoside and cyclohexyl, applied in the field of its preparation, 5-cyclohexyl arabinoside, can solve the problems of limited anti-leukemia activity and difficult clinical application of arabinoside, to avoid heavy metal residues, The effect of simplifying compositing operations

Active Publication Date: 2015-05-27
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing pyrimidine 5-modified arabinosides have limited anti-leukemic activity and are difficult to be used in clinical applications

Method used

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  • 5-cyclohexyl uracil arabinoside, preparation method and application thereof
  • 5-cyclohexyl uracil arabinoside, preparation method and application thereof
  • 5-cyclohexyl uracil arabinoside, preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] In a 50mL round bottom flask, add arabouridine (II, 0.244g, 1mmol), triethylamine (6.3mL, 4.5mol), 4-diaminopicoline (0.02g, 0.16mmol) and 20mL of acetonitrile, ice In a water bath, keep the temperature below 5°C, add acetic anhydride (3.4mL, 3.6mmol) dropwise within 10 minutes, remove the ice-water bath, raise the temperature to 60°C, continue the reaction for 1 hour, and cool down to room temperature. The raw material reacted completely. Slowly add 1 mL of methanol dropwise, remove the solvent on a rotary thin-film evaporator, add 5 mL of ethanol, stir at room temperature for 1 hour, white needle-like crystals precipitate, filter, and wash the filter cake with 5 mL of ethanol. The filter cake was dried to obtain 0.35 g with a yield of 95% (yield is based on II), which is the compound whose hydroxyl group is protected by acetyl group.

[0025] Colorless oil. 1 H NMR (CDCl 3 , 400MHz) δ10.38(s, 1H), 7.64(d, J=6.4Hz, 1H), 6.29(d, J=6.4Hz, 1H), 6.17(d, J=5.2Hz, 1H), 5....

Embodiment 2

[0027] Hydroxyl-protected compound (III, 0.14g, 0.5mmol), peroxide and tert-butyl (0.19mL, 1mmol) and 10mL cyclohexane were added to a reaction tube equipped with a Teflon sealing plug, and reacted at 140°C for 24 hours , cooled to room temperature, TLC traced the reaction process, showing that the reaction of the raw materials was complete. The solvent was removed on a rotary thin-film evaporator, and purified by column chromatography to obtain 0.19 g of oily product 5-cyclohexyl-triacetylararabine, with a yield of 87% (yield based on III), namely compound IV.

[0028] Colorless oil. 1 H NMR (CDCl 3 , 400MHz) δ9.60(s, 1H), 7.16(s, 1H), 6.29(d, J=4.0Hz, 1H), 5.37-5.36(m, 1H), 5.09(d, J=2Hz, 1H) , 4.41(d, J=5.2Hz, 1H), 4.17-4.14(m, 1H), 2.59-2.53(m, 1H), 2.12(s, 3H), 2.09(s, 3H), 2.06(s, 3H ), 1.85-1.70(m, 6H), 1.22-1.01(m, 4H); 13 C NMR (CDCl 3 , 100MHz) δ170.5, 169.7, 168.4, 163.1, 149.8, 135.0, 119.5, 84.1, 80.3, 76.4, 74.7, 62.6, 34.8, 32.4, 26.5, 26.4, 26.0, 20.7, 20....

Embodiment 3

[0030] Add 5-cyclohexyl-triacetylararabine (IV, 0.22 g, 0.5 mmol) and 10 ml of ammonia in methanol solution into the reaction bottle, seal it, and react at room temperature for 24 hours. TLC plates followed the progress of the reaction, showing complete reaction of starting materials. Remove the solvent on a rotary thin film evaporator, add methanol for recrystallization, and filter to obtain a white solid, which is 0.16 g of 5-cyclohexyl-arabinuridine, with a yield of 82% (the yield is based on IV).

[0031] The product obtained was a white solid.. 1 H NMR (DMSO-d 6 , 400MHz) δ9.67(s, 1H), 7.12(s, 1H), 6.18(d, J=5.2Hz, 1H), 5.35-5.34(m, 1H), 5.14(d, J=2Hz, 1H) , 4.45(d, J=5.2Hz, 1H), 4.17-4.15(m, 1H), 2.60-2.57(m, IH), 1.88-1.72(m, 6H), 1.24-1.08(m, 4H); 13 C NMR (CDCl 3 , 100MHz) δ163.8, 148.7, 135.7, 120.5, 86.1, 80.7, 76.8, 74.0, 62.3, 34.8, 32.5, 26.2, 26.0, 25.8; HRMS calcd for C 15 h 23 N 2 o 6 [M+H + ] 327.1551, found 327.1550.

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Abstract

The invention discloses 5-cyclohexyl uracil arabinoside, a preparation method thereof and application in leukemia treatment. The synthetic method avoids a heavy metal catalyst in the conventional synthetic method, avoids heavy metal residue in a product, simplifies the synthesis operation, and is suitable for research and further large-scale preparation of medicaments.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and specifically relates to 5-cyclohexyl araburidine, its preparation method and application. technical background [0002] Many 5-substituted pyrimidine nucleoside compounds have good pharmacological activity, such as 5-fluorouridine (5-FU) and tegafur (tegafur) are good antitumor drugs, compound iodine (IDU), compound (BVDU) has good antiviral activity. The arabinopyrimidine nucleosides also have a wide range of uses, such as the anti-leukemia drug cytarabine hydrochloride, the anti-HSV-1 and HSV-2 anti-HSV-2 fluorocytidine (FIAC) and the like. Therefore, the arabinoside modified at the 5-position of pyrimidine has dual pharmacophore (as shown in Formula 1). [0003] [0004] Formula 1 [0005] Leukemia is a kind of clonal malignant disease with abnormal hematopoietic stem cells. The leukemia cells in its clones lose the ability to further differentiate and mature and stagnate at di...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/09C07H1/00A61K31/7072A61P35/00A61P35/02
Inventor 夏然郭海明渠桂荣牛红英张倩李建平姜源
Owner HENAN NORMAL UNIV
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