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A kind of synthetic method of nucleoside compound

A compound and alkyl technology, which is applied in the field of drug synthesis, can solve problems such as low stereoselectivity, high dosage and concerns about drug toxicity

Active Publication Date: 2018-08-31
扬州硒瑞恩生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Gemcitabine is the only first-line drug for the treatment of advanced pancreatic cancer so far, but its existing preparation methods still have problems such as low stereoselectivity, and its high dosage and drug toxicity are also worrying

Method used

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  • A kind of synthetic method of nucleoside compound
  • A kind of synthetic method of nucleoside compound
  • A kind of synthetic method of nucleoside compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Preparation of compound α-1-bromo-2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-dibenzoate

[0051] According to the literature (Howell, et.al., Journal of Organic Chemistry 1988, v.p.85-88) method, from the commercially available compound 2-deoxy-2,2-difluoro-D-erythro-pentofuranose-3 , 5-Dibenzyl-1-methanesulfonate is converted to the compound α-1-bromo-2-deoxy-2,2-difluoro-D-erythro-pentafuranosyl-3,5-benzidine esters. Concrete preparation method is as follows:

[0052] In the 100ml of chloroform was added at room temperature with 36g (3.0eq) of 33% hydrogen bromide acetic acid solution, and the reaction system was stirred at room temperature for 6 days. After the reaction was finished, 150 ml of water was added each time for washing, twice in total. Then wash with 150 ml of saturated aqueous sodium bicarbonate each time, twice in total. The organic phase was dried over anhydrous magnesium sulfate, and desolvated under reduced pressure to obtain a pale yello...

Embodiment 2

[0054] Preparation of 2-selenocytosine

[0055] 2-Chlorocytosine (2g, 15.4mmol) was added to the sodium selenohydride ethanol solution protected by argon (preparation process: selenium (3g, 38.0mmol) and sodium borohydride (1.75g, 46.2mmol) were added to absolute ethanol ( 100mL) at 10°C for 30 minutes), heated to reflux for 48 hours, cooled, added 10mL of water, filtered with suction, suspended the filter cake in 15ml of absolute ethanol, then added 220mg of sodium borohydride, stirred for 30 minutes, filtered with suction, and dried , an off-white solid (1.1 g) was obtained with a yield of 39%.

[0056] The analysis data is: 1 H-NMR(DMSO-d6)δ: 12.39(s,1H),7.69and 7.84(ss,2H),7.40(d,J=6.0Hz,1H),6.07(d,J=6.0Hz,1H); 13 C-NMR (DMSO-d6) δ: 175.7, 161.6, 142.6, 97.6; HRMS (ESI-TOF), C4H5N3Se, [M+Na]=197.9538 (calc.197.9546).

Embodiment 3

[0058] Preparation of 2-thiocytosine

[0059] Under nitrogen protection, add metal sodium (4.8g) to n-butanol (88mL) at 40-50°C, stir to dissolve, then add thiourea (16g) and 3,3-diethoxy Propionitrile (28g), heated to reflux for 5 hours, cooled to room temperature, adjusted pH to 7-8 with acetic acid, filtered to obtain a yellow solid, recrystallized with water to obtain light yellow 2-thiocytosine (12g), yield 48% .

[0060] analyze data: 1 H-NMR (600 MHz, DMSO-d6) δ: 11.94 (s, 1H), 7.54 (s, 2H), 7.39 (s, 1H), 5.91 (s, 1H).

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Abstract

The invention relates to a synthesis method of a nucleoside compound, in particular to a preparation method of a compound shown as formula I and a compound shown as formula II in the specification. In the formula I and formula II, R1 and R2 are respectively a hydroxyl protecting group independently, preferably benzoyl, triphenylmethyl, disubstituted phenyl, acetyl or tert-butyldimethylsilyl; R3 and R4 are alkyl (preferably alkyl of C1-C10, more preferably methyl and ethyl) or halogen (like F, Cl or Br); and B is any of the following groups shown as the specification, wherein R5 is hydrogen or alkyl (preferably alkyl of C1-C10, more preferably methyl); X is hydroxyl or amino; and Y is sulfur or selenium.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing a class of nucleoside compounds. Background technique [0002] Gemcitabine hydrochloride (Gemcitabine hydrochloride), the chemical name is 2'-deoxy-2', 2'-difluorocytidine hydrochloride (β-isomer), as shown in the following structure 1, it is a nucleoside homologue and belongs to Cell cycle specific antineoplastic agents. Gemcitabine is a potent anticancer ("antineoplastic" or "cytotoxic") drug, classified as an antimetabolite, and is a first-line antineoplastic agent. In 1996, the US FDA approved gemcitabine hydrochloride (trade name Gemzar) developed by Eli Lilly and Company as a first-line drug for the treatment of pancreatic cancer, and in 1998 it was approved for the treatment of non-small cell lung cancer. The global sales share in 2009 was US$1.7 billion, and its patent expired in 2010. Gemcitabine can selectively inhibit the DNA and RNA synthesis...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/073C07H19/173C07H1/00A61P35/00
CPCY02P20/55
Inventor 黄震约瑟夫·沙龙杨召仪刘大学
Owner 扬州硒瑞恩生物医药科技有限公司
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