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A kind of preparation method of purine nucleotide intermediate

A technology for purine nucleotides and intermediates, which is applied in the field of preparation of purine nucleotide intermediates, can solve problems such as unfavorable industrial production, low yield and the like, and achieves simple operation, high yield and purity, and mild reaction conditions. Effect

Active Publication Date: 2022-03-25
NANJING OCEAN PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] This route first adopts methylation after addition and deprotection, the yields are 57% and 84% respectively, the yields are low, and the post-treatment needs to be purified by column, which is not conducive to industrial production

Method used

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  • A kind of preparation method of purine nucleotide intermediate
  • A kind of preparation method of purine nucleotide intermediate
  • A kind of preparation method of purine nucleotide intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] A preparation method of a purine nucleotide intermediate, the specific steps are:

[0030]

[0031] (1) Synthesis of compound IV

[0032] Add compound V (50g, 0.33mol) and thionyl chloride (47.6g, 0.4mol) to the reactor, control the temperature at 40°C, slowly add 46.8g of 30% hydrogen peroxide dropwise, keep warm for 3 hours after the dropwise addition, and cool To 20°C, neutralize pH 6-7.5 with 2.5M liquid caustic soda, filter with suction, and dry to obtain compound IV (52.6 g, 0.31 mol), with a yield of 94% and a purity of 99.4%.

[0033] (2) Synthesis of compound III

[0034] Add compound IV (20 g, 0.12 mol), methylamine (7.1 g, 0.23 mol) and ethanol (100 mL) into the reactor, heat the mixture to 110 ° C for 10 h, add potassium carbonate (18 g, 0.13 mol), stirred for 2 h and then filtered, the filtrate was concentrated until solids were precipitated, and left to stand overnight in the refrigerator. After filtration, the filter cake was recrystallized with met...

Embodiment 2

[0038] A preparation method of a purine nucleotide intermediate, the specific steps are:

[0039]

[0040] (1) Synthesis of compound IV

[0041] Add compound V (50g, 0.33mol) and thionyl chloride (41.6g, 0.35mol) to the reactor, control the temperature at 50°C, slowly add 54.2g of 30% hydrogen peroxide dropwise, keep warm for 3 hours after the dropwise addition, and cool To 20°C, neutralize pH 6-7.5 with 2.5M liquid caustic soda, filter with suction, and dry to obtain compound IV (51.5 g, 0.304 mol), with a yield of 92% and a purity of 99.5%.

[0042] (2) Synthesis of compound III

[0043] Add compound IV (20 g, 0.12 mol), methylamine (5 g, 0.16 mol) and N-methylpyrrolidone (100 mL) into the reactor, heat the mixture to 110 ° C for 10 h, add triethylamine under ice-bath cooling (22.3g, 0.22mol), stirred for 2h and then filtered, the filtrate was concentrated until solids were precipitated, and left to stand overnight in the refrigerator. After filtration, the filter cake...

Embodiment 3

[0047] A preparation method of a purine nucleotide intermediate, the specific steps are:

[0048]

[0049] (1) Synthesis of compound IV

[0050] Add compound V (50g, 0.33mol) and thionyl chloride (54.7g, 0.46mol) to the reactor, control the temperature at 20°C, slowly add 45.3g of 30% hydrogen peroxide dropwise, keep warm for 3 hours after the dropwise addition, and cool To 20°C, neutralize pH 6-7.5 with 2.5M liquid caustic soda, filter with suction, and dry to obtain compound IV (50.9 g, 0.3 mol) with a yield of 91% and a purity of 99.2%.

[0051] (2) Synthesis of compound III

[0052]Add compound IV (20g, 0.12mol), methylamine (6.2g, 0.2mol) and tetrahydrofuran (100mL) into the reactor, heat the mixture to 110°C for 10h, add N,N-diiso Propylethylamine (23 g, 0.18 mol) was stirred for 2 hours and then filtered. The filtrate was concentrated until solids were precipitated, and left in the refrigerator overnight. After filtration, the filter cake was recrystallized with m...

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Abstract

The present invention relates to the technical field of pharmaceutical intermediates, in particular to a method for preparing a purine nucleotide intermediate, the synthetic route of which comprises the following steps: 1) chlorination reaction of raw material compound V and thionyl chloride / hydrogen peroxide reaction system , to obtain compound IV; 2) react compound IV with methylamine to obtain compound III; 3) react compound III and compound II under a catalyst to obtain compound I. The present invention improves the synthetic route of the purine nucleotide intermediate, methylamination first, and then addition deprotection, mild reaction conditions, simple operation, high yield and purity, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, in particular to a method for preparing a purine nucleotide intermediate used for HCV treatment. Background technique [0002] Hepatitis C (HCV) is an RNA single-stranded virus and a member of the genus Hepacivirus. It is estimated that 75% of all liver disease cases are caused by HCV. HCV infection can lead to cirrhosis and liver cancer, and if kept developing, can lead to liver failure requiring liver transplantation. Approximately 71 million people worldwide suffer from chronic HCV infection, and approximately 399,000 people die from HCV each year, mainly from cirrhosis and hepatocellular carcinoma. [0003] ((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxyl-4 -Methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester is a drug under research by Altea Pharmaceuticals. The drug is a novel phosphoramidate prodrug with strong ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H1/00C07H1/06C07H19/167
CPCC07H1/00C07H1/06C07H19/167
Inventor 石利平叶金星陈本顺徐春涛邱磊李大伟孙伟振程瑞华万新强江涛朱萍许鹏
Owner NANJING OCEAN PHARMA TECH