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Technique for producing 2,6-dichlorine purine nucleosides by chemical synthesis method

A technology of dichloropurine nucleoside and dichloropurine nucleoside high-quality products, applied in the field of chemical synthesis production 2, can solve the problems of difficult separation, reduced yield, non-single aminolysis products, etc.

Inactive Publication Date: 2009-02-04
HENAN NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] The starting material of this method is rare and expensive nucleosides, and the ammonolysis product in the last step is not single and difficult to separate, so this method is not suitable for industrialization
[0018] In summary, among the methods of synthesizing 2,6-dichloropurine nucleoside reported internationally at present, none of the raw materials is easy to get, the process is reasonable, and it is suitable for industrial production. Alkaline conditions have been adopted, so it is very easy to cause the product to be not single, so the yield is reduced and the separation is difficult. Based on the above reasons and due to the needs of the market, we have developed a production method for synthesizing 2,6-dichloropurine nucleosides. New Technology

Method used

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  • Technique for producing 2,6-dichlorine purine nucleosides by chemical synthesis method
  • Technique for producing 2,6-dichlorine purine nucleosides by chemical synthesis method
  • Technique for producing 2,6-dichlorine purine nucleosides by chemical synthesis method

Examples

Experimental program
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Effect test

Embodiment 1

[0027] (1) Add 500Kg, β-D-1,2,3,5-tetraacetyl ribofuranose (II) into a 10,000-liter stainless steel reactor with stirring and heat to melt, then add 189Kg in batches under stirring 2,6 -dichloropurine (I) and 1.6kg of bis-p-nitrophenol phosphate, heated to reflux under stirring, connected to a vacuum to remove the acetic acid generated by the reaction in time, after the reaction was completed, remove the vacuum to obtain 2,6-dichloro-9 -(β-D-2',3',5'-triacetyl ribofuranose)purine (III) 371-402Kg, the conversion rate is 83-90%.

[0028] (2) Add 371Kg (III) and 2200 liters of methanol into a 10,000-liter stainless steel reactor with stirring, add concentrated hydrochloric acid 4 dropwise at 0°C-5°C, keep the temperature and continue the reaction until the reaction is complete (1-4h ), continue to keep the temperature at 0°C-5°C, add solid NaHCO3 to adjust to pH=7. Suction filtration under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure to o...

Embodiment 2

[0030] (1) Add 321Kg, β-D-1,2,3,5-tetraacetyl ribofuranose (II) and 600 liters of dichloroethane in a 10,000-liter stainless steel reactor with stirring, and add in batches under stirring 189Kg2, 6-dichloropurine (I) and 1.6kg bis-p-nitrophenol phosphonate are heated to reflux under stirring, after the completion of the reaction, connect the vacuum to remove the acetic acid generated by the solvent and the reaction, and after vacuum drying, get 2 , 6-dichloro-9-(β-D-2′,3′,5′-triacetyl ribofuranose)purine (III) 304-344Kg, the conversion rate is 68-77%.

[0031] (2) Add 304Kg (III) and 2000 liters of methanol into a 10,000-liter stainless steel reactor with stirring, add concentrated hydrochloric acid 4 dropwise at 0°C-5°C, keep the temperature and continue the reaction until the reaction is complete (1-4h ), continue to keep the temperature at 0°C-5°C, add solid NaHCO3 to adjust to pH=7. Suction filtration under reduced pressure, and the filtrate was concentrated to dryness un...

Embodiment 3

[0033] (1) Add 500Kg, β-D-1,2,3,5-tetraacetyl ribofuranose (II) into a 10,000-liter stainless steel reactor with stirring and heat to melt, then add 189Kg2,6- Dichloropurine (I) and 1.8kg of two p-fluorophenol phosphates were heated to reflux under stirring, and the acetic acid generated by the reaction was removed in time by vacuuming, and after the reaction was completed, the vacuum was removed to obtain 2,6-dichloro-9- (β-D-2', 3', 5'-triacetyl ribofuranose) purine (III) 286-344Kg, the conversion rate is 64-77%.

[0034] (2) Add 286Kg (III) and 1900 liters of methanol into a 10,000 liter stainless steel reactor with stirring, add concentrated hydrochloric acid 4 dropwise at 0°C-5°C, keep the temperature and continue the reaction until the reaction is complete (1-4h ), continue to keep the temperature at 0°C-5°C, add solid NaHCO3 to adjust to pH=7. Suction filtration under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure to obtain off-wh...

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Abstract

The invention discloses a manufacturing method of 2, 6-dichloropurine nucleoside, which comprises the following steps: 1) placing beta-1, 2, 3, 5-tetraacetyl furan ribonucleic acid and organic solvent into reacting autoclave; stirring; adding 2, 6-dichloropurine and phenolic ester phosphate compound catalyst batch by batch; heating to reflux; removing solvent and reacted acetic acid in the vacuum; obtaining 2, 6-dichlorine-9-(beta-D-2', 3' 5'-triacetyl furan ribonucleic acid) purine; 2) placing 2, 6-dichlorine-9-(beta-D-2', 3' 5'-triacetyl furan ribonucleic acid) purine and carbinol into autoclave; dripping condensed alcaine under 0-5 deg.c; keeping the temperature; adding solid alkaline to adjust pH value to 6.5-7.5; decompressing; sucking; condensing; obtaining the product.

Description

Technical field: [0001] The invention relates to a synthesis process of organic compounds, in particular to a process for producing 2,6-dichloropurine nucleoside by chemical synthesis. Background technique: [0002] 2,6-dichloropurine riboside (2,6-dichloropurine riboside) itself is a good antitumor drug, and it is also a good intermediate for antibacterial, antiviral and antitumor drugs. For example, 2-chloroadenosine and 2-amino-6-chloropurine nucleoside produced from 2,6-dichloropurine nucleoside have good medicinal value. Studies in recent years have shown that 2-chloroadenosine has anti-epileptic and potent expansion of coronary arteries, and can be used to treat angina pectoris, myocardial infarction, coronary insufficiency, arteriosclerosis, essential hypertension, cerebrovascular disorders, and sequelae of stroke and progressive myocardial atrophy. Takuma; JamesA et al's research shows that: 2-amino-6-chloropurine nucleoside has the function of inhibiting infection...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/167C07H1/00
Inventor 渠桂荣杨西宁郭海明蔡玉英何元庆王秀强徐绍红李建平
Owner HENAN NORMAL UNIV
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