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Preparation method of acyclovir intermediate N(2),9-diacetyl guanine

A technology for diacetylguanine and intermediates, which is applied in the field of preparation of N,9-diacetylguanine, an intermediate of acyclovir, can solve the problems of high safety risks, low product quality, and large amount of "three wastes". Achieve the effect of low safety risk, low raw material cost and stable product quality

Active Publication Date: 2020-10-16
潍坊奥通药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Aiming at the problems of low product quality, high safety risk and large amount of "three wastes" existing in the traditional process, the present invention provides a new preparation method with the advantages of environmental protection, low safety risk, high product yield and excellent quality.

Method used

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  • Preparation method of acyclovir intermediate N(2),9-diacetyl guanine
  • Preparation method of acyclovir intermediate N(2),9-diacetyl guanine
  • Preparation method of acyclovir intermediate N(2),9-diacetyl guanine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Dissolve 50g of 2,4-diamino6-hydroxy-5-carboxamidopyrimidine (MW169.14, 0.30mol) in 100g of acetic acid (MW60.05, 1.66mol), slowly raise the temperature to 60-70°C, and control the temperature At 60-70°C, slowly add 86g of 80% acetic anhydride acetic acid solution (MW102.09, 0.67mol) dropwise, and the dropping time is controlled at 6h.

[0055] After dropping, begin vacuum distillation to reclaim the acetic acid solvent. After concentrating to dryness, about 60.9 g of the concentrated residual solid is obtained, which is 2-acetylamino-4-amino-6-hydroxyl-5-formamidopyrimidine (II). The yield is about 96.1%, and the purity is 98.2%. Recovery of acetic acid can be applied repeatedly.

[0056] Add 5g of catalyst A (sodium acetate) and 300g of xylene to compound (II), start stirring and heating, raise the temperature to 125-135°C, reflux for dehydration reaction for 14h, when no obvious water droplets are produced in the water separator, the reaction ends. Begin to cool do...

Embodiment 2

[0060] Dissolve 50g of 2,4-diamino6-hydroxy-5-carboxamidopyrimidine (MW169.14, 0.30mol) in 120g of recovered acetic acid (MW60.05, 1.66mol), slowly raise the temperature to 60-70°C, and control At a temperature of 60-70°C, slowly add 85g of 85% acetic anhydride acetic acid solution (MW102.09, 0.71mol) dropwise, and the dropping time is controlled at 7h.

[0061] After dropping, begin vacuum distillation to reclaim the acetic acid solvent. After concentrating to dryness, about 60.5 g of the concentrated residual solid is obtained, which is 2-acetylamino-4-amino-6-hydroxyl-5-carboxamidopyrimidine (II). The yield is about 95.5%, and the purity is 98.5%. Recovery of acetic acid can be applied repeatedly.

[0062] Add 5g of catalyst A (tetrabutylammonium bromide) and 300g of recovered xylene to compound (II), start stirring and heating, raise the temperature to 115-125°C, reflux for dehydration reaction for 15 hours, when there are no obvious water droplets in the water separator ...

Embodiment 3

[0064] Dissolve 50g (MW193.16, 0.26mol) of 2-acetylamino-6-hydroxypurine (Ⅲ) and 3g of sodium acetate in 500g of 75% acetic anhydride in acetic acid solution (MW102.09, 3.67mol), start stirring and heating, and heat up to 125-135°C and react for 8 hours.

[0065] After the reaction is complete, cool down to 5-15°C, heat and crystallize for 2 hours, filter, and dry to obtain about 59.9 g of off-white crystalline solid powder, which is N(2), 9-diacetylguanine (IV), with a molar yield of 98.0 %, purity 99.1%. After detecting the acetic anhydride content in the filtered mother liquor, it can be applied mechanically directly or after recovering acetic acid by distillation, and then applied mechanically to step (1).

[0066] The N(2),9-diacetylguanine structure analysis data prepared in this example are as follows:

[0067] ESI-MS (M / Z): The ion peak at m / z236 in the ESI-MS positive ion mass spectrum corresponds to the [M+H]+ ion of the sample, and the stronger ion peak at m / z194 ...

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Abstract

The invention discloses a preparation method of an acyclovir intermediate N(2),9-diacetyl guanine, which comprises the following steps: dissolving 2, 4-diamino-6-hydroxy-5-formamido pyrimidine in acetic acid, dropwisely adding an acetic anhydride acetic acid solution, and carrying out selective acylation reaction to obtain 2-acetamido-4-amino-6-hydroxy-5-formamido pyrimidine; carrying out cyclization reaction on 2-acetamido-4-amino-6-hydroxy-5-formamido pyrimidine under the action of a catalyst A to obtain 2-acetamido-6-hydroxypurine; subjecting 2-acetamido-6-hydroxypurine to an acylation reaction in an acetic anhydride and acetic acid mixed solvent under the action of a catalyst C, and obtaining N(2),9-diacetyl guanine. Compared with a traditional process, the synthesis process has the advantages that a large amount of water is not introduced, a large amount of inorganic salt is not generated, used solvents can be recycled, the process is simple and convenient to operate, the productyield is slightly higher than that in the prior art, and the quality meets the corresponding quality standard.

Description

technical field [0001] The invention belongs to the technical field of preparation of intermediates of antiviral drugs of the Aciclovir class, and in particular relates to a preparation method of N(2), 9-diacetylguanine, an intermediate of Acyclovir. Background technique [0002] Clovir drugs, mainly including acyclovir, ganciclovir, valacyclovir and faciclovir, are broad-spectrum antiviral drugs. It is clinically used to treat herpes simplex and diseases related to HSV infection, such as erythema multiforme, herpes zoster, first and recurrent genital herpes, HSV encephalitis, chickenpox, herpes zoster and VZV encephalitis, AIDS, Pneumonia, enteritis and retinitis caused by severe CMV infection in organ transplantation and malignant tumor patients. [0003] The synthesis method of N(2), 9-diacetylguanine, the traditional synthesis method is mainly based on acetylation reaction of guanine or guanosine as raw material. This process has also been industrialized for decades. T...

Claims

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Application Information

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IPC IPC(8): C07D473/32
CPCC07D473/32
Inventor 晏金华刘晓磊张帅魏海鹏章纯斌
Owner 潍坊奥通药业有限公司
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