阅读说明：本技术 一种双乙酰鸟嘌呤反应终点判断和成品质量控制的方法 (Method for judging reaction end point of diacetylguanine and controlling quality of finished product ) 是由 徐诚 李晓晖 杨明高 汪宏福 于 2020-07-27 设计创作，主要内容包括：本发明属于双乙酰鸟嘌呤生产过程中质量控制技术领域,尤其为一种高效便捷的双乙酰鸟嘌呤反应终点判断和成品质量控制的方法,以鸟嘌呤为起始原料,以醋酐和醋酸混合物为酰化试剂和溶剂,在催化剂作用,升温至120-140度,反应生成双乙酰鸟嘌呤,取双乙酰鸟嘌呤样品(反应液需进行前处理)适量,用非质子溶剂配制成紫外分光光度法合适的范围内吸光度澄清溶液,用紫外分光光度计检测两处的处吸光度值,计算两种波长下吸光度比值,通过与合格双乙酰鸟嘌呤比较,本法根据鸟嘌呤反应生成双乙酰鸟嘌呤过程中其反应液吸光度出现红移这一发现,采用紫外双波长吸光度比值检测法对比合格成品可快速准确的对反应终点和成品质量进行控制。(The invention belongs to the technical field of quality control in the production process of diacetyl guanine, in particular to a method for efficiently and conveniently judging reaction endpoint and controlling the quality of a finished product of diacetyl guanine, which takes guanine as an initial raw material, takes a mixture of acetic anhydride and acetic acid as an acylation reagent and a solvent, heats the mixture to 140 ℃ under the action of a catalyst, reacts to generate diacetyl guanine, takes a proper amount of diacetyl guanine sample (reaction liquid needs to be pretreated), prepares an absorbance clarified solution in a proper range of an ultraviolet spectrophotometry by using an aprotic solvent, detects absorbance values at two positions by using an ultraviolet spectrophotometer, calculates absorbance ratio under two wavelengths, compares the absorbance ratio with qualified diacetyl guanine, finds that the absorbance of the reaction liquid appears red shift in the process of generating diacetyl guanine according to the reaction of guanine, and compares the absorbance of the qualified finished product by using an ultraviolet dual-wavelength ratio detection method to control the reaction endpoint and the quality of the finished product rapidly and accurately And (5) preparing.)

1. A method for judging the reaction endpoint of diacetylguanine and controlling the quality of finished products is characterized by comprising the following operation steps:

step (1): taking guanine as an initial raw material, taking a mixture of acetic anhydride and acetic acid as an acylation reagent and a solvent, heating to 120-140 ℃ under the action of a catalyst, carrying out acylation reaction to generate diacetyl guanine, taking a small amount of reaction liquid, cooling to 20-50 ℃, filtering to obtain a diacetyl guanine filter cake, washing with a small amount of acetic acid or acetic anhydride, and filtering to obtain a wet diacetyl guanine product;

the dried finished product can be directly carried out in the next step;

step (2): preparing a 0.2-0.7 absorbance clarified solution allowed by an ultraviolet spectrophotometry by using three solvents of acetonitrile, DMSO and DMF or two or three mixed solvents of the three solvents, detecting absorbance values at 306nm and 270nm by using an ultraviolet spectrophotometer or scanning at 250-350 wave band, and calculating absorbance ratio under two wavelengths (wave crest and wave trough);

and (3): detecting the absorbance ratio of the control diacetylguanine at two wavelengths by the same method, comparing the absorbance ratio with a sample, judging that the reaction is insufficient or the quality of the sample is unqualified if the value of the sample is less than the control, and judging that the reaction is sufficient and the quality of a finished product is qualified if the value of the sample is equal to or exceeds the control.

2. The method for judging the reaction endpoint of diacetylguanine and controlling the quality of finished products according to claim 1, wherein: the method is suitable for a synthesis line which takes guanine as a starting material and takes a mixture of acetic anhydride and acetic acid as an acylating reagent and a solvent, the reaction liquid needs to be cooled to 20-50 ℃, and a filter cake is washed by a small amount of acetic acid or acetic anhydride after filtration to obtain a wet product.

3. The method for judging the reaction endpoint of diacetylguanine and controlling the quality of finished products according to claim 1, wherein: the sample preparation solvent is acetonitrile, DMSO, DMF or a mixture of two or three of them, the ultraviolet spectrophotometer detects the absorbance values at two positions in the two ranges of wavelength 300-310nm and wavelength 268-278nm, and calculates the absorbance ratio at the two positions.

4. The method for judging the reaction endpoint of diacetylguanine and controlling the quality of finished products according to claim 1, wherein: and comparing the absorbance ratio of the sample at two wavelengths with a reference, if the absorbance ratio is smaller than the reference, judging that the reaction is insufficient or the quality of the sample is unqualified, and if the absorbance ratio is equal to or larger than the reference, judging that the reaction is sufficient or the quality of a finished product is qualified.

Technical Field

The invention belongs to the technical field of quality control in a diacetylguanine production process, and particularly relates to a method for judging reaction end point of diacetylguanine and controlling quality of a finished product.

Background

Diacetylguanine is an important intermediate of raw material medicines of a plurality of nucleotide analogues such as acyclovir, ganciclovir, valacyclovir hydrochloride and the like, a synthesis method taking guanine as an initial raw material is published, but reaction end point control and finished product quality control have no effective method all the time, monoacetylguanine and guanine are generated by rapidly deacylating in systems such as water, methanol, ethanol and the like due to extremely unstable properties, the purine ring structure is difficult to dissolve in most organic solvents, the end point control and the finished product quality are difficult to control by conventional methods such as a liquid phase and the like, the quality of the product can be evaluated by further synthesizing a next product, huge risks are caused for the production and process optimization of the product, and severe fluctuation of the quality of downstream products is also caused.

Disclosure of Invention

To solve the problems set forth in the background art described above. The invention provides a method for judging the reaction endpoint of diacetylguanine and controlling the quality of a finished product, which has the characteristics of rapidness and effectiveness.

In order to achieve the purpose, the invention provides the following technical scheme: a method for judging the reaction endpoint of diacetylguanine and controlling the quality of finished products comprises the following operation steps:

step (1): taking guanine as an initial raw material, taking a mixture of acetic anhydride and acetic acid as an acylation reagent and a solvent, heating to 120-140 ℃ under the action of a catalyst, carrying out acylation reaction to generate diacetyl guanine, taking a small amount of reaction liquid, cooling to 20-50 ℃, filtering to obtain a diacetyl guanine filter cake, washing with a small amount of acetic acid or acetic anhydride, and filtering to obtain a wet diacetyl guanine product. The dried finished product can be directly used for the next step.

Step (2): preparing clear solution with absorbance of 0.2-0.7 allowed by ultraviolet spectrophotometry with three solvents of acetonitrile, DMSO and DMF or two or three mixed solvents thereof, detecting absorbance values at 306nm and 270nm with an ultraviolet spectrophotometer, or scanning at 250-350 waveband, and calculating absorbance ratio at two wavelengths (peak and trough).

And (3): detecting the absorbance ratio of the control diacetylguanine at two wavelengths by the same method, comparing the absorbance ratio with a sample, judging that the reaction is insufficient or the quality of the sample is unqualified if the value of the sample is less than the control, and judging that the reaction is sufficient and the quality of a finished product is qualified if the value of the sample is equal to or exceeds the control.

Compared with the prior art, the invention has the beneficial effects that:

1. the existing liquid phase methods all use a reverse phase chromatography system, need to use a dry finished product, and use water or methanol and the like as a sample preparation solvent or a mobile phase can cause rapid decomposition of the diacetylguanine, so that a real result cannot be obtained, and the repeatability is poor.

2. The method can quickly and accurately control the quality of the diacetylguanine, cannot cause the diacetylguanine to decompose, and can be applied to the control of the reaction end point in the production process and the quality control of finished products.

Drawings

FIG. 1 is a graph of production 2005008 batches of spectral peak detection

FIG. 2 is a graph of production 2005009 batches of spectral peak detection

FIG. 3 is a spectrum peak detection chart of production qualified 2005006 control batch

FIG. 4 is a spectral peak detection plot of a 100% diacetylguanine sample 1 solution;

FIG. 5 is a spectral peak detection plot of a 100% diacetylguanine sample 2 solution;

FIG. 6 is a graph of the spectral peak detection of a 99% diacetylguanine 1% guanine sample 1 solution;

FIG. 7 is a graph of the spectral peak detection of a solution of 99% diacetylguanine 1% guanine sample 2;

FIG. 8 is a graph of 306/273nm absorbance ratio of guanine in 0, 1%, 2%, 3%, 4% and 5% test diacetylguanine sample solution;

FIG. 9 is a graph showing the 306/273nm absorbance ratio of a sample solution containing monoacetylguanine in 0, 1%, 2%, 3%, 4% and 5%.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Referring to the drawings, the present invention provides a technical solution: