CN114388071A

CN114388071A - Method and device for managing compound synthesis path and storage medium

Info

Publication number: CN114388071A
Application number: CN202111673476.8A
Authority: CN
Inventors: 倪晓姗; 魏巍; 包卿; 郝华
Original assignee: Mingdu Zhiyun Zhejiang Technology Co Ltd
Current assignee: Mingdu Zhiyun Zhejiang Technology Co Ltd
Priority date: 2021-12-31
Filing date: 2021-12-31
Publication date: 2022-04-22
Anticipated expiration: 2041-12-31
Also published as: CN114388071B

Abstract

The invention discloses a management method, a device and a storage medium of a compound synthesis path, which are characterized in that main and auxiliary reactants and information of each reaction parameter are input into a cell corresponding to a primary reaction of a drug synthesis process feeding table, a compound database is called to inquire each reaction formula which can be matched, main products and by-products of the selected reaction formula are input into a corresponding product cell, then products of a previous stage reaction are obtained as the reactants of the current stage and are input into the reactant cell of the current stage, and the main and auxiliary products of the current stage reaction are generated according to the selected other reactants and the information of the reaction parameters and are input into the product cell of the current stage until the configuration of the process feeding table is completed. The management method of the compound synthesis path can greatly shorten the configuration time of the compound synthesis path feeding table and effectively improve the working efficiency and scientific research output of experimenters.

Description

Method and device for managing compound synthesis path and storage medium

Technical Field

The invention relates to the technical field of medicine informatization, in particular to a method and a device for managing a compound synthesis path and a storage medium.

Background

Drug development is a long process, and the dilemma of long development period, low development achievement rate and high development cost exists. The process route of drug research and synthesis is the most important link in the drug research and development process, and in the process of drug imitation research, a sample with parameters consistent with those of a reference substance is obtained through multi-stage chemical reaction. To obtain a drug effect consistent with that of a reference preparation, a final appropriate drug synthesis process route can be found through continuous repeated synthesis and analysis verification, and a foundation is laid for subsequent process amplification. In the existing research and development work of medicine enterprises, repeated experiments are carried out for many times by depending on researchers to obtain the optimal medicine synthesis process route, so that the optimal solution of the process route is found, the research and development time and the sample quality are difficult to guarantee, and a large amount of reagent and reactant costs are consumed. When an experimenter makes a synthetic route of a pharmaceutical compound, reaction data of each step before and after the process, including complex information such as main reactants, side reactants, main products, byproducts, reaction condition parameters of the stage, catalysis condition parameters and the like, are required to be manually input in a synthetic route process table, and the input information is complex and tedious and is easy to make a business trip.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a management method of a compound synthesis path, which comprises the following steps:

s1, acquiring main and side reactants and reaction parameter information input into a cell corresponding to a primary reaction of a drug synthesis process feeding table, calling a compound database to inquire each reaction formula which can be matched, and inputting a main product and a side product of the selected reaction formula into a corresponding product cell of the step, wherein the reaction parameter information comprises reaction condition parameters and catalysis condition parameters;

s2, acquiring a main product or a by-product in the previous stage reaction as a reactant of the stage reaction, recording the reactant into a reactant cell of the stage reaction, generating a main and an auxiliary product of the stage reaction according to the selected other reactants and reaction parameter information, and inputting the main and auxiliary product into the stage product cell;

and S3, obtaining reaction information of each stage after the configuration of the process feeding table is completed, and generating a compound synthesis path formed by the association of the front and the back of the multi-stage chemical reaction.

Preferably, the step S2 specifically includes:

acquiring at least one product information in the previous stage of reaction as a main reactant of the current stage of reaction and recording the information into a reactant cell of the current stage of reaction; after action instructions on the rest of the spare reactant cells are detected, main reactant information in other recorded reactant cells of the reaction is obtained, a compound database is searched according to the main reactant, each side reactant which can carry out chemical reaction with the main reactant is obtained by traversing the compound database, and an alternative side reactant group corresponding to the spare reactant cells is generated.

Preferably, the drug synthesis process feeding table is configured to arrange chemical reaction information of each level before and after the drug synthesis process in sequence from top to bottom in each row of the table according to the sequence before and after the reaction, and the main and side reactant information, the main and side product information and the reaction parameter information of each level of reaction are all correspondingly arranged in each cell in the same row.

Preferably, the step S2 specifically includes:

after detecting the translation instruction of the whole line of data, judging whether the reactant unit cells of the line to be moved have the same compound as that in at least one product unit cell in the line at the target position;

if the data exists, the moving line is inserted into the target position of the feeding table, the original target position data and the data of each line below are moved downwards by one line, and otherwise, the data of each line is refused to be moved;

after the moving line is inserted into the target position of the feeding table, judging whether the same compound as that in at least one reactant unit cell in the next line of the target position exists in the product unit cell of the moving line, and if so, finishing the line data translation response; otherwise, adjusting the information in the reactant unit cells in the next row, and readjusting the reactants and the products in the subsequent rows.

Preferably, the step S2 specifically includes:

after detecting the line inserting command, moving the original target position data and the data of each line below downwards by one line;

acquiring the information in each product cell in a row at a target position as a first compound group, and acquiring the information in reactant cells at the original target position as a second compound group;

searching reaction formula information in a compound database, and acquiring a correlation chemical formula with at least one compound in a first compound group as a reactant and at least one compound in a second compound group as a product;

and taking the reactant information corresponding to each searched associated chemical formula as an alternative reactant group recorded in the reactant unit cell of the insertion row, taking the corresponding product information as an alternative product group input into the product unit cell of the insertion row, acquiring the corresponding product information in the alternative product group after confirming the reactant in the reactant unit cell, and supplementing the corresponding product information into the product unit cell of the insertion row.

Preferably, the step S2 specifically includes:

checking newly added row data in the feeding table to obtain newly added reactant cell information and product cell information in the feeding table;

judging whether a compound which is the same as at least one product in the product cell of the previous line exists in the newly added reactant cell, if not, marking the newly added reactant cell and the product cell of the previous line;

and judging whether a compound which is the same as at least one reactant in the reactant cell in the next row exists in the newly added product cell, and if not, marking the newly added product cell and the reactant cell in the next row.

The invention also discloses a management system of the compound synthesis path, which comprises the following components: the first reaction creating module is used for acquiring main and auxiliary reactants and information of each reaction parameter input into a cell corresponding to a primary reaction of a drug synthesis process feeding table, calling a compound database to inquire each reaction formula which can be matched, and inputting a main product and a side product of the selected reaction formula into a corresponding product cell of the step, wherein the reaction parameter information comprises a reaction condition parameter and a catalysis condition parameter; the second reaction creating module is used for acquiring a main product or a byproduct in the previous stage reaction as a reactant of the current stage reaction, inputting the reactant into a reactant cell of the current stage reaction, generating a main byproduct of the current stage reaction according to the selected other reactants and reaction parameter information, and inputting the main byproduct into the product cell of the current stage; and the path information module is used for acquiring reaction information of each level after the configuration of the process feeding table is completed and generating a compound synthesis path formed by the association of the front and the back of the multi-level chemical reaction.

Preferably, the second reaction creating module includes: the main reactant generating module is used for acquiring at least one product information in the previous stage reaction as a main reactant of the current stage reaction and inputting the main reactant into the reactant cell of the current stage reaction; and the secondary reactant generation module is used for acquiring main reactant information in other recorded reactant cells of the level of reaction after detecting action instructions on the rest of spare reactant cells, searching the compound database according to the main reactant, traversing the compound database to acquire each secondary reactant which can perform chemical reaction with the main reactant, and generating an alternative secondary reactant group corresponding to the spare reactant cells.

The invention also discloses a management device of the compound synthesis path, which comprises a memory, a processor and a computer program stored in the memory and capable of running on the processor, wherein the processor executes the computer program to realize the steps of the management method of the compound synthesis path.

The invention also discloses a computer-readable storage medium storing a computer program which, when executed by a processor, implements the steps of the method for managing the synthesis pathway of a compound as described above.

The invention discloses a management method, a device and a storage medium of a compound synthesis path, and provides an intelligent entry method of a compound synthesis path feeding table for drug experimenters. Therefore, the configuration time of the feeding table of the synthetic route of the medicine compound is greatly shortened, and meanwhile, optimal reaction information at all levels can be recommended to be input into the feeding table of the synthetic route according to the process data of the compound database, so that the working efficiency and scientific research output are effectively improved.

Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.

Drawings

The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the invention and together with the description serve to explain the invention without limiting the invention. In the drawings:

FIG. 1 is a schematic flow diagram of a method for managing the synthetic pathway of a compound according to one embodiment.

FIG. 2 is a schematic diagram of a portion of a dosing table for a drug synthesis process according to an embodiment disclosed herein.

FIG. 3 is a schematic diagram of an exemplary disclosed compound database.

Fig. 4 is a schematic flowchart of step S2 according to an embodiment.

Fig. 5 is another specific flowchart of step S2 according to the embodiment disclosed.

Fig. 6 is another specific flowchart of step S2 according to the embodiment disclosed.

Fig. 7 is a flowchart illustrating the genetic algorithm of step S4 disclosed in the examples.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the drawings of the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention.

In the present invention, unless otherwise specifically defined and limited, technical or scientific terms used herein shall have the ordinary meaning as understood by those of ordinary skill in the art to which the present invention belongs. The use of "first," "second," and similar terms in the description and claims of the present application do not denote any order, quantity, or importance, but rather the terms are used to distinguish one element from another. Also, the use of the terms "a" or "an" and the like do not denote a limitation of quantity, but rather denote the presence of at least one.

In the process of researching the imitation drugs, in order to obtain a sample with parameters consistent with those of a reference substance, a multi-step reaction is carried out, a product of the reaction can be used as a reactant of the next step reaction, and the most appropriate synthesis process route of the drug compound can be obtained through the research of various process routes. At present, the drug research and development experimental process is generally divided into four steps, including experimental scheme design, experimental execution, experimental result analysis, summary and report. Outputting an experimental scheme design according to related data of preliminary investigation and query, such as pharmacopoeia, documents, historical data and an external related database, and carrying out experiments according to the experimental scheme design, wherein the experimental conditions and the experimental process records are included. And subsequently, analyzing the experiment result according to the original data, the calculation result, the audit record, the comment, the rechecking result and the like of the experiment record, and outputting a final experiment report. At present, when an experimenter makes a synthetic route of a medicine compound, reaction data of each step before and after the process is required to be manually input in a synthetic route process table, the reaction data comprises complex information of main reactants, side reactants, main products, byproducts, reaction condition parameters of the stage, catalysis condition parameters and the like, and the input information is complex and tedious and is easy to go on business.

The embodiment discloses a management method of a compound synthesis path, which can be used in a feeding table configuration unit in various compound synthesis software such as a drug research and development auxiliary system. As shown in FIG. 1, the method for managing the synthetic pathway of the compound may comprise the following steps.

Step S1, obtaining main and side reactants and each reaction parameter information input in the corresponding cell of the primary reaction of the drug synthesis process feeding table, calling a compound database to inquire each reaction formula which can be matched, and inputting the main product and the side product of the selected reaction formula into the corresponding product cell of the step, wherein the reaction parameter information comprises reaction condition parameters and catalysis condition parameters.

As shown in fig. 2, the feeding table of the pharmaceutical synthesis process is configured to arrange chemical reaction information of each level before and after the pharmaceutical synthesis process in sequence from top to bottom in each row of the table, and the main and side reactant information, the main and side product information, and the reaction parameter information of each level of reaction are all arranged in each cell in the same row correspondingly. The feeding table presents specific information of each step in the drug synthesis process route in a table form, for example, each main and side reactant, main and side product, catalytic condition parameter and reaction condition parameter of the primary reaction in the synthesis process route are recorded and presented in units of rows or columns. The arrangement sequence of each row or each column can be used as the front-back sequence of each stage of reaction of the synthesis process route. In this embodiment, the step may specifically include the following. In this embodiment, the step S1 may further include the following steps.

Step S11, establishing a compound database, wherein the compound database comprises basic data of chemical structural formula and basic reaction formula data, and the basic reaction formula data comprises but is not limited to main and side reactants, main and side products, reaction condition parameters and catalytic condition parameters. In this embodiment, as shown in fig. 3, the compound database of the present system is built mainly by three ways, i.e., docking the external compound database, self-constructing MarvinJS, and importing ELN experimental record data. The step S11 may specifically include content.

And step S111, an external compound database is connected, and the basic data of the chemical structural formula of each compound is obtained through CAS number and/or structural formula retrieval. Docking to an external compound database, e.g., PubChem: a free use database for storing the chemical structural formula of the small molecule and the biological activity information thereof, and similarly, data sources such as PharmaPendium, animalTFDB and the like are also provided, and after the interfaces are connected, corresponding compounds are searched through CAS numbers, structural formulas and the like.

Step S112, a compound that is not present in the desired database is created by the editor, to which attributes of the reactants, catalysts and/or products are assigned and corresponding CAS number and Smiles strings are generated and saved to the compound database.

Specifically, the compound structural formula can be manually created through a MarvinJS structural formula editor, and a corresponding CAS number and Smiles character string can be generated. Where Smile is a simplified molecular language, a linear symbol used to input and represent molecular reactions, is an ASCII code, and Smiles structures are used to store chemical information and chemical information. Various chemical equations may be drawn simultaneously, including reactants, catalysts, and products. In addition, the compound data of the system can be quoted in an editor, and the artificially created structural formula, the artificially created product and the like are stored in a database, so that the subsequent optimization analysis and use are facilitated.

The chemical formula created using the MarvinJS structural editor tool does not require additional reformatting. The structural formula imported from other external editors can be imported through format files such as xml and MOL, format conversion is required, the structural formula is generally content uniquely identified by smiles format character strings or Inch key, structural formula structure-activity relationship checking can be performed in the process, for example, common composition checking of rings, functional groups, groups and repeated groups is performed, and the correction of error conditions such as loss of reaction conditions and reaction relationships in the reaction formula caused by the imported format conversion is very helpful. The compound database of the system itself can be directly formed by importing functions, compound registration, and reactive registration.

And S113, acquiring experiment record data in the electronic experiment record system, carrying out data structuralization processing on the experiment record data, splitting and classifying the experiment record data, and classifying and recombining the data according to a preset rule and the same yield range, the same reaction type, the same reactant and/or the same product.

The electronic experiment recording system ELN is used for facilitating researchers to record experiment data in time, an experiment recording module of the electronic experiment recording system ELN comprises rich texts, structural formulas, spreadsheets, calculation formulas, accessories, experiment instruments, experiment materials and other forms, and data formats are basically in standard character strings, numbers and other formats. In the step, various ELN systems can be connected through a background interface, required electronic experiment record data is obtained and then subjected to data structuring, and then the front end is subjected to splitting, classifying and recombining display. The splitting operation can be marked according to the splitting of data types, character strings, characters and the like. The classification operation can be classified and filed according to the same type of data and the same type of labels. The recombination operation can automatically recombine various data types according to the preset rule of the system to form a module meeting the patent requirement. The preset rules include the following categories: reaction structure, reaction yield, reaction solvent, reagent catalyst, reaction time, reaction temperature, reaction pressure, reaction type and the like. The reactions with the same yield range, the same reaction type, the same substrate, the same product and other conditions are classified together, and the evaluation of a drug laboratory technician is facilitated.

In this embodiment, the step S11 may further include: the compound types in the compound database are classified differently according to the physicochemical properties of the compounds, wherein the physicochemical properties of the compounds comprise but are not limited to high boiling point, medium boiling point and low boiling point, and the compounds are classified according to the catalytic types, wherein the catalytic types comprise but are not limited to heterogeneous catalysis and biological catalysis. And simultaneously generating an identity number for the compound in the compound database, wherein the identity number comprises a classification code, time information and a flow code. Specifically, the classification is made according to the kind of the compound, and includes classification according to physicochemical properties of the substance, such as a high boiling point, a medium boiling point, and a low boiling point; classifying according to the physical state of the substance, such as properties of liquid, solid and the like; the method is characterized in that the method is classified according to the catalytic types including heterogeneous catalysis, biological catalysis and the like, each type is endowed with a unique code, a unique number is automatically generated for the classified compounds in the system, the numbering rule can be classification code + year, month and day + number of running water level, the running water code is reset according to the day, the running water level overflow is avoided, each reactant and each catalyst have the unique code and can be associated when a process route is formed by combination, and the method is convenient to quote, pair and inquire.

The database is integrated with compound data, structural formula data, reaction formula data, and the like. Through the steps, the construction of a basic part, namely a compound database, in the compound synthesis path management method is realized, and data support is provided for the development of the subsequent steps.

And step S12, carrying out material balance on the chemical reaction processes in the compound database, and recording the product yield or yield in each chemical reaction into the corresponding reaction formula of the compound database. In this example, compound dosing was performed with the following computational logic formula for automatic mass balance:

the field calculation formula of each material is as follows: theoretical charge amount is MW mol amount; actual feeding amount is the theoretical feeding amount/purity; actual charge amount is VOL × density; molarity ═ molar weight/volume.

Logic between materials: b molar weight/a molar weight ═ b.eq/a.eq; the molar weight of the output is also the same logic.

The step S12 may further include: the compound database judges the product yield, the yield and the catalytic condition parameters corresponding to each chemical reaction formula obtained from the electronic experiment recording system, and gives an alarm if the product yield, the yield and the catalytic condition parameters are larger than a preset range; if the data is in the preset range, comparing each input data with the theoretical value of the data, and adjusting the parameters according to the preset proportion until the relative average deviation of the adjusted parameters relative to the previous adjusted value is lower than the preset value.

Specifically, the specific processes of setting the standard threshold of the input value, early warning and automatic adjustment are as follows: in the center of basic setting, the nominal unit of parameters such as reactants, catalysts and the like and the upper and lower limits of the design range can be configured. When the experimenter actually fills in the process or the value calculated according to the reaction formula exceeds the design range, the experimenter can give out a highlight early warning and other prompts. For the calculated result, the system is designed with a set of numerical feedback compensation mechanism, the deviation F between the result and the theoretical design is adjusted correspondingly in the design range of the parameters in proportion, and the relative average deviation F compared with the previous time is calculated every time of adjustment until the relative average deviation F is close to a stable value or within the actually specified deviation range, namely the acceptable range of a designer. Enough samples are provided for the compensation mechanism in subsequent reaction and mass data to reach the degree close to the perfection

The step S12 further includes determining the input reactant attribute information, and if the input reactant attribute information is a first attribute, where the first attribute is a molar quantity, an actual charge quantity, a theoretical charge quantity, or a purity, entering a first attribute obtaining mode and stopping the input of second attribute information, where the first attribute obtaining mode includes:

if the input is the molar weight, the theoretical feeding amount is automatically calculated, the actual feeding amount is automatically calculated when a purity value exists, and the actual feeding amount is calculated according to the purity of 100% when no purity value exists.

If the theoretical feeding amount is input, the molar amount is automatically calculated, the actual feeding amount is automatically calculated when a purity value exists, and the actual feeding amount is calculated according to the purity of 100% when no purity value exists.

If the purity is input, automatically calculating the actual feeding amount when the theoretical feeding amount exists, or automatically calculating the theoretical feeding amount when the actual feeding amount exists, and if the theoretical feeding amount and the actual feeding amount both exist, changing the theoretical feeding amount according to the purity.

If the actual input is the actual input, the theoretical input is calculated when the purity exists, or the purity is automatically calculated when the theoretical input exists, if the purity and the theoretical input exist, the theoretical input is changed according to the purity, and if the purity and the theoretical input do not exist, the theoretical input is calculated according to the purity of 100%.

If the theoretical material charge is input, the actual material charge is calculated when the purity exists, or the purity is automatically calculated when the actual material charge exists, if the purity and the actual material charge exist, the actual material charge is changed according to the purity, and if the purity and the actual material charge do not exist, the actual material charge is calculated according to the purity of 100%.

Specifically, when the manual input field is the molar quantity, the actual feeding quantity, the theoretical feeding quantity and the purity, the mode is the quality mode, and in the mode, density information in the volume field is automatically calculated, and the density information is emptied if the density information is not in the volume field. Specifically, when the molar weight is input, the theoretical charge amount is automatically calculated, because the MW is unchanged, the actual charge amount is automatically calculated according to the purity, and if the purity information column is empty, the actual charge amount is calculated according to the purity of 100%. When the theoretical feeding amount is input, the molar weight is automatically calculated, and the actual feeding amount is automatically calculated according to the purity. When the purity is input, if the theoretical feeding amount exists, the actual feeding amount is automatically calculated, if the theoretical feeding amount exists, the theoretical feeding amount is automatically calculated, if both the theoretical feeding amount and the theoretical feeding amount exist, the logic of unchanging the actual feeding amount is adopted, and if both the theoretical feeding amount and the theoretical feeding amount are empty, the theoretical feeding amount and the theoretical feeding amount are not processed. When inputting the actual input, calculating the theoretical input if there is purity, automatically calculating the purity if there is theoretical input, if there is both, then calculating the theoretical input according to the logic that the purity is not changed, if both are empty, then calculating the theoretical input according to the purity of 100%. When inputting the theoretical input amount, if there is actual input amount, then automatically calculating the purity, if there is purity, then automatically calculating the actual input amount, if there are both, then the purity is not changed, if both are empty, then calculating the actual input amount according to the purity of 100%.

In this embodiment, step S12 further includes determining the input reactant attribute information, and if the input reactant attribute information is a second attribute, entering a second attribute obtaining mode and stopping the input of the first attribute information, where the second attribute is a volume, a molar concentration, or a density, and the second attribute obtaining mode includes: if the input volume is the volume, automatically calculating the volume molarity, automatically calculating the actual feeding amount when the density value exists, calculating the theoretical feeding amount and the molarity according to the purity value, and emptying the stored actual feeding amount value when the density value does not exist; if the density is input, the actual feeding amount is automatically calculated when a volume value exists, and the theoretical feeding amount and the molar amount are calculated according to the purity value.

Specifically, when the input field is volume, molarity, or density, the input field is a volume mode in which the theoretical charge is emptied and the actual charge must be calculated by inputting the density. When the volume is input, the volume molarity is automatically calculated, if the density exists, the actual feeding amount is automatically calculated, then the theoretical feeding amount and the molarity are continuously calculated according to the purity, and if the density does not exist, the actual feeding amount is emptied. When inputting density, if the volume is not empty, the actual feeding amount is automatically calculated, and then the theoretical feeding amount and the molar amount are continuously calculated according to the purity. If the volume is empty, the volume is automatically calculated when the actual feeding amount is not empty, and the volume is not processed when the actual feeding amount is also empty.

And step S2, acquiring the main product or by-product in the previous stage reaction as the reactant of the stage reaction, recording the main product or by-product into the reactant cell of the stage reaction, generating the main and by-product of the stage reaction according to the selected other reactants and reaction parameter information, and inputting the main and by-product into the product cell of the stage.

In the previous step, a basic compound database has been established, which already contains basic data and basic reaction formulas of various compound structural formulas, i.e. contains objects participating in chemical reactions: the method comprises the following steps of firstly, quickly establishing a next reaction operation, and directly taking a product of the previous step as a reactant of the next step, wherein the main and side reactants, a reaction condition parameter, a catalysis condition parameter, a main and side product and the like are associated through compound identity numbers. Meanwhile, the system can directly recommend a plurality of suitable reactants, reaction conditions and catalysis conditions according to the reaction rules set in the library. Of course, manual intervention may still be performed at this time, and some of the condition parameters or reactants may be added or deleted as appropriate. For example, the system may automatically construct a set target for meeting, based on certain rules. For example, the reactants may be selected manually according to their physical and chemical properties, thermodynamic properties, crystal structure, separation and purification methods or conditions, etc., and then the route is re-established.

In the synthesis reaction, the product generated in the current experiment can be continuously subjected to the next reaction, so that the manual operation can be reduced by quickly establishing the experiment of the next reaction. The method comprises the steps of quickly creating an experimental record of the next reaction by synthesizing a product of a reaction formula, creating the experimental record under the same experiment, automatically adding a structural formula module, automatically including the product generated in the previous experiment in the structural formula, for example, including information such as reactant, molecular weight mw, molecular formula, cas number, batch number, source and the like, and realizing a synthetic general route by binding the reaction formula relationship in each step.

In this embodiment, as shown in fig. 4, the step S2 specifically includes:

and step S21, acquiring at least one product information in the previous stage reaction as the main reactant of the current stage reaction and recording the product information into the reactant cell of the current stage reaction.

Step S22, after detecting the action orders on the rest spare reactant cells, obtaining the main reactant information in other recorded reactant cells of the reaction, searching the compound database according to the main reactant, traversing the compound database to obtain each side reactant which can carry out chemical reaction with the main reactant, and generating the alternative side reactant group corresponding to the spare reactant cells. Specifically, upon detecting that the operator needs to input a side reactant, compound information in other entered reactant cells in the row is obtained, the compound database is searched to obtain reaction formulas that can form a reaction with the entered compounds, and the reactants not entered in the reaction formulas are used as alternative side reactant groups that can be selected by the operator as the optional reactants in the pull-down menu of reactant cells. In this step, it may further include: if the compound recorded in the vacant reactant unit cell is selected, the corresponding reaction formula has residual compound which needs to participate in the reaction but is not recorded in the row of reactant unit cells, a new vacant reactant unit cell is additionally inserted behind the row of reactant unit cells, and the residual unconjugated reactant is recorded in the unit cell.

In this embodiment, as shown in fig. 5, step S2 may further include the following specifically.

Step S101, after detecting the translation command of the whole line of data, judging whether the reactant unit cell of the line to be moved has the same compound with at least one product unit cell in the line at the target position.

And S102, if the data exists, inserting the moving line into the target position of the feeding table and moving the original target position data and the data of the following lines downwards by one line, otherwise, refusing to move the line of data.

Step S103, after the moving line is inserted into the target position of the feeding table, judging whether a compound which is the same as that in at least one reactant cell in the next line of the target position exists in the product cell of the moving line, and if so, finishing the line data translation response; otherwise, adjusting the information in the reactant unit cells in the next row, and readjusting the reactants and the products in the subsequent rows. Therefore, drug research personnel can quickly adjust the feeding table, conveniently adjust the sequence of each reaction step in the edited compound synthesis path, automatically detect the association between the adjustment step and the reaction of the front-stage step and the back-stage step, and readjust the reaction steps which cannot be associated.

In another embodiment, as shown in fig. 6, step S2 may further include the following specifically.

In step S201, after the line insertion command is detected, the original target position data and the following data of each line are moved downward by one line.

Step S202, obtaining the information in each product unit cell in a row on the target position as a first compound group, and obtaining the information in the reactant unit cell at the original target position as a second compound group.

Step S203 searches the reaction formula information in the compound database, and acquires a correlation chemical formula having at least one compound in the first compound group as a reactant and at least one compound in the second compound group as a product.

And step S204, using the retrieved reactant information corresponding to each associated chemical formula as an alternative reactant group recorded in the reactant unit cell of the insertion row, using the corresponding product information as an alternative product group input into the product unit cell of the insertion row, and acquiring the corresponding product information in the alternative product group and supplementing the corresponding product information into the product unit cell of the insertion row after confirming the reactant in the reactant unit cell.

The insertion instruction of the feeding table can conveniently insert a new reaction step into the edited compound synthesis path, automatically detect the association between the inserted new reaction step and the reactions of the previous and subsequent steps, alarm and automatically adjust the reactions which cannot be associated, and greatly facilitate the efficiency of experimenters for adjusting the compound synthesis path.

In another specific embodiment, step S2 may further specifically include:

step S301, calling a compound database to query a corresponding reaction formula according to initial reactant information, reaction condition parameters and catalysis condition parameters, and acquiring a main product and a byproduct of the reaction;

step S302, searching each reaction formula in a reactant database according to the information of the main product of the previous stage reaction, traversing each reaction formula taking the main product as the main reactant and taking the main reactant as a starting point, inquiring whether a product in the reaction formula is the reaction formula of the chemical formula of the required synthetic drug, and if so, inputting the basic reaction formula data of the reaction formula into alternative reaction formula data for selection; if not, continuously traversing all second-stage reaction formulas by taking all main products of the current-stage reaction formulas as reactants, inquiring whether reaction formulas with products as chemical formulas of synthetic drugs exist in the second-stage reaction formulas, and if so, recording all basic reaction formula data of the multi-stage reaction formulas into alternative reaction formula data for selection; otherwise, the third level is continuously traversed until no subsequent reaction formula exists or the preset level of the system is reached. Through the steps, the experimenter only needs to input the initial reactant and the final drug compound which is expected to be synthesized, the system can search all possible compound synthesis paths which take the reactant as one reactant in the synthesis path and finally generate the required drug compound from the chemical database, and the possible compound synthesis paths are selected by the experimenter, so that the working efficiency of the experimenter is effectively improved.

In this embodiment, the step S2 may further specifically include:

and checking the newly added row of data in the feeding table to obtain the newly added reactant cell information and product cell information in the feeding table.

And judging whether the newly added reactant unit cell has a compound which is the same as at least one product in the product unit cell in the previous row, and if not, marking the newly added reactant unit cell and the product unit cell in the previous row.

And judging whether a compound which is the same as at least one reactant in the reactant cell in the next row exists in the newly added product cell, and if not, marking the newly added product cell and the reactant cell in the next row. In this embodiment, the system can turn off the compound input auto-correlation function of the dosing table, and all rows can be self-input of reactants and products, as well as reaction conditions and catalytic conditions. And at the moment, the verification can be carried out at the end, a verification link of intermediate reactants and products is provided during the verification, and if the product of the previous step is not the reactant of the next step, the relevant cells which fail to pass the verification are highlighted. In particular, these calibration rules may also be set for the same selected reactants, and for automatic deduplication, for example, compounds with identical CAS numbers and identical structural formulas, and sometimes the same ring system, may have the same name but different CAS numbers and structural formulas. Errors such as mismatch of physicochemical parameters of the selected reactants, out of specification, etc., suggest that the reactants have boiling point, hydrophilicity, water solubility, etc. The separation and purification method does not meet the requirements and the like, and prompts are given, and automatic elimination or manual intervention is performed. When the substructures are retrieved and matched, the protection of the ring system prompts the experimenter to confirm.

According to the management method of the compound synthesis path disclosed by the embodiment, a drug experimenter provides an intelligent entry method of a compound synthesis path feeding table, and can automatically inquire a corresponding matched reaction formula in which a reactant can participate in a compound database according to initial reactant information input in a drug synthesis process feeding table, automatically enter a product of the selected reaction formula into a product unit cell corresponding to the reaction, simultaneously automatically inquire the compound database according to the initial reactant information in subsequent reactions at all stages, give a selectable reactant at the stage for the experimenter to select, automatically generate corresponding adaptive reaction condition parameters and corresponding catalytic condition parameters according to the selected reactant, and automatically complete entry of the reaction information at the stage of the feeding table by using the product of the reaction formula. Therefore, the configuration time of the synthetic path feeding table of the medicine compound is greatly shortened, and meanwhile, optimal reaction information at all levels can be recommended to be input into the synthetic path feeding table according to the process data of the compound database, so that the working efficiency and scientific research output are effectively improved.

In another specific embodiment, the step S3 may further include the following steps: and changing reaction condition parameters or catalysis condition parameters of all levels in each drug synthesis path, sequentially selecting the yield of the drug synthesis path under different parameters, and obtaining the drug synthesis path with the optimal yield and the corresponding reaction condition parameters and catalysis condition parameters to form the optimal drug synthesis process.

In this embodiment, in this step, a model of a compound synthesis path is constructed based on the above-mentioned compound database having complete basic data of chemical structural formula and basic reaction formula data, and the DOE experiment optimization design is performed according to conditions such as main reactant and catalyst, and the conditions such as product and yield are automatically calculated. The rules related to the calculation results can be reversely obtained according to a large number of sample calculation results provided by historical data, the optimal rules are obtained according to the calculated optimal results, and classification is carried out according to types to form a rule base. Subsequently, for different types of composite plans, corresponding optimization rules may be recommended. In addition, because the range covered by the number of samples is limited, which may cause a problem of a locally optimal solution, the corresponding rules and standards need to be adjusted and repaired. By continuously perfecting the rules and standards of the results, sufficient samples are provided for the compensation mechanism by mass data such as subsequent reaction type data and the like, so that the compensation mechanism reaches a near-perfect degree. The method can adopt an Elasticissearch professional search engine, utilize the powerful search function of the Elasticissearch engine, match with the modes of rolling and loading search results and the like, improve the search efficiency as much as possible and avoid the influence on the efficiency of mass data search.

Furthermore, in the step, an asynchronous iterative computation method can be adopted, the computation process is divided into a plurality of subdivision units, each unit participates in one computation, all iterations fluctuate within a certain upper and lower limit range and do not exceed a theoretical calibration range, for example, the deviation of any 30 iterative computations does not exceed 5%, and the computation efficiency can also be optimized by adjusting the iteration times and the unit density granularity.

Based on the drug synthesis path model initially obtained in step S3, the design variables are changed, a large number of models of different parameters under different conditions are solved, and different parameters are sequentially selected by the above-mentioned multiple combination modes of physicochemical characteristics, catalyst type, ring system, major-minor reaction type, crystal structure, thermodynamic characteristics, and the like. The method can effectively assist researchers to explore a wide design space and lay a foundation for SO (automatic Sequential Optimization). By carrying out gradient model and solving on the multivariable of the original model, the optimal scheme can be obtained by accurately solving. The sequential optimization method can automatically select an optimal scheme according to the constraint conditions.

In this embodiment, the step S4 further specifically includes: carrying out multi-group experimental division by taking main and auxiliary reactants, main and auxiliary products, reaction condition parameters and catalysis condition parameters as condition factors, setting the minimum particle size to be 1 equivalent and the number of samples to be N, equally dividing each factor into N parts, combining the conditions by an enumeration method, and respectively sequencing and combining other condition factors by taking one condition factor as a fixed value to form a sample.

The step S4 further includes obtaining a local optimal solution by population iterative computation using a genetic algorithm based on a preset factor range, an optimization objective function, and a compound database, as shown in fig. 7, which specifically includes: taking the product yield N and the yield d as expression forms of a genetic algorithm, adopting a {0,1} binary string to represent population individuals, and establishing a mapping relation between the population individuals and a gene form; acquiring the binary string coded in the step and randomly generating an initial population; selecting a group of individuals from the population randomly by adopting a fitness function Fit [ f (N, d) ] -f (N, d), taking the best individual as a father individual, and repeating the operation for multiple times until the selection is finished; and (3) crossing the single individuals, wherein the crossing range is [1, num ], num is the number of variables, and the variables are exchanged until the crossing point does not exceed the limit.

In this embodiment, the whole optimization procedure flow mainly includes the following four parts:

inputting and setting: the variable definition of the synthesis experiment plan comprises the factor definition and range setting of reactants, catalysts, temperature and humidity, main reaction and the like.

Output setting: the reaction product includes output factor type, evaluation baseline setting, theoretical yield, and optimization objective function determination.

Multiple groups of experimental schemes: and carrying out multiple groups of experimental division according to the reaction conditions and the range set by the factors. The basic conditions for the synthesis plan, the reactants, the catalyst, the environmental conditions, the main and side reaction settings, and other factors are set in advance, the minimum particle size is set to 1 equivalent, the number of samples is N, and each factor is divided into N parts.

The enumeration method combines various conditions, quickly matches the conditions, preferentially sorts reactants, conditions, catalysts and the like according to the formula conditions, can intervene in the later period by human to properly increase some actually required factors, and can know the contents of the subdivided combined units before the calculation is started.

Optimal solution of reaction output and determination of a synthetic general route: based on the set conditions, factor range, optimized objective function and basic database, the last step is performed. By utilizing the characteristics of the genetic algorithm and through population iterative computation, the local optimal solution can be optimized, and the genetic algorithm optimization method of the specific objective function comprises the following processes:

multivariate coding: the product yield N and the yield d are taken as expression forms of genetic algorithms, the mapping relation between the expression forms and the gene forms is established to be codes, and a {0,1} binary string is adopted to represent population individuals in the embodiment.

Planning an initial population: the binary string encoded by the multivariate encoding step randomly generates an initial population. In this embodiment, the initial population size is initially set to 20.

Fitness is as follows: the fitness function is formed by converting an objective function, and the fitness function adopted in the embodiment is as follows: fit [ f (N, d) ] -f (N, d).

Individual preference: randomly selecting a group of individuals from the population, taking the best individual as a parent, and repeating the operation for multiple times until the selection is completed.

Crossing individuals: in the embodiment, a single individual is crossed, the crossing range is [1, num ], num is the number of variables, and the variables are interchanged until the crossing point is not out of the limit.

Taking the parents of two 6-bit variables as an example, the following is shown:

assuming that the intersection is at bit 3, the two children generated after the intersection operation are as follows:

mutation operation: the population crossing operation causes the variation of the offspring individuals, and assuming that the variation rate is 0.01, the variable value of the individuals is randomly changed, and the variation of the fourth position of one individual is shown as follows.

And (3) convergence judgment: in the embodiment, the best and worst individuals are consistent as a convergence criterion, the optimization is ended, otherwise, the fitness step is carried out, and the next round of circulation is started. And partial parent individuals in the new population are replaced by partial excellent child individuals in the iterative process, so that the optimization performance of the genetic algorithm can be improved.

By using genetic algorithms to simulate natural selection, the problem can be solved by parallel computing, requiring only a small number of possibilities to be evaluated simultaneously.

The compound synthesis path management method disclosed in the above embodiment establishes a compound database including basic data of each chemical structural formula and basic reaction formula data by using a built-in chemical structural formula editor, a butt-joint electronic experiment recording system, and a third-party compound database, automatically performs a feeding reaction and material accounting based on the previously acquired compound and reaction formula data in the compound database, constructs a pharmaceutical compound synthesis path process route, and performs multiple sets of optimization by setting a reaction factor parameter range, an optimization object, boundary conditions, and the like, thereby completing modeling and optimization of the pharmaceutical compound synthesis process route. The problem of medicine researcher need consume a large amount of time in carrying out a large amount of repeated experiments in the research process to need to consume a large amount of reagents and raw materials when carrying out the technology improvement, lead to research and development cost height in the future is solved, provide the powerful guarantee for technology enlargies and optimization, effectively improved work efficiency and scientific research output.

In addition, the auxiliary drug development system applying the method can be used based on a browser end, and the constraint of a client side is eliminated. The method can record the data through electronic experiments, import the electronic experiment record data of other manufacturers, open an external compound database, the electronic experiment record and an independently established database, and compare and analyze the real data of experimenters, thereby verifying the reliability and the convergence of process route optimization, greatly reducing the time and the material cost in later-stage drug project development, and improving the success rate of synthesis output. By the compound synthesis path management method, the optimal solution of the synthesis reaction path can be found by the method before an experimental scheme is drawn up, and more possibility and prospect are provided for drug research and development; the time of relying on manpower, material to carry out the actual experiment has been reduced, has improved experimental efficiency, reduces repeated experiment, greatly shortens the research and development cycle.

In another embodiment, a system for managing a synthesis pathway of a compound is disclosed, comprising: the first reaction creating module is used for acquiring main and auxiliary reactants and information of each reaction parameter input into a cell corresponding to a primary reaction of a drug synthesis process feeding table, calling a compound database to inquire each reaction formula which can be matched, and inputting a main product and a side product of the selected reaction formula into a corresponding product cell of the step, wherein the reaction parameter information comprises a reaction condition parameter and a catalysis condition parameter; the second reaction creating module is used for acquiring a main product or a byproduct in the previous stage reaction as a reactant of the current stage reaction, inputting the reactant into a reactant cell of the current stage reaction, generating a main byproduct of the current stage reaction according to the selected other reactants and reaction parameter information, and inputting the main byproduct into the product cell of the current stage; and the path information module is used for acquiring reaction information of each level after the configuration of the process feeding table is completed and generating a compound synthesis path formed by the association of the front and the back of the multi-level chemical reaction.

Wherein the second reaction creation module comprises: the main reactant generating module is used for acquiring at least one product information in the previous stage reaction as a main reactant of the current stage reaction and inputting the main reactant into the reactant cell of the current stage reaction; and the secondary reactant generation module is used for acquiring main reactant information in other recorded reactant cells of the level of reaction after detecting action instructions on the rest of spare reactant cells, searching the compound database according to the main reactant, traversing the compound database to acquire each secondary reactant which can perform chemical reaction with the main reactant, and generating an alternative secondary reactant group corresponding to the spare reactant cells.

The specific functions of the above-mentioned compound synthesis path management system correspond to those of the compound synthesis path management methods disclosed in the previous embodiments one to one, so that detailed descriptions thereof will be omitted, and specific reference may be made to each of the above-disclosed compound synthesis path management methods. It should be noted that, in the present specification, the embodiments are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments may be referred to each other.

In still other embodiments, there is provided a compound synthesis pathway management apparatus, including a memory, a processor, and a computer program stored in the memory and executable on the processor, the processor implementing the steps of the compound synthesis pathway management methods as described in the embodiments above when executing the computer program.

Wherein the compound synthesis path management device may include, but is not limited to, a processor, a memory. The server may include, but is not limited to, a processor, a memory. It will be appreciated by those skilled in the art that the schematic diagram is merely an example of a server and is not intended to limit the server device, and that it may include more or less components than those shown, or some components may be combined, or different components, for example, the server device may also include input output devices, network access devices, buses, etc.

The Processor may be a Central Processing Unit (CPU), other general purpose Processor, a Digital Signal Processor (DSP), an Application Specific Integrated Circuit (ASIC), an off-the-shelf Programmable Gate Array (FPGA) or other Programmable logic device, discrete Gate or transistor logic, discrete hardware components, etc. The general purpose processor may be a microprocessor or the processor may be any conventional processor or the like, which is the control center of the server device and connects the various parts of the overall server device using various interfaces and lines.

The memory may be used to store the computer programs and/or modules, and the processor may implement the various functions of the server device by running or executing the computer programs and/or modules stored in the memory, as well as by invoking data stored in the memory. The memory may mainly include a program storage area and a data storage area, wherein the program storage area may store an operating system, an application program required for at least one function, and the like, and the memory may include a high speed random access memory, and may further include a non-volatile memory, such as a hard disk, a memory, a plug-in hard disk, a Smart Media Card (SMC), a Secure Digital (SD) Card, a Flash memory Card (Flash Card), at least one magnetic disk storage device, a Flash memory device, or other volatile solid state storage device.

The compound synthesis pathway management method, if implemented as a software functional unit and sold or used as a stand-alone product, may be stored in a computer-readable storage medium. Based on such understanding, all or part of the flow of the method according to the embodiments of the present invention may also be implemented by a computer program, which may be stored in a computer-readable storage medium, and when the computer program is executed by a processor, the steps of the method embodiments may be implemented. Wherein the computer program comprises computer program code, which may be in the form of source code, object code, an executable file or some intermediate form, etc. The computer-readable medium may include: any entity or device capable of carrying the computer program code, recording medium, usb disk, removable hard disk, magnetic disk, optical disk, computer Memory, Read-Only Memory (ROM), Random Access Memory (RAM), electrical carrier wave signals, telecommunications signals, software distribution medium, and the like. It should be noted that the computer readable medium may contain content that is subject to appropriate increase or decrease as required by legislation and patent practice in jurisdictions, for example, in some jurisdictions, computer readable media does not include electrical carrier signals and telecommunications signals as is required by legislation and patent practice.

Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

In summary, the above-mentioned embodiments are only preferred embodiments of the present invention, and all equivalent changes and modifications made in the claims of the present invention should be covered by the claims of the present invention.

Claims

1. A method for managing a synthesis pathway of a compound, comprising the steps of:

2. The method for managing a chemical synthesis pathway according to claim 1, wherein the step S2 specifically includes:

acquiring at least one product information in the previous stage of reaction as a main reactant of the current stage of reaction and recording the information into a reactant cell of the current stage of reaction;

after action instructions on the rest of the spare reactant cells are detected, main reactant information in other recorded reactant cells of the reaction is obtained, a compound database is searched according to the main reactant, each side reactant which can carry out chemical reaction with the main reactant is obtained by traversing the compound database, and an alternative side reactant group corresponding to the spare reactant cells is generated.

3. The method of managing a synthesis pathway for a compound according to claim 2, wherein: the drug synthesis process feeding table is configured to arrange chemical reaction information of each level before and after a drug synthesis process in sequence from top to bottom in each row of the table according to the sequence before and after reaction, and main and auxiliary reactant information, main and auxiliary product information and reaction parameter information of each level of reaction are correspondingly arranged in each cell in the same row.

4. The method for managing a chemical synthesis pathway according to claim 3, wherein the step S2 specifically includes:

5. The method for managing a chemical synthesis pathway according to claim 3 or 4, wherein the step S2 specifically includes:

6. The method for managing a chemical synthesis pathway according to claim 3, wherein the step S2 specifically includes:

7. A system for managing a synthesis pathway of a compound, comprising:

the first reaction creating module is used for acquiring main and auxiliary reactants and information of each reaction parameter input into a cell corresponding to a primary reaction of a drug synthesis process feeding table, calling a compound database to inquire each reaction formula which can be matched, and inputting a main product and a side product of the selected reaction formula into a corresponding product cell of the step, wherein the reaction parameter information comprises a reaction condition parameter and a catalysis condition parameter;

the second reaction creating module is used for acquiring a main product or a byproduct in the previous stage reaction as a reactant of the current stage reaction, inputting the reactant into a reactant cell of the current stage reaction, generating a main byproduct of the current stage reaction according to the selected other reactants and reaction parameter information, and inputting the main byproduct into the product cell of the current stage;

and the path information module is used for acquiring reaction information of each level after the configuration of the process feeding table is completed and generating a compound synthesis path formed by the association of the front and the back of the multi-level chemical reaction.

8. The management system of a chemical compound synthesis pathway of claim 7, wherein said second reaction creation module comprises:

the main reactant generating module is used for acquiring at least one product information in the previous stage reaction as a main reactant of the current stage reaction and inputting the main reactant into the reactant cell of the current stage reaction;

and the secondary reactant generation module is used for acquiring main reactant information in other recorded reactant cells of the level of reaction after detecting action instructions on the rest of spare reactant cells, searching the compound database according to the main reactant, traversing the compound database to acquire each secondary reactant which can perform chemical reaction with the main reactant, and generating an alternative secondary reactant group corresponding to the spare reactant cells.

9. A management apparatus for a compound synthesis pathway, comprising a memory, a processor, and a computer program stored in the memory and executable on the processor, wherein: the processor, when executing the computer program, realizes the steps of the method according to any of claims 1-6.

10. A computer-readable storage medium storing a computer program, characterized in that: the computer program realizing the steps of the method according to any of claims 1-6 when executed by a processor.