JPS6285331A - Design processing method for composite path of chemical substance - Google Patents

Abstract

PURPOSE:To derive automatically a composite path of a chemical substance by performing an operation for obtaining a three-dimensional coordinate of a molecule which has been optimized by an energy calculation, based on structural information, as for a starting substance and an intermediate substance. CONSTITUTION:Information related to a composite path which has been obtained by a design processing operation is formed as a reaction formula, and also can be displayed two-dimensionally and three-dimensionally by combining a virtual transition structure. In case a starting substance is also set together with a target T, a desired composite path can be determined by executing a reverse synthesizing operation until it coincides with one of precursors T1-Ti, or executing it by combining a synthesizing operation beginning with the starting substance with the reverse synthesizing operation for tracing back from the target substance T.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of the Invention] The present invention relates to a method and method for designing synthetic routes for chemical substances, and more specifically, for designing synthetic routes for chemical substances based on stored chemical reaction information. It relates to a method for designing and processing.

[Technical Background of the Invention] In recent years, with the development of computers, various methods for recording structural information of chemical substances, particularly organic compounds, have been proposed and are being used. A huge amount of organic compounds and organic chemical reactions have been researched and elucidated to date, but it is possible to search for known chemical substances or chemical reactions in a short time by effectively utilizing this known information. It is desired to find a method for synthesizing known substances or new substances having desired properties. To this end, as a form of expression for chemical substances and chemical reactions, a computer-processable (
In other words, there is a need to develop and utilize forms of expression that allow computers to make logical decisions.

The method for recording chemical substances is W L N (Wisw
Typical methods include linear notation methods such as esser Linear Notation (Esser Linear Notation) and methods using join tables.
,R,Heller,R,J,Fald+5ann,
E. Hyde (Eds): “Comput
er Representati.

n and Manipulation of
Chemical Information Layeration” (J
ohn Wiley and 5ons, New Y
Ark, 1974) [Wipke, Heller, Feltman, Hyde (eds.): Computer Representation and Handling of Chemical Information (John Wiley and Sons)]. connection table
For example, ble) is a table that summarizes the type of each atom in the structural formula of a chemical substance, the atom to which it is bonded, and the type of bond. It has the advantage of being able to be searched for.

In addition, methods for recording information regarding structural changes (chemical reactions) of chemical substances have also been proposed, but so far no satisfactory expression method is known.
There is a method of recording information regarding chemical reactions using a reaction code, which is specifically described by J. Vallg, 0.
5cheiner:Chemical Information
tion Systems'', E, Ash, E,
Hyde (Eds), (Ellis Horwood
Limlted, 1975) p, 241-258
[The method described in [Pearl, Shiner: "Chemical Information Systems", edited by Ash, Hyde (Ellis-Horewood Company]) 1. A. Lobeck, Angew.
Chew, Intern.

Ed, Engl., 9.578 (1970) [o
The method described in J. Beck, Angewante Hiemi Internacional Rental and Edijon Φin Conflict English], and H.
-1nf, Camput.

Sci., 19.141 (1979) [Ziegler, Journal of Chemical Information and Commercial Science]. This method has a drawback in that it cannot record new chemical reactions when they are discovered, since the viewpoint of chemical reaction expression is fixed. Another drawback is that structural information on chemical substances and information on changes thereof are recorded in separate formats, making it impossible to perform effective information retrieval.

Separately, a recording method devised from the standpoint of designing synthetic routes for chemical substances is also known. for example.

El, Corey, R.D., Gramer, W.
, J. Howe, J. Am, Chera.
Sac, 94.440 (1972) [Kohli, Cramer.

Houe, Journal of American Chemical Society 1.1. υgi, J., Bauer, J.B.
raudt.

J, Fr1edrich, J, Gasteiger
, L. Jochum, W. 5chubert,
Angew, Chew, Intern, Ed.
Engl,, 18.111 (+979) [Ugi,
Bauer, Braut, Friedrich, Gasteiger,
There is a method described in Jochum, Schubert, Angewante Hiemi International Edition in English]. However, this method is not suitable for recording individual chemical reactions.

Until now, various forms of expression such as those mentioned above have been used. A synthesis route for a desired chemical substance is designed based on chemical reaction information (chemical reaction file) recorded and stored in N. In other words, a large number of chemical reactions and reaction-related information are registered in advance in a computer, and a route for synthesizing the final target chemical substance from available starting materials (
Attempts are being made to determine the extent to which continuous reactions (multi-step reactions) can be achieved within a short period of time. For example, by making full use of tens of thousands of chemical reaction files, we can sequentially extract precursors of a compound to be synthesized.
synthesis) to determine the synthesis route of the target substance.

In this synthetic route design system, input of the target substance or specific starting material into the computer and output of the determined synthetic route can be performed in the form of a structural formula or three-dimensional structural diagram that chemists are usually accustomed to. It is desirable to be able to do this, and in-computer design based on input conditions can be done using an atom-bond tracing method (atom bond tracing method) using a bond table.
Furthermore, the registration of a huge amount of information and the 1' product can be done by using an expression format that can easily register a wide variety of chemical structures and store it without occupying a large memory capacity. Therefore, it is required to be able to easily convert between the computer processing circuit representation form and the input/output structural diagram.

[Summary of the Invention] An object of the present invention is to provide a novel processing method for designing a synthetic route for a specific chemical substance using chemical reaction information.

Another object of the present invention is to provide a processing method for designing a synthesis route for a specific chemical substance based on chemical reaction information in an expression form that can be processed by a computer, and displaying and recording it in the form of a reaction formula. It is something to do.

That is, the present invention is a method for designing a synthetic route for a chemical substance based on information regarding a large number of chemical reactions that produce at least one product substance from at least one starting material, wherein the information regarding the chemical reactions is based on topological information. (1) between the structure of the starting material and the structure of the product superimposed on
The bond between nodes that exists in common in the starting material and the product material, (2) the bond between nodes that exists only in the starting material, and (3) the bond between nodes that exists only in the product material are respectively expressed separately. It is given as a bond table containing information about the imaginary transition structure and/or the bonds and nodes between these nodes, and [1] A synthetic route consisting of two or more reaction steps to produce the target substance. A method for designing a synthetic route for a chemical substance, characterized in that the decision is made based on the imaginary transition structure and/or the bonding table; [2] A synthetic route consisting of two or more reaction steps from a starting material to a target substance is designed. A method for designing a synthetic route for a chemical substance, characterized in that the process is determined based on an imaginary transition structure and/or a bond table; A method for designing a synthetic route for a chemical substance characterized by making predictions based on a table;

According to the method of the present invention, by using a huge amount of chemical reaction information of ψ recorded and stored (registered) as an imaginary transition structure and/or a bond table, and performing suitable processing based on input setting conditions, It is possible to automatically derive the synthesis route for the desired chemical substance.

In the present invention, an imaginary transition structure (imaginary tr
Ansition 5 structures (hereinafter abbreviated as ITS) is a structural change of a substance involved in a chemical reaction that includes (1) bonds that exist only in the starting material, (
A two-dimensional or three-dimensional structural diagram (figure) that is differentiated into three types: 2) bonds that exist only in the product, and (3) bonds that exist in common in both. This structural diagram can represent chemical reactions in a form that is visually familiar (and easily understandable) to engineers in accordance with conventional structural formulas and three-dimensional structural diagrams of compounds.

In addition, a connection table is a simple and clear list of combinations such as the types of nodes in a chemical reaction, the partner nodes that connect to the nodes, and the connections between these nodes that are differentiated into the three types mentioned above. This combination table allows chemical reaction information to be stored on a recording medium without requiring a large capacity.

In particular, by using a bond table as a registration form, information can be easily processed by a computer, and chemical reactions can be registered easily.
Management becomes easier.

In the above imaginary transition structure and bond table, a chemical reaction is basically a node Cm consisting of atoms, atomic groups, etc.
) and nodes, and the bonds between nodes in the reaction system are expressed in three different types. Therefore, the imaginary transition structure and bond table registered in a computer directly represent the changes in bonds in the reaction system, and they also reflect not only chemical reactions but also chemical substances related to reactions (starting materials and products of reactions). To this end, this heavy transition structure and/or bond table is used to determine the synthesis route (reaction route) can be easily derived by focusing on bond changes.

Furthermore, according to the method of the present invention, the target substance and/or starting material can be input in the form of a structural formula with which engineers are accustomed.

Even when input as a structural formula, the heavy transition structure is in a form similar to the structural formula, so the types of functional groups, substitution positions, ring structures, etc. included in the structural formula can be easily recognized. In addition, if the target material and/or starting material are input as a combination of node types and bond types between nodes, it is possible to easily convert them into the form of a bond table, or to input them as a bond table. Direct input can also be easily performed. Furthermore, since nodes can be arbitrarily selected when inputting target substances and/or starting materials, it is possible to easily recognize chemical substance structures and efficiently proceed with synthetic route design. It is.

In particular, based on a chemical substance input via graphics in the form of a structural formula, the synthesis route can be predicted and determined on an atomic basis using a bond table. Also,
The determined synthetic route can be displayed and recorded as a reaction formula consisting of a two-dimensional or three-dimensional structural diagram via a heavy transition structure.

Furthermore, by applying various processes to the chemical reaction information expressed in heavy transition structures and/or bond tables, we can generate reaction lines that express bond changes specific to reactions, ring structures specific to ring-opening and ring-closing reactions, etc. The information obtained by extracting not only individual reactions but also multiple consecutive reactions (multi-step reactions) into a single heavy transition structure and/or bonding table can be input to a computer as different types of reaction information. Since they can be registered, synthetic route design can proceed more efficiently by using these additional information files.

In addition, not only the starting materials and intermediate products, but also reaction characteristics including the reaction conditions for the reaction center 1 can be added to the determined synthetic route in a wide and meaningful manner, helping users to understand and make decisions. This facilitates the selection of the final synthetic route.

The determined synthetic route can be obtained in the form of a computer-processable bonding table or in the form of a heavy transition structure or reaction formula that is easy for engineers to visually understand, and the obtained information can be recorded on a blank sheet of paper or It can be displayed on a screen such as a cathode ray tube, or furthermore, it can be recorded and saved on a suitable recording medium.

Based on the registered reaction information, it is possible to predict all logically possible synthetic routes and determine the most efficient route, which is the ultimate goal of engineers involved in chemical synthesis. Synthetic route design for organic compounds with complex structures, which are in great demand, can be done in a short time using computers, and information can be obtained with high density.

In addition to these advantages, the method of the present invention allows prediction of reaction mechanisms and reaction products when complex compounds are reacted under certain conditions.
ation of organic reaction
) can also be done. Furthermore, the obtained information can be used for structural analysis and molecular design of chemical substances, which are in great demand for engineers involved in drug manufacturing.
It can be advantageously used for things such as modeling.

[Structure of the Invention] In the method for designing a synthetic route for a chemical substance (synthetic route design system) of the present invention, bonds between nodes can be divided into bonds that exist only in the starting material, bonds that exist only in the product substance, and bonds that are common to both. Predicting and determining the synthesis route of the target substance or the reaction route of the starting material using a database of heavy transition structures that are classified into three types of bonds that exist in This operation provides information about the synthetic route of the chemical substance.

In the design processing method of the present invention, an information file regarding chemical reactions used as a database is recorded and stored in a computer as a heavy transition structure and/or a bonding table.
registered).

Specifically, the reaction will be explained by taking as an example a reaction in which ethyl acetate is hydrolyzed with hydrochloric acid.

This chemical reaction is CH3COOCH2CH3+ H20+ HCtan→CH
2COOH+ CH3CH20H+ HCtan (reaction formula 1
) The zero-reaction imaginary transition structure (ITS) can be expressed as follows.

Here, i) the symbol - represents a bond that is present in common in the starting material and the product, i) the symbol 10 represents a bond that is present only in the starting material, and 1ii) the symbol... It represents a bond that exists only in the product.

In other words, an imaginary transition structure (ITS) is a two-dimensional or three-dimensional structure in which the structure of the starting material and the structure of the generated material are topologically superimposed, and the bonds between each node are differentiated into the three types i) to 1ii) above. It refers to the original structure, and 1, which is topologically superimposed, specifically refers to matching the nodes that appear in the structure of the starting material and the nodes that appear in the structure of the generated material, and combining these structures into one. say.

In the imaginary transition structure (ITS) according to the present invention, the 7-does of substances involved in chemical reactions are expressed in units of atoms contained in the filament (starting material group) and the product system (product material group). or a methyl group [the above node (
1,), (5)], may be expressed in units of atomic groups such as functional groups such as methylene group [node (4)], Some nodes appearing in the system may be omitted from the representation.

Furthermore, the distinction between the three types of bonds is not limited to the symbols i) to 1ii) above.

For example, the numbers (1, 2, 3) hJ can be displayed using simple letters, or the color divisions (black, red, green) can be judged by the user using their five senses.

Any means may be used as long as it can be processed by a computer.

Hereinafter, in the present invention, i) A bond common to the starting material and the product material (symbol -) is referred to as a "colorless bond," and 11) A bond that exists only in the starting material (symbol -4-) is referred to as a "colorless bond."
1■) The bond (memory...) that exists only in the generated substance is called the outbound bond J.
This will be called the large bond A, and the outgoing bond and the large bond will be collectively called the r-colored bond A.

Specifically, the types of bonds that appear in the imaginary transition structure in the present invention are summarized in Table 1. In Table 1, the horizontal numbers mean indicators of bond entry and exit.

In Table 1, for example, the bond represented by the symbol "..." is a single 1n-bond, and can be represented by a pair of numbers (0+1). Here, 0 means that no bond exists in the original system before the reaction, and +1 means that a single bond is present in the product system after the reaction. Similarly, the bond represented by i-1-J is a single out-bo
nd ) and is expressed as (1-1), which means that a single bond exists in the original system before the reaction, but the single bond disappears in the product system after the reaction. Furthermore, the bond represented by (2-1) is an outstanding double bond.
nd singly cleaved), and “=1
It is written as .

In this way, the type of bond is also a pair of numbers: (a, b)
[However, a is an integer representing the bond multiplicity in the starting material, and b is an integer representing the change in the bond multiplicity in the chemical reaction.] In this case, the bond multiplicity is two. Even the above can be expressed concisely. Note that the comma (1) in the notation of (a, b) can be omitted. Also, according to this notation, chemistry Particularly preferred for recording reactions.

Chemical reactions also. Each node can be represented as a connection table containing information about the node to which the node is connected and the connections between the nodes.

Table 2 shows the bonding table for the hydrolysis reaction of the ester. Note that the bonding table also includes information regarding the two-dimensional coordinates (xy coordinates) of each node.

As shown in Table 2, the bond table includes all nodes and their two-dimensional coordinates (nodes ( 1) is a list in which all nodes connected to each node and the types of connections between these nodes are listed in order of node number.

Note that it is possible to create a bonding table based on the imaginary transition structure of a reaction, and conversely, if the bonding table includes position information of each node, it is possible to create an imaginary transition structure from the bonding table. can. In other words, it can be said that the imaginary transition structure and the bond table are two sides of the same coin as a form of registration and display of chemical reaction information.

The connection table may also include information regarding the position coordinates of each node as described above.

The imaginary transition structure and/or bond table may contain additional information, if desired, including information on the charge and stereochemistry of each node; various physical property values and spectral information of chemical substances involved in the reaction; and enthalpy, temperature, and time of the reaction. , the catalyst used, the atmosphere, the yield of the reaction phase 1 reaction, the presence or absence of by-products, etc. may be described.Furthermore, the imaginary transition structure and/or bond table may contain information on the accumulation and management of chemical reaction information. and reactive groups, each separately to facilitate searching.
It is preferable that a reaction number etc. be attached.

Imaginary transition structures and/or coupling tables may be registered in the database by storing them in a storage device within a computer, or by storing them in a suitable storage medium (magnetic disk, optical disk, magnetic tape, etc.). It may also be recorded and saved via.

In addition, the registered imaginary transition structure and/or connection table is
It can be recorded on various recording materials such as plain paper using an appropriate recording device, or it can be displayed (graphic display) on a color cathode ray tube connected to a computer or electronic device.

For details on the expression form of chemical reactions and the registration and accumulation method of reaction information,
No. 45 and Japanese Patent Application No. 60-180875.

Using information files about numerous chemical reactions registered in the computer in the form of imaginary transition structures and/or bond tables, the synthesis route for a specific chemical substance can be predicted and determined by the method described below. be done.

The synthetic route design according to the present invention can be roughly classified into the following three types depending on the setting conditions.

(I) Set the target substance and determine its synthetic route. (n) Set the starting material and target substance and determine the synthetic route between them. (III) Set the starting material and predict the reaction route. , the target material and/or starting material configuration input is
This is done in the form of a conventional chemical structural formula, a combination table of two entries, or a combination thereof. Even if the input is in the form of a structural formula, it can be automatically converted into a computer-processable connection table form by computer processing based on the structural conditions, which is a preferred method.

At this time, in order to increase the efficiency of synthetic route design, a part of the 7-do may be represented by an atomic group, or even simplified letters and symbols (HA-=halogen, MT = metal), conditions such as aromatic, heterocyclic, etc. may be added, functional groups may be divided into electron-withdrawing groups and electron-tetravalent groups, or the entered structural formula may be changed. Computers recognize the types of functional groups, substitution positions, chemical properties, number and type of rings, their sizes, and the atoms and bonds that make up the rings (perc).
Alternatively, after performing this process on the chemical structure input in units of atoms, it is also possible to group the chemical structures into appropriate atomic groups and newly recognize them as nodes. This structural recognition is extremely important for efficient synthesis in synthetic route design, especially in conformity analysis. It is in the F1 preparation stage.

Input is performed using character terminals such as regular teletypewriters and chemical typewriters designed to draw chemical structural formulas; and graphic terminals that use keyboards, joysticks, light pens, etc. be able to. The latter image terminal is easy to use in that it allows two-dimensional figures to be drawn directly on a graphic display. No matter which terminal you use, you can enter questions in the form of questions.

Next, a synthetic route is predicted and determined based on these setting conditions.

When designing a synthetic route, from the reaction information file registered as an imaginary transition structure and/or a bonding table,
The chemicals involved in the reaction (ie, starting materials and products) are recognized.

Taking the above ester hydrolysis reaction as an example, the starting material for the reaction is an incoming bond (symbol...
By ignoring the .) and considering it as non-bonding, and by ignoring the outgoing bond (symbol +) from ITSI and considering it as non-bonding, the following structural formulas are derived, respectively.

Original thread (6) (7) HCfL 1 degree 5 (8) (7) If the H-0 sentence ITS is a three-dimensional imaginary transition structure, the structures of the starting material and the product material can be expressed as a three-dimensional structural diagram. be led out.

Further, from the reaction bond table, a bond table regarding starting materials and product materials can be derived by the method described below.

For example, the bonds between nodes are expressed as a pair of numbers (a, b) as shown in Table 2 [where a is an integer representing the bond multiplicity in the starting material and b is the change in bond multiplicity in the chemical reaction. is an integer representing ], the starting material is obtained by considering the multiplicity of connections between each node as a, and the product material is obtained by considering the multiplicity of connections between each node as a+b. , respectively.

Specifically, in the process of designing a synthetic route, the starting material of the reaction is recorded as a precursor by performing such processing on the imaginary transition structure and/or bond table of the reaction to be proposed.

Alternatively, in advance, an operation of extracting the yarn and the generation system from the ITS5 and/or the connection table that serves as the database [respectively, projection to the yarn (projection t
o the starting stage, P S
), the projection J to the r-generating system (projec
tion to the product stage
, PP)], and the information on the obtained starting materials and product materials may be separately registered in the computer as chemical substance files.

When registering chemical substance information, the ITS may be recorded together with the structural diagram of the yarn and production system, and the substance number may be recorded for each structural diagram and/or bond table to facilitate the accumulation and use of information. Alternatively, the name of the substance may be attached.

Details of the PS and PP operations are described in the specification of Japanese Patent Application No. 1986 filed on August 22, 1985 by the same applicant.

In addition, in order to facilitate the design of the synthetic route, the reaction I
Perform operations to extract reaction paths, ring structures, etc. from the TS and/or bond table, and register information about the obtained reaction paths and ring structures in the computer as separate reaction path files and ring structure files, and then By using this file as a list of reaction formats, synthetic route design can be advantageously proceeded.

Here, the reaction string
refers to a partial reaction structure in which multiple high bonds and incoming bonds are alternately connected, and represents changes in bonds specific to a reaction.

For example, taking the above-mentioned ester hydrolysis reaction (reaction formula 1) as an example, it can be obtained by extracting only high bonds (symbol +) and incoming bonds (symbols...) from ITSI.

The reaction path is also (2) −(3) +(10)−(11)+(8) −
(7) It can be represented by the character string +(2). Here, the symbol - represents a high bond, and the symbol 10 represents an incoming bond.

In addition, the reaction path can also be extracted from the reaction bond table.

Although there is one reaction path in the above ITSI, there may be two or more reaction paths depending on the reaction. Generally, organic reactions can be classified according to the number of reaction paths. Organic reactions expressed by ITS that include one reaction path are called ona-string reactions.
). Similarly, ITSs containing two reaction paths and three reaction paths are defined as two reaction paths (two-3t
ring reaction) and three-strand reaction (t
hree-string reaction). From this, it is possible to divide the reaction in the middle of the reaction path.
On the other hand, a reaction that has multiple reactants can be considered to be a continuous reaction of two or more steps.

Details of the reaction extraction procedure are described in the specification of Japanese Patent Application No. 1983 filed on September 5, 1985 by the applicant. By using these reaction files, it is possible to improve design efficiency and shorten processing time.

Furthermore, the term "ring structure" refers to a cyclic structure that appears in ITS, and indicates an expression specific to one reaction.

Ring structures involved in chemical reactions can be roughly divided into the following five types.

(I) ring of ring open
iB) The open ring is a ring structure tube containing only one high bond, and all remaining bonds are colorless bonds, and corresponds to the ring-opening reaction. Therefore, the starting material in a reaction exhibiting an open ring has a ring structure.

(II) Ring of ring c
levage) A ring cleavage ring refers to a ring structure that contains two or more high bonds and all remaining bonds are colorless bonds. Thus, the starting materials in reactions that exhibit ring cleavage have a ring structure.

(II ring of ring e[a
, 5ure) A closed ring refers to a ring structure that includes one incoming bond and all remaining bonds are colorless bonds, and corresponds to a ring closing reaction. Therefore, the product product in a reaction exhibiting a closed ring has a ring structure.

(IV) ring of ring fo
rmation) A ring in a ring production refers to a ring structure containing two or more incoming bonds, and all remaining bonds are colorless bonds,
Therefore, the product substance in a reaction exhibiting a ring of ring formation has a ring structure.

(V) ring of rearrangement
aent) A rearranged ring refers to a ring structure in which the ring structure includes one high bond and one closed bond, and all remaining bonds are colorless bonds.

Specifically, the explanation will be given using an example of an open ring.

For example, in the ester hydrolysis reaction represented by Reaction Formula 2, →HO2C(CH2) s COOH +C2H5OH (Reaction Formula 2) ITS is represented as follows.

First, from the ITS2, a portion of all colorless and colored bonds in which the bonds are connected in a cyclic manner to form a ring of - is recognized and detected.

The obtained ring structure (Ring 1) is a six-membered ring consisting of one high bond and five colorless bonds, and is an open ring.

This closed ring is also It can be expressed as a character string.

The ring structure can also be extracted directly from the reaction bond table.

The above five types of ring structures are, for example, the above (a).

b) Using the notation, it can be classified as follows.

Colorless and colored bonds each have the following conditions: i) Colorless bond: a≠0, a+b≠0 ii) High bond: a≠0, b=o, a+b=0 1ii) Incoming bond: a=O, Since b≠0 and &+b≠0 are satisfied, the ring structures are classified as shown in Table 3 below. In Table 3, the ring is an n-membered ring (n is a positive integer), and m is a positive integer in the range of 2≦m<n.

Third table ring structure a#Oa+b=Oa=0a+b≠O n-110 n-mm0 n-101 1V nm Omn-211 VI n OOIn addition, ring structure v
I is the case where the ring structure is present without change in both the starting material and the product.

Details of this ring extraction operation are described in the specification of Japanese Patent Application No. 1983 filed on September 9, 1986 by the present applicant.

When a synthesis route includes a reaction that involves a change in the ring structure, such as a ring-opening reaction or a ring-closing reaction, using this ring structure file can further improve design efficiency and shorten processing time. .

Furthermore, an operation is performed in advance to create ITSs and/or bonding tables for multiple consecutive reactions based on the ITSs and/or bonding tables for individual reactions, and the ITSs and/or bonding tables for the obtained multi-step reactions are separately created. It can also be registered in a computer as a multi-step reaction file and used for synthetic route design. Thereby, it is possible to predict the synthetic route in several steps at once, and design efficiency can be improved.

ITS and bonding tables for multistep reactions can be found, for example, in the above (a
, b) is obtained by performing the following arithmetic processing based on the combination table for the unit reactions of each stage expressed in the notation.

In other words, the connections between each node in each step of the reaction are
A pair of numbers (aXt, bx') [where i is 1≦i≦
n is a positive integer in the range of n, where n is a positive integer of 2 or more representing the interlayer order of the total reaction, BX+ is an integer representing the bond multiplicity in the starting material of the i-step reaction, and bXI is the integer of the i-step reaction. is an integer representing the change in the bond multiplicity in the reaction, where X represents the bond between nodes], then axjkwaxj 1) xjk = bx'+ bXj+++, ・+ bx
1+bx' [where j and k are each 1≦j
is a positive integer that satisfies the condition <k≦n, axjk is an integer representing the bond multiplicity in the starting material of the reaction from stage j to stage 2, and 1) Xjk is a positive integer that satisfies the condition is an integer representing a change in the degree of connection multiplicity, where

bx”).

In addition, continuous multi-step reactions are synthesized by the raact genus (raact).
ion-rout's classSes).

For example, in a sequential reaction consisting of five steps, SAP,
→P2→P3→P, →P, :FRBCDE (Here, ox means the synthesis space of the five-step reaction, S means the starting material of the five-step reaction, P, ~Ps means the reaction of each step. If the ITS and/or bond table of each step (meaning the product substance) is simply represented as A, B, C1, etc., the synthetic route genera of this sequential reaction can be summarized in a file as shown in Table 4. I can do it.

IT in the synthetic root attribute file shown in Table 4
Focusing on S, all ITSs located to the right and below this ITS represent partial reactions of this ITS. For example, for DCH, CB, B, DC,
It can be said that C and D are ITS representing the partial reactions.

If you design a synthetic route using this synthetic route genus file, when ITS (DCB) is adopted (hit), all the reactions in the previous steps up to solving this file and obtaining this DCB will be performed. It can be output.

Details of the ITS of the multi-step reaction and/or the operation of creating a linkage table are described in the specification of Japanese Patent Application No. 1983 filed on September 13, 1986 by the present applicant.

By appropriately utilizing the various information files regarding the chemical reactions described above, synthetic route design can be carried out by
For example, the following method is used.

When designing a synthetic route for a set target substance, first, the target substance is regarded as a reaction product, and precursors (intermediates) of the target substance are detected by finding the starting materials as well as possible reactions. . Starting material A
In the unit reaction (A+B) that produces product B from
This reaction process is called synthesis, whereas the process of B and A is called retrosynthesis. By sequentially performing such adaptive composition analysis, intermediate reactions and intermediate products can be discovered one after another, and finally an available raw material can be arrived at.

The adaptive composition analysis will be specifically explained using the example of the synthetic tree shown in FIG.

For example, precursors up to T and -Ti (where i is a positive integer of 1 or more) that may be compatible with the target substance T are detected.

Next, we will explore the possibility of compatible compositions for all of these precursors. For example, for T3, precursors from T31 to T3j (where j is a positive integer of 1 or more) are detected, and for T32 among them, T321-
T3zh (k is a positive integer greater than or equal to 1)
Precursors up to are detected. By repeating these operations, a synopsis tree (syn
thetic tree) is completed.

In order to efficiently proceed with synthetic route design in the method of the present invention, the system basically uses a list of reaction formats (for example, the above-mentioned reaction record file and ring structure file are examples) and the difficulty of the reaction. It is necessary to have the means and the means to evaluate. Here, the list of reaction formats indicates the scope of the system (the so-called frontage), and the means of evaluating the difficulty level indicates the precision and depth of the system.

In the adaptive synthesis of compounds with complex structures, it is desirable to be able to arrive at a raw material with a simple structure in as few steps as possible, and to achieve this, it is necessary to simplify the skeleton of the target substance as early as possible by utilizing a list of reaction formats. It is necessary to

In addition, in the process of creating this synthetic tree, especially in the case of complex target substances, intermediate products are changed to reduce the difficulty of the reaction in order to prevent the exponential increase in precursors and find a more efficient synthetic route. I,

The selection may be performed automatically by setting various judgment conditions in advance, or semi-automatically through an appropriate input means during the process. The reactivity (steric hindrance, electronegativity, enthalpy of reaction, yield, etc.) depends on the environment such as substituents. Furthermore, if the reaction information file has additional information such as the above, whether one reaction is batch type or continuous, stationary phase or fluid phase, etc.
The presence or absence of by-products, catalysts such as oxidizing agents, and environmental atmosphere such as radioactivity can be added to the judgment conditions.

If the process is to be performed semi-automatically, it is preferable that the process can be performed interactively between the user and the computer via structural formulas.

This selection need not be made at each stage; for example, the route may be automatically abandoned when the level of difficulty cumulatively falls below a set value.

By repeating such adaptive synthesis operations until the precursor becomes an available compound, a synthetic route for the target substance can be designed. The completion of this series of operations can also be carried out by providing an appropriate judgment circuit regarding the availability of precursor substances, or by input judgment from the outside. Furthermore, if desired, appropriate judgment conditions are set for the plurality of synthetic routes obtained, such as a route that maintains the maximum common part, a route that has fewer changes in bonding, etc., and , a more feasible synthetic route can also be selected and determined.

In the process of compatible synthesis operations, especially when input judgment by the user is required, the above synthetic tree and the structural formula of each precursor are displayed on the screen in a graphic display to inform the user of the progress of the synthetic route design. It is preferable that you can.

In addition, if a starting material is set together with the target material, the above-mentioned compatible synthesis operation can be performed until at least one precursor matches this starting material, or the synthesis operation starting from the starting material and the target substance can be combined. A desired synthetic route can be determined by performing it in combination with backward adaptive synthesis operations.

Furthermore, when only the starting materials are set, it is possible to enumerate and predict possible reactions, including unknown reactions, by performing synthetic operations.

It can be advantageously used when attempting to predict all possibilities of synthesis methods or reaction mechanisms of industrial raw materials. Furthermore, it is possible to predict what kind of reaction mechanism and what kind of reaction products will be produced when complex compounds are reacted under certain conditions.

In this way, it is possible to design a synthetic route for a specific chemical substance. If the above chemical reaction information file includes various data such as reaction conditions, presence or absence of by-products, yield, physical properties of starting materials and product materials, and literature information as additional information, the chemical reaction information file may be expressed as a reaction formula, etc. It is possible to obtain not only the synthetic route but also this additional information.

The information regarding the synthesis route obtained through the above design processing operations can be displayed as a reaction formula on a graphic display such as a CRT, or further two-dimensionally or three-dimensionally by combining imaginary transition structures. At this time,
For starting materials and intermediate materials, operations must be performed to obtain optimized three-dimensional coordinates of molecules through energy calculations (molecular force field calculations, etc.) based on structural information obtained as two-dimensional structural diagrams. It is also possible to obtain a three-dimensional structure diagram (three-dimensional structure, space-filling diagram, etc.). Furthermore, a structural diagram viewed from any angle can be enlarged or reduced and displayed on the display.

Further, the obtained information can be recorded (hard copy) on an appropriate recording material such as plain paper, or can be recorded and saved on an appropriate recording medium such as a magnetic disk.

[Brief explanation of drawings]

FIG. 1 is a diagram showing an example of a synthetic tree according to the method of the present invention. Patent applicant: Fuji Photo Film Co., Ltd. Agent
Patent Attorney Yasushi Yanagawa 1st Design

Claims (1)

[Claims] 1. A method for designing a synthetic route for a chemical substance based on information regarding a large number of chemical reactions that produce at least one product from at least one starting material, the method comprising: , between the topologically superimposed structure of the starting material and the structure of the product material (1)
The bond between nodes that exists in common in the starting material and the product material, (2) the bond between nodes that exists only in the starting material, and (3) the bond between nodes that exists only in the product material are respectively expressed separately. It is given as a bonding table containing information about the imaginary transition structure and/or the bonds and nodes between these nodes, and the synthesis route consisting of two or more reaction steps to generate the target substance is expressed by the imaginary transition structure and 1. A method for designing a synthetic route for a chemical substance, characterized in that the synthesis route is determined based on/or a bond table. 2. In the above imaginary transition structure, the connections between nodes are characters,
2. A method for designing a synthetic route for a chemical substance according to claim 1, wherein the chemical substance is distinguished by a symbol, color, or a combination thereof. 3. In the above bond table, the bonds between nodes are represented by a pair of numbers (a, b) [where a is an integer representing the bond multiplicity in the starting material, and b is an integer representing the change in bond multiplicity in the chemical reaction. 2. A method for designing a synthetic route for a chemical substance according to claim 1, wherein the method is distinguished by: 4. The method for designing a synthesis route for a chemical substance according to claim 1, characterized in that the synthesis route for the target substance is displayed and recorded on a recording material or on the screen of a display device. 5. A method for designing a synthetic route for a chemical substance based on information regarding a large number of chemical reactions that produce at least one product from at least one starting material, the information regarding the chemical reactions being topologically superimposed. Between the structure of the starting material and the structure of the product (1)
The bond between nodes that exists in common in the starting material and the product material, (2) the bond between nodes that exists only in the starting material, and (3) the bond between nodes that exists only in the product material are respectively expressed separately. It is given as a bond table containing information about the imaginary transition structure and/or the bonds and nodes between these nodes, and the synthetic route consisting of two or more reaction steps from the starting material to the target material is expressed as the imaginary transition structure and 1. A method for designing a synthetic route for a chemical substance, characterized in that the synthesis route is determined based on/or a bond table. 6. In the above imaginary transition structure, the connections between nodes are characters,
6. The method for designing a synthetic route for a chemical substance according to claim 5, wherein the chemical substance is distinguished by symbols, colors, or a combination thereof. 7. In the above bond table, the bonds between nodes are represented by a pair of numbers (a, b) [where a is an integer representing the bond multiplicity in the starting material, and b is an integer representing the change in bond multiplicity in the chemical reaction. 6. The method for designing a synthetic route for a chemical substance according to claim 5, wherein the method is distinguished from the following. 8. The method for designing a synthetic route for a chemical substance according to claim 5, characterized in that the synthetic route from the starting material to the target substance is displayed and recorded on a recording material or on the screen of a display device. 9. A method for designing a synthetic route for a chemical substance based on information regarding a large number of chemical reactions that produce at least one product from at least one starting material, the information regarding the chemical reactions being topologically superimposed. Between the structure of the starting material and the structure of the product (1)
The bond between nodes that exists in common in the starting material and the product material, (2) the bond between nodes that exists only in the starting material, and (3) the bond between nodes that exists only in the product material are respectively expressed separately. is given as an imaginary transition structure and/or a bonding table containing information about the bonds and nodes between these nodes, and one or more reaction paths of the starting materials are determined based on the imaginary transition structure and/or the bonding table. A method for designing synthetic routes for chemical substances characterized by prediction. 10. The synthetic route for a chemical substance according to claim 9, wherein in the imaginary transition structure, the bonds between nodes are distinguished by letters, symbols, colors, or a combination thereof. Design processing method. 11. In the above bond table, the bonds between nodes are represented by a pair of numbers (a, b) [where a is an integer representing the bond multiplicity in the starting material, and b is an integer representing the change in bond multiplicity in the chemical reaction. 10. The method for designing a synthetic route for a chemical substance according to claim 9, wherein 12. The method for designing a synthetic route for a chemical substance according to claim 9, characterized in that the reaction route of the starting material is displayed and recorded on a recording material or on the screen of a display device.