Analytical apparatus, analytical methods and computer program products

Abstract

The present invention provides an analytical apparatus, an analytical method, and a computer program product. The analytical apparatus estimates the endpoint of a chemical reaction in which the concentration of at least one raw material is unknown. It comprises: a spectrum acquisition unit that acquires spectroscopic spectra of the chemical reaction system at multiple time points; a calculation unit that calculates characteristic quantities of the spectroscopic spectra at each time point based on the spectroscopic spectra at the multiple time points; and an estimation unit that estimates the endpoint of the chemical reaction based on the changes in the characteristic quantities calculated by the calculation unit.

Description

Technical Field

[0001] This invention relates to analytical apparatus, analytical methods, and computer program products. Background Technology

[0002] Patent document 1 describes "a factory operation control method based on near-infrared analysis, which controls the factory operation based on the measurement value obtained by near-infrared analysis of a sample, characterized in that: near-infrared analysis of the sample is performed based on a pre-made calibration line; the measurement value of the near-infrared analysis method is compared with the allowable value; when the measurement value is outside the allowable value, it is analyzed by a general analysis method; the measurement value of the general analysis method is compared with the allowable value; when the measurement value of the general analysis method is within the allowable value, the data of past near-infrared analysis is input to calculate the predicted value; when the predicted value is outside the allowable value, the near-infrared analysis device is checked; when the predicted value is within the allowable value, the calibration line is supplemented and evaluated." (Claim 1). Patent document 2 describes a method for determining the parameters of an unknown quantitative function F(r) by numerical calculation in a manner that minimizes the value expressed by mathematical formula 1, given that "the valence of the atomic group is f, the response from the analyzer is r, the number of unstable intermediates is L, the quantification function is F(r), the quantity of known components is M, the number of reaction solution samples is n, the concentration of known components is c, the sum of the concentration of added components in the sample and the valence is C, and the number of analyses is m." (Abstract) Patent document 3 describes "a method for monitoring pharmaceutically related chemical reactions, characterized in that Raman spectral samples of a solution containing chemical components in a reaction vessel are continuously obtained by solution irradiation based on substantial monochromatic radiation, and scattered radiation is detected. For the Raman spectral sample, a first principal component associated with a potential variability index of the continuously occurring reaction is processed by a multivariate data analysis (MVDA) method, which is independent of calibration using reference measurements of an object with a known composition, and the progress of the chemical reaction is measured based on the at least one first principal component and, if necessary, further based on one or more principal components generated by one or more prior reactions of the same kind" (claim 1). Patent document 4 describes "an optical analysis system comprising, in a chemical reaction system for synthesizing a product from a first raw material and a second raw material: an irradiation unit that irradiates the first raw material and the second raw material with irradiation light before the start of synthesis, and irradiates a mixture comprising the first raw material, the second raw material, and the product with irradiation light after the start of synthesis; a detection unit that detects a measurement light, the measurement light being a measurement light based on the irradiation light irradiated by the irradiation unit, and including information related to the spectroscopic spectra of each of the first raw material, the second raw material, and the mixture; and a calculation unit that calculates the spectroscopic spectra of each of the first raw material, the second raw material, and the mixture, and calculates the spectroscopic spectrum of the product based on each spectroscopic spectrum, the product comprising any one of an unisomerized compound and a pair of compounds having an optical isomer relationship with each other" (claim 1). Patent document 5 describes "a spectroscopic analysis method, which, based on the premise that the measured spectrum obtained by measuring a sample is represented by a combination of values ​​obtained by multiplying the pure spectrum of a predetermined number of components by the concentration value of each pure spectrum, separates the pure spectra of the number of components from a plurality of measured spectra, and performs spectroscopic analysis on the plurality of measured spectra using a multivariate curve decomposition (MCR) method for calculating the concentration value of each pure spectrum, the spectroscopic analysis method being characterized in that an equilibrium model corresponding to the equilibrium state of the sample coexisting with three or more chemical species is set, at least one chemical equilibrium equation corresponding to the equilibrium model is set, and the MCR is started on the plurality of measured spectra." (A) For the calculated concentration value, the optimal values ​​of the thermodynamic parameters constituting the chemical equilibrium will be obtained by fitting the concentration curve based on the chemical equilibrium equation. (B) Obtain a new concentration value from the chemical equilibrium equation using the optimal values ​​of the thermodynamic parameters, use this new concentration value to separate the pure spectrum, and calculate the concentration value. And by repeatedly performing such processes (A) and (B), the thermodynamic parameters corresponding to the equilibrium model, the pure spectrum, and the concentration value of each pure spectrum are obtained. (Claim 1) Patent document 6 describes "a reaction control system for an olefin oxygen addition reaction, comprising: a reactor, having a stirrer for reacting olefin oxygen with a compound containing active hydrogen atoms and / or an alkyl ester of fatty acids; a calculation unit, which calculates at least one property selected from the hydroxyl value and cloud point of the reaction product based on the near-infrared absorption spectrum of the reaction liquid in the reaction by providing a pipeline for taking out a portion of the reaction liquid from the reactor and returning it to the reactor via a near-infrared absorption spectroscopy unit, or by directly providing a detection end of a near-infrared absorption spectroscopy unit in the reactor; and a unit for controlling the amount of olefin oxygen supplied to the reactor based on the calculated value" (claim 1). Existing technical documents Patent Document 1: Japanese Patent Publication No. 2000-298512 Patent Document 2: Japanese Patent Publication No. 2001-318088 Patent Document 3: Japanese Patent Publication No. 2002-534674 Patent Document 4: Japanese Patent Publication No. 2019-211400 Patent Document 5: Japanese Patent Publication No. 2024-113582 Patent Document 6: Japanese Patent Publication No. 2000-1451 Summary of the Invention

[0003] In a first aspect of the present invention, an analytical apparatus is provided for estimating the endpoint of a chemical reaction in which the concentration of at least one raw material is unknown. The analytical apparatus includes a spectrum acquisition unit, a calculation unit, and an estimation unit. The spectrum acquisition unit acquires spectroscopic spectra of the chemical reaction system at multiple time points. The calculation unit calculates characteristic quantities of the spectroscopic spectra at each time point based on the spectroscopic spectra at the multiple time points. The estimation unit estimates the endpoint of the chemical reaction based on the changes in the characteristic quantities calculated by the calculation unit.

[0004] The analytical apparatus described above also includes a determination unit. The determination unit can determine the amount of a raw material of unknown concentration used in the chemical reaction system based on the endpoint of the chemical reaction estimated by the estimation unit. The raw material of unknown concentration is a material of unknown concentration.

[0005] In the above-mentioned analytical apparatus, the raw material with unknown concentration may be the product of a chemical reaction in the preliminary stage of the chemical reaction of the presumed object.

[0006] In the aforementioned analysis apparatus, the computing unit can calculate the principal components of the spectroscopic spectra at multiple time points as characteristic quantities by performing principal component analysis on the spectroscopic spectra at multiple time points.

[0007] In the above-mentioned analysis device, the calculation unit can calculate the value based on the peak area and / or peak intensity as a characteristic quantity, wherein the peak area and / or peak intensity are the peak area and / or peak intensity of a specific wavelength contained in the spectroscopic spectrum of each time point included in multiple time points.

[0008] In the aforementioned analytical apparatus, the estimation unit can estimate the endpoint of a chemical reaction based on the first derivative of the characteristic quantity with respect to elapsed time.

[0009] In the aforementioned analytical apparatus, the estimation unit can estimate the endpoint of a chemical reaction as the time point at which the absolute value of the first derivative of the characteristic quantity with respect to the elapsed time exceeds a threshold.

[0010] The analytical apparatus described above also includes a preprocessing unit for preprocessing the spectroscopic spectrum. The calculation unit can calculate characteristic quantities based on the spectroscopic spectrum preprocessed by the preprocessing unit.

[0011] In the above-described analytical apparatus, as a preprocessing step, the preprocessing unit can apply any one or more of baseline correction, first derivative, and second derivative to the spectroscopic spectrum.

[0012] In the aforementioned analytical apparatus, the chemical reaction can be part of a continuous reaction in which the product is used as a new raw material to repeatedly carry out subsequent reactions.

[0013] In the above-mentioned analytical apparatus, the chemical reaction can be a reaction in which a second monomer different from the first monomer is polymerized in a polymer composed of repeated first monomers to generate a block copolymer.

[0014] In a second aspect of the invention, an analytical method is provided to estimate the endpoint of a chemical reaction in which the concentration of at least one raw material is unknown. The analytical method includes a spectral acquisition stage, a calculation stage, and an estimation stage. In the spectral acquisition stage, spectroscopic spectra of the chemical reaction system at multiple time points can be acquired. In the calculation stage, characteristic quantities of the spectroscopic spectra at each time point can be calculated based on the spectroscopic spectra at the multiple time points. In the estimation stage, the endpoint of the chemical reaction can be estimated based on the changes in the characteristic quantities calculated in the calculation stage.

[0015] In a third aspect of the invention, a computer program product is provided, comprising a program for estimating the endpoint of a chemical reaction in which the concentration of at least one raw material is unknown. The computer executes the program to perform a spectral acquisition stage, a calculation stage, and an estimation stage. In the spectral acquisition stage, spectroscopic spectra of the chemical reaction system at multiple time points can be acquired. In the calculation stage, characteristic quantities of the spectroscopic spectra at each time point can be calculated based on the spectroscopic spectra at the multiple time points. In the estimation stage, the endpoint of the chemical reaction can be estimated based on the changes in the characteristic quantities calculated in the calculation stage.

[0016] Furthermore, the above summary of the invention does not list all the features of the invention. Moreover, combinations of these feature groups can also constitute an invention. Attached Figure Description

[0017] Figure 1 This is an example of a continuous reaction in this embodiment. Figure 2 This illustrates an example of the structure of the analysis apparatus 50 in this embodiment. Figure 3 This is an example of the flow of the analysis method of this embodiment. Figure 4 express Figure 3 An example of a subprocess of the S300 process. Figure 5 This represents an example of a chemical reaction that is the subject of this embodiment. Figure 6 An example of a graph representing the characteristic quantities of this embodiment. Figure 7 Another example of a graph representing the characteristic quantities of this embodiment. Figure 8 Examples of computer 2200 that can implement the present invention in whole or in part are shown. Detailed Implementation

[0018] The present invention will now be described through embodiments thereof, but these embodiments do not limit the invention as defined in the claims. Furthermore, not all combinations of the features described in the embodiments are necessary for the solution of the invention.

[0019] Figure 1 This is an example of a continuous reaction in this embodiment. Figure 1 This is an example of a reaction used to generate product 30 having a structure derived from multiple raw materials A, B, C...Z. First, in the first stage of the reaction, raw material B12 is added to raw material A10 to react with it, yielding intermediate AB14. Next, in the second stage of the reaction, raw material C16 reacts with intermediate AB14 to yield intermediate ABC18. In subsequent stages of the reaction, raw material D20, etc., are similarly reacted with intermediates one after another to make the reaction continuous, thereby ultimately yielding product 30 (ABCD...Z) having a structure derived from raw material A, raw material B, raw material C, raw material D...Z. Such a reaction can also be carried out in a large-scale plant.

[0020] Here, the concentrations and amounts of the reactants (e.g., reactant A10, reactant B12, reactant C16, reactant D20, etc.) are known, but the concentrations of intermediates (e.g., intermediate AB14, intermediate ABC18, etc.) depend on the extent of the forward and side reactions in each stage and / or the yield of purification, and are therefore not necessarily definite. A calibration line is needed to accurately measure the concentration of the intermediates. To obtain the calibration line, a sample of the pre-purified intermediate is required, and based on this, standard samples of various concentrations are generated for analysis using HPLC or similar methods.

[0021] However, according to this method, the purification of intermediates and the preparation of calibration lines not only require time and cost, but it is also difficult to grasp the progress of the reaction (e.g., the degree of raw material consumption or the endpoint of the chemical reaction) by measuring the amount of intermediates in real time during the reaction. On the other hand, according to the analytical apparatus 50 of this embodiment described later, the progress of the reaction and the amount of intermediates generated can be grasped in real time.

[0022] Figure 2 This illustrates an example of the structure of the analytical apparatus 50 according to this embodiment. The analytical apparatus 50 in this embodiment analyzes the progress of a chemical reaction in real time. For example, the analytical apparatus 50 estimates the concentration of at least one raw material as the endpoint of an unknown chemical reaction. For example, the chemical reaction may be part of a continuous reaction in which the product is used as a new raw material and subsequent reactions are repeatedly carried out. The analytical apparatus 50 includes a reaction unit 100 and a calculation unit 200.

[0023] The reaction section 100 receives raw materials and products, and performs a chemical reaction that is the subject of analysis. The reaction section 100 can be a known reactor structure. For example, the reaction section 100 may include a reaction tank 110, a raw material supply section 120, a stirrer 130, and a spectrophotometer 140.

[0024] The reaction vessel 110 provides space for carrying out a chemical reaction. The reaction vessel 110 can be a known reaction container. The reaction vessel 110 can have a volume and shape corresponding to the scale of the reaction being carried out. For example, the reaction vessel 110 can be generally cylindrical.

[0025] The raw material supply unit 120 supplies materials required for the reaction to the reaction tank 110. For example, the raw material supply unit 120 supplies the reaction raw materials, catalysts, solvents, or mixtures thereof to the reaction tank 110. The raw material supply unit 120 can be implemented using known structures such as tanks and pumps. The raw material supply unit 120 is controlled by the calculation unit 200. The raw material supply unit 120 may include a metering pump.

[0026] A mixer 130 agitates a fluid (also referred to as a "chemical reaction system") containing reactants and products present in a reaction tank 110. The mixer 130 may include rotating stirring blades. The raw material and shape of the stirring blades can be selected according to the viscosity, reactivity, etc., of the chemical reaction system.

[0027] The spectrophotometer 140 acquires the spectrophotometric spectrum of the chemical reaction system. In particular, the spectrophotometer 140 can be an online spectrophotometric measurement device capable of real-time measurement. The spectrophotometer 140 can acquire known spectra, such as ultraviolet-visible absorption spectra, near-infrared absorption spectra, infrared absorption spectra, or Raman spectra. The spectrophotometer 140 supplies the measurement results to the processing unit 200. A light source corresponding to the target wavelength of the spectrophotometer 140 can also be separately provided in the reaction unit 100.

[0028] Based on or instead of this, the reaction section 100 may also have other elements required for reaction control. For example, the reaction section 100 may also have an exposure device, a cooling device, a heating device, a reflux device, and / or baffles, etc., as needed.

[0029] In the case of a continuous reaction, multiple reaction units 100 can be provided. In this case, the product or its purified form contained in the reaction unit 100 where the first reaction has taken place can be supplied via piping or the like to other reaction units 100 where a second reaction is taken after the first reaction.

[0030] The analytical apparatus 50 may also be without a reaction section 100. In this case, the analytical apparatus 50 may also communicate with an external reactor, which corresponds to the reaction section 100, control the reaction of the external reactor, and obtain data from the external reactor.

[0031] The calculation unit 200 acquires data measured in the reaction unit 100 and controls the reaction in the reaction unit 100. The calculation unit 200 may include a reaction control unit 210, a spectrum acquisition unit 220, a preprocessing unit 225, a calculation unit 230, an estimation unit 240, and a determination unit 250.

[0032] The computing unit 200 can be a computer such as a PC (personal computer), tablet computer, smartphone, workstation, server computer or general-purpose computer, or a computer system connected to multiple computers.

[0033] Instead, the arithmetic unit 200 can be a dedicated computer designed for chemical reaction analysis, or it can be dedicated hardware implemented by dedicated circuitry. The arithmetic unit 200 can be implemented by a single device (computer), or it can be implemented by multiple devices that share the tasks. In the arithmetic unit 200, although not specifically described below, it is equipped with memory, hard disk, etc., to appropriately store the information required for processing and to transfer information between various processing modules such as the calculation unit 230 and the estimation unit 240.

[0034] The reaction control unit 210 controls the operation of the raw material supply unit 120, causing the raw material supply unit 120 to supply the raw materials for the chemical reaction to the reaction tank 110. For example, the reaction control unit 210 supplies the desired amount of raw materials to the reaction tank 110 by controlling the operation of the pump in the raw material supply unit 120. Instead of controlling the supply of raw materials for the chemical reaction, the reaction control unit 210 can also control the supply of other materials (e.g., catalysts and / or solvents) that are directly or indirectly required in the chemical reaction.

[0035] In the case of a continuous reaction, the reaction control unit 210 can also control the movement of products or their refined products among multiple reaction units 100. For example, the reaction control unit 210 can use a pump or the like to supply the products or their refined products contained in the reaction unit 100 where the first reaction has taken place to other reaction units 100 where a second reaction is taking place after the first reaction via piping or the like.

[0036] The spectrum acquisition unit 220 acquires the spectroscopic spectra of the chemical reaction system at multiple time points. The spectrum acquisition unit 220 can continuously acquire spectroscopic spectra from the spectrophotometer 140.

[0037] The preprocessing unit 225 preprocesses the spectroscopic spectrum acquired by the spectral acquisition unit 220. As preprocessing, the preprocessing unit 225 can apply any one or more of baseline correction, first derivative, and second derivative to the spectroscopic spectrum.

[0038] The calculation unit 230 calculates characteristic quantities of the spectroscopic spectra at multiple time points. For example, the calculation unit 230 can calculate the principal components of the spectroscopic spectra at each time point included in the multiple time points as characteristic quantities by performing principal component analysis on the spectroscopic spectra at multiple time points. The calculation unit 230 can calculate characteristic quantities based on the spectroscopic spectra preprocessed by the preprocessing unit 225 or the spectroscopic spectra acquired by the spectrum acquisition unit 220.

[0039] The estimation unit 240 estimates the endpoint of the chemical reaction based on the change in the characteristic quantity calculated by the calculation unit 230. The estimation unit 240 can estimate the endpoint of the chemical reaction based on the nth-order differential value of the characteristic quantity with respect to the elapsed time (where n is a natural number).

[0040] The determining unit 250 determines the amount of raw material with unknown concentration used in the chemical reaction system, i.e., raw material with unknown concentration, based on the endpoint of the chemical reaction estimated by the estimating unit 240. For example, the determining unit 250 can determine the amount of raw material with unknown concentration based on the total amount and stoichiometry of raw material with known concentration used up to the endpoint of the chemical reaction. For example, the determining unit 250 can determine the initial concentration of an intermediate in a continuous reaction or the amount of intermediate used.

[0041] Thus, the analytical apparatus 50 of this embodiment can analyze the progress and endpoint of a chemical reaction in real time by using spectrophotometry. Furthermore, according to this embodiment, the analysis time and cost can be reduced compared to methods using calibration lines, etc.

[0042] Figure 3 This illustrates an example of the flow of the analytical method of this embodiment. The analytical apparatus 50 analyzes the chemical reaction, for example, by performing processes S100 to S700. The order of processes S100 to S700 can be changed, or some processes can be omitted.

[0043] First, in S100, the chemical reaction that is the subject of analysis begins. The reaction can be started by supplying the materials required for the chemical reaction (e.g., raw materials, catalysts, and / or solvents) to the reaction tank 110. The supply of materials can be controlled by the raw material supply unit 120, which is controlled by the reaction control unit 210. Alternatively, the materials can be supplied by a unit different from the raw material supply unit 120. A portion of the materials can be pre-supplied to the reaction tank 110.

[0044] In the case of a continuous reaction, the products from the preceding reaction can be used in reaction tank 110 as at least a portion of the raw materials (so-called intermediates) for subsequent reactions. Alternatively, intermediates can be supplied to reaction tank 110 via piping or the like from other reaction tanks where preceding reactions have taken place.

[0045] For example, in Figure 1 In the continuous reaction shown, if raw material A is pre-supplyed to the reaction tank 110, after the reaction in S100 begins, the reaction control unit 210 can supply raw material B from the raw material supply unit 120 to the reaction tank 110. After the reaction in S100 begins, the reaction control unit 210 can also supply all raw materials (e.g., raw material A and raw material B) from the raw material supply unit 120 to the reaction tank 110. In the second stage of the reaction, the reaction control unit 210 can supply raw material C from the raw material supply unit 120 to the reaction tank 110, which pre-stores intermediate AB as a product of the first stage reaction.

[0046] The reaction control unit 210 can control the supply amount of raw materials by controlling the raw material supply unit 120. For example, the reaction control unit 210 can supply a certain volume (e.g., 1 ml, 10 ml, 100 ml, etc.) or a certain weight (e.g., 1 g, 10 g, 100 g, etc.) of raw materials per hour (e.g., per second or per minute). Figure 1 The raw material supply unit 120 is controlled in a manner that allows for the control of the raw material supply unit 120 in the first stage of the reaction (raw material B or raw material C in the second stage of the reaction). For example, the reaction control unit 210 can control the supply amount by instructing the raw material supply unit 120, which acts as a metering pump, to provide the hourly supply amount and / or the supply time.

[0047] The reaction unit 100 can provide heat and light to the chemical reaction system as needed, thereby initiating and / or promoting the chemical reaction. The reaction unit 100 can also agitate the chemical reaction system during the reaction using a stirrer 130, thereby promoting the chemical reaction. For example, the reaction control unit 210 can control the stirrer 130, heating device, and / or exposure device of the reaction unit 100 to control the initiation and / or promotion of the chemical reaction.

[0048] Next, in S200, the analysis device 50 acquires the spectroscopic spectra of the chemical reaction system at multiple time points. The spectroscopic acquisition unit 220 acquires the spectroscopic spectral data of the chemical reaction system after the start of the reaction from the spectroscopic sensor 140. The spectroscopic acquisition unit 220 can acquire the spectroscopic spectra at multiple time points. The spectroscopic acquisition unit 220 can acquire the spectroscopic spectra of the reaction sequentially in real time. The spectroscopic acquisition unit 220 supplies the spectroscopic spectra to the calculation unit 200.

[0049] Next, in S300, the analysis device 50 calculates the characteristic quantity based on the spectroscopic spectrum obtained in S200.

[0050] Figure 4 express Figure 3 This is an example of a subprocess of S300 in the process flow. The preprocessing unit 225 and the calculation unit 230 can execute the processing of S300 by executing the processing of S310 to S320. In addition to S310 to S320, other processes can also be executed. Some of the processing of S310 to S320 can also be omitted.

[0051] In S310, the preprocessing unit 225 preprocesses the spectroscopic spectrum acquired by the spectrum acquisition unit 220 in S200. The preprocessing unit 225 can use known preprocessing methods on the spectroscopic spectrum. For example, the preprocessing unit 225 can perform normalization, standardization, removal of pre-set solvent components, baseline correction, first derivative, second derivative, or combinations thereof on each of the spectroscopic spectra at multiple time points. As an example, the preprocessing unit 225 can perform baseline correction on the spectroscopic spectra at each time point.

[0052] Next, in S320, the calculation unit 230 quantifies the features of the spectroscopic spectrum that were preprocessed in S310 and calculates the feature quantities of the spectroscopic spectrum at each time point. Thus, the calculation unit 230 outputs the feature quantities of the spectroscopic spectrum at each time point.

[0053] For example, the calculation unit 230 can calculate the score obtained by performing principal component analysis (PCA) on the spectroscopic spectra at multiple time points, which is the principal component of the spectroscopic spectra at each of the multiple time points, and use it as a characteristic quantity. As an example, the calculation unit 230 can calculate the first principal component in the principal component analysis and use it as a characteristic quantity.

[0054] The calculation unit 230 can perform principal component analysis using all the spectroscopic spectra obtained from multiple time points from the start of the reaction to the current time point. Alternatively, the calculation unit 230 can perform principal component analysis using spectroscopic spectra from the current time point to a predetermined time point (e.g., 360 spectroscopic spectra at 10-second intervals from 60 minutes ago to the current time point).

[0055] The calculation unit 230 can also determine the wavelength range that changes in the spectroscopic spectrum due to a chemical reaction, and set this determined wavelength range as the wavelength range to be analyzed in principal component analysis. Alternatively, the calculation unit 230 can have the user input the wavelength range to be analyzed during principal component analysis. The calculation unit 230 can also apply independent component analysis (ICA) and / or multivariate spectral decomposition (MCR) to the spectroscopic spectrum to calculate characteristic quantities, either based on or instead of principal component analysis.

[0056] The calculation unit 230 can also calculate characteristic quantities of the spectroscopic spectrum at each time point based on the peak shape of the spectroscopic spectrum, thereby replacing principal component analysis and the like. For example, the calculation unit 230 can calculate the peak area and / or peak intensity values ​​of a specific wavelength contained in the spectroscopic spectrum at each time point, which are included in multiple time points, as characteristic quantities.

[0057] In S400 following S300, the estimation unit 240 estimates the endpoint of the chemical reaction based on the change in the characteristic quantity calculated in S300. The estimation unit 240 can detect the endpoint of the chemical reaction and determine that the chemical reaction has ended if the change in the characteristic quantity meets predetermined conditions. The estimation unit 240 can also determine that the chemical reaction is continuing if the change in the characteristic quantity does not meet predetermined conditions.

[0058] The estimation unit 240 can estimate the endpoint of a chemical reaction based on the numerical value of the characteristic quantity relative to the elapsed time or the nth-order differential value of the characteristic quantity (where n is a natural number). For example, the estimation unit 240 can calculate the first-order or second-order differential value of the characteristic quantity relative to the elapsed time.

[0059] The estimation unit 240 can estimate the endpoint of a chemical reaction by comparing a characteristic quantity or a value based on the characteristic quantity with a threshold. For example, the estimation unit 240 can estimate the endpoint of a chemical reaction based on whether the characteristic quantity or the value based on the characteristic quantity is above or below the threshold. For example, the estimation unit 240 can estimate the endpoint of a chemical reaction based on whether the characteristic quantity or the value based on the characteristic quantity is within a predetermined numerical range.

[0060] As an example, the estimation unit 240 can estimate the endpoint of a chemical reaction at a time point where the absolute value of the characteristic quantity relative to the differential value (e.g., the first-order differential value) over time is above a threshold. As another example, the estimation unit 240 can estimate the endpoint of a chemical reaction at a time point where the absolute value of the characteristic quantity is below a threshold. Specific examples of the processing by the estimation unit 240 will be described later.

[0061] Next, in S500, the estimation unit 240 determines whether the chemical reaction has ended at the current time point. If the estimation unit 240 determines in S400 that the chemical reaction has ended, the analysis device 50 proceeds to S600. If the chemical reaction has not ended, the analysis device 50 continues the chemical reaction and continues to acquire the spectroscopic spectrum in S200.

[0062] If the chemical reaction continues, the analytical apparatus 50 can also restart the S200 process after a predetermined standby time (e.g., 1 to 300 seconds). For example, the S200 process can be restarted at intervals (e.g., 1 to 300 seconds) after the acquisition of the spectroscopic spectrum of S200. This is because acquiring the spectroscopic spectrum again after a very short time cannot be expected to result in any changes, which would waste storage and / or computational resources.

[0063] If it is determined that the chemical reaction has ended at the current time point, the estimation unit 240 may also sample the chemical reaction system as needed and analyze it using HPLC or similar methods to confirm whether the unknown concentration of the raw material (e.g., intermediate AB) has disappeared. If the unknown concentration of the raw material (e.g., intermediate AB) has not disappeared, the processing in S200 can be further continued.

[0064] The processing of S200 to S500 can also be performed simultaneously and in parallel, rather than sequentially.

[0065] In S600, the reaction control unit 210 controls the operation of the raw material supply unit 120, stopping the supply of raw materials for the chemical reaction. For example, it can be... Figure 1In the first stage of the reaction, the supply of raw material B is stopped, and in the second stage of the reaction, the supply of raw material C is stopped. The reaction control unit 210 can also control the temperature (e.g., cooling or heating) and / or add a reaction stopping agent, either based on or in lieu of stopping the supply of raw materials. This conserves the use of raw materials and other resources that do not contribute to the chemical reaction.

[0066] Next, in S700, the determining unit 250 determines the amount of the unknown concentration raw material used in the chemical reaction system, i.e., the unknown concentration raw material, based on the endpoint of the chemical reaction estimated in S400. The determining unit 250 determines the amount and concentration of the unknown concentration raw material and the amount of product based on the total amount of known concentration raw materials added from the start of the reaction to the endpoint of the reaction and the stoichiometry of the chemical reaction. The unknown concentration raw material may be the product of a previous stage of the chemical reaction of the target chemical reaction (e.g., is...). Figure 1 The product of the first stage reaction and one of the raw materials of the second stage, intermediate AB).

[0067] In the stoichiometry of a chemical reaction, the molar amount of raw material consumed (x) with known concentration is denoted as y (y=mx), and the molar amount of product generated is denoted as z (z=nx). Here, m and n are the molar ratios of the chemical reaction based on stoichiometry. The concentration of the raw material with known concentration is denoted as M. X Let the total amount be X. Let the concentration of the raw material with unknown concentration be M. Y Let the total amount (initial amount) be Y. Let the amount of product generated be Z.

[0068] In this case, the determining unit 250 can, for example, calculate y = (M X The initial (consumed) molar amount y of the raw material with unknown concentration is determined by (×X)×(mx / x), and M is calculated. Y =(M X The concentration M of the raw material with unknown concentration is determined by (×X)×(mx / x)×(1 / Y). Y The determination unit 250, for example, can be achieved by calculating z = (M... X The molar amount z of the product (an intermediate in subsequent chemical reactions) is determined by (×X)×(nx / x).

[0069] Figure 5 This represents an example of a chemical reaction that is the subject of this embodiment. The analytical apparatus 50 of this embodiment, for example, can be... Figure 5 The peptide synthesis reaction shown is used in this experiment. The R, R', and R'' groups in the compounds shown can be any organic groups. For example, R can be any functional group (side chain), R' can be a protecting group, and R'' can be a peptide or amino acid that forms the intermediate. Figure 1The second stage of the reaction can be Figure 5 The reaction shown depicts the reaction of raw material C with intermediate AB to produce intermediate ABC. Here, the concentration of raw material C is known.

[0070] exist Figure 5 In the reaction shown, the molar ratio of the raw material C consumed in the reaction, intermediate AB, and the generated intermediate ABC is 1:1:1 (i.e., x:y:z = 1:1:1). Therefore, the determining unit 250 can calculate the total amount (e.g., the weight or volume of raw material C) of raw material C, which is a raw material with a known concentration, from the start of the reaction to the end of the reaction, based on the amount of raw material C added to the chemical reaction system per unit time multiplied by the time from the start of the reaction to the end of the reaction.

[0071] The analytical method and apparatus of this embodiment can also be applied to various synthetic reactions other than peptide synthesis reactions. The analytical method and apparatus of this embodiment are particularly suitable for chemical reactions in which the molar ratio of reactants and products is known. For example, the analytical apparatus and method of this embodiment can also be used, based on or replacing peptides, for the synthesis of compounds such as nucleic acids or polysaccharides that repeatedly contain constant structures. The analytical apparatus and method of this embodiment can also be applied not to continuous reactions, but to single reactions involving reactants of unknown concentration.

[0072] Next, the determination unit 250 calculates the molar amount M of raw material C based on the known concentration and total amount of raw material C (and, if necessary, the density of raw material C). C The determination unit 250 is capable of determining the molar amount M. C The same amount is determined as the molar amount M consumed by intermediate AB, which is a raw material with unknown concentration. AB And the molar amount M of intermediate ABC as the product ABC .

[0073] Furthermore, it is determined that the 250-unit uses the molar amount M consumed. AB The concentration of intermediate AB before reaction is determined by the amount (volume or weight) of the input intermediate AB, which is a raw material with unknown concentration. The determination unit 250 can use the amount (volume or weight, etc.) of the product before and / or after purification and the molar amount M generated. ABC The concentration (volume concentration or weight concentration, etc.) of intermediate ABC, which is a product, is determined. In this way, the determination unit 250 can determine the amount and concentration of raw materials and products with unknown concentrations based on the endpoint of the chemical reaction and the molar ratio of raw materials and products in the chemical reaction.

[0074] The process can be terminated after S700, or alternatively, other reactions using the product as a starting material can be performed. For example, it can be carried out... Figure 1The subsequent reactions in the continuous reaction shown can be performed before proceeding to the subsequent reactions. Products can be separated, purified, moved, and / or byproducts and raw materials can be removed. The S100 to S700 processes can also be repeated in the subsequent reactions.

[0075] Thus, according to this embodiment, by analyzing the spectroscopic spectrum of the chemical reaction system, the concentration and amount of unknown reactants can be calculated in real time, simultaneously with the extent of the chemical reaction and the estimation of its endpoint. Furthermore, according to this embodiment, compared to methods using calibration lines, the progress of a chemical reaction can be analyzed rapidly and at low cost within a short time. In particular, according to this embodiment, compared to individual batch synthesis, it is more suitable for the analysis of intermediates in continuous reactions where information about the reactants is difficult to obtain.

[0076] Figure 6 An example of a graph representing the characteristic quantities of this embodiment. Figure 6 The horizontal axis represents the chemical reaction that produces intermediate ABC. Figure 1 The time elapsed after the start of the second phase (represented as "reaction time (minutes)"). Figure 6 The vertical axis on the left represents the change of the first principal component over time obtained by the calculation unit 230 through principal component analysis of the spectroscopic spectra at multiple time points, corresponding to a curve that decreases to the right. Figure 6 The vertical axis on the right represents the total amount of raw material C added relative to the chemical reaction system.

[0077] As shown in the figure, the value of the first principal component begins to decrease immediately after the reaction and then continues to decrease at a roughly constant slope until time point 620. The constant rate of change in the value of the first principal component indicates that the composition of the chemical reaction system also changes at a constant rate. This suggests that before time point 620, the chemical reaction proceeded at a roughly constant rate.

[0078] If time point 620 (represented as 22.4 min in the graph) is reached, it indicates that the slope of the line segment representing the first principal component changes abruptly to positive. This signifies that an anomaly has occurred in the reaction, which was proceeding at a constant rate. That is, the abrupt change in slope suggests that at time point 620, the reactants other than reactant C (e.g., intermediate AB) have been depleted and the chemical reaction has ceased.

[0079] In S400 immediately following time point 620, the estimation unit 240 can detect the change in the slope of such a first principal component. Figure 6A sharp change in the slope of the first principal component is reflected in the value of the nth-order differential (e.g., the first-order differential). For example, when the first principal component is used as a characteristic quantity, the estimation unit 240 calculates the nth-order differential (e.g., the first-order differential) of the first principal component. If the nth-order differential (or its absolute value) is above a threshold, it is determined that the slope of the first principal component has changed sharply (i.e., the chemical reaction has ended).

[0080] If the amount of raw material C added up to time point 620 is 1.7 mmol as shown in the figure, the determination unit 250 determines the amount of intermediate AB reacting with raw material C to be the same as 1.7 mmol of raw material C. Furthermore, the determination unit 250 also determines the amount of intermediate ABC, which is the product, to be 1.7 mmol.

[0081] On the other hand, as shown in the diagram, starting from the beginning of the reaction, reactant C was continuously added, with the total amount added continuously increasing. Addition of reactant C was stopped at time point 610. At time point 620, the chemical reaction ceased to proceed; therefore, from time point 620 to time point 610, reactant C, which did not contribute to the reaction, was unnecessarily added.

[0082] The estimation unit 240 in this embodiment can determine in real time whether the chemical reaction has ended. Therefore, according to this embodiment, after time point 620, unnecessary supply of raw materials can be quickly stopped.

[0083] Figure 7 Another example of a graph representing the characteristic quantities of this embodiment. Figure 7 The horizontal axis represents the chemical reaction that produces intermediate ABC. Figure 1 The time elapsed after the start of the second phase (represented as "reaction time (minutes)"). Figure 7 The vertical axis represents the peak area of ​​intermediate AB detected by analyzing the chemical reaction system using high performance liquid chromatography (HPLC).

[0084] As shown in the figure, the peak area begins to decrease immediately after the reaction and then continues to decrease at a roughly constant slope until time point 710. The constant rate of decrease in peak area indicates that the specific components contained in the chemical reaction system are also decreasing at a constant rate. This suggests that prior to time point 710, the consumption of unsupplied raw materials (e.g., intermediate AB) proceeds at a roughly constant rate.

[0085] If time point 710 is reached (marked around 25 minutes in the graph), the decrease in peak area value stops. This indicates that the raw material other than raw material C (e.g., intermediate AB) has been depleted, and the reaction has stopped. Since the calculation unit 230 uses the peak area in the wavelength region corresponding to intermediate AB in the spectrophotometer as a characteristic quantity, the change of this characteristic quantity over time is expected to represent... Figure 7 The curve graph shows the same trend.

[0086] In S400, the estimation unit 240 can detect changes in the peak area of ​​the spectroscopic spectrum. The flattening of the peak area slope of the spectroscopic spectrum is reflected in the value of the peak area itself and / or the value of the nth derivative of the peak area (e.g., the first derivative).

[0087] For example, when using peak area as a characteristic quantity, the estimation unit 240 determines that the chemical reaction has ended if the value of the peak area is below a threshold set near 0. Alternatively, the estimation unit 240 may determine that the chemical reaction has ended if the nth (e.g., first) derivative (or its absolute value) of the peak area is above the threshold.

[0088] The calculation unit 230 can use the peak intensity of a specific wavelength region as a characteristic quantity, based on or instead of the peak area of ​​the specific wavelength region. The calculation unit 230 can use the peak area and / or peak intensity corresponding to a single peak, or it can use the peak area and / or peak intensity corresponding to multiple peaks instead.

[0089] Furthermore, various embodiments of the present invention can be described with reference to flowcharts and block diagrams, where a module can represent (1) a stage of the process of performing an operation or (2) a part of a device that performs the operation. Specific stages and parts can be implemented by dedicated circuits, programmable circuits supplied together with computer-readable instructions stored on a computer-readable medium, and / or processors supplied together with computer-readable instructions stored on a computer-readable medium. Dedicated circuits may include digital and / or analog hardware circuits, and may also include integrated circuits (ICs) and / or discrete circuits. Programmable circuits may include reconfigurable hardware circuits, including logic AND, logic OR, logic XOR, logic NAND, logic NOR and other logic operations, flip-flops, registers, field-programmable gate arrays (FPGAs), programmable logic arrays (PLAs), and other memory elements.

[0090] Computer-readable media can include any tangible device capable of storing instructions executable by a suitable device. Consequently, a computer-readable medium having instructions stored therein includes a product containing instructions executable by means of means for performing operations specified by a flowchart or block diagram. Examples of computer-readable media include: electronic storage media, magnetic storage media, optical storage media, electromagnetic storage media, semiconductor storage media, etc. More specific examples of computer-readable media include: floppy disks, magnetic disks, hard disks, random access memory (RAM), read-only memory (ROM), erasable programmable read-only memory (EPROM or flash memory), electrically erasable programmable read-only memory (EEPROM), static random access memory (SRAM), optical disc read-only memory (CD-ROM), digital multipurpose disc (DVD), Blu-ray disc, memory stick, integrated circuit card, etc.

[0091] Computer-readable instructions include any one of source code and object code described by any combination of one or more programming languages, including assembly instructions, instruction set architecture (ISA) instructions, machine instructions, machine-dependent instructions, microcode, firmware instructions, status setting data, or existing procedural programming languages ​​such as Smalltalk (registered trademark), JAVA (registered trademark), C++, and "C" or similar programming languages.

[0092] Computer-readable instructions can be provided via a local area network (LAN), wide area network (WAN) such as the Internet, to the processor or programmable circuit of a programmable data processing device such as a general-purpose computer, a special-purpose computer, or other computers, and are executed in order to create means for performing the operations specified by a flowchart or block diagram. Examples of processors include: computer processors, processing units, microprocessors, digital signal processors, controllers, microcontrollers, etc.

[0093] Figure 8 Examples of computer 2200 that can implement the present invention wholly or partially are shown. Through a program installed on computer 2200, computer 2200 can perform operations associated with an apparatus or one or more parts of that apparatus as an embodiment of the present invention, or execute that operation or those one or more parts, and / or computer 2200 can execute processes or stages of processes of embodiments of the present invention. To enable computer 2200 to perform specific operations associated with several or all of the modules in the flowcharts and block diagrams described in this specification, such a program can be executed by CPU 2212. The program can be provided as a computer program product containing the program.

[0094] The computer 2200 of this embodiment includes a CPU 2212, RAM 2214, a graphics controller 2216, and a display device 2218, which are interconnected via a main controller 2210. The computer 2200 also includes input / output units such as a communication interface 2222, a hard disk drive 2224, a DVD-ROM drive 2226, and an IC card drive, which are connected to the main controller 2210 via an input / output controller 2220. The computer also includes conventional input / output units such as a ROM 2230 and a keyboard 2242, which are connected to the input / output controller 2220 via an input / output chip 2240.

[0095] CPU 2212 operates according to the program stored in ROM 2230 and RAM 2214, thereby controlling each unit. Graphics controller 2216 acquires image data generated by CPU 2212 from frame buffers or other storage provided in RAM 2214 or from its own storage, and displays the image data on display device 2218.

[0096] Communication interface 2222 enables communication with other electronic devices via a network. Hard disk drive 2224 stores programs and data used by CPU 2212 within computer 2200. DVD-ROM drive 2226 reads programs or data from DVD-ROM 2201 and provides programs or data to hard disk drive 2224 via RAM 2214. IC card drive reads programs and data from IC card and / or writes programs and data to IC card.

[0097] ROM 2230 stores a boot program and / or programs that depend on the hardware of computer 2200 and are executed by computer 2200 when activated. Input / output chip 2240 can also connect various input / output units to input / output controller 2220 via parallel port, serial port, keyboard port, mouse port, etc.

[0098] The program is provided by a computer-readable medium such as a DVD-ROM 2201 or an IC card. The program is read from the computer-readable medium and installed in a hard disk drive 2224, RAM 2214, or ROM 2230, which are also examples of computer-readable media, and executed by the CPU 2212. The information processing described within these programs is read into the computer 2200, thereby enabling cooperation between the program and the aforementioned various types of hardware resources. An apparatus or method can be constructed to perform the manipulation or processing of information by using the computer 2200.

[0099] For example, when communication is performed between computer 2200 and an external device, CPU 2212 can execute a communication program loaded in RAM 2214, and instruct communication interface 2222 to perform communication processing based on the processing described in the communication program. Under the control of CPU 2212, communication interface 2222 reads transmission data stored in a transmission buffer processing area provided in a recording medium such as RAM 2214, hard disk drive 2224, DVD-ROM 2201, or IC card, sends the read transmission data to the network, or writes received data received from the network to a receive buffer processing area provided on the recording medium, etc.

[0100] CPU 2212 can read all or necessary portions of files or databases stored on external recording media such as hard disk drive 2224, DVD-ROM drive 2226 (DVD-ROM 2201), IC cards, etc., into RAM 2214, and perform various types of processing on the data in RAM 2214. Then, CPU 2212 writes the processed data back to the external recording media.

[0101] Various types of information, such as programs, data, tables, and databases, can be stored in recording media and processed. CPU 2212 performs various types of processing described throughout this disclosure on data read from RAM 2214 and writes the results back to RAM 2214. These various types of processing include operations specified by a sequence of program instructions, information processing, conditional judgments, conditional branches, unconditional branches, information retrieval / replacement, etc. Furthermore, CPU 2212 can retrieve information from files, databases, etc., within the recording medium. For example, if multiple entries, each having an attribute value associated with a second attribute, are stored in the recording medium, CPU 2212 can retrieve from these multiple entries an entry that matches a condition specifying the attribute value of the first attribute, and read the attribute value of the second attribute stored in that entry, thereby obtaining the attribute value of the second attribute associated with the first attribute that satisfies a predetermined condition.

[0102] The programs or software modules described above can be stored on or near the computer 2200 on a computer-readable medium. Furthermore, recording media such as hard disks or RAM provided in a server system connected to a dedicated communication network or the Internet can be used as computer-readable media, thereby providing the program to the computer 2200 via the network.

[0103] The present invention has been described above using embodiments, but the technical scope of the present invention is not limited to the scope described in the above embodiments. It will be apparent to those skilled in the art that various modifications or improvements can be made to the above embodiments. As can be seen from the claims, such modifications or improvements may also be included within the technical scope of the present invention.

[0104] The execution order of actions, processes, steps, and stages in the apparatus, systems, programs, and methods shown in the claims, description, and drawings is not specifically stated as "earlier" or "before." Furthermore, it should be noted that any order is permissible as long as the output of the preceding process is not used in the subsequent process. Regarding the flow of actions in the claims, description, and drawings, even if terms such as "firstly," "next," etc., are used for ease of explanation, it does not imply that they must be performed in that order. The expression "A and / or B" can mean "A, B, or A and B." The expression "A, B, and / or C" can mean "any one of A, B, and C, or any combination of two or more of them." Explanation of reference numerals in the attached figures

[0105] 10 Raw Material A, 12 Raw Material B, 14 Intermediate AB, 16 Raw Material C, 18 Intermediate ABC, 20 Raw Material D, 30 Product, 50 Analytical Apparatus, 100 Reaction Section, 110 Reaction Tank, 120 Raw Material Supply Section, 130 Stirrer, 140 Spectrophotometer, 200 Computation Section, 210 Reaction Control Section, 220 Spectrum Acquisition Section, 225 Preprocessing Section, 230 Calculation Section, 240 Estimation Section, 250 Determination Section, 610 Time Point, 620 Time Point, 710 Time Point, 2200 Computer, 2201 DVD-ROM, 2210 Main Controller, 2212 CPU, 2214 RAM, 2216 Graphics Controller, 2218 Display Device, 2220 Input / Output Controller, 2222 Communication Interface, 2224 Hard Disk Drive, 2226 DVD-ROM drive, 2230 ROM, 2240 input / output chip, 2242 keyboard.

Claims

1. An analytical apparatus for estimating the endpoint of a chemical reaction in which the concentration of at least one raw material is unknown, wherein the apparatus comprises: The spectrometer acquisition unit acquires the spectroscopic spectra of the chemical reaction system at multiple time points. The computing unit calculates the characteristic quantities of the spectroscopic spectrum at each time point based on the spectroscopic spectra at the plurality of time points; and The estimation unit estimates the endpoint of the chemical reaction based on the changes in characteristic quantities calculated by the calculation unit.

2. The analytical apparatus according to claim 1, wherein, It also includes a determining unit that determines the amount of a raw material of unknown concentration used in the chemical reaction system based on the endpoint of the chemical reaction estimated by the estimating unit. The raw material of unknown concentration is a raw material of unknown concentration.

3. The analytical apparatus according to claim 2, wherein, The raw material of unknown concentration is the product of the preceding stage of the chemical reaction of the presumed object.

4. The analytical apparatus according to claim 1, wherein, The computing unit calculates the principal components of the spectroscopic spectra of each time point included in the plurality of time points as the feature quantity by performing principal component analysis on the spectroscopic spectra of the plurality of time points.

5. The analytical apparatus according to claim 1, wherein, The calculation unit calculates a value based on peak area and / or peak intensity as the characteristic quantity, wherein the peak area and / or peak intensity are the peak area and / or peak intensity of a specific wavelength contained in the spectroscopic spectrum of each time point included in the plurality of time points.

6. The analytical apparatus according to claim 1, wherein, The estimation unit estimates the endpoint of the chemical reaction based on the first derivative of the characteristic quantity with respect to the elapsed time.

7. The analytical apparatus according to claim 1, wherein, The estimation unit estimates the time point when the absolute value of the first derivative of the characteristic quantity with respect to the elapsed time is above a threshold as the endpoint of the chemical reaction.

8. The analytical apparatus according to claim 1, wherein, The analytical apparatus also includes a preprocessing unit for preprocessing the spectroscopic spectrum. The calculation unit calculates the characteristic quantity based on the spectroscopic spectrum preprocessed by the preprocessing unit.

9. The analytical apparatus according to claim 8, wherein, As a preprocessing step, the preprocessing unit applies any one or more of baseline correction, first derivative, and second derivative to the spectroscopic spectrum.

10. The analytical apparatus according to any one of claims 1 to 9, wherein, The chemical reaction is part of a continuous process in which the product is used as a new raw material to repeatedly carry out subsequent reactions.

11. The analytical apparatus according to claim 1, wherein, The chemical reaction is a reaction in which a second monomer, different from the first monomer, is polymerized in a polymer composed of repeated first monomers to form a block copolymer.

12. An analytical method for estimating the endpoint of a chemical reaction in which the concentration of at least one reactant is unknown, wherein: In the spectral acquisition stage, the spectroscopic spectra of the chemical reaction system at multiple time points are obtained. In the calculation phase, the characteristic quantities of the spectroscopic spectrum at each time point are calculated based on the spectroscopic spectra at the multiple time points. as well as In the estimation phase, the endpoint of the chemical reaction is estimated based on the changes in characteristic quantities calculated in the calculation phase.

13. A computer program product comprising a program for estimating the endpoint of a chemical reaction in which the concentration of at least one raw material is unknown. The computer performs the following by executing the program: In the spectral acquisition stage, the spectroscopic spectra of the chemical reaction system at multiple time points are obtained. In the calculation phase, the characteristic quantities of the spectroscopic spectrum at each time point are calculated based on the spectroscopic spectra at the multiple time points. as well as In the estimation phase, the endpoint of the chemical reaction is estimated based on the changes in characteristic quantities calculated in the calculation phase.

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