Prediction method for actual hydrogen bond forming ability of organic compound containing intramolecular hydrogen bond and application of prediction method in prediction of partition coefficient between two phases

Abstract

The invention provides a method for predicting the actual hydrogen bond forming ability of an organic compound containing intramolecular hydrogen bonds and application of the method in prediction of a partition coefficient between two phases, and relates to the technical field of intramolecular hydrogen bonds. The actual hydrogen bond forming ability result of the organic compound containing the intramolecular hydrogen bond, which is obtained by the prediction method provided by the invention, can be used for accurately predicting various physicochemical properties such as a distribution coefficient of the compound, and a large amount of related experimental data of contribution of certain specific groups to the physicochemical properties does not need to be obtained and concluded; the method provided by the invention has the characteristics of simplicity in operation, simple steps, high universality, short time consumption, low cost and accurate calculation results of the physical and chemical properties such as the distribution coefficient.

Description

Technical Field

[0001] The present invention relates to the technical field of intramolecular hydrogen bonds, and in particular to a method for predicting the actual hydrogen bond forming ability of an organic compound containing intramolecular hydrogen bonds and its application in predicting a distribution coefficient between two phases. Background Art

[0002] Intramolecular hydrogen bonds (IMHB) of organic compounds significantly affect their lipophilicity and physicochemical properties. It is reported that IMHB can significantly improve the membrane permeability and bioavailability of drugs, thereby increasing the success rate of drug research and development. Drug design strategies based on IMHB have also attracted the interest of pharmacologists. It is of great significance to study the quantitative effects of IMHB on the lipophilicity and various physicochemical properties of organic compounds and drugs.

[0003] Although there are experimental and computational methods to explore the effects of IMHB on the physicochemical properties of organic compounds, these methods are based on the contribution of certain specific groups to the physicochemical properties, require a large amount of experimental data, and have the disadvantages of complex steps, low accuracy, and poor universality. Therefore, it is necessary to develop a simple, universal, and accurate method to calculate the effects of IMHB on various physicochemical properties of compounds. Summary of the invention

[0004] In view of this, the object of the present invention is to provide a method for predicting the actual hydrogen bond forming ability of an organic compound containing intramolecular hydrogen bonds and its application in predicting the partition coefficient between two phases. The actual hydrogen bond forming ability of an organic compound containing intramolecular hydrogen bonds obtained by the prediction method provided by the present invention is used to predict various physical and chemical properties of the compound. The method is simple, has strong versatility, and the calculation results of physical and chemical properties such as the partition coefficient are accurate.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides a method for predicting the actual hydrogen bond forming ability of an organic compound containing intramolecular hydrogen bonds, characterized in that it comprises the following steps:

[0007] Based on the two-dimensional structure of intramolecular hydrogen-bonded organic compounds, the hydrogen-bonding ability of HBD and HBA without IMHB formation was obtained. HBD and H HBA and generate the three-dimensional structure that may form IMHB through molecular simulation software;

[0008] By the H HBD and H HBA According to formula (1), ΔG of IMHB is obtained HB ;

[0009] The ΔG of IMHB is obtained according to the three-dimensional structure of the organic compound containing intramolecular hydrogen bonds. restr_bond ;

[0010] By the ΔG HB and ΔG restr_bond According to formula (2), the ΔG of each IMHB is obtained IMHB ;

[0011] By the ΔG IMHB According to formula (3), K IMHB ;

[0012] By the H HBD and K IMHB According to formula (4), H IM HBD , by the H HBA and K IMHB According to formula (5), H IM HBA ;

[0013] Among them, HBD represents hydrogen bond donor, HBA represents hydrogen bond acceptor, and IMHB represents intramolecular hydrogen bond;

[0014] ΔG HB =-(H HBD ×H HBA ) / H w Formula (1);

[0015] ΔG IMHB =ΔG HB +ΔG restr_bond Formula (2);

[0016]

[0017] H IM HBD =H HBD / (1+K IMHB ) Formula (4);

[0018] H IM HBA =H HBA / (1+K IMHB ) Formula (5);

[0019] Among them, H w It represents the hydrogen bond forming ability of the lone electron pair on hydrogen atoms or oxygen in water, which is 7.02 kJ / mol;

[0020] H HBD It indicates the hydrogen bonding ability of HBD when IMHB is not formed;

[0021] H HBAIt indicates the hydrogen bonding ability of HBA when IMHB is not formed;

[0022] ΔG HB It represents the free energy change of intramolecular hydrogen bond formation between HBD and HBA in a nonpolar environment;

[0023] ΔG restr_bond represents the sum of the free energy changes of inhibiting the rotatable bonds between HBD and HBA;

[0024] K IMHB It is expressed as the equilibrium constant in a nonpolar environment;

[0025] H IM HBD It indicates the actual hydrogen bonding ability of HBD when forming IMHB;

[0026] H IM HBA It indicates the actual hydrogen bonding ability of HBA when forming IMHB.

[0027] Preferably, the organic compound containing intramolecular hydrogen bonds includes a compound whose hydrogen bond donor and hydrogen bond acceptor can form hydrogen bonds after rotating single bonds.

[0028] The present invention also provides the application of the prediction method described in the above technical solution in predicting the physicochemical properties of organic compounds containing intramolecular hydrogen bonds.

[0029] Preferably, the physicochemical properties include the partition coefficient between two phases or the penetration rate in the skin.

[0030] Preferably, the two phases include water-organic phase, air-organic phase, air-water, air-blood or air-human brain.

[0031] Preferably, the organic phases in the water-organic phase and the air-organic phase independently include chloroform, n-octanol or alkane.

[0032] The present invention also provides a method for predicting the partition coefficient of an organic compound containing intramolecular hydrogen bonds between two phases, comprising the following steps:

[0033] According to the prediction method described in the above technical solution, the H IM HBD and H IM HBA ;

[0034] The sum of the hydrogen bond forming abilities of all hydrogen bond donors of the tested organic compound containing intramolecular hydrogen bonds that do not form IMHB M_HBD , H HBD and the H IM HBDAccording to formula (6), the sum of the hydrogen bond forming abilities of all hydrogen bond donors in the IMHB molecule is obtained: IM M_HBD ;

[0035] H IM M_HBD =H M_HBD +H IM HBD -H HBD Formula (6);

[0036] The sum of the hydrogen bond forming abilities of all hydrogen bond acceptors that do not form IMHB is calculated by measuring the intramolecular hydrogen bond-containing organic compound molecule. M_HBA , H HBA and the H IM HBA According to formula (7), the sum of the hydrogen bond forming abilities of all hydrogen bond acceptors of the IMHB molecules is obtained as H IM M_HBA , H IM M_HBD ;

[0037] H IM M_HBA =H M_HBA +H IM HBA -H HBA Formula (7);

[0038] According to the known organic compounds without intramolecular hydrogen bonds, H M_HBD , H M_HBA and ΔG tr_depol Obtain k1, k2, k3 and c1 of formula (I), and according to k1, k2, k3, c1 and the H of the organic compound containing intramolecular hydrogen bonds to be tested IM M_HBD , H IM M_HBA and ΔG tr_depo , according to formula (I), the distribution coefficient of the organic compound containing intramolecular hydrogen bonds to be tested between the two phases is obtained;

[0039] logP sol =k1×ΔG tr_depol +k2×H M_HBD +k3×H M_HBA +c1 formula (I);

[0040] Among them, P sol is the distribution coefficient; logP sol is the logarithm of the distribution coefficient; k1, k2, k2 and c1 are equation constants.

[0041] The ΔG tr_depolThe free energy change of a compound when it is transferred from water to a nonpolar solvent, assuming that all atoms in the compound are nonpolar atoms.

[0042] Preferably, the organic phase comprises chloroform, n-octanol or alkane.

[0043] The present invention also provides a method for predicting the partition coefficient of an organic compound containing intramolecular hydrogen bonds in a water-organic phase, comprising the following steps:

[0044] According to the prediction method described in the above technical solution, the H IM M_HBD and H IM M_HBA ;

[0045] Calculate the S of known organic compounds containing intramolecular hydrogen bonds and the organic compounds to be tested containing intramolecular hydrogen bonds respectively. M ; The S M According to its molecular formula calculation, when the molecular formula of the compound is C c H h O o N n S s F f Cl cl Br br I i When the S M The value is c+0.3h+o+n+2s+0.6f+1.8cl+2.2br+2.6i-0.2Nc3-0.6Nc4; Nc3 is the sp connecting the three heavy atoms 3 The number of carbon atoms, Nc4 is the sp connecting four heavy atoms 3 Number of carbon atoms;

[0046] According to the known organic compounds without intramolecular hydrogen bonds, H M_HBD , H M_HBA , S M , by multiple linear regression, the partition coefficient of the tested organic compound containing intramolecular hydrogen bonds in water-organic phase represented by formula (II) is obtained;

[0047] logP sol =k4×S M +k5×H M_HBD +k6×H M_HBA +c2 Formula (II);

[0048] Among them, P sol Partition coefficient; logP sol Logarithm of the partition coefficient; k4, k5, k6 and c2 are equation constants.

[0049] Preferably, the organic phase in the water-organic phase comprises chloroform, alkane or n-octanol.

[0050] The actual hydrogen bond forming ability results of organic compounds containing intramolecular hydrogen bonds obtained by the prediction method provided by the present invention can accurately predict various physicochemical properties such as the distribution coefficient of the compound, without the need to obtain a large amount of relevant experimental data on the contribution of certain specific groups to the physicochemical properties and then summarize them. The method provided by the present invention has the characteristics of simple operation, simple steps, strong versatility, short time consumption, low cost and accurate prediction results of physicochemical properties such as the distribution coefficient. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 The equilibrium diagram between the compound not forming IMHB (left) and forming IMHB (right);

[0052] Figure 2 It is a structural diagram of an organic compound containing intramolecular hydrogen bonds in Example 1, wherein HBD: blue hydrogen atom, HBA: red atom. DETAILED DESCRIPTION

[0053] The present invention provides a method for predicting the actual hydrogen bond forming ability of an organic compound containing intramolecular hydrogen bonds, comprising the following steps:

[0054] Based on the two-dimensional structure of intramolecular hydrogen-bonded organic compounds, the hydrogen-bonding ability of HBD and HBA without IMHB formation was obtained. HBD and H HBA and generate the three-dimensional structure that may form IMHB through molecular simulation software;

[0055] By the H HBD and H HBA According to formula (1), ΔG of IMHB is obtained HB ;

[0056] The ΔG of IMHB is obtained according to the three-dimensional structure of the organic compound containing intramolecular hydrogen bonds. restr_bond ;

[0057] By the ΔG HB and ΔG restr_bond According to formula (2), the ΔG of each IMHB is obtained IMHB ;

[0058] By the ΔG IMHB According to formula (3), K IMHB ;

[0059] By the H HBD and K IMHB According to formula (4), H IMHBD , by the H HBA and K IMHB According to formula (5), H IM HBA ;

[0060] Among them, HBD represents hydrogen bond donor, HBA represents hydrogen bond acceptor, and IMHB represents intramolecular hydrogen bond;

[0061] ΔG HB =-(H HBD ×H HBA ) / H w Formula (1);

[0062] ΔG IMHB =ΔG HB +ΔG restr_bond Formula (2);

[0063]

[0064] H IM HBD =H HBD / (1+K IMHB ) Formula (4);

[0065] H IM HBA =H HBA / (1+K IMHB ) Formula (5);

[0066] Among them, H w It represents the hydrogen bond forming ability of the lone electron pair on hydrogen atoms or oxygen in water, which is 7.02 kJ / mol;

[0067] H HBD It indicates the hydrogen bonding ability of HBD when IMHB is not formed;

[0068] H HBA It indicates the hydrogen bonding ability of HBA when IMHB is not formed;

[0069] ΔG HB It represents the free energy change of intramolecular hydrogen bond formation between HBD and HBA in a nonpolar environment;

[0070] ΔG restr_bond represents the sum of the free energy changes of inhibiting the rotatable bonds between HBD and HBA;

[0071] K IMHB It is expressed as the equilibrium constant in a nonpolar environment;

[0072] H IM HBDIt indicates the actual hydrogen bonding ability of HBD when forming IMHB;

[0073] H IM HBA It indicates the actual hydrogen bonding ability of HBA when forming IMHB.

[0074] In the present invention, the ΔG tr_depol , H HBD and H HBA For details of the calculation, please refer to the published article: D. Chen, N. Oezguen, P. Urvil, C. Ferguson, SM Dann, TC Savidge, Regulation of promoter-ligand binding affinity by hydrogen bond pairing. Sci. Adv. 2, e1501240 (2016).

[0075] In the present invention, the molecular simulation software preferably includes SYBYL.

[0076] In the present invention, the organic compound containing intramolecular hydrogen bonds preferably includes a compound whose hydrogen bond donor and hydrogen bond acceptor can form hydrogen bonds after rotating a single bond. In the present invention, the organic compound containing intramolecular hydrogen bonds preferably includes any one of the following compounds:

[0077]

[0078] In the present invention, when the distance between the HBD and HBA is greater than 95% of the sum of the van der Waals radii of the HBD and HBA, the HBD and HBA do not form an IMHB; when the distance between the HBD and HBA is not greater than 95% of the sum of the van der Waals radii of the HBD and HBA, the HBD and HBA form an IMHB.

[0079] In the present invention, the ΔG of the IMHB restr_bond is the ΔG of all single bonds between HBD and HBA restr_bond sum.

[0080] In the present invention, the H w is 7.02 kJ / mol. In the present invention, suppressing a C(sp 3 )-C(sp 3 ) ΔG of chemical bond restr_bond is 3.7 kJ / mol, suppressing the ΔG of other chemical bonds restr_bond It will be adjusted based on factors such as the size of the group on the bond.

[0081] In the present invention, there is a balance between HBD and HBA not forming IMHB (left, open form) and forming IMHB (right, close form) in the organic compound containing intramolecular hydrogen bonds, see Figure 1 When HBD and HBA do not form IMHB (see Figure 1 middle left), their hydrogen bonding abilities (denoted by H HBD and H HBA can be obtained according to the structures of related compounds. When HBD and HBA form IMHB (see Figure 1 There is electron transfer between HBD and HBA, which results in the actual hydrogen bonding ability between HBD and HBA being lower than that between H HBD and H HBA The actual hydrogen bonding abilities of HBD and HBA are expressed as IM HBD and H IM HBA Indicated by H IM HBD / H IM HBA With H HBD / H HBA The relationship depends on the equilibrium constant K for the formation of IMHB. IMHB .

[0082] The prediction method provided by the present invention can accurately predict the influence of IMHB on the hydrogen bond forming ability of compounds, thereby realizing accurate prediction of the physicochemical properties of organic compounds containing intramolecular hydrogen bonds. The method is simple and has strong versatility, and the calculation results of physicochemical properties such as the distribution coefficient are accurate.

[0083] The present invention also provides an application of the prediction method described in the above technical solution to the physicochemical properties of organic compounds containing intramolecular hydrogen bonds. The actual hydrogen bond forming ability results of organic compounds containing intramolecular hydrogen bonds obtained by the prediction method provided by the present invention are used to accurately predict various physicochemical properties such as the distribution coefficient of the compound, without the need to obtain a large amount of relevant experimental data on the contribution of certain specific groups to the physicochemical properties and then summarize them. The method provided by the present invention has the characteristics of simple operation, simple steps, strong versatility, short time consumption, low cost, and accurate calculation results of physicochemical properties such as the distribution coefficient.

[0084] In the present invention, the physicochemical properties preferably include the partition coefficient of the organic compound containing intramolecular hydrogen bonds between two phases or the penetration rate of the organic compound containing intramolecular hydrogen bonds in the skin.

[0085] In the present invention, the two phases preferably include water-organic phase, air-organic phase, air-water, air-blood or air-human brain. In the present invention, the organic phases in the water-organic phase and the air-organic phase independently preferably include chloroform, n-octanol or alkane; the alkane preferably includes C6-C16 alkane, more preferably includes C6 alkane, C7 alkane, C8 alkane, C9 alkane, C10 alkane, C11 alkane, C12 alkane, C13 alkane, C14 alkane, C15 alkane, C16 alkane, and further preferably cyclohexane or hexadecane.

[0086] The present invention also provides a method for predicting the partition coefficient of an organic compound containing intramolecular hydrogen bonds between two phases, comprising the following steps:

[0087] According to the prediction method described in the above technical solution, the H IM HBD and H IM HBA ;

[0088] The sum of the hydrogen bond forming abilities of all hydrogen bond donors of the tested organic compound containing intramolecular hydrogen bonds that do not form IMHB M_HBD , H HBD and the H IM HBD According to formula (6), the sum of the hydrogen bond forming abilities of all hydrogen bond donors in the IMHB molecule is obtained: IM M_HBD ;

[0089] H IM M_HBD =H M_HBD +H IM HBD -H HBD Formula (6);

[0090] The sum of the hydrogen bond forming abilities of all hydrogen bond acceptors that do not form IMHB is calculated by measuring the intramolecular hydrogen bond-containing organic compound molecule. M_HBA , H HBA and the H IM HBA According to formula (7), the sum of the hydrogen bond forming abilities of all hydrogen bond acceptors of the IMHB molecules is obtained as H IM M_HBA , H IM M_HBD ;

[0091] H IM M_HBA =H M_HBA +H IM HBA -H HBA Formula (7);

[0092] According to the known organic compounds without intramolecular hydrogen bonds, H M_HBD , H M_HBA and ΔG tr_depol Obtain k1, k2, k3 and c1 of formula (I), and according to k1, k2, k3, c1 and the H of the organic compound containing intramolecular hydrogen bonds to be tested IM M_HBD , H IM M_HBA and ΔG tr_depo , according to formula (I), the distribution coefficient of the organic compound containing intramolecular hydrogen bonds to be tested between the two phases is obtained;

[0093] logP sol =k1×ΔG tr_depol +k2×H M_HBD +k3×H M_HBA +c1 formula (I);

[0094] Among them, P sol is the distribution coefficient; logP sol is the logarithm of the distribution coefficient; k1, k2, k2 and c1 are equation constants.

[0095] In the present invention, the two phases preferably include water-organic phase, air-organic phase, air-water, air-blood or air-human brain. In the present invention, the organic phases in the water-organic phase and the air-organic phase independently include chloroform, n-octanol or alkane; the alkane preferably includes C6-C16 alkane, more preferably includes C6 alkane, C7 alkane, C8 alkane, C9 alkane, C10 alkane, C11 alkane, C12 alkane, C13 alkane, C14 alkane, C15 alkane, C16 alkane, and further preferably cyclohexane or hexadecane.

[0096] In a specific embodiment of the present invention, when the organic phase is hexadecane, the formula (I) is as follows:

[0097] logP 16 =-0.1729×ΔG tr_depol -0.1731×H M_HBD -0.1748×H M_HBA +0.0342.

[0098] In a specific embodiment of the present invention, when the organic phase is chloroform, the formula (I) is as follows:

[0099] logP chl =-0.1632ΔG tr_depol -0.1625×H M_HBD -0.1016×H M_HBD+0.3220.

[0100] The present invention also provides a method for predicting the partition coefficient of an organic compound containing intramolecular hydrogen bonds in a water-organic phase, comprising the following steps:

[0101] According to the prediction method described in the above technical solution, the H IM M_HBD and H IM M_HBA ;

[0102] Calculate the S of known organic compounds containing intramolecular hydrogen bonds and the organic compounds to be tested containing intramolecular hydrogen bonds respectively. M ; The S M According to its molecular formula calculation, when the molecular formula of the compound is C c H h O o N n S s F f Cl cl Br br I i When the S M The value is c+0.3h+o+n+2s+0.6f+1.8cl+2.2br+2.6i-0.2Nc3-0.6Nc4; Nc3 is the sp connecting the three heavy atoms 3 The number of carbon atoms, Nc4 is the sp connecting four heavy atoms 3 Number of carbon atoms;

[0103] According to the known organic compounds without intramolecular hydrogen bonds, H M_HBD , H M_HBA , S M , by multiple linear regression, the partition coefficient of the tested organic compound containing intramolecular hydrogen bonds in water-organic phase represented by formula (II) is obtained;

[0104] logP sol =k4×S M +k5×H M_HBD +k6×H M_HBA +c2 Formula (II);

[0105] Among them, P sol is the distribution coefficient; logP sol is the logarithm of the distribution coefficient; k4, k5, k6 and c2 are equation constants.

[0106] In the present invention, the organic phase in the water-organic phase preferably includes chloroform, n-octanol or alkanes; the alkanes preferably include C6 to C16 alkanes, more preferably C6 alkanes, C7 alkanes, C8 alkanes, C9 alkanes, C10 alkanes, C11 alkanes, C12 alkanes, C13 alkanes, C14 alkanes, C15 alkanes, C16 alkanes, and further preferably cyclohexane or hexadecane.

[0107] The present invention has no particular limitation on the types and numbers of the known organic compounds containing intramolecular hydrogen bonds and the organic compounds containing intramolecular hydrogen bonds to be tested. Organic compounds containing intramolecular hydrogen bonds well known to those skilled in the art may be used.

[0108] To further illustrate the present invention, the following detailed description is made of the method for predicting the actual hydrogen bond forming ability of an organic compound containing intramolecular hydrogen bonds and its application, and the method for predicting the distribution coefficient of an organic compound containing intramolecular hydrogen bonds in an aqueous phase and an organic phase in combination with the embodiments. However, they should not be construed as limiting the scope of protection of the present invention.

[0109] In the following examples, H w The value is 7.02 kJ / mol. Since the charge reduction between HBD and HBA is caused by the electron transfer between them, it is required that the distance between HBA and HBD is significantly smaller than the sum of their van der Waals radii, ΔG restr_bond is the sum of the free energy changes of inhibiting the rotatable bonds between HBD and HBA, inhibiting a C(sp 3 )-C(sp 3 ) ΔG of chemical bond restr_bond The ΔG of the CN bond in Ar-NH2 and Ar-NO2 in the examples is 3.7 kJ / mol. restr_bond The value is 0; the ΔG of the CO bond in Ar-OH restr_bond The value is 2.4 kJ / mol; the ΔG of the CO bond in Ar-OCH3 restr_bond The value is 0.7 kJ / mol, where Ar represents a benzene ring. tr_depol It is the free energy change when a compound is transferred from an aqueous phase to a nonpolar solvent assuming that all atoms in the compound are nonpolar atoms.

[0110] Example 1

[0111] 1. Calculate using equations (1) to (5) Figure 2 The hydrogen bonding ability of HBD (blue hydrogen atoms) and HBA (red atoms) that form IMHB in the 9 compounds shown, the specific steps are as follows:

[0112] according to Figure 2 The two-dimensional structure of the compound obtained the hydrogen bonding ability of HBD and HBA when IMHB was not formed.HBD and H HBA The three-dimensional structure of the possible IMHB was generated by molecular simulation software. HBD and H HBA According to formula (1), the ΔG of each IMHB is obtained HB , the ΔG of each IMHB was obtained according to the three-dimensional structure of the compound restr_bond value, given by the ΔG HB and ΔG restr_bond According to formula (2), the ΔG of each IMHB is obtained IMHB , given by the ΔG IMHB According to formula (3), K IMHB , by the H HBD and K IMHB According to formula (4), H IM HBD , by the H HBD and K IMHB According to formula (5), H IM HBA The results are shown in Table 1. The effect of each IMHB on the hydrogen bond forming ability of the compound ΔH IMHB (Calculated value) is (H HBD +H HBA ) and (H IM HBD +H IM HBA ) (i.e., ΔH IMHB＝ (H HBD +H HBA )-(H IM HBD +H IM HBA )), the results are shown in Table 1.

[0113] In order to demonstrate the accuracy of the prediction method provided by the present invention, the effects of these IMHBs on the hydrogen bond forming ability of the compounds were obtained through the experimental data of the water / hexadecane partition coefficient or the water / cyclohexane partition coefficient of these compounds, and the results were expressed as ΔH IMHB (Experimental value) is shown. The results show that ΔH IMHB (calculated value) and ΔH IMHB (experimental value) is very close and has a good correlation, indicating that the prediction method provided by the present invention can accurately obtain the influence of IMHB on the hydrogen bond forming ability of the compound.

[0114]

[0115] 2. Prediction of the physicochemical properties of IMHB-containing compounds

[0116] 2.1 Calculation of water / hexadecane partition coefficient (logP) of IMHB compounds using formula (8) 16 ) model, which is as follows:

[0117] logP 16 =-0.1729×ΔG tr_depol -0.1731×H M_HBD -0.1748×H M_HBA +0.0342

[0118] N=166, R 2 =0.997, SD=0.155, F=16439

[0119] Formula (8);

[0120] N is the number of samples; R 2 is the square of the correlation coefficient; SD is the standard error; F is the statistic; H M_HBD and H M_HBA They are the sum of the hydrogen bond forming abilities of all hydrogen bond donors and all hydrogen bond acceptors in the molecule, respectively.

[0121] Calculate using this model Figure 2 The logP values ​​of 9 compounds in 16 The results are shown in Table 2 logP 16 The "Count Value (excluding IMHB)" column of the calculation is consistent with the experimental value (logP 16 The “experimental values” column in the table are quite different, indicating that formula (6) cannot accurately predict the logP of IMHB compounds. 16 .

[0122] Table 2 Effect of the hydrogen bonding ability of the modified IMHB according to the present invention on the calculation of logP of IMHB-containing compounds 16 Improved accuracy

[0123]

[0124] Then the H calculated by the prediction method provided by the present invention is IM M_HBD and H IM M_HBA , use H IM M_HBD and H IM M_HBA Substituting H in formula (8) M_HBD and H M_HBA Post-prediction Figure 2 The logP values ​​of 9 compounds in 16 The results are shown in Table 2 logP 16The calculated value is very close to the experimental value, indicating that the prediction method of the present invention can accurately calculate the logP of IMHB-containing compounds. 16 value.

[0125] 2.2 Using equation (9) to predict the water / chloroform partition coefficient (logP chl ) model, which is as follows:

[0126] logP chl =-0.1632×ΔG tr_depol -0.1625×H M_HBD -0.1016×H M_HBA +0.3220

[0127] N=80, R 2 =0.978, SD=0.287, F=563

[0128] Formula (9)

[0129] Calculate using this model Figure 2 The logP values ​​of the six compounds in chl The results are shown in Table 3 logP chl The "Count Value (excluding IMHB)" column of the calculation is consistent with the experimental value (logP chl The “experimental value” column) is very different, indicating that formula (9) cannot accurately predict the logP of IMHB compounds. chl .

[0130] Table 3 Effect of the hydrogen bonding ability of the modified IMHB according to the present invention on the calculation of logP of compounds containing IMHB chl Improved accuracy

[0131]

[0132] Then the H calculated by the prediction method provided by the present invention is IM M_HBD and H IM M_HBA , use H IM M_HBD and H IM M_HBA Substituting H in formula (9) M_HBD and H M_HBA Then calculate the logP of these compounds chl The results are shown in Table 3 logP chl The calculated result is very close to the experimental value, indicating that the prediction method provided by the present invention can accurately calculate the logP value of IMHB-containing compounds. chl value.

[0133] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for predicting the actual hydrogen bond forming ability of an organic compound containing intramolecular hydrogen bonds, characterized in that: The following steps are involved: Based on the two-dimensional structure of intramolecular hydrogen-bonded organic compounds, the hydrogen-bonding ability of HBD and HBA without IMHB formation was obtained. HBD and H HBA and generate the three-dimensional structure that may form IMHB through molecular simulation software; By the H HBD and H HBA According to formula (1), ΔG of IMHB is obtained HB ; The ΔG of IMHB is obtained according to the three-dimensional structure of the organic compound containing intramolecular hydrogen bonds. restr_bond ; By the ΔG HB and ΔG restr_bond According to formula (2), the ΔG of each IMHB is obtained IMHB ; By the ΔG IMHB According to formula (3), K IMHB ; By the H HBD and K IMHB According to formula (4), H IM HBD , by the H HBA and K IMHB According to formula (5), H IM HBA ; Among them, HBD represents hydrogen bond donor, HBA represents hydrogen bond acceptor, and IMHB represents intramolecular hydrogen bond; ΔG HB =-(H HBD ×H HBA ) / H w Formula (1); ΔG IMHB = ΔG HB + ΔG restr_bond Equation (2); H IM HBD =H HBD / (1+K IMHB ) Formula (4); H IM HBA =H HBA / (1+K IMHB ) Formula (5); Among them, H w It represents the hydrogen bond forming ability of the lone electron pair on hydrogen atoms or oxygen in water, which is 7.02 kJ / mol; H HBD It indicates the hydrogen bonding ability of HBD when IMHB is not formed; H HBA It indicates the hydrogen bonding ability of HBA when IMHB is not formed; ΔG HB It represents the free energy change of intramolecular hydrogen bond formation between HBD and HBA in a nonpolar environment; ΔG restr_bond represents the sum of the free energy changes of inhibiting the rotatable bonds between HBD and HBA; K IMHB It is expressed as the equilibrium constant in a nonpolar environment; H IM HBD It indicates the actual hydrogen bonding ability of HBD when forming IMHB; H IM HBA It indicates the actual hydrogen bonding ability of HBA when forming IMHB.

2. The prediction method according to claim 1, characterized in that: The organic compound containing intramolecular hydrogen bonds includes compounds whose hydrogen bond donors and hydrogen bond acceptors can form hydrogen bonds after rotating single bonds.

3. Application of the prediction method according to claim 1 or 2 in predicting the physicochemical properties of organic compounds containing intramolecular hydrogen bonds.

4. The use according to claim 3, characterized in that: The physicochemical properties include the partition coefficient between two phases or the penetration rate in the skin.

5. The use according to claim 4, characterized in that: The two phases include water-organic phase, air-organic phase, air-water, air-blood or air-human brain.

6. The prediction method according to claim 4, characterized in that: The organic phases in the water-organic phase and the air-organic phase independently include chloroform, n-octanol or alkane.

7. A method for predicting the partition coefficient of an organic compound containing intramolecular hydrogen bonds between two phases, characterized in that: The following steps are involved: The prediction method according to any one of claims 1 to 2 is used to obtain the H of the organic compound containing intramolecular hydrogen bonds to be tested. IM HBD and H IM HBA ; The sum of the hydrogen bond forming abilities of all hydrogen bond donors of the tested organic compound containing intramolecular hydrogen bonds that do not form IMHB M_HBD , H HBD and the H IM HBD According to formula (6), the sum of the hydrogen bond forming abilities of all hydrogen bond donors in the IMHB molecule is obtained: IM M_HBD ; H IM M_HBD =H M_HBD +H IM HBD -H HBD Formula (6); The sum of the hydrogen bond forming abilities of all hydrogen bond acceptors that do not form IMHB is calculated by measuring the intramolecular hydrogen bond-containing organic compound molecule. M_HBA , H HBA and the H IM HBA According to formula (7), the sum of the hydrogen bond forming abilities of all hydrogen bond acceptors of the IMHB molecules is obtained as H IM M_HBA , H IM M_HBD ; H IM M_HBA =H M_HBA +H IM HBA -H HBA Formula (7); According to the known organic compounds without intramolecular hydrogen bonds, H M_HBD , H M_HBA and ΔG tr_depol Obtain k1, k2, k3 and c1 of formula (I), and according to k1, k2, k3, c1 and the H of the organic compound containing intramolecular hydrogen bonds to be tested IM M_HBD , H IM M_HBA and ΔG tr_depo , according to formula (I), the distribution coefficient of the organic compound containing intramolecular hydrogen bonds to be tested between the two phases is obtained; logP sol =k1×ΔG tr_depol +k2×H M_HBD +k3×H M_HBA +c1 formula (I); Among them, P sol is the distribution coefficient; logP sol is the logarithm of the distribution coefficient; k1, k2, k2 and c1 are equation constants. The ΔG tr_depol It is the free energy change when a compound is transferred from aqueous phase to nonpolar solvent assuming that all atoms in the compound are nonpolar atoms.

8. The prediction method according to claim 7, characterized in that: The organic phase includes chloroform, n-octanol or alkane.

9. A method for predicting the partition coefficient of an organic compound containing intramolecular hydrogen bonds in water-organic phase, characterized in that: The following steps are involved: According to the prediction method according to any one of claims 1 to 2, H of the organic compound containing intramolecular hydrogen bonds to be tested is obtained respectively. IM M_HBD and H IM M_HBA ; Calculate the S of known organic compounds containing intramolecular hydrogen bonds and the organic compounds to be tested containing intramolecular hydrogen bonds respectively. M ; The S M According to its molecular formula calculation, when the molecular formula of the compound is C c H h O o N n S s F f Cl cl Br br I i When the compound's S M The value is c+0.3h+o+n+2s+0.6f+1.8cl+2.2br+2.6i-0.2Nc3-0.6Nc4; Nc3 is the sp connecting the three heavy atoms 3 The number of carbon atoms, Nc4 is the sp connecting four heavy atoms 3 Number of carbon atoms; According to the known organic compounds without intramolecular hydrogen bonds, H M_HBD , H M_HBA , S M , by multiple linear regression, the partition coefficient of the tested organic compound containing intramolecular hydrogen bonds in water-organic phase represented by formula (II) is obtained; logP sol =k4×S M +k5×H M_HBD +k6×H M_HBA +c2 Formula (II); Among them, P sol is the distribution coefficient; logP sol is the logarithm of the distribution coefficient; k4, k5, k6 and c2 are equation constants.

10. The prediction method according to claim 9, characterized in that: The organic phase in the water-organic phase includes chloroform, alkane or n-octanol.

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