CN114891025A - Preparation method of selenium-containing anti-influenza medicine - Google Patents

Preparation method of selenium-containing anti-influenza medicine Download PDF

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CN114891025A
CN114891025A CN202210226404.7A CN202210226404A CN114891025A CN 114891025 A CN114891025 A CN 114891025A CN 202210226404 A CN202210226404 A CN 202210226404A CN 114891025 A CN114891025 A CN 114891025A
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CN114891025B (en
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孙敏
郝小林
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Nanjing Zhengxiang Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to the field of biological medicine, in particular to a preparation method of a selenium-containing anti-influenza medicine. The structure of the anti-influenza drug is shown as a formula (I), and the synthesis method comprises the following steps: the pyridotriazine diketone derivative shown in the formula (II) and the dihydrodibenzoselenium derivative shown in the formula (III) selectively generate the compound shown in the formula (I) in the presence of a coupling reagent. The compound shown in the formula (I) can be used for treating influenza or preparing other medicaments for treating the influenza.

Description

Preparation method of selenium-containing anti-influenza medicine
Technical Field
The invention relates to the field of biological medicine, in particular to a preparation method of a selenium-containing anti-influenza medicine.
Background
Influenza viruses belong to the Orthomyxoviridae (Orthomyxoviridae) which are enveloped viruses containing a single-stranded negative-sense RNA genome. Over the past decades, two types of therapy have been generally available for treating influenza viruses: m2 ion channel inhibitors and neuraminidase inhibitors. However, influenza viruses not only exhibit broad resistance to M2 ion channel inhibitors, but also develop antiviral resistance to neuraminidase inhibitors in succession.
The Cap-dependent endonuclease inhibitor inhibits the virus from obtaining the Cap structure of the 5' end of the host mRNA from the host cell by controlling the key link of the replication of the influenza virus, thereby inhibiting the transcription of the self mRNA of the influenza virus and achieving the effect of treating the influenza. Moreover, since there is no protease with similar mechanism in the host cell, the Cap-dependent endonuclease inhibitor does not affect the host cell. In 2018, the first cap-dependent endonuclease (CEN) inhibitor baroxavir (baloxavir marboxil) (trade name: Xofluza)) was approved in the United states and Japan for the treatment of influenza A and B. Bacloxavir ester was approved for NMPA marketing in china at 29/4 of 2021, and indicated for the treatment of influenza in patients 12 years of age and older, including patients at high risk of influenza complications. The prodrug baloxavir disoproxil is metabolized in vivo to be converted into the active ingredient baloxavir. Barosavir inhibits the influenza virus Polymerase Acid (PA) protein endonuclease, so that the synthesis of virus RNA is inhibited, and the influenza virus replication can be effectively inhibited.
The patent CN109311911A of SAYEYI corporation discloses a preparation method of Barosavir, which comprises the following reaction route:
Figure BDA0003539350820000011
intermediate 13 is subjected to substituent conversion (yield: 87.2%), coupling (yield: 84.6%), deprotection (yield: 90.7%) and the like to obtain the baloxavir represented by formula V. The process has long reaction route and complicated operation, and the total yield of the baroxavir shown in the formula V obtained from the intermediate 13 is only about 65%.
Patent application publication No. WO2021007506a1 provides a novel selenium-containing anti-influenza drug which is a Cap-dependent endonuclease inhibitor, can be used to treat influenza, exhibits excellent biological activity and pharmacokinetic properties including good oral bioavailability, and is not affected by food intake. When the selenium-containing anti-influenza drug was prepared by a method similar to that in CN109311911A, the reaction scheme was as follows:
Figure BDA0003539350820000021
the intermediate 11-R is subjected to the procedures of substituent conversion (yield is 78.2%), coupling (yield is 32.6%), deprotection (yield is 86.3%) and the like to obtain the selenium-containing anti-influenza drug shown as the formula B-1. Starting from the intermediate 11-R, the selenium-containing anti-influenza medicine shown in B-1 is obtained through three steps of reactions, and the total yield is only 22%.
As described above, new preparation methods are required for anti-influenza drugs containing selenium.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide the preparation method of the selenium-containing anti-influenza medicine, which has the advantages of simple process route, good selectivity and high total yield and is suitable for industrial production. Specifically, the method does not need to carry out the processes of substituent conversion and deprotection, can selectively generate the selenium-containing anti-influenza drug by one-step coupling process, greatly improves the yield while simplifying the reaction route, and is very suitable for industrial production.
The selenium-containing anti-influenza medicine is shown as a formula (I), and the compound shown as the formula (I) can be used for treating influenza or preparing other medicines for treating the influenza, and has the following structure:
Figure BDA0003539350820000022
wherein R is 1 、R 2 、R 3 And R 4 Each independently selected from hydrogen or halogen; preferably, R 1 、R 2 、R 3 And R 4 One or both of which are halogens.
A method for preparing a compound of formula (I), said method comprising: the pyridotriazinedione derivative shown in the formula (II) and the dihydrodibenzoselenepine derivative shown in the formula (III) generate a compound shown in the formula (I) in the presence of a coupling reagent, and the reaction route is shown as follows:
Figure BDA0003539350820000031
wherein, R is 1 、R 2 、R 3 And R 4 Each independently selected from hydrogen or halogen; preferably, R 1 、R 2 、R 3 And R 4 One or both of which are halogen; more preferably, R 1 And R 2 Is hydrogen, R 3 And R 4 Is fluorine;
p is a hydroxyl protecting group; preferably, the hydroxyl protecting group is benzyl (Bn), substituted benzyl, benzyloxycarbonyl (Cbz), triphenylmethyl, tert-butyldimethylsilyl (TBDMS), Trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), Triethylsilyl (TES), triisopropylsilyl (DIPS), 2- (trimethylsilyl) ethoxymethyl, dihydropyranyl, bromopropenyl, ethylformyl, acetyl or benzoyl, etc.; more preferably, the hydroxyl protecting group is benzyl (Bn), or benzyl substituted on the phenyl ring of the benzyl by 1-2 methyl, methoxy, or halogen. (ii) a
The coupling reagent is a phosphoric acid anhydride reagent, wherein the phosphoric acid anhydride reagent comprises an alkyl phosphoric acid anhydride and an aryl phosphoric acid anhydride, wherein the alkyl phosphoric acid anhydride is selected from the group consisting of: propyl phosphoric anhydride (T3P), ethyl methylphosphinic anhydride (EMPA); aryl phosphoric anhydrides, such as: phenyl phosphonic anhydride; the coupling reagent can also be other condensing agents of phosphate and phosphoramide type, such as: diphenylphosphoryl chloride (DPP-Cl), diethyl cyanophosphate (DECP), diphenylphosphoryl azide (DPPA), thiomethylphosphoryl azide (MPTA), bis (2-oxo-3-oxazolidinyl) phosphoryl chloride (BOP-Cl). Preferably, the phosphoric anhydride reagent is an alkyl phosphoric anhydride reagent, more preferably propyl phosphoric anhydride (T3P).
In some embodiments, the preparation method of the present invention further comprises the steps of:
step 1: dissolving a compound shown in a formula (II) and a compound shown in a formula (III) in an organic solvent 1 at room temperature (15-35 ℃), cooling a reaction solution to-10 ℃, dropwise adding an acidic reagent 1, and heating the reaction solution to room temperature after dropwise adding until the reaction solution turns turbid from clear;
step 2: dropwise adding a coupling reagent solution and an acidic reagent 2 into the turbid solution obtained in the step (1), heating to 40-100 ℃, and continuing to react for 12-48 hours;
and step 3: after monitoring the completion of the reaction, a post-treatment is carried out to obtain the compound of formula (I).
In alternative embodiments, the organic solvent 1 in step 1 is selected from one or more of lower alkane solvents, halogenated lower alkane solvents, ether solvents, nitrile solvents, ketone solvents, ester solvents, amide solvents, or sulfoxide solvents; preferably, selected from ester solvents; more preferably, the ester-based solvent is selected from one or more of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, n-pentyl acetate, isopentyl acetate, and neopentyl acetate.
In alternative embodiments, the acidic reagent 1 in step 1 and the acidic reagent 2 in step 2 are the same or different and are inorganic acids or organic acids; preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, and the like; preferably, the organic acid is formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, or the like; more preferably, the acidic reagent 1 and the acidic reagent 2 are the same or different and are respectively selected from one or more of benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid. Most preferably, acidic reagent 1 is trifluoromethanesulfonic acid and acidic reagent 2 is methanesulfonic acid.
In an alternative embodiment, the coupling reagent solution is produced by dissolving propyl phosphate anhydride (T3P) in an ester solvent selected from one or more of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, n-pentyl acetate, isoamyl acetate, and neopentyl acetate.
In alternative embodiments, the coupling reagent itself is in a liquid state, or may be insoluble in other solvents, and is directly added dropwise to the reaction system.
In alternative embodiments, the molar equivalent ratio of the compound of formula (II) to the compound of formula (III) is from 1:1 to 1:1.5, more preferably from 1:1 to 1: 1.2.
In alternative embodiments, the molar equivalent ratio of the compound of formula (II) to the acidic reagent 1 is from 1:1 to 1:2, more preferably from 1:1 to 1: 1.5.
In alternative embodiments, the molar equivalent ratio of the compound of formula (II) to the acidic reagent 2 is from 1:1 to 1:5, more preferably from 1:2 to 1: 5.
The invention has the advantages of
1. The process route is short (one-step method), the repeated protection and removal of the protecting group are avoided, the condition is mild, and the total yield is high; the process is stable in a ten gram level, and is suitable for industrial production.
2. The method has high process selection, can effectively reduce the generation of the enantiomer of the compound shown as the formula (I), the enantiomer of the compound shown as the formula (I) has a structure shown as the formula (I-A), and when the reaction is finished, the content of the formula (I-A) in a reaction liquid is lower than 5 percent, and R is higher than R 1 、R 2 、R 3 And R 4 As defined in formula (I).
Figure BDA0003539350820000051
Drawings
FIG. 1 is a graph showing the results of HPLC analysis of the reaction mixture at the completion of the reaction in example 1 of the present invention.
FIG. 2 is a graph showing the results of HPLC analysis of the final product of example 1 of the present invention.
FIG. 3 is a graph showing the results of HPLC analysis of the reaction mixture at the completion of the reaction in example 2 of the present invention.
FIG. 4 is a graph showing the results of HPLC analysis of the final product of example 2 of the present invention.
Detailed Description
The following examples are illustrative and are intended to be illustrative of the invention and are not to be construed as limiting the invention. Also, some of the terms appearing herein are explained and illustrated only for the convenience of those skilled in the art and should not be construed as limiting the scope of the present invention.
Reference to "halogen" is to fluorine, chlorine, bromine or iodine.
Reference to a "hydroxy protecting group" is a reference to the functionality of a hydroxy substituent to block or protect the hydroxy group, and suitable protecting groups include, but are not limited to, benzyl (Bn), substituted benzyl, benzyloxycarbonyl (Cbz), triphenylmethyl, t-butyldimethylsilyl (TBDMS), Trimethylsilyl (TMS), t-butyldiphenylsilyl (TBDPS), Triethylsilyl (TES), triisopropylsilyl (DIPS), 2- (trimethylsilyl) ethoxymethyl, dihydropyranyl, bromopropenyl, ethylformyl, acetyl or benzoyl, and the like.
Reference to "substituted benzyl" or "substituted benzyl" means that the phenyl ring of the benzyl group is substituted with one or more methyl, methoxy, or halogen groups; such as benzyl substituted on the phenyl ring with 1-2 methyl, methoxy, or halogen; including but not limited to p-methoxybenzyl and 2, 4-dimethoxybenzyl.
The "organic solvent" mentioned may be one or more selected from a lower alkane solvent, a halogenated lower alkane solvent, an ether solvent, a nitrile solvent, a ketone solvent, an ester solvent, an amide solvent or a sulfoxide solvent; the lower alkane solvent can be selected from cyclohexane, n-hexane, n-heptane, n-pentane, isopentane, petroleum ether, isooctane or cyclopentane, etc.; the halogenated lower alkane solvent can be selected from dichloromethane or chloroform; the ether solvent can be selected from tetrahydrofuran, dioxane, isopropyl ether or methyl tert-butyl ether; the nitrile solvent may be selected from acetonitrile or propionitrile; the ketone solvent can be selected from acetone, methyl ethyl ketone or butanone; the ester solvent can be selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, n-amyl acetate, isoamyl acetate or neopentyl acetate; the amide-based solvent may be selected from N, N-Dimethylformamide (DMF) or N-methylpyrrolidone (NMP); the sulfoxide solvent is selected from dimethyl sulfoxide (DMSO).
In describing the results of HPLC, specific values are given for retention time, though. However, it will be appreciated by those skilled in the art that these specific values of retention time are merely used as references, and that in practice the retention time values may fluctuate during the test. When the retention time is represented by "about," this change in retention time is reflected.
Example 1
Figure BDA0003539350820000061
Dissolving a compound (20.0g, 61mmol) of a formula (II) and a compound (21.1g, 67mmol) of a formula (III) in 140mL of n-butyl acetate (BuOAc) at room temperature, cooling a reaction system to 0-10 ℃ after complete dissolution, slowly dropwise adding trifluoromethanesulfonic acid (TfOH, 9.2g, 61mmol), and heating to room temperature after dropwise adding is completed to obtain a suspension. 38.9g of a 50% by weight ethyl propyl phosphate anhydride (T3P) acetate solution containing 19.45g (61mmol) of T3P was added dropwise to the reaction mixture; methanesulfonic acid (17.6g, 183mmol) was added dropwise, and after the addition was completed, the reaction system was heated to 60 ℃ to continue the reaction. At 23 hours from the reaction, HPLC monitoring was carried out, wherein the content of the compound of formula (II) was 4.99%, the content of the compound of formula (I) was 76.62%, and the content of the compound of formula (I-A) was 3.23%, and the results of the detailed analysis are shown in FIG. 1. After the reaction was completed, it was cooled to room temperature. And (2) performing suction filtration to obtain a filter cake, washing with BuOAc, dissolving the filter cake in acetonitrile with the volume 4 times that of the filter cake, then dropwise adding methyl tert-butyl ether (MTBE) until all solids are separated out, and then performing filtration, MTBE and water washing, drying and other processes to obtain the compound shown in the formula (I), wherein the yield is 64.9%, the purity is 98.56%, and the content of the compound shown in the formula (I-A) is 0.42%. The specific analysis results are shown in figure 2.
Identifying the structure of formula (I): 1 H NMR(300MHz,DMSO)δ11.80(s,1H),7.45–7.28(m,2H),7.24 (d,J＝7.0Hz,1H),7.17(d,J＝7.7Hz,1H),7.14–7.02(m,2H),6.90(dd,J＝10.7,4.1Hz,1H), 5.80(s,1H),5.55(d,J＝7.7Hz,1H),5.29(dd,J＝12.7,2.2Hz,1H),4.59(dd,J＝9.9,2.9Hz, 1H),4.43(d,J＝12.1Hz,1H),4.19–3.94(m,2H),3.66(t,J＝10.6Hz,2H),3.43(dd,J＝11.6, 9.3Hz,1H),3.15–2.97(m,1H).
MS test value 532([ M + H ]] + )。
Example 2
Figure BDA0003539350820000071
At room temperature, dissolving the compound (2.0kg, 1.0eq) of the formula (II) and the compound (2.1kg, 1.1eq) of the formula (III) in 14L of n-butyl acetate (BuOAc), cooling the reaction system to 0-10 ℃ after complete dissolution, slowly dropwise adding trifluoromethanesulfonic acid (TfOH, 918g, 1.0eq), and heating to room temperature after dropwise adding is completed to obtain a suspension. 97.4g of ethyl propyl phosphate anhydride (T3P) ethyl acetate solution with the weight ratio of 50 percent is continuously dripped into the reaction liquid, wherein the content of T3P is 3895g (1.0 eq); methanesulfonic acid (1764g, 3.0eq) is added dropwise, and after the addition is finished, the reaction system is heated to 55-60 ℃ for continuous reaction. After the reaction proceeded to 38 hours, HPLC monitoring was carried out, wherein the content of the compound of formula (II) was 4.25%, the content of the compound of formula (I) was 78.80%, and the content of the compound of formula (I-A) was 3.35%, and the results of the detailed analysis are shown in FIG. 3. After the reaction was completed, the compound of the formula (I) was obtained in a yield of 66.0% and a purity of 99.68% by the post-treatment in a similar manner to example 1, wherein the content of the formula (I-A) was 0.27%. The specific analysis results are shown in figure 4.

Claims (14)

1. A method for preparing a compound of formula (I), comprising: the pyridotriazine diketone derivative shown in the formula (II) and the dihydrodibenzoselenium derivative shown in the formula (III) generate a compound shown in the formula (I) in the presence of a coupling reagent, and the reaction route is shown as follows:
Figure FDA0003539350810000011
wherein, R 1 、R 2 、R 3 And R 4 Each independently selected from hydrogen or halogen; p is a hydroxyl protecting group;
the method is characterized in that the coupling reagent is a phosphoric anhydride reagent.
2. The process according to claim 1, characterized in that said phosphoric anhydride reagent is an alkyl phosphoric anhydride, preferably propyl phosphoric anhydride.
3. The method of claim 1, wherein R is 1 、R 2 、R 3 And R 4 One or both of which are halogen; preferably, R 1 And R 2 Is hydrogen, R 3 And R 4 Is fluorine.
4. The method of claim 1, wherein the hydroxyl protecting group is selected from the group consisting of benzyl, substituted benzyl, benzyloxycarbonyl, triphenylmethyl, tert-butyldimethylsilyl, trimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, triisopropylsilyl, 2- (trimethylsilyl) ethoxymethyl, dihydropyranyl, bromopropenyl, ethylformyl, acetyl and benzoyl.
5. The method according to claim 4, wherein the hydroxyl protecting group is benzyl, or benzyl substituted with 1 to 2 methyl, methoxy, or halogen on the benzene ring of benzyl. .
6. The method of claim 1, further comprising the steps of:
step 1: dissolving a compound shown in a formula (II) and a compound shown in a formula (III) in an organic solvent 1 at room temperature (15-35 ℃), cooling a reaction solution to-10 ℃, dropwise adding an acidic reagent 1, and heating the reaction solution to room temperature after dropwise adding until the reaction solution turns turbid from clear;
step 2: dropwise adding a coupling reagent solution and an acidic reagent 2 into the turbid solution obtained in the step (1), heating to 40-100 ℃, and continuing to react for 12-48 hours;
and step 3: after monitoring the completion of the reaction, a post-treatment is carried out to obtain the compound of formula (I).
7. The method according to claim 6, wherein the organic solvent 1 in step 1 is an ester solvent.
8. The method according to claim 7, wherein the ester solvent is one or more selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, n-pentyl acetate, isoamyl acetate, and neopentyl acetate.
9. The method according to claim 7, wherein the acidic reagent 1 in step 1 and the acidic reagent 2 in step 2 are the same or different and are an inorganic acid or an organic acid.
10. The method according to claim 7, wherein the acidic reagent 1 and the acidic reagent 2 are the same or different and are each selected from one or more of benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid.
11. The method of claim 7, wherein the coupling reagent solution is produced by dissolving propyl phosphate anhydride (T3P) in an ester solvent selected from one or more of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, n-pentyl acetate, isoamyl acetate, and neopentyl acetate; the coupling reagent is in a liquid state, and can also be insoluble in other solvents and directly dripped into a reaction system.
12. The process according to claim 7, wherein the molar equivalent ratio of the compound of formula (II) to the compound of formula (III) is 1:1 to 1:1.5, more preferably 1:1 to 1: 1.2.
13. The process according to claim 7, wherein the molar equivalent ratio of the compound of formula (II) to the acidic reagent 1 is 1:1 to 1:2, more preferably 1:1 to 1: 1.5.
14. The process according to claim 7, wherein the molar equivalent ratio of the compound of formula (II) to the acidic reagent 2 is from 1:1 to 1:5, more preferably from 1:2 to 1: 5.
CN202210226404.7A 2022-03-09 2022-03-09 Preparation method of selenium-containing anti-influenza medicine Active CN114891025B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112521386A (en) * 2019-09-19 2021-03-19 周雨恬 Polycyclic pyridone compound with antiviral effect and pharmaceutical composition and application thereof
CN113226327A (en) * 2019-07-11 2021-08-06 南京征祥医药有限公司 Compounds useful for the treatment of influenza virus infections
CN113286793A (en) * 2018-09-10 2021-08-20 共结晶制药公司 Pyrrolopyrazine and pyridotriazine influenza virus replication inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113286793A (en) * 2018-09-10 2021-08-20 共结晶制药公司 Pyrrolopyrazine and pyridotriazine influenza virus replication inhibitors
CN113226327A (en) * 2019-07-11 2021-08-06 南京征祥医药有限公司 Compounds useful for the treatment of influenza virus infections
CN112521386A (en) * 2019-09-19 2021-03-19 周雨恬 Polycyclic pyridone compound with antiviral effect and pharmaceutical composition and application thereof

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