CN107056636B - Oseltamivir derivative and preparation method and application thereof - Google Patents

Oseltamivir derivative and preparation method and application thereof Download PDF

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CN107056636B
CN107056636B CN201710037299.1A CN201710037299A CN107056636B CN 107056636 B CN107056636 B CN 107056636B CN 201710037299 A CN201710037299 A CN 201710037299A CN 107056636 B CN107056636 B CN 107056636B
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oseltamivir
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CN107056636A (en
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刘新泳
张健
展鹏
鞠翰
孔秀杰
孙卓森
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Shandong University
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Abstract

The invention discloses an oseltamivir derivative and a preparation method and application thereof. The derivative has a structure shown in a general formula I, the invention also discloses a preparation method of the oseltamivir derivative, application of the oseltamivir derivative serving as an avian influenza virus neuraminidase inhibitor, and application of a composition containing one or more compounds in preparation of the oseltamivir derivativeApplication in preparing anti-influenza virus medicine.

Description

Oseltamivir derivative and preparation method and application thereof
Technical Field
The invention relates to an oseltamivir derivative, a preparation method thereof and application of the oseltamivir derivative as an influenza virus neuraminidase inhibitor, belonging to the technical field of organic compound synthesis and medical application.
Background
Influenza, referred to as influenza (influenza or flu), is an acute upper respiratory infectious disease caused by influenza virus, has the characteristics of high transmission speed, strong infectivity, short latency, strong pathogenicity, capability of causing various complications and the like, and poses great threat to human life and health, tens of thousands of people die of influenza every year around the world, and the animal influenza can not only cause death of a large number of various birds, mammals and other animals, but also cause great loss of social economy and great social panic. Neuraminidase (NA) is a functional protein of influenza virus, plays an important role in the virus life process, and is an important target point for designing anti-influenza drugs. At present, the only oral NA inhibitor oseltamivir phosphate (oseltamivir phosphate) belongs to cyclohexene NA inhibitors, is a first choice medicament for resisting influenza, and plays an important role in the prevention and treatment of the influenza. However, the highly pathogenic H5N1 avian influenza virus and a variety of seasonal H1N1 and H3N2 influenza virus strains are resistant to the current viruses. Zanamivir (zanamivir) and peramivir (peramivir) which is newly marketed are administered mainly by inhalation or intravenous injection, which is inconvenient for patients and resistant virus strains appear. In view of the current situation of resistance to influenza and the potential threat of influenza virus, the development of novel and efficient NA inhibitors is still of great significance. The active center of Group-1 NA (N1, N4, N5 and N8) is directly communicated with a larger 150-cavity nearby, the pocket can be used as an auxiliary binding site, and the chemical structure of oseltamivir (oseltamivir) is further modified, so that the novel anti-influenza drug which has high activity, high selectivity and anti-drug resistance and independent intellectual property is found.
Figure BDA0001213279730000011
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an oseltamivir derivative and a preparation method thereof, and also provides application of the oseltamivir derivative as a neuraminidase inhibitor in preparation of anti-influenza virus drugs.
The technical scheme of the invention is as follows:
1. oseltamivir derivatives
An oseltamivir derivative, or a pharmaceutically acceptable salt, ester or prodrug thereof, having a structure shown in formula I:
Figure BDA0001213279730000021
wherein R is1Is an amide, sulfonamide, acrylamide, amidino, guanidino, or amine group containing one or more aromatic groups; r2Hydrogen, methyl, ethyl, substituted or unsubstituted benzyl, phenethyl, phenylpropyl.
According to the invention, the oseltamivir derivative has a structure shown in the following structural formula IA-1, IA-2, IA-3, IB-1, IB-2, IB-3, IC-1 or ID-1:
Figure BDA0001213279730000022
wherein n in each of the above structures represents the number of carbon atoms of the carbon chain in parentheses;
R2hydrogen, methyl, ethyl, substituted or unsubstituted benzyl, phenethyl, phenylpropyl; r3、R4Each independently is hydrogen, C1-C3A linear or branched alkyl group;
ar is substituted or unsubstituted phenyl, other substituted or unsubstituted aromatic heterocyclic ring;
the substituents on the phenyl or other aromatic heterocyclic rings are selected from halogen and C1-C12Alkyl, partially or fully fluoro substituted C1-C3Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkoxy, partially or fully fluoro substituted C1-C3Alkoxy radical, C1-C12Alkylthio radical, C3-C12Cycloalkylthio, partially or fully fluoro substituted C1-C3Alkylthio, mercapto, amino, cyano, nitro, mono-or di-C1-C12Alkyl-substituted amino, C2-C12Aliphatic amides, phenyl, thienyl, and other aromatic heterocycles; aromatic methyl, aromatic carbonyl, aromatic oxy, aromatic thio, unsubstituted or N-alkyl substituted aromatic amino, aromatic amide, aromatic substituted aliphatic amide, aromatic sulfone group or aromatic sulfoxide group;
the aromatic ring or the aromatic heterocyclic ring is various substituted benzene rings, various substituted six-membered heterocyclic rings, various substituted five-membered heterocyclic rings, various substituted six-membered fused six-membered heterocyclic rings, various substituted five-membered fused five-membered heterocyclic rings, various substituted benzo five-membered heterocyclic rings or various substituted benzo six-membered heterocyclic rings.
As used herein, "pharmaceutically acceptable salts" means salts of the compounds which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and lower animals without undue toxicity, irritation, and allergic response and the like, are commensurate with a reasonable benefit-to-risk ratio, are generally water or oil soluble or dispersible, and are effective for their intended use. Including pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts, which are contemplated for use herein and are compatible with the chemistry of the compounds of formula I, a list of suitable salts is provided in s.m. berge et al, j.pharm.sci.,1977,66, pages 1-19.
The term "prodrug" as used herein refers to pharmaceutically acceptable derivatives such that the resulting biotransformation product of these derivatives is the active drug as defined for the compound of formula I.
According to a further preferred embodiment of the present invention, the oseltamivir derivative is one of the compounds having the following structure:
Figure BDA0001213279730000031
Figure BDA0001213279730000041
2. preparation method of oseltamivir derivative
A preparation method of oseltamivir derivatives comprises one of the following methods:
(1) the preparation method of the oseltamivir derivative (IA-1) comprises the following steps: oseltamivir carboxylate, corresponding aldehyde, and acid in a corresponding solvent to form an intermediate transition state similar to schiff base; obtaining an ester target product through selective reduction, and obtaining a carboxylic acid target product through hydrolysis of the ester target product; the molar ratio of the corresponding aldehyde to the oseltamivir carboxylate is 1-2:1, and the molar ratio of the acid to the oseltamivir carboxylate is 0.5-3: 1;
the reaction formula is as follows:
Figure BDA0001213279730000042
the reagent and the conditions are that (i) the solvent, the acid, the selective reducing agent and the certain temperature are adopted; (ii) solvent, alkali and certain temperature.
Wherein n is 1,2, 3; r2Ar is as described above for general formula IA-1.
In condition i of the invention, the solvent is methanol, ethanol, N-propanol, isopropanol, acetone, tetrahydrofuran, dioxane, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide or a combination of any two solvents; the acid is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or corresponding acid phosphate and various organic acids, and the selective reducing agent is sodium cyanoborohydride or sodium triacetoxyborohydride; the certain temperature is 0-100 ℃; the solvent in the condition ii is methanol, ethanol, n-propanol, isopropanol, acetone, tetrahydrofuran, dioxane, water and a combination of water and any other solvent; the alkali is one of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide; the certain temperature is 0-100 ℃.
The corresponding aldehyde is substituted or unsubstituted aryl formaldehyde, acetaldehyde or propionaldehyde.
The substituents on the phenyl group or other aromatic heterocyclic ring in Ar of the aldehyde used in the preparation method of the present invention are phenyl, thienyl, and other aromatic heterocyclic rings, aromatic thio, unsubstituted or N-alkyl substituted aromatic amino, which need to be prepared separately, and the preparation method is shown in specific examples.
(2) The preparation method of the oseltamivir derivative (IA-2) comprises the following steps: oseltamivir carboxylate, corresponding aldehyde, and acid in a corresponding solvent to form an intermediate transition state similar to schiff base; selectively reducing to obtain an ester target product, and hydrolyzing the ester target product to obtain a carboxylic acid target product; the ratio of the corresponding aldehyde to the oseltamivir carboxylate is 2-4:1, and the ratio of the acid to the oseltamivir carboxylate is 0.5-3: 1;
the reaction formula is as follows:
Figure BDA0001213279730000051
the reagent and the conditions are that (i) the solvent, the acid, the selective reducing agent and the certain temperature are adopted; (ii) solvent, alkali and certain temperature.
Wherein n is 1,2, 3; r2Ar is as described for formula IA-2 above;
conditions i and ii of the present invention are the same as those described in (1).
(3) Preparation method of oseltamivir derivative (IA-3)
The reaction formula is as follows:
Figure BDA0001213279730000052
the reagent and the conditions are that (i) the solvent, the acid, the selective reducing agent and the certain temperature are adopted; (ii) solvent, alkali and certain temperature.
R2Ar is as described in formula IA-3, R3And R4Independently selected from H, methyl, ethyl.
Conditions i and ii of the present invention are the same as those described in (1).
(4) The preparation method of the oseltamivir derivative (IB-1) comprises the following steps: condensing the oseltamivir carboxylate or the salt thereof and the corresponding acid to obtain an ester target product, and hydrolyzing the ester target product to obtain a carboxylic acid target product.
The reaction formula is as follows:
Figure BDA0001213279730000061
the reagent and the condition are that (i) the solvent, the condensing agent and the alkali are used at a certain temperature; (ii) solvent, alkali and certain temperature.
Wherein n is 0,1,2, 3; r2Ar is represented by the general formula IB-1.
In condition i of the invention, the solvent is one of dichloromethane, N dimethylformamide, N-methylpyrrolidone, DMSO, acetone, tetrahydrofuran or dioxane; the condensing agent is one of HATU, HBTU, HCTU and TBTU or the combination of EDC and HOBt; the base is one of triethylamine, diisopropylethylamine, N-methylmorpholine, N-alkyl piperidine or pyridine; the certain temperature is 0-60 ℃. The conditions described under condition ii are the same as those described under (1) condition ii.
(5) Preparation method of oseltamivir derivative (IB-2)
The reaction formula is as follows:
Figure BDA0001213279730000062
the reagents and conditions are as described in (4); r2Ar is represented by the general formula IB-2;
the preparation method of the oseltamivir derivative (IB-2) is the same as that in (4).
(6) The preparation method of the oseltamivir derivative (IB-3) comprises the following steps: condensing oseltamivir carboxylate or salts thereof and corresponding sulfonyl chloride under the action of an acid-binding agent to obtain an ester target product, and hydrolyzing the ester target product to obtain a carboxylic acid target product.
The reaction formula is as follows:
Figure BDA0001213279730000071
the reagent and the conditions are that (i) the solvent, the acid-binding agent and the temperature are controlled; (ii) solvent, alkali and certain temperature.
Wherein n is 0,1,2, 3; r2Ar is represented by the general formula IB-3.
In condition i of the invention, the solvent is one of dichloromethane, N-dimethylformamide, N-methylpyrrolidone, DMSO, acetone, tetrahydrofuran, dioxane, toluene or xylene; the acid-binding agent is one of triethylamine, diisopropylethylamine, N-methylmorpholine, N-alkyl piperidine, pyridine, sodium carbonate, potassium carbonate or cesium carbonate; the certain temperature is 0-60 ℃. The conditions described under condition ii are the same as those described under (1) condition ii.
(7) The preparation method of the oseltamivir derivative (IC-1) comprises the following steps: condensing oseltamivir carboxylate and corresponding carbonylimidothioic acid methyl ester hydroiodide to obtain an ester target product, and hydrolyzing the ester target product to obtain a carboxylic acid target product.
The reaction formula is as follows:
Figure BDA0001213279730000072
reagent and condition (i) solvent, certain temperature; (ii) solvent, alkali and certain temperature.
Wherein n is 0,1,2, 3; r2Ar is represented by the general formula IC-1.
In condition i of the invention, the solvent is one of methanol, ethanol, n-propanol or isopropanol; the certain temperature is 0-60 ℃. The conditions described under condition ii are the same as those described under (1) condition ii.
(8) The preparation method of the oseltamivir derivative (ID-1) comprises the following steps: oseltamivir and corresponding N-tert-butyl formate- (Z) -N' -aryl-S-methyl isothiourea are condensed to obtain a tert-butoxycarbonyl protected intermediate, a protecting group is removed by acid to obtain an ester target product, and the ester target product is hydrolyzed to obtain a carboxylic acid target product.
The reaction formula is as follows:
Figure BDA0001213279730000081
the reagent and the condition are that (i) the solvent and the alkali are used at a certain temperature; (ii) solvent, acid and certain temperature; (iii) solvent, alkali and certain temperature.
Wherein n is 0,1,2, 3; r2Ar is represented by the general formula ID-1.
In condition i of the invention, the solvent is one of methanol, ethanol, n-propanol, isopropanol, acetonitrile, tetrahydrofuran or acetone; the certain temperature is 0-60 ℃. In condition ii of the present invention, the solvent is one of dichloromethane, chloroform, dichloroethane, acetonitrile, tetrahydrofuran, acetone, ethyl acetate, diethyl ether or isopropyl ether, the acid is one of trifluoroacetic acid, hydrochloric acid or sulfuric acid, and the temperature is 0 to 60 ℃. The conditions described under the condition iii are the same as those described under the condition (1) ii.
In the preparation method of the oseltamivir derivative (IA-1), when the substituent on the phenyl or other aromatic heterocyclic ring in Ar on the aldehyde is phenyl, thienyl, other aromatic heterocyclic ring, aromatic sulfenyl and unsubstituted or N-alkyl substituted aromatic amino, the preparation method needs to be independently prepared, and comprises the following steps:
(1) a process for the preparation of an aldehyde (a) comprising the steps of: aromatic boric acid and brominated aromatic aldehyde are subjected to palladium catalytic coupling under the protection of nitrogen to obtain a target product.
The reaction formula is as follows:
Figure BDA0001213279730000082
and (iii) solvent, catalyst, acid binding agent, certain temperature and inert gas protection.
Ar2Substituted or unsubstituted phenyl, and other substituted or unsubstituted aromatic heterocycles. Ar (Ar)3The heterocyclic compound is various substituted benzene rings, various substituted hexatomic heterocyclic rings, various substituted pentatomic heterocyclic rings, various substituted hexatomic and hexatomic heterocyclic rings, various substituted pentatomic and pentatomic heterocyclic rings, various substituted benzo pentatomic heterocyclic rings or various substituted benzo hexatomic heterocyclic rings.
In condition iii of the present invention, the solvent is one of N, N-dimethylformamide, DMSO, N-methylpyrrolidone, acetone, tetrahydrofuran, dioxane, toluene, or xylene, and one of C1-C6 single-chain or branched aliphatic alcohols; the catalyst is the combination of tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, palladium chloride, palladium acetate and corresponding ligands of triphenylarsenic, tri-n-butylphosphine, trimethoxy phosphorus, 2-bis (diphenylphosphine) ethane, 1, 3-bis (diphenylphosphine) propane, 1, 5-bis (diphenylphosphine) pentane and 1, 8-bis (diphenylphosphine) octane; the acid-binding agent is one of sodium carbonate, potassium carbonate, cesium carbonate, trisodium phosphate and tripotassium phosphate; the inert gas is nitrogen or argon; the certain temperature is 60-200 ℃.
(2) A process for the preparation of an aldehyde (b) comprising the steps of: aromatic mercaptan and fluoro-aromatic aldehyde generate target products under alkaline conditions.
The reaction formula is as follows:
Figure BDA0001213279730000091
the reagent and the conditions (iv) solvent, acid binding agent and certain temperature.
Ar2Ar as described for the above aldehyde (a)2；Ar4Ar as described for the above aldehyde (a)3。
In condition iv of the present invention, the solvent is one of N, N dimethylformamide, DMSO, N-methylpyrrolidone, acetone, tetrahydrofuran, or dioxane; the acid-binding agent is one of sodium carbonate, potassium carbonate or cesium carbonate; the certain temperature is 60-200 ℃.
(3) A process for the preparation of an aldehyde (c) comprising the steps of: aromatic amine and brominated aromatic aldehyde are subjected to palladium catalytic coupling under the protection of nitrogen to obtain a target product.
The reaction formula is as follows:
Figure BDA0001213279730000092
the reagent and the condition (v) are solvent, catalyst, acid-binding agent, certain temperature and inert gas protection.
Ar2Ar as described for the above aldehyde (a)2；Ar5Ar as described for the above aldehyde (a)3；R5Is C1-C6Single chain or branched aliphatic alkanes.
In condition v of the present invention, the solvent is one of N, N dimethylformamide, DMSO, N-methylpyrrolidone, tetrahydrofuran, dioxane, toluene, and xylene; the catalyst is the combination of tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, palladium chloride, palladium acetate and corresponding ligands of 1,1 '-binaphthyl-2, 2' -diphenylphosphine, tri-n-butylphosphine, trimethoxy phosphorus, 2-bis-diphenylphosphinoethane, 1, 3-bis (diphenylphosphine) propane, 1, 5-bis (diphenylphosphine) pentane and 1, 8-bis (diphenylphosphine) octane; the acid-binding agent is one of sodium carbonate, potassium carbonate, cesium carbonate, sodium bis (trimethylsilyl) amide, sodium tert-butoxide or potassium tert-butoxide; the certain temperature is 60-200 ℃. The inert gas is nitrogen or argon.
3. Application of oseltamivir derivative
The activity of the partial oseltamivir derivatives synthesized by the method is screened at a cellular level against avian influenza H5N1, H5N2, H5N6 and H5N8, and oseltamivir hydrochloride, zanamivir, ribavirin, amantadine hydrochloride and rimantadine hydrochloride are used as positive controls. Their anti-avian influenza activity data are listed in table 1.
As can be seen from Table 1, oseltamivir derivatives of the present inventionThe compound is a series of cyclohexene NA inhibitors with novel structures, and shows extremely strong activity of resisting H5 avian influenza. EC for partial compound to inhibit four H5 type avian influenza50The values exceed positive control drug oseltamivir hydrochloride carboxylic acid, wherein the activity of the compounds IA-1-4 and IA-1-7 is particularly outstanding, and the EC of IA-1-4 on H5N1, H5N2, H5N6 and H5N850All lower than five positive controls and a10 in CN201410119920, with EC against H5N2 strain50The value is lower than one tenth of that of oseltamivir hydrochloride carboxylic acid; EC of IA-1-7 on H5N1, H5N2, H5N6, H5N850All lower than five positive controls and a10 in CN201410119920, with EC against H5N6 strain50The value is lower than one tenth of that of oseltamivir hydrochloride carboxylic acid. All compounds also showed high safety, and all compounds were more than 100 μ M cytotoxic. Therefore, the novel oseltamivir derivatives have further research and development values and can be used as lead compounds for resisting influenza.
The oseltamivir derivative can be used as an influenza virus neuraminidase inhibitor. In particular to the application of the neuraminidase inhibitor in preparing anti-influenza virus medicines.
An anti-influenza pharmaceutical composition comprising the oseltamivir derivative and one or more pharmaceutically acceptable carriers or excipients.
The invention provides an oseltamivir derivative with a brand-new structure, a preparation method thereof, an anti-influenza activity screening result thereof and the first application thereof in the field of antivirus. Experiments prove that the novel oseltamivir derivative can be used as an influenza virus neuraminidase inhibitor and has high application value. In particular to the application of the compound as an NA inhibitor in preparing anti-influenza virus medicines.
The specific implementation mode is as follows:
the following examples are given to aid in the understanding of the invention, but are not intended to limit the scope of the invention. The synthetic routes involved in the examples are as described above in "2, methods for the preparation of oseltamivir derivatives".
Example 1:
preparation of ethyl (3R,4R,5S) -4-acetamido-5- ((4-nitrobenzyl) amino) -3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylate (1)
Figure BDA0001213279730000101
Oseltamivir phosphate (0.41g,1mmol), 4-nitrobenzaldehyde (0.15g,1.2mmol) and sodium cyanoborohydride (0.12g,2mmol) were weighed out and stirred in 20mL of ethanol solution at 30 ℃ for 5h (TLC detection reaction completed, developing solvent: ethyl acetate). Evaporating to remove the solvent, adding 20mL of water, extracting with 20mL of ethyl acetate for three times, drying with anhydrous magnesium sulfate, filtering, evaporating to remove the solvent, and then performing flash column chromatography to obtain a white solid, namely the compound (3R,4R,5S) -4-acetamido-5- ((4-nitrobenzyl) amino) -3- (pentane-3-oxyl) cyclohexene-1-alkene-1-carboxylic acid ethyl ester, wherein the yield is as follows: 76.3 percent.
Preparation of (3R,4R,5S) -4-acetamido-5- ((4-nitrobenzyl) amino) -3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylic acid (IA-1-1)
Figure BDA0001213279730000111
0.30g of ethyl (3R,4R,5S) -4-acetamido-5- ((4-nitrobenzyl) amino) -3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylate was dissolved in 20mL of ethanol, and 10mL of a 15% potassium hydroxide solution was added thereto, followed by stirring at room temperature for 2 hours. The ethanol was evaporated, 20mL of water was added, and the pH was adjusted to 4 with hydrochloric acid. Extracting with 20mL ethyl acetate for three times, drying with anhydrous magnesium sulfate, filtering, and evaporating to remove the solvent to obtain a white solid, namely the compound (3R,4R,5S) -4-acetamido-5- ((4-nitrobenzyl) amino) -3- (pentane-3-oxyl) cyclohexene-1-alkene-1-carboxylic acid (IA-1-1), wherein the yield is as follows: 80.2 percent.
1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝8.7Hz,2H),8.02(d,J＝9.1Hz,1H),7.62(d,J＝8.7Hz,2H),6.56(s,1H),4.03(d,J＝8.1Hz,1H),3.89(q,J＝15.1Hz,3H),3.72(q,J＝9.1Hz,2H),2.73(td,J＝10.1,5.4Hz,1H),2.64(dd,J＝17.5,4.1Hz,1H),2.04(dd,J＝17.4,9.6Hz,1H),1.87(s,3H),1.42(ddp,J＝26.8,13.3,6.7,6.3Hz,4H),0.82(dt,J＝15.1,7.4Hz,6H).
Example 2:
preparation of ethyl (3R,4R,5S) -4-acetamido-5- ((3-trifluoromethylbenzyl) amino) -3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylate (2)
Figure BDA0001213279730000112
The procedure was as in example 1, except that 3-trifluoromethylbenzaldehyde was used as a starting material.
The product was obtained as a white solid in yield: 77.1 percent.
Preparation of ethyl (3R,4R,5S) -4-acetamido-5- ((3-trifluoromethylbenzyl) amino) -3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylate (IA-1-2)
Figure BDA0001213279730000121
The procedure is as in example 1, except that compound 2 is used as the starting material.
The product was obtained as a white solid in yield: 79.3 percent.
1H NMR(400MHz,DMSO-d6)δ12.71(s,1H),9.90(s,1H),9.53(s,1H),8.22(d,J＝9.0Hz,1H),7.99(s,1H),7.87(d,J＝7.6Hz,1H),7.76(d,J＝7.8Hz,1H),7.66(t,J＝7.7Hz,1H),6.66(s,1H),4.30(s,3H),4.05(q,J＝8.9Hz,1H),3.53–3.46(m,1H),2.96(dd,J＝17.1,4.8Hz,1H),2.77–2.65(m,1H),1.91(s,3H),1.42(qq,J＝14.1,8.8,7.9Hz,4H),0.84(t,J＝7.4Hz,3H),0.80(t,J＝7.4Hz,3H).
Example 3:
preparation of 4- (benzo [ b ] thiophen-2-yl) benzaldehyde (3-1)
Figure BDA0001213279730000122
Benzo [ b ] thiophene-2-boronic acid (1.78g, 10mmol), 4-bromobenzaldehyde (1.85g, 10mmol), potassium carbonate (4.1g, 30mmol), tetrakis (triphenylphosphine) palladium (0.08g, 0.069mol), DMSO (30mL) were added to the flask, heated to 120 ℃ under nitrogen, and stirred for 12 hours. Adding the reaction mixture into 150mL of water, extracting for 3 times by using 50mL of ethyl acetate, drying by anhydrous magnesium sulfate, filtering, evaporating to remove the solvent, and then carrying out flash column chromatography separation to obtain a light yellow oily substance, namely the compound 4- (benzo [ b ] thiophene-2-yl) benzaldehyde (3-1), wherein the yield is as follows: 82.5 percent.
Preparation of ethyl (3R,4R,5S) -4-acetamido-5- ((4- (benzo [ b ] thiophen-2-yl) benzyl) amino) -3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylate (2)
Figure BDA0001213279730000131
The procedure is as in example 1, except that 4- (benzo [ b ] thiophen-2-yl) benzaldehyde is used as the starting material.
The product was obtained as a colorless oil in yield: 75.8 percent.
Preparation of (3R,4R,5S) -4-acetamido-5- ((4- (benzo [ b ] thiophen-2-yl) benzyl) amino) -3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylic acid (IA-1-3)
Figure BDA0001213279730000132
The procedure is as in example 1, except that compound 3 is used as the starting material.
The product was obtained as a white solid in yield: 81.6 percent.
1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝1.5Hz,1H),8.16(d,J＝8.9Hz,1H),8.10(d,J＝8.4Hz,1H),7.81(dd,J＝9.5,6.9Hz,3H),7.73–7.61(m,3H),7.53(d,J＝5.4Hz,1H),6.66(s,1H),4.22(dt,J＝22.4,11.1Hz,3H),4.03(q,J＝9.0Hz,1H),3.41–3.12(m,3H),2.94(dd,J＝17.2,4.7Hz,1H),2.72–2.58(m,1H),1.95(s,3H),1.52–1.36(m,4H),0.89–0.77(m,6H).
Example 4:
preparation of ethyl (3R,4R,5S) -4-acetamido-5- ((4- (diethylamino) benzyl) amino) -3- (pentan-3-oxy) cyclohexen-1-ene-1-carboxylate (4)
Figure BDA0001213279730000133
The procedure was as in example 1, except that 4-diethylaminebenzaldehyde was used as a starting material.
The product was obtained as a pale yellow oil. Yield: 70.3 percent.
Preparation of (3R,4R,5S) -4-acetamido-5- ((4- (diethylamino) benzyl) amino) -3- (pentan-3-oxy) cyclohexen-1-ene-1-carboxylic acid (IA-1-4)
Figure BDA0001213279730000141
The procedure is as in example 1, except that the starting material is compound 4.
The product was obtained as a white solid in yield: 66.8 percent.
1H NMR(400MHz,DMSO-d6)δ7.94(d,J＝9.0Hz,1H),7.11(d,J＝8.6Hz,2H),6.60(d,J＝8.7Hz,2H),6.56(s,1H),4.02(d,J＝7.4Hz,1H),3.76(dd,J＝17.8,10.7Hz,3H),3.59(d,J＝12.7Hz,1H),3.35–3.26(m,5H),2.91–2.81(m,1H),2.72(d,J＝13.1Hz,1H),2.24–2.09(m,1H),1.86(s,3H),1.41(tq,J＝14.0,7.0Hz,4H),1.06(t,J＝7.0Hz,6H),0.83(t,J＝7.4Hz,3H),0.79(t,J＝7.4Hz,3H).
Example 5:
preparation of ethyl (3R,4R,5S) -4-acetamido-5- ((4- (1H-pyrrol-1-yl) benzyl) amino) -3- (pentan-3-oxy) cyclohexen-1-ene-1-carboxylate (5)
Figure BDA0001213279730000142
The procedure is as in example 1, except that 4- (1H-pyrrol-1-yl) benzaldehyde is used as the starting material.
The product was obtained as a white solid in yield: 70.4 percent.
Preparation of (3R,4R,5S) -4-acetamido-5- ((4- (1H-pyrrol-1-yl) benzyl) amino) -3- (pentan-3-oxy) cyclohexen-1-ene-1-carboxylic acid (IA-1-5)
Figure BDA0001213279730000151
The procedure is as in example 1, except that compound 5 is used as the starting material.
The product was obtained as a white solid in yield: 69.2 percent.
1H NMR(400MHz,DMSO-d6)δ8.05(d,J＝8.8Hz,1H),7.66–7.50(m,4H),7.42–7.36(m,2H),6.64(s,1H),6.31–6.23(m,2H),4.18(d,J＝7.2Hz,1H),4.08(q,J＝13.8,13.0Hz,2H),3.93(q,J＝9.2Hz,1H),3.35–3.06(m,3H),2.93–2.71(m,2H),1.92(s,3H),1.43(qt,J＝13.8,7.0Hz,4H),0.87–0.77(m,6H).
Example 6:
preparation of 4- (ethyl (phenyl) amino) benzaldehyde (6-1)
Figure BDA0001213279730000152
N-Ethylaniline (1.21g, 10mmol), 4-bromobenzaldehyde (1.85g, 10mmol), cesium carbonate (7.5g, 20mmol), palladium acetate (0.08g), BINAP (0.16g), toluene (30mL) were added to the flask, heated to 110 ℃ under nitrogen, and stirred for 12 hours. Adding the reaction mixture into 150mL of water, extracting for 3 times by using 50mL of ethyl acetate, drying by magnesium sulfate, filtering, evaporating to remove the solvent, and then carrying out flash column chromatography separation to obtain a light yellow oily substance, namely the compound 4- (ethyl (phenyl) amino) benzaldehyde (6-1), wherein the yield is as follows: 70.9 percent.
Preparation of ethyl (3R,4R,5S) -4-acetamido-5- ((4- (ethyl (phenyl) amino) benzyl) amino) -3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylate (6)
Figure BDA0001213279730000153
The procedure is as in example 1, except that 4- (ethyl (phenyl) amino) benzaldehyde is used as the starting material.
The product was obtained as a white oil. Yield: 73.7 percent.
Preparation of (3R,4R,5S) -4-acetamido-5- ((4- (ethyl (phenyl) amino) benzyl) amino) -3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylic acid (IA-1-6)
Figure BDA0001213279730000161
The procedure is as in example 1, except that the starting material is compound 6.
The product was obtained as a white solid in yield: 76.5 percent.
1H NMR(400MHz,DMSO-d6)δ7.94(d,J＝9.1Hz,1H),7.22(dt,J＝8.6,3.6Hz,4H),6.93(d,J＝8.6Hz,3H),6.79(d,J＝8.7Hz,2H),6.54(s,1H),4.08(d,J＝8.1Hz,1H),3.99–3.79(m,3H),3.65(q,J＝7.0Hz,2H),3.29(p,J＝5.5Hz,1H),3.19–3.10(m,1H),2.73(dd,J＝17.2,4.9Hz,1H),2.50-2.30(m，2H),1.80(s,3H),1.33(dp,J＝19.0,6.9Hz,4H),1.02(t,J＝7.0Hz,3H),0.74(t,J＝7.4Hz,3H),0.69(t,J＝7.4Hz,3H).
Example 7:
preparation of 4- (phenylthio) benzaldehyde (7-1)
Figure BDA0001213279730000162
Thiophenol (2..2g, 20mmol), 4-fluorobenzaldehyde (2.48g, 20mmol), potassium carbonate (5.52g, 40mmol), DMSO30mL were added to the flask, heated to 120 ℃ and stirred for 12 hours. Adding the reaction mixture into 150mL of water, extracting for 3 times by using 50mL of ethyl acetate, drying by magnesium sulfate, filtering, evaporating to remove the solvent, and then carrying out flash column chromatography separation to obtain a light yellow solid, namely the compound 4- (phenylthio) benzaldehyde (7-1), wherein the melting point: 56-58 ℃ and yield: and (3.5).
Preparation of ethyl (3R,4R,5S) -4-acetamido-3- (pentane-3-oxy) -5- ((4- (phenylthio) benzyl) amino) cyclohexen-1-ene-1-carboxylate (7)
Figure BDA0001213279730000171
The procedure is as in example 1, except that 4- (phenylthio) benzaldehyde is used as the starting material.
The product was obtained as a colorless oil. Yield: 69.4 percent.
Preparation of (3R,4R,5S) -4-acetamido-3- (pentane-3-oxy) -5- ((4- (phenylthio) benzyl) amino) cyclohexen-1-ene-1-carboxylic acid (IA-1-7)
Figure BDA0001213279730000172
The procedure is as in example 1, except that the starting material is compound 7.
The product was obtained as a white solid in yield: 73.6 percent.
1H NMR(400MHz,DMSO-d6)δ7.97(d,J＝8.6Hz,1H),7.39(d,J＝7.9Hz,2H),7.35–7.30(m,2H),7.29–7.22(m,5H),6.56(s,1H),4.08(d,J＝6.6Hz,1H),4.03–3.86(m,2H),3.85–3.77(m,1H),3.44(s,1H),3.25–2.93(m,2H),2.72(d,J＝14.2Hz,1H),2.36(s,1H),1.82(s,3H),1.35(tp,J＝13.7,6.9Hz,4H),0.77(t,J＝7.4Hz,3H),0.72(t,J＝7.4Hz,3H).
Example 8:
preparation of ethyl (3R,4R,5S) -4-acetamido-3- (pentane-3-oxy) -5- ((4- (benzenesulfonyl) benzyl) amino) cyclohexen-1-ene-1-carboxylate (8)
Figure BDA0001213279730000173
The procedure is as in example 1, except that 4- (phenylsulfonyl) benzaldehyde is used as the starting material.
The product was obtained as a white oil. Yield: 72.8 percent.
Preparation of (3R,4R,5S) -4-acetamido-3- (pentane-3-oxy) -5- ((4- (benzenesulfonyl) benzyl) amino) cyclohexen-1-ene-1-carboxylic acid (IA-1-8)
Figure BDA0001213279730000181
The procedure is as in example 1, except that the starting material is compound 8.
The product was obtained as a white solid in yield: 69.7 percent.
1H NMR(400MHz,Methanol-d4)δ8.05–7.93(m,4H),7.70–7.60(m,3H),7.59–7.54(m,2H),6.81(s,1H),4.35(d,J＝13.5Hz,1H),4.22(s,1H),4.18(d,J＝5.0Hz,1H),4.10(dd,J＝10.8,8.2Hz,1H),3.44(dp,J＝16.9,5.6Hz,2H),2.97(dd,J＝17.4,5.3Hz,1H),2.53(ddt,J＝15.1,9.8,2.4Hz,1H),2.00(s,3H),1.51(dhept,J＝13.8,6.6Hz,4H),0.90(d,J＝7.4Hz,3H),0.86(d,J＝7.5Hz,3H).
Example 9:
preparation of 5-phenylthiophene-2-carbaldehyde (9-1)
Figure BDA0001213279730000182
Phenylboronic acid (2.42g, 20mmol), 5-bromothiophene-2-carbaldehyde (3.84g, 20mmol), potassium carbonate (4.1g, 30mmol), tetrakis (triphenylphosphine) palladium (0.08g), DMSO (30mL) were added to the flask, heated to 120 ℃ under nitrogen, and stirred for 12 hours. Adding the reaction mixture into 150mL of water, extracting for 3 times by using 50mL of ethyl acetate, drying by magnesium sulfate, filtering, evaporating to remove the solvent, and then carrying out flash column chromatography separation to obtain a light yellow oily substance, namely the compound 5-phenylthiophene-2-formaldehyde (9-1), wherein the yield is as follows: 77.1 percent.
Preparation of ethyl (3R,4R,5S) -4-acetamido-3- (pentane-3-oxy) -5- (((5-phenylthiophenyl-2-yl) methyl) amino) cyclohexen-1-ene-1-carboxylate (9)
Figure BDA0001213279730000191
The procedure is as in example 1, except that 5-phenylthiophene-2-carbaldehyde is used as the starting material.
The product was obtained as a white solid in yield: 68.9 percent.
Preparation of ethyl (3R,4R,5S) -4-acetamido-3- (pentane-3-oxy) -5- (((5-phenylthiophenyl-2-yl) methyl) amino) cyclohexen-1-ene-1-carboxylate (IA-1-9)
Figure BDA0001213279730000192
The procedure is as in example 1, except that the starting material is compound 9.
The product was obtained as a white solid in yield: 79.6 percent.
1H NMR(400MHz,Methanol-d4)δ7.98(s,1H),7.95(dd,J＝6.5,3.2Hz,2H),7.49(dd,J＝5.1,1.7Hz,3H),6.87(s,1H),4.74–4.60(m,2H),4.26(d,J＝7.8Hz,1H),4.17(dd,J＝10.8,8.3Hz,1H),3.64(td,J＝10.3,5.6Hz,1H),3.45(p,J＝5.6Hz,1H),3.09(dd,J＝17.2,5.3Hz,1H),2.64(dd,J＝17.2,10.0Hz,1H),2.07(s,3H),1.61–1.46(m,4H),0.95–0.90(m,3H),0.90–0.85(m,3H).
Example 10:
preparation of ethyl (3R,4R,5S) -4-acetamido-5- (bis (thien-3-ylmethyl) amino) -3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylate (10)
Figure BDA0001213279730000193
Figure BDA0001213279730000201
Oseltamivir phosphate (0.41g,1mmol), thiophene-3-formaldehyde (0.269g,2.4mmol) and sodium cyanoborohydride (0.24g,4mmol) were weighed into 20mL of ethanol solution and stirred at 30 ℃ for 5h (TLC detection reaction completed, developing solvent: ethyl acetate). The solvent was distilled off, 20mL of water was added, extraction was carried out three times with 20mL of ethyl acetate, drying was carried out over anhydrous magnesium sulfate, filtration was carried out, the solvent was distilled off, and then flash column chromatography separation was carried out to obtain an oily substance, i.e., the compound (3R,4R,5S) -4-acetamido-5- (bis (thien-3-ylmethyl) amino) -3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylic acid ethyl ester (10), with a yield of 74.4%.
Preparation of ethyl (3R,4R,5S) -4-acetamido-5- (bis (thien-3-ylmethyl) amino) -3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylate (IA-2-1)
Figure BDA0001213279730000202
The procedure is as in example 1, except that the starting material is compound 10.
The product was obtained as a white solid in yield: 73.0 percent.
1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),7.78(d,J＝8.6Hz,1H),7.43(dd,J＝4.8,3.0Hz,2H),7.33–7.24(m,2H),7.01(d,J＝4.7Hz,2H),6.55(s,1H),4.05–3.87(m,2H),3.69(d,J＝14.1Hz,2H),3.53(d,J＝14.1Hz,2H),2.85(td,J＝10.7,4.8Hz,1H),2.51(s,2H),2.27–2.12(m,1H),1.91(s,3H),1.42(ddq,J＝18.9,13.6,6.9Hz,4H),0.83(t,J＝6.8Hz,3H),0.79(t,J＝7.4Hz,3H).
Example 11:
preparation of ethyl (3R,4R,5S) -4-acetamido-5- (((E) -3- (4-fluorophenyl) allyl) amino) -3- (pentan-3-yloxy) cyclohexen-1-ene-1-carboxylate (11)
Figure BDA0001213279730000203
The procedure was as in example 1, except that (E) -3- (4-fluorophenyl) acrolein was used as a starting material.
The product was obtained as a colorless oil. Yield: 78.2 percent.
Preparation of ethyl (3R,4R,5S) -4-acetamido-5- (((E) -3- (4-fluorophenyl) allyl) amino) -3- (pentan-3-oxy) cyclohexen-1-ene-1-carboxylate (IA-3-1)
Figure BDA0001213279730000211
The procedure is as in example 1, except that the starting material is compound 11.
The product was obtained as a white solid in yield: 62.9 percent.
1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝8.9Hz,1H),7.46(q,J＝8.6Hz,4H),7.37–7.24(m,1H),6.81(d,J＝15.9Hz,1H),6.65(s,1H),6.44–6.30(m,1H),4.22(d,J＝8.3Hz,1H),3.95–3.84(m,1H),3.77(ddt,J＝20.9,13.7,6.9Hz,2H),3.50-3.20(3H),2.86(dd,J＝17.2,5.0Hz,1H),2.60-2.40(1H),1.92(s,3H),1.42(tt,J＝13.3,6.9Hz,4H),0.84(t,J＝7.4Hz,3H),0.79(t,J＝7.4Hz,3H).
Example 12:
preparation of ethyl (3R,4R,5S) -5- (2- ([1,1' -biphenyl ] -4-yl) acetamide) -4-acetamido-3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylate (12)
Figure BDA0001213279730000212
Oseltamivir phosphate (0.41g,1mmol), 2- ([1,1' -biphenyl ] -4-yl) acetic acid (0.22g,1.2mmol) and HATU (0.45g,1.2mmol) were weighed out and stirred in a solution of 20mL of dichloromethane and 5mL of triethylamine at 30 ℃ for 8 hours (TLC detection of the developer after completion of the reaction: ethyl acetate). Removing the solvent by evaporation, adding 30mL of water, extracting with 30mL of ethyl acetate for three times, drying over anhydrous magnesium sulfate, filtering, removing the solvent by evaporation, and then performing flash column chromatography to obtain a white solid, namely the compound (3R,4R,5S) -5- (2- ([1,1' -biphenyl ] -4-yl) acetamide) -4-acetamido-3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylic acid ethyl ester (12), wherein the yield is as follows: 82.6 percent.
Preparation of (3R,4R,5S) -5- (2- ([1,1' -biphenyl ] -4-yl) acetamide) -4-acetamido-3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylic acid (IB-1-1)
Figure BDA0001213279730000221
The procedure is as in example 1, except that the starting material is compound 12.
The product was obtained as a white solid in yield: 78.6 percent.
1H NMR(400MHz,DMSO-d6)δ12.64(s,1H),8.03(d,J＝8.8Hz,1H),7.79(d,J＝9.1Hz,1H),7.64(d,J＝7.5Hz,2H),7.58(d,J＝7.9Hz,2H),7.46(t,J＝7.5Hz,2H),7.35(t,J＝8.5Hz,3H),6.61(s,1H),4.05(d,J＝7.5Hz,1H),3.90(dt,J＝15.2,7.8Hz,1H),3.79(q,J＝9.2Hz,1H),3.50–3.35(m,3H),2.50–2.39(m,1H),2.20(dd,J＝17.1,10.5Hz,1H),1.64(s,3H),1.40(tp,J＝14.6,7.1Hz,4H),0.83(t,J＝7.2Hz,3H),0.75(t,J＝7.2Hz,3H).
Example 13:
preparation of (3R,4R,5S) -4-acetamido-5-cinnamamide-3- (pentane-3-oxy) cyclohexene-1-ene-1-carboxylic acid ethyl ester (13)
Figure BDA0001213279730000222
The procedure is as in example 12, except that the starting material is cinnamic acid.
The product was obtained as a white solid in yield: 84.6 percent.
Preparation of (3R,4R,5S) -4-acetamido-5-cinnamamide-3- (pentane-3-oxy) cyclohexene-1-ene-1-carboxylic acid (IB-2-1)
Figure BDA0001213279730000231
The procedure is as in example 1, except that the starting material is compound 13.
The product was obtained as a white solid in 79.4% yield.
1H NMR(400MHz,DMSO-d6)δ12.59(s,1H),7.98(d,J＝8.9Hz,1H),7.84(d,J＝9.2Hz,1H),7.56(d,J＝7.2Hz,2H),7.47–7.32(m,4H),6.65(s,1H),6.60(d,J＝15.8Hz,1H),4.13(d,J＝8.1Hz,1H),4.06(tt,J＝9.9,5.2Hz,1H),3.83(t,J＝9.0Hz,1H),3.41(p,J＝5.5Hz,1H),2.57(dd,J＝17.6,5.1Hz,1H),2.29–2.18(m,1H),1.74(s,3H),1.42(th,J＝13.8,7.0Hz,4H),0.85(t,J＝7.3Hz,3H),0.77(t,J＝7.3Hz,3H).
Example 14:
preparation of ethyl (3R,4R,5S) -5- ([1,1' -biphenyl ] -4-sulfonamide) -4-acetamido-3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylate (14)
Figure BDA0001213279730000232
Oseltamivir phosphate (0.41g,1mmol) and [1,1' -biphenyl ] -4-sulfonyl chloride (0.25g,1mmol) are weighed and stirred in 20mL dichloromethane and 5mL triethylamine solution for 8h at 25-30 ℃ (TLC detection reaction finished developing agent: ethyl acetate). Removing the solvent by evaporation, adding 30mL of water, extracting with 30mL of ethyl acetate for three times, drying with anhydrous magnesium sulfate, filtering, removing the solvent by evaporation, and then performing flash column chromatography to obtain a white solid, namely the compound (3R,4R,5S) -5- ([1,1' -biphenyl ] -4-sulfonamide) -4-acetamido-3- (pentane-3-oxyl) cyclohexene-1-alkene-1-carboxylic acid ethyl ester (12), wherein the yield is as follows: 84.7 percent.
Preparation of (3R,4R,5S) -5- ([1,1' -biphenyl ] -4-sulfonamide) -4-acetamido-3- (pentane-3-oxy) cyclohexen-1-ene-1-carboxylic acid (14) (IB-3-1)
Figure BDA0001213279730000241
The procedure is as in example 1, except that the starting material is compound 14.
The product was obtained as a white solid in yield: 78.6 percent.
1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),7.92–7.83(m,4H),7.77–7.66(m,4H),7.52(d,J＝15.0Hz,2H),7.44(t,J＝7.3Hz,1H),6.55(s,1H),4.10(d,J＝8.2Hz,1H),3.67(q,J＝9.0Hz,1H),3.35–3.21(m,2H),2.31(dd,J＝17.6,5.3Hz,1H),2.17(dd,J＝17.7,10.3Hz,1H),1.69(s,3H),1.38(ddp,J＝20.8,13.7,6.9Hz,4H),0.81(t,J＝7.4Hz,3H),0.76(t,J＝7.4Hz,3H).
Example 15:
ethyl (3R,4R,5S) -5- (((Z) - [1,1' -biphenyl ] -4-yl (amino) methylene) amine) -4-acetamido-3- (pentan-3-yloxy) cyclohexen-1-ene-1-carboxylate hydroiodide
Figure BDA0001213279730000242
Oseltamivir (0.62g,2mmol) and [1,1' -biphenyl ] -4-carbonylimidothioic acid methyl ester hydroiodide (0.71g,2mmol) are weighed and stirred in 30mL ethanol at 25-30 ℃ for 4h (TLC detection of developing solvent after reaction: ethyl acetate). Removing the solvent by evaporation, adding 30mL of water, extracting for 3 times by using 30mL of ethyl acetate, drying with anhydrous magnesium sulfate, filtering, removing the solvent by evaporation, and then performing flash column chromatography to obtain a white solid, namely the compound (3R,4R,5S) -5- (((Z) - [1,1' -biphenyl ] -4-yl (amino) methylene) amine) -4-acetamido-3- (pentane-3-oxy) cyclohexene-1-ene-1-carboxylic acid ethyl ester hydroiodide (15), with the yield: 67.2 percent.
(3R,4R,5S) -5- (((Z) - [1,1' -biphenyl ] -4-yl (amino) methylene) amine) -4-acetamido-3- (pentan-3-yloxy) cyclohexen-1-ene-1-carboxylic acid (IC-1-1)
Figure BDA0001213279730000251
The procedure is as in example 1, except that the starting material is compound 15.
The product was obtained as a white solid in yield: 62.9 percent.
1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),9.60(s,1H),9.26(s,1H),7.90(d,J＝8.1Hz,2H),7.77(t,J＝5.9Hz,4H),7.52(t,J＝7.4Hz,2H),7.46(d,J＝7.2Hz,1H),6.48(s,1H),4.36(s,2H),3.95(q,J＝9.2Hz,1H),2.76(d,J＝14.1Hz,1H),2.59(d,J＝9.3Hz,1H),1.89(s,1H),1.85(s,3H),1.56–1.32(m,4H),0.86(t,J＝7.2Hz,3H),0.81(t,J＝7.2Hz,3H).
Example 16:
preparation of ethyl (3R,4R,5S) -5- ((Z) -2- ([1,1' -biphenyl ] -4-ylmethyl) guanidino) -4-acetamido-3- (pentan-3-yloxy) cyclohexen-1-ene-1-carboxylate (16)
Figure BDA0001213279730000252
Oseltamivir (0.62g,2mmol), N-formic acid tert-butyl ester- (Z) -N '- ([1,1' -biphenyl ] -4-ylmethyl) -S-methylisothiourea (0.71g,2mmol) were weighed, stirred in 30mL dry acetonitrile and 5mL triethylamine for 16h at 30 ℃ (TLC detection of the developer after completion of the reaction: ethyl acetate). The solvent was distilled off, 30mL of water was added, extraction was carried out 3 times with 30mL of ethyl acetate, drying over anhydrous magnesium sulfate was washed with dilute hydrochloric acid, filtration was carried out, and the solvent was distilled off to give a pale yellow oil which was used directly in the next step.
The oil obtained in the previous step was dissolved in 15mL of dichloromethane, 15mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off to give a pale yellow oil (16) which was used directly in the next step.
Preparation of (3R,4R,5S) -5- ((E) -2- ([1,1' -biphenyl ] -4-ylmethyl) guanidino) -4-acetamido-3- (pentan-3-yloxy) cyclohexen-1-ene-1-carboxylic acid (ID-1-1)
Figure BDA0001213279730000261
This procedure is identical to the second step of example 1, except that the starting material was a pale yellow oil from the previous step.
The product was obtained as a white solid in yield: 25.7 percent.
1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),8.06(d,J＝8.4Hz,1H),7.70–7.65(m,4H),7.60(s,1H),7.53–7.44(m,3H),7.39(dd,J＝7.7,4.0Hz,3H),6.65(s,1H),4.44(d,J＝5.7Hz,2H),4.13(s,1H),3.80(d,J＝8.2Hz,2H),3.5-3.2(m,2H),2.67(d,J＝15.6Hz,1H),2.30(dd,J＝16.3,7.9Hz,1H),1.79(s,3H),1.42(th,J＝14.0,7.0Hz,4H),0.82(dt,J＝19.8,7.4Hz,6H).
Example 17:
in vitro anti-influenza virus activity assay for target compounds
Test materials and methods:
(1) H5N1, H5N2, H5N6, H5N8 influenza virus strains: provided by poultry research institute of agricultural academy of Shandong province.
(2) Chicken Embryo Fibroblasts (CEF): provided by poultry research institute of agricultural academy of Shandong province.
(3) Sample treatment: the samples were dissolved in DMSO to make appropriate concentrations just before use and diluted with maintenance solution, 6 dilutions each.
(4) Positive control drug: oseltamivir hydrochloride carboxylic acid, zanamivir, ribavirin, amantadine hydrochloride and rimantadine hydrochloride.
(5) The test method comprises the following steps: diluting the sample, mixing with influenza virus solution, inoculating to chicken embryo fibroblast after a period of time, incubating, testing the titer of mixed solution and blank solution at different concentrations, and calculating the inhibition rate and EC50。
The experimental method comprises the following steps:
first, CC of each novel oseltamivir derivative was determined50(drug concentration that causes 50% of CEF cells to develop lesions). The determination method comprises the following steps: the drug to be tested is prepared into 2000 mu M mother solution by DMSO, and the cell maintenance solution is diluted to the corresponding concentration during the experiment. Monolayers of or cellular CEF cells have been grown in 96-well plates, the culture broth removed and replaced with cell maintenance solutions containing different concentrations of the diluted drug, respectively. 3 replicates were set for each concentration, along with a normal cell control. Placing at 37 ℃ and 5% CO2Culturing for 72h in an incubator. And (4) observing the cytotoxicity condition of the drug treated at different concentrations under an inverted microscope, and determining the cell survival rate by using an MTS colorimetric method. Calculating CC of drugs50。
Cell viability ═ 100% (mean OD value of drug group/mean OD value of cell control group) ×
Inoculating CEF cells in growth phase into 96-well plate, and culturing at 37 deg.C with 5% CO2After growing into a monolayer in the incubator, the culture medium is discarded, washed twice, and 100TCID of the mixed test compound is added50200. mu.L of the virus suspension (1) at 37 ℃ with 5% CO2After incubation for 72 h. The pathological effect of the drug group cells was visualized by microscope. The whole experimental process is set as a cell control group without any treatment,virus control group without test drug added. Removing supernatant of observed cell culture plate, washing with PBS twice, determining and calculating virus inhibition rate by MTS colorimetric method, and calculating EC of medicine50。。
Viral inhibition rate (drug-treated (drug + virus) OD-virus control OD)/(cell control OD-virus control OD)
The cellular level of activity against H5N1, H5N2, H5N6 and H5N8 was screened for some of the synthetic novel oseltamivir derivative derivatives according to the above experimental methods, and CC of each novel oseltamivir derivative50Are all larger than 100 mu M. The activity results of a part of the novel oseltamivir derivative derivatives are shown in table 1.
TABLE 1 Structure of partial oseltamivir derivatives and positive control drugs and their in vitro anti-influenza virus activity (CEF cells)
Figure BDA0001213279730000271
Figure BDA0001213279730000281
Figure BDA0001213279730000291
Figure BDA0001213279730000301
Note:a EC50a concentration of a compound that protects 50% of CEF cells infected with avian influenza virus from cytopathic effects; a represents the compound EC50<0.5. mu.M, B represents Compound EC50In the range of 0.5-5. mu.M, C represents the compound EC50In the range of 5-50. mu.M, C represents the compound EC50>50 mu M; oseltamivir carboxylate, Zanamivir, Ribavirin, 1-Adamantanamine hydrochloride, Rimantadine hydrochloride represent controls, respectivelyThe drugs oseltamivir carboxylic acid, zanamivir, ribavirin, amantadine hydrochloride and rimantadine hydrochloride.

Claims (5)

1. An oseltamivir derivative or a pharmaceutically acceptable salt thereof, characterized by having a structural formula shown below:
Figure FDA0002987042990000011
2. the process for preparing oseltamivir derivatives according to claim 1, comprising the steps of:
the preparation method of the oseltamivir derivatives IA-1-4, IA-1-6 and IA-1-7 comprises the following steps: oseltamivir carboxylate, corresponding aldehyde, and acid in a corresponding solvent to form an intermediate transition state similar to schiff base; obtaining an ester target product through selective reduction, and obtaining a carboxylic acid target product through hydrolysis of the ester target product; the molar ratio of the corresponding aldehyde to the oseltamivir carboxylate is 1-2:1, and the molar ratio of the acid to the oseltamivir carboxylate is 0.5-3: 1;
the reaction formula is as follows:
Figure FDA0002987042990000012
the reagent and the conditions are that (i) the solvent, the acid, the selective reducing agent and the certain temperature are adopted; (ii) solvent, alkali and certain temperature;
wherein R is2Hydrogen, methyl, ethyl, substituted or unsubstituted benzyl, phenethyl, phenylpropyl; ar has the following structural formula respectively:
Figure FDA0002987042990000021
in condition i of the invention, the solvent is methanol, N-propanol, isopropanol, acetone, tetrahydrofuran, dioxane, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide or a combination of any two solvents; the acid is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or corresponding acid phosphate and various organic acids, and the selective reducing agent is sodium cyanoborohydride or sodium triacetoxyborohydride; the certain temperature is 0-100 ℃; the solvent in the condition ii is methanol, n-propanol, isopropanol, acetone, tetrahydrofuran, dioxane, water and a combination of water and any other solvent; the alkali is one of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide; the certain temperature is 0-100 ℃;
the corresponding aldehydes are each of the following formulae:
Figure FDA0002987042990000022
3. the process for preparing oseltamivir derivatives IA-1-4, IA-1-6 and IA-1-7 of claim 2, wherein the corresponding aldehydes b and c are prepared separately as follows:
(1) the preparation method of the aldehyde b comprises the following steps: coupling N-ethylaniline and bromobenzaldehyde under the protection of nitrogen by palladium catalysis to obtain a target product;
the reaction formula is as follows:
Figure FDA0002987042990000023
reagent and conditions (iii) solvent, catalyst, acid-binding agent, certain temperature, inert gas protection;
in condition iii of the present invention, the solvent is one of N, N dimethylformamide, DMSO, N-methylpyrrolidone, tetrahydrofuran, dioxane, toluene, and xylene; the catalyst is the combination of tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, palladium chloride, palladium acetate and corresponding ligands of 1,1 '-binaphthyl-2, 2' -diphenylphosphine, tri-n-butylphosphine, trimethoxy phosphorus, 2-bis-diphenylphosphinoethane, 1, 3-bis (diphenylphosphine) propane, 1, 5-bis (diphenylphosphine) pentane and 1, 8-bis (diphenylphosphine) octane; the acid-binding agent is one of sodium carbonate, potassium carbonate, cesium carbonate, sodium bis (trimethylsilyl) amide, sodium tert-butoxide or potassium tert-butoxide; the certain temperature is 60-200 ℃; the inert gas is nitrogen or argon;
(2) the preparation method of the aldehyde c comprises the following steps: generating a target product by using benzenethiol and p-fluorobenzaldehyde under an alkaline condition;
the reaction formula is as follows:
Figure FDA0002987042990000031
the reagent and the conditions are (iv) solvent, acid-binding agent and certain temperature;
in condition iv of the present invention, the solvent is one of N, N dimethylformamide, DMSO, N-methylpyrrolidone, acetone, tetrahydrofuran, or dioxane; the acid-binding agent is one of sodium carbonate, potassium carbonate or cesium carbonate; the certain temperature is 60-200 ℃.
4. The use of the oseltamivir derivative of any one of claim 1 in the preparation of a medicament for the treatment of influenza.
5. A pharmaceutical composition against influenza virus comprising the oseltamivir derivative of any of claim 1 and one or more pharmaceutically acceptable carriers or excipients.
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