CN102659615B - Derivatives of oseltamivir, and preparation method and medical application thereof - Google Patents

Abstract

The present invention relates to the field of medicinal chemistry, in particular to a class of oseltamivir derivatives (I), wherein the definitions of R ₁ , R ₂ , L and X are the same as those in the description. The invention also discloses the preparation method of the derivative and its use in treating infectious diseases, especially infectious diseases caused by influenza virus.

Description

Oseltamivir derivative, its preparation method and its medical use

technical field

The invention relates to the field of medicinal chemistry, in particular to a class of oseltamivir derivatives, their preparation method and their use in treating infectious diseases, especially infectious diseases caused by influenza virus.

Background technique

Influenza (commonly referred to as flu) is an acute respiratory infectious disease caused by influenza virus, which ranks first among infectious diseases in affecting human health and causing economic losses. Worldwide, 20% of children and 5% of adults are infected with influenza A (A) or type B (B) every year. Influenza has a high mortality rate, which seriously endangers human health and life, and also causes huge economic losses to humans. It has not only attracted widespread attention all over the world, but also is a viral infectious disease that our country focuses on prevention and control.

At the beginning of the new year in 2009, after the deaths of humans infected with swine flu (later corrected by WHO and renamed as the new H1N1 influenza A virus variant) in Mexico, as of May 20, within a short period of 3 to 4 months In China, it has swept more than 40 countries in North America and Europe, and spread to South America, Australia, the Middle East, Asia and other countries and regions. More than 11,000 people have been diagnosed with influenza A cases, and more than 80 cases have died. The epidemic is still ongoing. The spread has not yet been effectively controlled. Therefore, there is an urgent need to develop highly efficient, harmless, anti-drug-resistant influenza virus drugs.

There are only two types of drugs clinically used for anti-influenza virus. One drug is an influenza virus M2 protein inhibitor, including amantadine and rimantadine. This drug is only effective against influenza A virus, and virus resistance will soon appear with severe central nervous system side effects. Therefore, the clinical application is greatly limited. According to reports, the resistance of influenza viruses to M2 protein inhibitors increased from 1.9% in 2002 to 91% in 2006, so the use of alkylamines is not recommended for the treatment of influenza at present. Another drug is a neuraminidase (NA) inhibitor, such as zanamivir (zanamivir), oseltamivir (oseltamivir), peramivir (peramivir), etc. All influenza viruses are effective, have good safety and tolerance, and can be used for the prevention and treatment of influenza. NA inhibitors are currently recommended anti-influenza drugs in many countries.

The Arg152Lys mutation of the B virus NA slightly reduces the sensitivity of the virus to zanamivir. After taking oseltamivir, the drug resistance is mainly attributed to the mutation of the NA active site of the virus. The NA mutations of the H3N2 subtype mainly include Arg292Lys, Glu119Val, Glu59Gly, His274Tyr, Asp198Asn and Ile222Val mutations, and the NA of the H1N1 virus appears The His274Tyr mutation occurred in the influenza B virus, the Asp198AsnNA mutation occurred in the influenza B virus, and the His274Tyr and Asn294Ser mutations of NA appeared in the H5N1 virus. In conclusion, some drug-resistant viruses emerged during the use of NA inhibitors.

Contents of the invention

The invention cleverly combines various fragments obtained by computer virtual screening with oseltamivir to design a kind of derivatives substituted with the 5-position amino of oseltamivir. Pharmacological experiments prove that the compound of the present invention has strong inhibitory effect on the growth of two subtypes of influenza virus neuraminidase A/PR/8/34 (H1N1) and A/Sydney/5/97 (H3N2) and clinical influenza virus It provides a new option for the treatment of viral influenza.

Compound general formula I of the present invention is as follows:

Where _R1 represents C1-C6 alkyl, C1-C6 aliphatic amine, 1-4 Y substituents substituted with 0-2 five-membered or six-membered aromatic rings selected from nitrogen atom, sulfur atom or oxygen atom Or 1 to 4 Y substituents containing 0 to 2 8-10 membered benzoheterocyclic rings selected from nitrogen atoms, sulfur atoms or oxygen atoms, wherein the substituent Y is H, halogen, NH ₂ , OH, NO ₂ , CN, OCH ₃ or OCF ₃ ;

R ₂ represents H or C ₂ H ₅ .

L represents -(CH ₂ )n-, n=1-3, -(CH ₂ CH ₂ C=O)-, -(CH ₂ C=O)-, -(O=CCH ₂ CH ₂ )- or - (O=CCH ₂ )-;

X represents _CH2 , O, S or NH.

Wherein R ₁ preferably represents a pyridine ring or a pyrazine ring.

_R also preferably represents tetrahydropyrrolyl, imidazolyl, piperidinyl, 4-oxopiperidinyl, morpholinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, N-phenyl Piperazinyl or N-benzylpiperazinyl.

_R also preferably represents n-butyl, n-propyl, isobutyl, tert-butyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, dimethylamino, dipropylamino, isobutylamino, cyclo Propylamino, cyclopentylamino or cyclohexylamino.

L preferably represents CH ₂ .

All pharmaceutically desirable salts of Compound I are acceptable in the present invention. The present invention provides pharmaceutical compositions comprising a compound of the invention in combination or association with a pharmaceutically acceptable carrier. More specifically, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention and a pharmaceutically acceptable carrier.

Some compounds of the present invention are:

(3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-2-methylanilino)-2-oxoethylamino)-3-(1-ethylpropoxy )-1-cyclohexene-1-carboxylic acid (I-1)

(3R, 4R, 5S)-4-acetylamino-5-(3-(4-chloro-2-methylanilino)-3-oxopropylamino)-3-(1-ethylpropoxy )-1-cyclohexene-1-carboxylic acid (I-2)

(3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloroanilino)-2-oxoethylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-3)

(3R, 4R, 5S)-4-acetylamino-5-(3-(4-chloroanilino)-3-oxopropylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-4)

(3R, 4R, 5S)-4-acetylamino-5-(2-(2-methylanilino)-2-oxoethylamino)-3-(1-ethylpropoxy)-1- Cyclohexene-1-carboxylic acid (I-5)

(3R, 4R, 5S)-4-acetylamino-5-(3-(2-methylanilino)-3-oxopropylamino)-3-(1-ethylpropoxy)-1- Cyclohexene-1-carboxylic acid (I-6)

(3R, 4R, 5S)-4-Acetamido-5-(2-(2-thiazolamino)-2-oxoethylamino)-3-(1-ethylpropoxy)-1-cyclohexyl Alkene-1-carboxylic acid (I-7)

(3R, 4R, 5S)-4-Acetamido-5-(3-(2-thiazolamino)-3-oxopropylamino)-3-(1-ethylpropoxy)-1-cyclohexyl Alkene-1-carboxylic acid (I-8)

(3R, 4R, 5S)-4-Acetamido-5-(2-(2-pyridylamino)-2-oxoethylamino)-3-(1-ethylpropoxy)-1-cyclohexyl Alkene-1-carboxylic acid (I-9)

(3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-2-methylanilino)ethylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-10)

(3R, 4R, 5S)-4-acetylamino-5-(3-(4-chloro-2-methylanilino)propylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-11)

(3R,4R,5S)-4-Acetamido-5-(2-(4-chloroanilino)ethylamino)-3-(1-ethylpropoxy)-1-cyclohexene-1- Carboxylic acid (I-12)

(3R, 4R, 5S)-4-Acetamido-5-(3-(4-chloroanilino)propylamino)-3-(1-ethylpropoxy)-1-cyclohexene-1- Carboxylic acid (I-13)

(3R,4R,5S)-4-Acetamido-5-(2-(2-methylanilino)ethylamino)-3-(1-ethylpropoxy)-1-cyclohexene-1 -Carboxylic acid (I-14)

(3R, 4R, 5S)-4-Acetamido-5-(3-(2-methylanilino)propylamino)-3-(1-ethylpropoxy)-1-cyclohexene-1 -Carboxylic acid (I-15)

(3R,4R,5S)-4-Acetamido-5-(3-(2,6-dimethylanilino)propylamino)-3-(1-ethylpropoxy)-1-cyclohexyl En-1-carboxylic acid (I-16)

(3R, 4R, 5S)-4-Acetamido-5-(3-(2,3-dimethylanilino)propylamino)-3-(1-ethylpropoxy)-1-cyclohexyl Alkene-1-carboxylic acid (I-17)

(3R,4R,5S)-4-Acetamido-5-(3-(2,5-dimethylanilino)propylamino)-3-(1-ethylpropoxy)-1-cyclohexyl Alkene-1-carboxylic acid (I-18)

(3R, 4R, 5S)-4-acetylamino-5-(3-(5-chloro-2-methylanilino)propylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-19)

(3R, 4R, 5S)-4-acetylamino-5-(3-(3-chloro-2-methylanilino)propylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-20)

(3R, 4R, 5S)-4-acetylamino-5-(3-(4-chloro-3-methylanilino)propylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-21)

(3R, 4R, 5S)-4-acetylamino-5-(3-(4-chloro-N-methylanilino)propylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-22)

(3R, 4R, 5S)-4-acetylamino-5-(2-(3-chloro-2-methylanilino)ethylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-23)

(3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-N-methylanilino)ethylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-24)

(3R,4R,5S)-4-Acetamido-5-(3-(2,4-dimethylanilino)propylamino)-3-(1-ethylpropoxy)-1-cyclohexyl En-1-carboxylic acid (I-25)

(3R, 4R, 5S)-4-Acetamido-5-(3-(4-methoxy-2-methylanilino)propylamino)-3-(1-ethylpropoxy)-1 -Cyclohexene-1-carboxylic acid (I-26)

(3R, 4R, 5S)-4-acetylamino-5-(2-(5-chloro-2-methylanilino)ethylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-27)

(3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-3-methylanilino)ethylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-28)

(3R, 4R, 5S)-4-acetylamino-5-(2-(6-chloro-2-methylanilino)ethylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-29)

(3R, 4R, 5S)-4-acetylamino-5-(3-(6-chloro-2-methylanilino)propylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-30)

(3R, 4R, 5S)-4-acetylamino-5-(3-(4-fluoro-2-methylanilino)propylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-31)

(3R, 4R, 5S)-4-Acetamido-5-(3-(2-mercaptobenzothiazolyl)propylamino)-3-(1-ethylpropoxy)-1-cyclohexene- 1-Carboxylic acid (I-32)

(3R, 4R, 5S)-4-Acetamido-5-(3-(2-mercaptobenzoxazolyl)propylamino)-3-(1-ethylpropoxy)-1-cyclohexene -1-Carboxylic acid (I-33)

(3R,4R,5S)-4-Acetamido-5-(2-(4-chloroanilino)acetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1- Carboxylic acid (I-34)

(3R, 4R, 5S)-4-Acetamido-5-(2-(1-hydrogen-imidazol-1-yl)acetamido)-3-(1-ethylpropoxy)-1-cyclohexyl En-1-carboxylic acid (I-35)

(3R,4R,5S)-4-Acetamido-5-(2-(cyclopropylamino)acetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid (I-36)

(3R, 4R, 5S)-4-acetamido-5-(2-(tert-butylamino)acetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ( I-37)

(3R, 4R, 5S)-4-Acetamido-5-(2-(cyclopentylamino)acetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxy Acid (I-38)

(3R, 4R, 5S)-4-Acetamido-5-(2-(isobutylamino)acetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxy Acid (I-39)

(3R,4R,5S)-4-Acetamido-5-(2-(isopropylamino)acetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid (I-40)

(3R,4R,5S)-4-Acetamido-5-(2-(dimethylamino)acetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid (I-41)

(3R,4R,5S)-4-Acetamido-5-(2-(diethylamino)acetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid (I-42)

(3R, 4R, 5S)-4-Acetamido-5-(2-(piperidin-1-yl)acetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1 -Carboxylic acid (I-43)

(3R, 4R, 5S)-4-acetylamino-5-(2-morpholinoacetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid (I -44)

(3R, 4R, 5S)-4-acetylamino-5-(2-(4-oxopiperidin-1-yl)acetamido)-3-(1-ethylpropoxy)-1-ring Hexene-1-carboxylic acid (I-45)

The preparation method of compound of the present invention is as follows:

(1) When R ₁ represents a substituted benzene ring and aromatic heterocycle, and L represents -(CH ₂ CH ₂ C=O)- or -(CH ₂ C=O)-, the synthesis method is as follows:

(2) When R ₁ represents a substituted benzene ring, and L represents -(CH ₂ )n-(n=1-3), the synthesis method is as follows:

(3) When R ₁ represents aliphatic hydrocarbon, fatty amine or heterocycle, and L represents -(O=CCH ₂ CH ₂ )- or -(O=CCH ₂ )-, the synthesis method is as follows:

wherein the meanings of R ₁ , L and X are as described above.

Where a-d represent the reaction conditions:

a: THF or CH ₂ Cl ₂ , DMAP, 10-20°C;

b: DMF, KI, 45-55°C;

c: 1mol/LiOH, THF, rt;

d: NaHCO ₃ , DMF, 40-50°C.

The compounds of the present invention are evaluated with several standard pharmacological test procedures, and the results show that the compounds of the present invention have two inhibitory effects on influenza virus neuraminidase A/PR/8/34 (H1N1) and A/Sydney/5/97 (H3N2) The growth of subtypes and clinical influenza viruses has a strong inhibitory effect, and the inhibitory effect on Group1-type enzymes is significantly greater than that of Group2-type enzymes, showing good selectivity. It can be used to prepare medicines for treating infectious diseases caused by influenza virus.

The following are the pharmacological tests and results of some compounds of the present invention.

One: Part of the compounds of the present invention are measured against influenza virus A/PR/8/34 (H1N1), A/Sydney/5 by Standard Fluorimetric Assay [Anal. Inhibitory activity of /97(H3N2) neuraminidase.

Positive drugs:

Oseltamivir, oseltamivir carboxylate, zanamivir experimental principle:

MUNANA (4-methylumbelliferyl-α-N-acetyl-neuraminate) is a specific substrate of influenza virus NA. The metabolites produced under the action of NA can produce 460nm fluorescence under the excitation of 355nm irradiation. The change of fluorescence intensity can be sensitive reflect the activity of NA.

experiment method:

Take 10 μl each of the prepared solutions of the above-mentioned compounds to be tested (the concentration of which is 0.1 mg/ml), add 30 μl of appropriate diluted NA, mix well, and react at room temperature, and set enzyme solution control and blank control at the same time. After 15 minutes, add 10 μl of 33 mmol L ^-1 MES (2-N-morphineline.ethanesulfonic acid) (pH 3.5) buffer solution, 10 μl of 4 mmol L calcium dichloride, 10 μl of 20 μmol L ^-1 substrate MUNANA, 3 μl of water, the total volume of the reaction system is 100 μl, mix thoroughly, incubate at 37°C for 15 min, add stop solution (150 μl of 14 mmol ^-1 ~NaOH, 83% ethanol), and measure the fluorescence intensity. Setting parameters: EX=355nm, EM=460nm. Calculate inhibition rate. Compound samples with an inhibition rate greater than 50% were re-screened, divided into 5 concentration gradients, and the half inhibitory concentration (IC ₅₀ ) of the sample to NA was calculated.

The experimental results are shown in Table 1.

Table 1 The compound of the present invention is to the inhibitory activity of influenza virus H1N1, H3N2 neuraminidase

It can be known from Table 1 that the compound of the present invention has good inhibitory activity on influenza virus A/PR/8/34 (H1N1), A/Sydney/5/97 (H3N2) neuraminidase. And some compounds of the present invention have neuraminic acid with comparable activity (such as compound I-11 H1N1 IC ₅₀ =2.322nM, compound I-21H1N1 IC ₅₀ =2.060nM) or stronger compared with positive control drugs (oseltamivir and oseltamivir carboxylate) Enzyme inhibition (compound I-20 H1N1 IC ₅₀ =0.600nM, compound I-28 H1N1 IC ₅₀ =0.579nM) and better selectivity against Group-1 enzymes, we can see from the table that the present invention is The _IC50 of most compounds against influenza virus H1N1 is generally lower than the _IC50 value of influenza virus H3N2. It can be seen that the inhibitory activity of the compounds of the present invention to H1N1 is generally higher than that of H3N2, while the inhibitory activity of oseltamivir against H1N1 is lower than that of H3N2. It can be seen that compared with oseltamivir, the compound of the present invention has significantly improved the inhibition of Group-1 enzymes, so compared with Group-2 enzymes, it can selectively inhibit Group-1 enzymes. Therefore, some compounds of the present invention can be used as anti-influenza virus drugs with better therapeutic effects.

Detailed ways

Example 1

2-Chloro-N-(4-chloro-2-methylphenyl)acetamide (II)

Add CH ₂ Cl ₂ to o-methyl p-chloroaniline (1.42g, 10mmol) to dissolve, add 2ml of triethylamine, and dropwise add CH ₂ Cl ₂ solution of chloroacetyl chloride (0.93g, 12mmol) to the system, the system generates a large amount of White smoke, and from a purple clear solution to dark green. After the dropwise addition was completed, the ice bath was removed, and the mixture was stirred at room temperature for 1 hour. Add 20ml of CH ₂ Cl ₂ to dilute, wash with saturated NH ₄ Cl twice, dry the CH ₂ Cl ₂ layer with anhydrous Na ₂ SO ₄ for 1 hour, spin dry CH ₂ Cl ₂ , add PE to wash, and suction filter to obtain 1.41g of gray product , yield 64.68%. mp132-133℃

Example 2

(3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-2-methylanilino)-2-oxoethylamino)-3-(1-ethylpropoxy )-1-cyclohexene-1-carboxylic acid ethyl ester (III)

Add oseltamivir 3.1g (10mmol), 2-chloro-N-(4-chloro-2-methylphenyl)acetamide 2.4g (12mmol), KI0.17 (1mmol) DMF in 100ml single-necked bottle 20mL, react at 45-55℃ for about 14h. After the reaction was detected by TLC, the reaction solution was poured into water, and the system precipitated a fine powdery solid, extracted three times with 70 mL of ethyl acetate, combined the organic layer, and dried over anhydrous NaSO ₄ . Silica gel column chromatography (ethyl acetate:methanol=10:1) yielded 1.68 g of a brown oily product as a solid, with a yield of 34%.

IR(KBr)v _max (cm ^-1 ) 3588, 3568, 3448, 2360, 2342, 1685, 1654, 1647, 1637, 1629, 1618, 1384, 669;

¹ H NMR (CDCl ₃ ) 0.86-0.91 (6H, m), 1.27-1.32 (4H, t, J=15.0Hz), 1.43-1.62 (4H, m), 1.93 (3H, s), 2.18 (3H, s), 2.17(3H, s), 2.27(2H, s), 2.41-2.62(1H, dd), 2.73-2.77(1H, t, J=12Hz), 3.36-3.40(1H, t, J=12.0 Hz), 3.55(2H, s), 3.94(1H, s), 4.18-4.25(2H, q), 4.28-4.32(1H, t), 6.87(1H, s), 6.96-6.99(1H, d, J = 9.0Hz), 7.13-7.15 (2H, d, J = 6.0Hz), 7.69-7.71 (1H, d, J = 6.0Hz), 9.26 (1H, s) ppm;

MS (EI) m/z 266 (M) ⁺ .

Example 3

(3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-2-methylanilino)-2-oxoethylamino)-3-(1-ethylpropoxy )-1-cyclohexene-1-carboxylic acid (I-1)

Add (3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-2-methylanilino)-2-oxoethylamino)-3-(1 -Ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester 1.4g (2.8mmol), then add 20mLTHF to dissolve, add 1mol/L LiOH15mL, stir at room temperature for 4h. After the reaction was detected by TLC, THF was removed by rotary evaporation. Concentrated hydrochloric acid was added dropwise under ice bath conditions to adjust the pH to 3-4. A khaki solid precipitated out of the system. Suction filtration and drying of the filter cake yielded 1.12 g of the product, with a yield of 85%. m.p.186-190°C.

IR(KBr)v _max (cm ^-1 ) 3650, 3415, 2965, 2360, 2342, 1685, 1654, 1647, 1637, 1545, 1484, 1384, 669;

¹ H NMR (DMSO-d ₆ ) 0.79-0.83 (6H, m), 1.15 (1H, s), 1.29 (3H, s), 1.35-1.43 (4H, m), 1.78 (1H, s), 2.18 ( 3H, s), 1.91 (2H, s), 2.09 (1H, s), 2.14-2.16 (2H, d, J=6.0Hz), 2.18 (1H, s), 3.08 (1H, m), 3.48-3.62 (3H, m), 4.02-4.15 (2H, m), 4.33-4.37 (1H, m), 4.97-5.18 (1H, d), 6.62 (1H, s), 7.23-7.24 (1H, d, J = 3.0Hz), 7.30-7.34(1H, d, J=12.0Hz), 7.41(1H, s), 7.71-7.74(1H, d, J=9.0Hz), 8.10-8.12(1H, d, J=6.0 Hz) ppm;

ESI-HRMS calcd for C ₂₃ H ₃₃ ClN ₃ O ₅ : 466.2103, found: m/z 466.2114 [M+H] ⁺ .

Example 4

4-Chloro-N-(2-chloroethyl)-2-methylaniline (IV)

Add o-methyl p-chloroaniline (3.00g, 21.2mmol), 1-bromo-2-chloroethane 3.66g (25.4mmol), sodium bicarbonate 2.67 (31.8mmol) DMF 10mL, 45- React at 55°C for about 24h. After the reaction was detected by TLC, the reaction solution was poured into water, extracted three times with 60 mL of ethyl acetate, and the organic layers were combined and dried over anhydrous NaSO ₄ . Silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) yielded 1.51 g of a brown oily product with a yield of 35%.

¹ H NMR (CDCl ₃ ) 2.16 (3H, s), 3.50-3.54 (2H, t, J=12.0Hz), 3.60 (1H, s), 3.74-3.77 (2H, t, J=9.0Hz), 6.55 -6.57 (1H, d, J=6.0Hz), 7.06-7.09 (2H, d, J=9.0Hz) ppm;

Example 5

(3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-2-methylanilino)ethylamino)-3-(1-ethylpropoxy)-1-cyclo Ethyl hexene-1-carboxylate (V)

Add oseltamivir 3.1g (10mmol), 4-chloro-N-(2-chloroethyl)-2-methylaniline 2.45g (12mmol), KI0.17 (1mmol) DMF 20mL in a 100ml single-necked bottle , 45-55 ℃ for about 16h. After the reaction was detected by TLC, the reaction solution was poured into water, extracted three times with 70 mL of ethyl acetate, and the organic layers were combined and dried over anhydrous NaSO ₄ . Silica gel column chromatography (ethyl acetate:methanol=10:1) yielded 1.58 g of a brown oily product as a solid, with a yield of 32%.

IR(KBr)v _max (cm ^-1 ) 3676, 3670, 3650, 3629, 3447, 2926, 2361, 1701, 1685, 1654, 1637, 1384;

¹ H NMR (CDCl ₃ ) 0.86-0.92 (6H, m), 1.27-1.32 (4H, t, J=15.0Hz), 1.45 (3H, s), 1.48-1.52 (4H, q), 1.95 (3H, s), 2.11(3H, s), 2.17(2H, s), 2.27(2H, s), 2.69-2.77(1H, dd, J=24.0Hz), 2.88-2.93(1H, m), 2.97-3.05 (1H, m), 3.17-3.18 (2H, d, J = 3.0Hz), 3.35-3.38 (1H, t, J = 9.0Hz), 3.70-3.77 (1H, q), 4.18-4.22 (2H, t , J=12.0Hz), 5.53 (1H, s), 6.49-6.51 (1H, d, J=6.0Hz), 6.80 (1H, s), 6.98-7.06 (2H, m) ppm;

MS(EI)m/e: 479(M) ⁺ ;

Example 6

(3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-2-methylanilino)ethylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-10)

Add (3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-2-methylanilino)ethylamino)-3-(1-ethylpropoxy Base)-1-cyclohexene-1-carboxylic acid ethyl ester 1.4g (2.8mmol), then add 20mLTHF to dissolve, add 1mol/LLiOH15mL, stir at room temperature for 4h. After the reaction was detected by TLC, THF was removed by rotary evaporation. Concentrated hydrochloric acid was added dropwise under ice bath conditions to adjust the pH to 3-4. A brown solid precipitated out of the system. Suction filtration and drying of the filter cake yielded 1.09 g of the product with a yield of 83%. m.p.205-210°C.

IR (KBr) v _max (cm ^-1 ) 3629, 3433, 2965, 2930, 2876, 1701, 1685, 1654, 1560, 1458, 1384, 609;

H NMR (DMSO-d ₆ ) 0.82-0.85 (6H, m), 1.22 (2H, s), 1.35 (3H, s), 1.42-1.45 (4H, q), 1.73 (2H, s), 1.90 (2H , s), 2.04(3H, s), 2.11(2H, s), 2.82(2H, m), 3.09(2H, m), 3.87-3.93(2H, m), 4.93(1H, s), 5.53( 1H, s), 6.49-6.52 (1H, d, J = 9.0Hz), 6.65-6.67 (2H, d, J = 6.0Hz), 6.87 (2H, s), 6.99 (2H, s), 7.70-7.72 (1H, d, J = 6.0Hz) ppm;

ESI-HRMS calcd for _C23H35ClN3O4 : 452.2311 _, found _: m/z 452.232 [ _M +H] ⁺ .

Example 7

(3R, 4R, 5S)-4-Acetamido-5-(2-chloroacetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester (VI )

Add THF to dissolve oseltamivir 2.00g (6.4mmol), add DMAP 1.00g (8.4mmol), drop chloroacetyl chloride 0.78g, (7.6mmol) THF solution in the system under ice-bath conditions, the system produces a large amount of White smoke, after the dropwise addition, remove the ice bath, and stir at room temperature for 3 hours. After removing THF by rotary evaporation, add 40ml CH ₂ Cl ₂ to dissolve, wash twice with saturated NH ₄ Cl, dry the CH ₂ Cl ₂ layer with anhydrous Na ₂ SO ₄ for 1 hour, perform silica gel column chromatography (ethyl acetate:methanol=10: 1) 1.93 g of a flesh-colored solid product was obtained, with a yield of 82%. mp175-177°C.

IR(KBr)v _max (cm ^-1 ) 3431, 3279, 2961, 2925, 2360, 2341, 1718, 1653, 1560, 1384, 1253, 1058, 668;

¹ H NMR (CDCl ₃ ) 0.85-0.93 (6H, m), 1.25 (1H, s), 1.27-1.32 (3H, t, J=15Hz), 1.43 (1H, s), 1.48-1.56 (4H, m ), 1.60 (1H, s), 1.99 (3H, s), 2.71-2.73 (1H, dd, J=6.0Hz), 2.77-2.78 (1H, dd, J=3.0Hz), 3.38-3.42 (1H, m), 3.93(2H, s), 3.98-4.14(1H, m), 4.17(1H, s), 4.18-4.25(1H, m), 5.52-5.54(1H, d, J=6.0Hz), 6.49 -6.51 (1H, d, J=6.0Hz), 6.85 (1H, s), 7.55 (1H, s) ppm; MS (EI) m/e: 388 (M) ⁺ ;

Example 8

(3R, 4R, 5S)-4-Acetamido-5-(2-(isobutylamino)acetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxy Ethyl acetate (VII)

Add (3R, 4R, 5S)-4-acetylamino-5-(2-chloroacetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1 into a 100ml single-necked bottle - Ethyl carboxylate 4.0g (11mmol), isobutylamine 1.3mL (13mmol), K ₂ CO ₃ 1.9g (14.2mmol) KI0.17g (1mmol) DMF 20mL, react at 45-55°C for about 3h. After the reaction was detected by TLC, the reaction solution was poured into water, extracted three times with 70 mL of ethyl acetate, and the organic layers were combined and dried over anhydrous NaSO ₄ . Silica gel column chromatography (ethyl acetate:methanol=10:1) gave 3.90 g of a yellow oily product with a yield of 88%.

m.p.238-240°C.

IR (KBr) v _max (cm ^-1 ) 433, 2958, 2926, 2361, 2344, 1718, 1654, 1648, 1560, 1459, 1384, 1248, 669;

¹ H NMR (CDCl ₃ ) 0.85-0.93 (12H, m), 1.27-1.32 (4H, q, J = 15.0 Hz), 1.45-1.56 (4H, m), 1.68-1.79 (2H, q), 1.92 ( 3H, s), 2.30-2.45(3H, m), 2.72-2.77(1H, d, J=15.0Hz), 3.23(1H, s), 3.24-3.39(1H, m), 4.04(1H, s) , 4.08-4.16 (2H, m), 4.17-4.24 (2H, q), 5.86 (1H, s), 6.81 (1H, s), 7.68 (1H, s) ppm; MS (EI) m/e: 425 (M) ⁺ ;

Example 9

(3R, 4R, 5S)-4-Acetamido-5-(2-(isobutylamino)acetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxy Acid (I-39)

Add (3R, 4R, 5S)-4-acetamido-5-(2-(isobutylamino)acetamido)-3-(1-ethylpropoxy)-1-cyclo Add 3.9 g (9.7 mmol) of ethyl hexene-1-carboxylate, then add 30 mL THF to dissolve, then add 1 mol/L LiOH 35 mL, and stir at room temperature for 4 h. After the reaction was detected by TLC, THF was removed by rotary evaporation. Concentrated hydrochloric acid was added dropwise under ice bath conditions to adjust the pH to 3-4. A brown solid precipitated out of the system. Suction filtration and drying of the filter cake yielded 3.63 g of the product, with a yield of 85%. m.p.198-201°C.

IR(KBr)v _max (cm ^-1 ) 3426, 2968, 1639, 1566, 1383, 1064, 1016, 609;

¹ H NMR (DMSO-d ₆ ) 0.75-0.96 (12H, m), 1.39-1.43 (4H, m), 1.68-1.79 (2H, q), 1.81 (3H, s), 1.97-2.08 (1H, m ), 2.21(1H, s), 2.30(2H, s), 2.70(2H, s), 3.10(1H, s), 3.60-3.73(2H, m), 3.94-3.95(1H, m), 4.19- 4.22 (1H, d, J = 9.0Hz), 6.62 (1H, s), 7.15-7.25 (2H, m), 8.04-8.06 (2H, d, J = 6.0Hz), 8.48-8.50 (2H, d, J = 6.0Hz) ppm;

ESI-HRMS calcd for C ₂₀ H ₃₆ N ₃ O ₅ : 398.2649, found: m/z 398.2656 [M+H] ⁺ .

Example 10

3-Chloro-N-(4-chloro-2-methylphenyl)propanamide (II)

The experimental operation was the same as in Example 1, o-methyl-p-chloroaniline (1.42g, 10mmol), 2ml of triethylamine, and chloropropionyl chloride (1.10g, 12mmol) were reacted to obtain 1.8g of a brown-gray solid. Yield 78.3%. m.p.128-129°C.

MS(EI)m/e: 231(M) ⁺ ;

Example 11

(3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-2-methylanilino)-2-oxopropylamino)-3-(1-ethylpropoxy )-1-cyclohexene-1-carboxylic acid ethyl ester (III)

The experimental operation is the same as Example 2, oseltamivir 3.1g (10mmol), 3-chloro-N-(4-chloro-2-methylphenyl) propanamide 2.6g (12mmol), KI0.17 (1mmol) DMF 20mL The reaction yielded 3.54 g of a brown oil. Yield 70%.

IR(KBr)v _max (cm ^-1 ) 3650, 3629, 3448, 1655, 1648, 1384;

¹ H NMR (CDCl ₃ ) 0.85-0.92 (6H, t, J=21.0Hz), 1.27-1.32 (3H, t, J=15.0Hz), 1.43-1.53 (4H, m), 1.96 (3H, s) , 2.17(1H, s), 2.25(3H, s), 2.38-2.46(2H, dd, J=24.0Hz), 2.67-2.72(2H, m), 3.04-3.06(1H, m), 3.16-3.18 (1H, m), 3.37-3.40 (2H, d, J = 9.0Hz), 3.91-3.94 (1H, q, J = 9.0Hz), 4.18-4.25 (2H, q, J = 21.0Hz), 6.83 ( 1H, s), 7.13-7.15 (2H, d, J = 6.0Hz), 7.76-7.79 (1H, d, J = 9.0Hz), 9.35 (1H, s) ppm;

MS(EI)m/e: 507(M) ⁺

Example 12

(3R, 4R, 5S)-4-acetylamino-5-(3-(4-chloro-2-methylanilino)-3-oxopropylamino)-3-(1-ethylpropoxy )-1-cyclohexene-1-carboxylic acid (I-2)

The experimental operation is the same as example 3, (3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-2-methylanilino)-2-oxopropylamino)-3-(1 -Ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester 1.0g (2mmol), 1mol/LliOH 8ml reaction obtains brown solid product 0.56g. Yield 51%, m.p. 192-196°C.

IR (KBr) v _max (cm ^-1 ) 3488, 2958, 2925, 2871, 2361, 2344, 1718, 1655, 1534, 1458, 1399, 1383, 1124, 1096, 621;

¹ H NMR (DMSO-d ₆ ) 0.77-0.86 (6H, m), 1.24 (2H, s), 1.36-1.42 (4H, m), 1.67-1.72 (2, q, J = 15.0 Hz), 1.82 ( 3H, s), 2.06(3H, s), 2.18(1H, s), 2.68-2.73(2H, m), 3.08-3.10(2H, t, J=6.0Hz), 3.65-3.67(1H, q, J=6.0Hz), 3.99(1H, s), 6.46-6.49(1H, d, J=9.0Hz), 6.61-6.66(1H, d, J=15.0Hz), 6.87(1H, s), 6.99- 7.02 (2H, d, J = 9.0Hz), 7.76-7.79 (1H, d, J = 9.0Hz) ppm;

ESI-HRMS calcd for C ₂₄ H ₃₄ ClN ₃ O ₅ : 480.226, found: m/z 480.2275[M+H] ⁺

Example 13

2-(3-Chloropropylmercapto)benzoxazole (IV)

Add 2-mercaptobenzoxazole (1.0g, 6.61mmol), 1-bromo-3-chloropropane (1.0g, 6.61mmol), K2CO3 (1.82g, 13.22mmol) and KI (0.11 g, 0.66mmol) and 20ml acetonitrile. After heating the reaction to reflux for 24 hours, the reaction solution was poured into 100 ml of ice water, and a yellow precipitate was deposited in the system. Suction filtration, drying the filter cake to obtain the product. Yellow solid 1.46g, yield 97.5%.

MS(EI)m/e: 227(M) ⁺

Example 14

(3R, 4R, 5S)-4-Acetamido-5-(3-(2-mercaptobenzoxazolyl)propylamino)-3-(1-ethylpropoxy)-1-cyclohexene -1-Carboxylic acid ethyl ester (III)

Experimental operation is the same as example 2, oseltamivir 3.1g (10mmol), 2-(3-chloropropyl mercapto) benzoxazole 2.7g (12mmol), KI0.17 (1mmol) DMF 20mL reaction obtains yellow oil 3.60 g. Yield 72%.

IR(KBr)v _max (cm ^-1 ) 3650, 3629, 3588, 3422, 2924, 1685, 1655, 1637, 1629, 1577, 1384;

¹ H NMR (CDCl ₃ ) 0.89-0.94 (6H, t, J=15.0Hz), 1.24-1.29 (3H, t, J=15.0Hz), 1.50-1.55 (4H, m), 2.08 (3H, s) , 2.78-2.84 (2H, t, J = 18.0Hz), 2.98 (1H, s), 3.12 (1H, s), 3.36-3.45 (4H, m), 4.15-4.22 (2H, q, J = 21.0Hz ), 6.81 (2H, s), 7.44-7.46 (1H, d, J=6.0Hz), 7.71-7.73 (1H, d, J=6.0Hz) ppm;

MS(EI)m/e: 503(M) ⁺

Example 15

(3R,4R,5S)-4-Acetamido-5-(3-(2-mercaptobenzoxazolyl)propylamino)-3-(1-ethylpropoxy)-1-cyclohexene -1-Carboxylic acid (I-33)

The experimental operation is the same as that of Example 3, (3R, 4R, 5S)-4-acetylamino-5-(3-(2-mercaptobenzoxazolyl)propylamino)-3-(1-ethylpropoxy) - 1.0g (2mmol) of ethyl 1-cyclohexene-1-carboxylate, reacted with 1mol/LliOH 8ml to obtain 0.88g of a brown solid product. Yield 94%, m.p. 215-219°C.

IR (KBr) v _max (cm ^-1 ) 3415, 2926, 2360, 2342, 1701, 1655, 1638, 1560, 1454, 1384, 1238, 1131, 1098, 747;

¹ H NMR (DMSO-d ₆ ) 0.76-0.86 (6H, m), 1.36-1.43 (4H, m), 1.89 (3H, s), 2.18-2, 26 (2H, m), 2.84-2.88 (1H , d, J=12.0Hz), 3.39-3.46 (4H, m), 3.84-3.94 (1H, m), 4.30-4.33 (1H, d, J=9.0Hz), 6.64 (2H, s), 7.33- 7.37 (1H, m), 7.64-7.67 (1H, m), 8.31-7.34 (1H, d, J=9.0Hz) ppm;

ESI-HRMS calcd for C ₂₄ H ₃₃ N ₃ O ₄ S ₂ : 492.1985, found: m/z 492.1979 [M+H] ⁺

Example 16

(3R,4R,5S)-4-Acetamido-5-(2-(diethylamino)acetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid Ethyl ester (VI)

The experimental operation is the same as in Example 8, (3R, 4R, 5S)-4-acetylamino-5-(2-chloroacetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1- Ethyl carboxylate 4.0g (11mmol), diethylamine 1g (13mmol), K ₂ CO ₃ 1.9g (14.2mmol) KI0.17g (1mmol) DMF 20mL, react at 45-55°C for about 3h. After the reaction was detected by TLC, the reaction solution was poured into water, extracted three times with 70 mL of ethyl acetate, and the organic layers were combined and dried over anhydrous NaSO ₄ . Silica gel column chromatography (ethyl acetate:methanol=10:1) gave 4.00 g of a yellow oily product with a yield of 90.9%.

IR(KBr)v _max (cm ^-1 ) 3650, 3629, 3448, 2959, 2925, 2360, 2343, 1654, 1648, 1384;

¹ H NMR (CDCl ₃ ) 0.78-0.86 (6H, q, J=24.0Hz), 0.92-0.98 (6H, q, J=18.0Hz), 1.20-1.25 (3H, t, J=15.0Hz), 1.41 -1.47(4H, m), 1.87(3H, s), 2.11-2.26(1H, m), 2.43-2.50(4H, m), 2.63-2.69(1H, d, J=18.0Hz), 2.94(3H , m), 3.26-3.30(1H, t, 12.0Hz), 4.07(1H, s), 3.95(1H, s).4.06(1H, s), 4.11-4.18(2H, q, J=21.0Hz) , 5.70(1H, s), 6.75(1H, s), 7.75(1H, s)ppm;

MS(EI)m/e: 425(M) ⁺ ;

Example 17

(3R,4R,5S)-4-Acetamido-5-(2-(diethylamino)acetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid (I-42)

The experimental operation is the same as that of Example 9, (3R, 4R, 5S)-4-acetylamino-5-(2-(diethylamino)acetamido)-3-(1-ethylpropoxy)-1-cyclohexyl 4.2 g (10 mmol) of ethyl ene-1-carboxylate was reacted with 1 mol/L LiOH 40 m to obtain 2.8 g of white powder. Yield 70.5%. m.p.135-137°C.

IR(KBr)v _max (cm ^-1 ) 3426, 2968, 1639, 1566, 1383, 1064, 1016, 609;

¹ H NMR (DMSO-d ₆ ) 0.78-0.86 (6H, q, J=24.0Hz), 1.18-1.20 (6H, t, J=6.0Hz), 1.41-1.42 (4H, m), 1.87 (3H, s), 2.11-2.26(1H, m), 2.11-2.32(4H, m), 2.76-2.78(1H, d, J=6.0Hz), 2.92(1H, s), 3.41(2H, s), 3.60 (1H,s), 3.80(1H,s), 3.95(1H,s), 4.20(1H,s), 6.64(1H,s), 7.18-7.27(1H,m), 7.98-8.08(1H,d ), 8.60(1H, s)ppm;

ESI-HRMS calcd for C ₂₀ H ₃₅ N ₃ O ₅ : 398.2649, found: m/z 398.2656[M+H] ⁺

Example 18

(3R,4R,5S)-4-Acetamido-5-(2-morpholinoacetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester (VI)

The experimental operation is the same as in Example 8, (3R, 4R, 5S)-4-acetylamino-5-(2-chloroacetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1- Ethyl carboxylate 4.0g (11mmol), morpholine 1g (13mmol), K ₂ CO ₃ 1.9g (14.2mmol) KI0.17g (1mmol) DMF 20mL, react at 45-55°C for about 3h. After the reaction was detected by TLC, the reaction solution was poured into water, extracted three times with 70 mL of ethyl acetate, and the organic layers were combined and dried over anhydrous NaSO ₄ . Silica gel column chromatography (ethyl acetate:methanol=10:1) gave 4.50 g of a yellow oily product with a yield of 93.2%.

IR(KBr)v _max (cm ^-1 ) 3650, 3629, 3448, 2959, 2925, 1718, 1685, 1648, 1560, 1384, 1116, 1059;

¹ H NMR (CDCl ₃ ) 0.86-0.93 (6H, q, J=21.0Hz), 1.27-1.32 (3H, t, J=15.0Hz), 1.48-1.55 (4H, m), 1.93 (3H, s) , 2.18(1H, s), 2.33-2.37(1H, m), 2.50(4H, m), 2.73-2.78(1H, d, J=15.0Hz), 2.97-3.05(2H, m), 3.36-3.39 (1H, m), 3.73-3.74 (4H, m), 4.04 (1H, s), 4.13 (2H, s), 4.18-4.25 (2H, q, J=21.0Hz), 5.90 (1H, s), 6.81(1H, s), 7.60(1H, s) ppm;

MS(EI)m/e: 439(M) ⁺

Example 19

(3R, 4R, 5S)-4-acetylamino-5-(2-morpholinoacetamido)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid (I -44)

The experimental operation is the same as in Example 9, (3R, 4R, 5S)-4-acetylamino-5-(2-morpholinoacetamido)-3-(1-ethylpropoxy)-1-cyclohexene- 4.2g (10mmol) of ethyl 1-carboxylate was reacted with 1mol/LLiOH40m to obtain 3.7g of yellow powder. Yield 90.3%. m.p.109-112°C.

IR (KBr) v _max (cm ^-1 ) 3426, 2967, 2360, 1640, 1565, 1383, 1123, 1084, 1018, 869, 613;

¹ H NMR (DMSO-d ₆ ) 0.76-0.86 (6H, m), 1.03-1.07 (1H, t, J=12.0Hz), 1.42 (4H, m), 1.80 (3H, s), 2.09 (3H, s), 3.40-3.42 (4H, m), 3.78-3.81 (4H, m), 4.15 (2H, s), 6.63 (1H, s), 6.81 (1H, s), 7.17-7.19 (1H, d, J=6.0Hz), 7.23-7.27 (2H, m), 8.0-8.03 (1H, d, J=9.0Hz) ppm;

ESI-HRMS calcd for C ₂₀ H ₃₄ N ₃ O ₆ : 412.2442, found: m/z 412.2448 [M+H] ⁺

Example 20

3-Chloro-N-(3-chloropropyl)-2-methylaniline (IV)

The experimental operation was the same as in Example 1. 4-Chloro-2-methylaniline (1.42g, 10mmol), 2ml of triethylamine, and 1-bromo-3-chloropropane (2.04g, 13mmol) were reacted to obtain 1.21g of brownish red oil. Yield 55.6%.

¹ H NMR (CDCl ₃ ) 2.09-2.17 (2H, m), 2.20 (3H, s), 3.35-3.40 (2H, t, J=15.0Hz), 3.49-3.53 (1H, t, J=12.0Hz) , 3.64-3.68 (2H, t, J=12.0Hz), 6.52-6.55 (1H, d, J=9.0Hz), 6.76-6.79 (1H, d, J=9.0Hz), 6.99-7.05 (1H, t , J=18.0Hz) ppm;

Example 21

(3R, 4R, 5S)-4-acetylamino-5-(3-(3-chloro-2-methylanilino)propylamino)-3-(1-ethylpropoxy)-1-cyclo Ethyl hexene-1-carboxylate (III)

Experimental operation is the same as example 2, oseltamivir 3.1g (10mmol), 3-chloro-N-(3-chloropropyl)-2-methylaniline 3.8g (12mmol), KI0.17 (1mmol) DMF 20mL reaction 4.40 g of a yellow oil was obtained. Yield 55.7%.

IR(KBr)v _max (cm ^-1 ) 3676, 3650, 3629, 3416, 1655, 1637, 1384, 762;

¹ H NMR (CDCl ₃ ) 0.81-0.91 (6H, m), 1.25-1.33 (4H, m), 1.44-1.49 (3H, t, J=15.0Hz), 1.96 (3H, s), 2.07 (1H, s), 2.17(3H, s), 2.18(3H, s), 2.70(1H, s), 2.88-2.95(1H, d, J=21.0Hz), 3.14-3.18(1H, t, J=12.0Hz ), 3.31-3.41 (4H, m), 3.63-3.67 (1H, t, J=12.0Hz), 4.20-4.24 (2H, q, J=12.0Hz), 6.55-6.57 (1H, d, J=6.0 Hz), 6.78 (1H, s), 6.99-7.04 (1H, t, J=15.0Hz) ppm;

MS(EI)m/e: 493(M) ⁺

Example 22

(3R, 4R, 5S)-4-acetylamino-5-(3-(3-chloro-2-methylanilino)propylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-20)

Experimental operation is the same as example 3, (3R, 4R, 5S)-4-acetylamino-5-(3-(3-chloro-2-methylanilino) propylamino)-3-(1-ethylpropoxy Base)-1-cyclohexene-1-carboxylic acid ethyl ester 0.98g (2mmol), 1mol/LliOH 8ml reacts to obtain brown solid product 0.73g. Yield 78%, m.p. 108-110°C.

IR(KBr)v _max (cm ^-1 ) 3432, 2961, 2926, 2874, 2360, 2342, 1701, 1655, 1577, 1560, 1459, 1383, 1126, 648, 616;

¹ H NMR (DMSO-d ₆ ) 0.76-0.86 (6H, m), 1.23 (1H, s), 1.36-1.46 (4H, m), 1.89 (3H, s), 2.09 (1H, s), 2.16 ( 3H, s), 2.70 (1H, s), 2.82-2.86 (1H, d, J = 12.0Hz), 3.17-3.21 (2H, t, J = 12.0Hz), 3.39-3.43 (2H, t, J = 12.0Hz), 3.85-3.91(1H, q, J=18.0Hz), 4.26(1H, s), 6.53-6.56(1H, d, J=9.0Hz), 6.65(1H, s), 6.98-7.03( 1H, t, J = 15.0Hz), 8.18-8.20 (1H, d, J = 6.0Hz), 9.03 (1H, s) ppm;

ESI-HRMS calcd for C ₂₄ H ₃₆ ClN ₃ O ₄ : 466.2467, found: m/z 466.2473[M+H] ⁺

Example 23

4-Chloro-N-(2-chloroethyl)-3-methylaniline (IV)

The experimental operation was the same as in Example 1. 4-Chloro-3-methylaniline (1.42g, 10mmol), 2ml of triethylamine, and 1-bromo-2-chloroethane (1.83g, 13mmol) were reacted to obtain 0.75g of yellow oil. Yield 37%.

¹ H NMR (CDCl ₃ ) 2.30 (3H, s), 3.46-3.50 (2H, t, J=12.0Hz), 3.59 (1H, s), 3.70-3.74 (2H, t, J=12.0Hz), 6.43 -6.45(1H, d, J=6.0Hz), 6.51(1H, s), 7.11-7.13(1H, d, J=6.0Hz), ppm;

Example 24

(3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-3-methylanilino)ethylamino)-3-(1-ethylpropoxy)-1-cyclo Ethyl hexene-1-carboxylate (III)

Experimental operation is the same as example 2, oseltamivir 3.1g (10mmol), 4-chloro-N-(2-chloroethyl)-3-methylaniline 3.6g (12mmol), KI0.17 (1mmol) DMF 20mL reaction 6.00 g of a brown oil was obtained. Yield 79%.

IR(KBr)v _max (cm ^-1 ) 3676, 3670, 3650, 3629, 3421, 2955, 2924, 2851, 2361, 1685, 1654, 1648, 1637, 1629, 1384;

¹ H NMR (CDCl ₃ ) 0.83-0.91 (6H, q, J=24.0Hz), 1.25-1.32 (3H, q, J=21.0Hz), 1.45-1.54 (4H, m), 1.97 (3H, s) , 2.36(3H, s), 2.81-2.82(1H, d, J=3.0Hz), 3.07(1H, s), 3.20(1H, s), 3.31-3.36(2H, m), 3.55(1H, s ), 3.95-3.97 (2H, d, J=6.0Hz), 4.18-4.26 (2H, q, J=24.0Hz), 6.41-6.44 (1H, d, J=9.0Hz), 6.50-6.51 (1H, d, J=3.0Hz), 6.79 (1H, s), 7.07-7.10 (1H, d, J=9.0Hz) ppm;

MS(EI)m/e: 479(M) ⁺

Example 25

(3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-3-methylanilino)ethylamino)-3-(1-ethylpropoxy)-1-cyclo Hexene-1-carboxylic acid (I-28)

The experimental operation is the same as that of Example 3, (3R, 4R, 5S)-4-acetylamino-5-(2-(4-chloro-3-methylanilino)ethylamino)-3-(1-ethylpropoxy Base)-1-cyclohexene-1-carboxylic acid ethyl ester 0.96g (2mmol), 1mol/LliOH 8ml reacts and obtains brown solid product 0.76g. Yield 86%, m.p. 196-200°C.

IR(KBr)v _max (cm ^-1 ) 3421, 2926, 2360, 2342, 1701, 1685, 1654, 1648, 1560, 1458, 1384, 1127, 669, 617;

¹ H NMR (DMSO-d ₆ ) 0.76-0.86 (6H, m), 1.36-1.46 (4H, m), 1.90 (3H, s), 2.22 (3H, s), 2.80-2.87 (1H, dd, J =21.0Hz), 2.89(2H, s), 3.38-3.42(2H, t, J=12.0Hz), 3.86-3.93(1H, q, J=21.0Hz), 4.27-4.29(1H, d, J= 6.0Hz), 6.47-6.51(1H, dd, J=12.0Hz), 6.63(1H, s), 7.06-7.09(1H, d, J=9.0Hz), 8.26-8.29(1H, d, J=9.0 Hz), 9.29(1H, s)ppm;

ESI- _HRMS calcd for _C23H34ClN3O4 : 452.2311 _, found: m/z 452.2311 [ _M +H] ^+.

Claims (7)

1. The compound of general formula (I) or a pharmaceutically acceptable salt:

Wherein R ₁ represents cyclopropyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl, C1-C6 alkyl, C1-C6 aliphatic amino, 1-4 Y substituents containing 0-2 A five-membered or six-membered aromatic ring selected from a nitrogen atom, a sulfur atom or an oxygen atom, substituted by 1 to 4 Y substituents containing 0 to 2 8-10-membered rings selected from a nitrogen atom, a sulfur atom or an oxygen atom Benzoheterocycle, and the number of heteroatoms is not 0, wherein the substituent Y is H, halogen, NH ₂ , OH, NO ₂ , CN, OCH ₃ or OCF ₃ ; R ₂ represents H or C ₂ H ₅ ; L represents -(CH ₂ )n-, n=1-3, -(CH ₂ CH ₂ C=O)-, -(CH ₂ C=O)-, -(O=CCH ₂ CH ₂ )- or - (O=CCH ₂ )-; X represents NH. 2. The compound or pharmaceutically acceptable salt of claim 1, wherein R ₁ represents a pyridine ring or a pyrazine ring. 3. The compound or pharmaceutically acceptable salt of claim 1, wherein R ₁ represents tetrahydropyrrolyl, imidazolyl or piperidinyl. 4. The compound or pharmaceutically acceptable salt of claim 1, wherein _R represents n-butyl, n-propyl, isobutyl, tert-butyl, isopentyl, dimethylamino, dipropylamino, isobutylamino , cyclopropylamino, cyclopentylamino or cyclohexylamino. 5. The compound or pharmaceutically acceptable salt of claim 1, wherein L represents _CH2 . 6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 7. The compound of claim 1 is used for the preparation of the medicine for the treatment of infectious diseases caused by influenza virus.