CN102659615A - Derivatives of oseltamivir, and method and medical application thereof - Google Patents
Derivatives of oseltamivir, and method and medical application thereof Download PDFInfo
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- CN102659615A CN102659615A CN2012101416570A CN201210141657A CN102659615A CN 102659615 A CN102659615 A CN 102659615A CN 2012101416570 A CN2012101416570 A CN 2012101416570A CN 201210141657 A CN201210141657 A CN 201210141657A CN 102659615 A CN102659615 A CN 102659615A
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Abstract
The invention relates to the field of medical chemistry, in particular to derivatives of oseltamivir (I). R1, R2, L and X are explained in the specifications. The invention also discloses a method for preparing the derivatives of oseltamivir and the purpose of the derivatives for treating infectious diseases, particularly the infectious diseases caused by influenza viruses.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to one type of Tamiflu verivate, their preparation method and the purposes in the infectious disease medicament that causes of treatment infection, particularly influenza virus thereof.
Background technology
Influenza (being commonly referred to influenza) is a kind of acute respiratory transmissible disease that is caused by influenza virus, and it influences human body financial loss healthy and that cause and is positioned at first of the communicable disease.Annual in the world wide all have 20% children and 5% grownup to infect first (A) type or second (B) type influenza.The mortality ratio of influenza is very high, and serious harm human beings'health and life also cause huge economy to decrease loss to the mankind.It not only causes extensive concern in the whole world, also is China's emphasis prevention and the viral infectious disease of controlling.
2009 at the beginning of New Year, and Mexico occurs after people infected pigs influenza (after the WHO corrigendum is renamed as new H1N1 influenza A virus variant) death; By May 20, in short 3～4 months, more than 40 countries in NA and Europe have been swept across; And involve a plurality of countries and regions such as South America, Australia, the Middle East, Asia, surpass 1.1 ten thousand people and be diagnosed as the influenza A case, 80 many cases of dying in heaven; So far epidemic situation is still spreading, and is not effectively controlled as yet.Therefore press for and develop efficiently, harmless, the influenza virus medicine of overriding resistance.
The medicine that is used for resisiting influenza virus clinically has only two types.A kind of medicine is the influenza m 2 protein suppressor factor; Comprise amantadine and Rimantadine; This medicine is only effective to influenza A virus, and can occur virus drug resistance very soon and with serious cns spinoff, therefore make clinical application receive very big restriction.It is reported, influenza virus to the resistance of M2 protein inhibitor from 2002 1.9% rise to 2006 91%, therefore the treatment influenza does not advise using alkanamine class medicine at present.Another kind of medicine is neuraminidase (neuraminidase; NA) suppressor factor; Like zanamivir (zanamivir), Tamiflu (oseltamivir), RWJ 270201 (peramivir) etc.; Such medicine is all effective for first, Influenza B virus, has security preferably and tolerance, can be used for the prevention and the treatment of influenza.The NA suppressor factor is the Tamiflu that the suggestion of present many countries is used.
The Arg152Lys sudden change of B virus NA makes virus slightly reduce the susceptibility of zanamivir.After taking Ao Sitawei; The resistance that produces is mainly owing to the sudden change of virus N A avtive spot; The NA sudden change of H3N2 hypotype mainly comprises Arg292Lys, Glu119Val, Glu59Gly, His274Tyr, Asp198Asn and Ile222Val sudden change; The His274Tyr sudden change has appearred in the NA of H1N1 virus, and the Asp198AsnNA sudden change has appearred in Influenza B virus, and His274Tyr and the Asn294Ser sudden change of NA appearred in H5N1 virus.In a word, in the use of NA suppressor factor, some resistance viruses have appearred.
Summary of the invention
Various fragments that the present invention obtains computer virtual screening dexterously and Tamiflu amalgamation are designed one type of substituted verivate of Tamiflu 5-bit amino together.Pharmacological evaluation proves; The compounds of this invention has stronger restraining effect to the growth of influenza neuraminidase A/PR/8/34 (H1N1) and two hypotypes of A/Sydney/5/97 (H3N2) and clinical influenza virus, for the treatment of viral influenza provides new selection.
Compound general formula I of the present invention is following:
R wherein
1The aliphatic amide of alkyl, the C1～C6 of expression C1～C6,1～4 Y substituting group be substituted to be contained 0～2 and is selected from that nitrogen-atoms, sulphur atom or Sauerstoffatom five yuan or hexa-atomic aromatic nucleus or 1～4 Y substituting group are substituted to contain 0～2 benzheterocycle that is selected from the 8-10 unit of nitrogen-atoms, sulphur atom or Sauerstoffatom, and wherein substituting group Y is H, halogen, NH
2, OH, NO
2, CN, OCH
3Or OCF
3
R
2Expression H or C
2H
5
L representes-(CH
2) n-, n=1-3 ,-(CH
2CH
2C=O)-,-(CH
2C=O)-,-(O=CCH
2CH
2)-or-(O=CCH
2)-;
X representes CH
2, O, S or NH.
R wherein
1Preferred expression pyridine ring or pyrazine ring.
R
1Also preferably represent Pyrrolidine base, imidazolyl, piperidyl, 4-oxo-piperidine base, morphine quinoline base, piperidone base, piperazinyl, N methyl piperazine base, N-Phenylpiperazinyl or N-benzyl diethylenediamine base.
R
1Also preferably represent normal-butyl, n-propyl, isobutyl-, the tertiary butyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, dimethylamino, dipropyl amino, isobutyl amine, cyclopropylamino, NSC 32389 base or cyclohexylamino.
L preferably representes CH
2
To meet the salt of pharmacy needs all be acceptable for all of compound I among the present invention.The present invention provides the medicinal compsns that comprises with acceptable carrier combinations pharmaceutically or bonded The compounds of this invention.Say that in more detail the present invention provides a kind of medicinal compsns, wherein contain the The compounds of this invention and the pharmaceutically acceptable carrier of treating significant quantity.
Part of compounds of the present invention is:
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloro-2-aminotoluene base)-2-oxoethyl is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-1)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(4-chloro-2-aminotoluene base)-3-oxopropyl is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-2)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloroanilino)-2-oxoethyl is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-3)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(4-chloroanilino)-3-oxopropyl is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-4)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(2-aminotoluene base)-2-oxoethyl is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-5)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(2-aminotoluene base)-3-oxopropyl is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-6)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(the 2-thiazole is amino)-the 2-oxoethyl is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-7)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(the 2-thiazole is amino)-the 3-oxopropyl is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-8)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(the 2-pyridine is amino)-the 2-oxoethyl is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-9)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloro-2-aminotoluene base) ethylamino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-10)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(4-chloro-2-aminotoluene base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-11)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloroanilino) ethylamino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-12)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(4-chloroanilino) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-13)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(2-aminotoluene base) ethylamino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-14)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(2-aminotoluene base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-15)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(2,6-dimethyl benzene amido) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-16)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(2 3 dimethyl aniline base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-17)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(2,5-dimethyl benzene amido) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-18)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(5-chloro-2-aminotoluene base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-19)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(3-chloro-2-aminotoluene base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-20)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(4-chloro-3-toluidine) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-21)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(4-chloro-methylphenylamine base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-22)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(3-chloro-2-aminotoluene base) ethylamino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-23)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloro-methylphenylamine base) ethylamino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-24)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(2,4-dimethyl benzene amido) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-25)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(4-methoxyl group-2-aminotoluene base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-26)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(5-chloro-2-aminotoluene base) ethylamino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-27)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloro-3-toluidine) ethylamino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-28)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(6-chloro-2-aminotoluene base) ethylamino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-29)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(6-chloro-2-aminotoluene base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-30)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(4-fluoro-2-aminotoluene base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-31)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(2-mercaptobenzothiazole base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-32)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(2-mercaptobenzoxazole base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-33)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloroanilino) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-34)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(1-hydrogen-imidazoles-1-yl) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-35)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(cyclopropyl amino) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-36)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(TERTIARY BUTYL AMINE base) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-37)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(NSC 32389 base) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-38)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(isobutyl amine) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-39)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(isopropylamine base) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-40)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(dimethylamino) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-41)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(diethylin) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-42)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(piperidines-1-yl) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-43)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-morpholino acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-44)
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-oxo-piperidine-1-yl) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-45)
The preparation method of The compounds of this invention is following:
(1) works as R
1Expression substituted benzene ring and fragrant heterocycle, L representes-(CH
2CH
2C=O)-or-(CH
2C=O)-time, compound method is following:
(2) work as R
1The expression substituted benzene ring, L representes-(CH
2) during n-(n=1-3), compound method is following:
(3) work as R
1Expression aliphatic hydrocarbon, aliphatic amide or heterocycle, L representes-(O=CCH
2CH
2)-or-(O=CCH
2)-time, compound method is following:
R wherein
1, L, X meaning be as indicated above.
The reaction conditions of a-d representative wherein:
A:THF or CH
2Cl
2, DMAP, 10-20 ℃;
b：DMF，KI，45-55℃；
c：1mol/LiOH，THF，rt；
d：NaHCO
3，DMF，40-50℃.
Compound of the present invention is estimated with several standard pharmacology inspection procedures; The result shows that The compounds of this invention has stronger restraining effect to the growth of influenza neuraminidase A/PR/8/34 (H1N1) and two hypotypes of A/Sydney/5/97 (H3N2) and clinical influenza virus; And obviously greater than Group2-type enzyme, embody good selectivity for the inhibition of Group1-type enzyme.Can be used to prepare the medicine of the infection that the treatment influenza virus causes.
Be the pharmacological testing and the result of part of compounds of the present invention below.
One: part of compounds of the present invention adopts standard fluorescence method (Standard Fluorimetric Assay) [Anal.Bio-chem.1979; 94,287-296] measure the inhibition of influenza virus A/PR/8/34 (H1N1), A/Sydney/5/97 (H3N2) neuraminidase active.
Positive drug:
Tamiflu (oseltamivir), carboxyl Tamiflu (oseltamivir carboxylate), zanamivir (zanamivir) experimental principle:
(4-methylumbelliferyl-α-N-acetyl-neuraminate) is the specific substrate of influenza virus NA to MUNANA; The meta-bolites that under the NA effect, produces excites down in the 355nm irradiation; Can produce 460nm fluorescence, the variation of fluorescence intensity can be reacted the activity of NA delicately.
TP:
Get each 10 μ l of obtain solution (its concentration is 0.1mg/ml) of above-mentioned testing compound, add the NA of an amount of dilution of 30 μ l, mixing is put in the room temperature and is reacted, and establishes contrast of enzyme liquid and blank simultaneously.After 15 minutes, add 33mmolL
-1MES (2-N-morphine woods. ethyl sulfonic acid) (pH 3.5) damping fluid 10 μ l, 4mmolL U-Ramin MC 10 μ l, 20umolL
-1Substrate MUNANA 10 μ l, water 3 μ l, reaction system TV are 100 μ l, abundant mixing is hatched 15min in 37 ℃, adds the stop buffer (14mmol of 150 μ l
-1～NaOH, 83% ethanol), measure fluorescence intensity level.Setup parameter: EX=355nm, EM=460nm.Calculate inhibiting rate.Inhibiting rate is carried out multiple sieve greater than 50% compound sample, divide 5 concentration gradients, calculation sample is to the half-inhibition concentration (IC of NA
50).
Experimental result is seen table 1.
Table 1 The compounds of this invention is active to the inhibition of influenza virus H1N1, H3N2 neuraminidase
Can know that by table 1 The compounds of this invention shows that to influenza virus A/PR/8/34 (H1N1), A/Sydney/5/97 (H3N2) neuraminidase good inhibition is active.And part of compounds of the present invention has, and specific activity is suitable (like compound I-11 H1N1 IC mutually with positive control drug (oseltamivir and oseltamivir carboxylate)
50=2.322nM, compound I-21H1N1 IC
50=2.060nM) or stronger neuraminic acid enzyme inhibition (compound I-20 H1N1 IC
50=0.600nM, compound I-28 H1N1 IC
50=0.579nM) and to Group-1 type enzyme better choice property, we can find out from table, most compounds of the present invention is to influenza virus H1N1 IC
50Generally be lower than IC to influenza virus H3N2
50Value; It is thus clear that The compounds of this invention will generally be higher than H3N2 to the inhibition activity of H1N1; And Tamiflu will be lower than H3N2 to the inhibition activity of H1N1; This shows that compound of the present invention compares the obvious inhibition that has improved Group-1 type enzyme with Tamiflu, can optionally suppress Group-1 type enzyme thereby compare with Group-2 type enzyme.Therefore part of compounds of the present invention can be used as the better anti-influenza virus medicament of result of treatment.
Embodiment
Embodiment 1
2-chloro-N-(4-chloro-2-aminomethyl phenyl) ethanamide (II)
Adjacent methyl p-Chlorobenzoic acid amide (1.42g, 10mmol) the middle CH that adds
2Cl
2Dissolving adds triethylamine 2ml, in system, drips chloroacetyl chloride (0.93g, CH 12mmol)
2Cl
2Solution, system produce a large amount of white cigarettes, and become blackish green by the purple settled solution.Dropwise, remove ice bath, stirring at normal temperature 1 hour.Add 20ml CH
2Cl
2Dilution, saturated NH
4Cl washes twice, CH
2Cl
2Layer is used anhydrous Na
2SO
4Dry 1 hour, revolve and do CH
2Cl
2, adding PE and wash, suction filtration gets grey product 1.41g, productive rate 64.68%.m.p.132-133℃
Embodiment 2
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloro-2-aminotoluene base)-2-oxoethyl is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester (III)
In the single neck bottle of 100ml, add Tamiflu 3.1g (10mmol), 2-chloro-N-(4-chloro-2-aminomethyl phenyl) ethanamide 2.4g (12mmol), KI0.17 (1mmol) DMF 20mL, the 45-55 ℃ of about 14h of reaction.After the TLC detection reaction finishes, reaction solution is poured in the water, system is separated out the finely powdered solid, merges organic layer, anhydrous Na SO behind the 70mL ethyl acetate extraction 3 times
4Dry.Silica gel column chromatography (ETHYLE ACETATE: methyl alcohol=10: 1) get brown oil product 1.68g solid, productive rate 34%.
IR(KBr)v
max(cm
-1)3588，3568，3448，2360，2342，1685，1654，1647，1637，1629，1618，1384，669；
1H?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＝12.0Hz)，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/z266(M)
+。
Embodiment 3
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloro-2-aminotoluene base)-2-oxoethyl is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-1)
Add (3R in the single neck bottle of 50mL; 4R; 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloro-2-aminotoluene base)-2-oxoethyl is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester 1.4g (2.8mmol); Add 20mLTHF dissolving back again and add 1mol/L LiOH15mL, stirring at room 4h.After the TLC detection reaction finishes, revolve and boil off THF.Drip concentrated hydrochloric acid under the condition of ice bath and regulate pH to 3-4.System is separated out the khaki color solid.Suction filtration, filter cake dry product 1.12g, productive rate 85%.m.p.186-190℃。
IR(KBr)v
max(cm
-1)3650，3415，2965，2360，2342，1685，1654，1647，1637，1545，1484，1384，669；
1H?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＝6.0Hz)ppm；
ESI-HRMS?calcd?for?C
23H
33ClN
3O
5：466.2103，found：m/z?466.2114[M+H]
+。
Embodiment 4
4-chloro-N-(2-chloroethyl)-2-aminotoluene (IV)
The adjacent methyl p-Chlorobenzoic acid amide of adding in the single neck bottle of 100ml (3.00g, 21.2mmol), 1-bromo-2-monochloroethane 3.66g (25.4mmol), sodium hydrogencarbonate 2.67 (31.8mmol) DMF 10mL, the 45-55 ℃ of about 24h of reaction.After the TLC detection reaction finishes, reaction solution is poured in the water, merged organic layer, anhydrous Na SO behind the 60mL ethyl acetate extraction 3 times
4Dry.Silica gel column chromatography (sherwood oil: ETHYLE ACETATE=15: 1) get brown oil product 1.51g, productive rate 35%.
1H?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；
Embodiment 5
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloro-2-aminotoluene base) ethylamino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester (V)
In the single neck bottle of 100ml, add Tamiflu 3.1g (10mmol), 4-chloro-N-(2-chloroethyl)-2-aminotoluene 2.45g (12mmol), KI0.17 (1mmol) DMF 20mL, the 45-55 ℃ of about 16h of reaction.After the TLC detection reaction finishes, reaction solution is poured in the water, merged organic layer, anhydrous Na SO behind the 70mL ethyl acetate extraction 3 times
4Dry.Silica gel column chromatography (ETHYLE ACETATE: methyl alcohol=10: 1) get brown oil product 1.58g solid, productive rate 32%.
IR(KBr)v
max(cm
-1)3676，3670，3650，3629，3447，2926，2361，1701，1685，1654，1637，1384；
1H?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)
+；
Embodiment 6
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloro-2-aminotoluene base) ethylamino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-10)
Add (3R in the single neck bottle of 50mL; 4R; 5S)-and 4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloro-2-aminotoluene base) ethylamino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester 1.4g (2.8mmol), add 20mLTHF dissolving back again and add 1mol/LLiOH15mL, stirring at room 4h.After the TLC detection reaction finishes, revolve and boil off THF.Drip concentrated hydrochloric acid under the condition of ice bath and regulate pH to 3-4.System is separated out brown solid.Suction filtration, filter cake dry product 1.09g, productive rate 83%.m.p.205-210℃。
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?calcdfor?C
23H
35ClN
3O
4：452.2311，found：m/z?452.232[M+H]
+。
Embodiment 7
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-chloracetyl amido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester (VI)
Add the THF dissolving among the Tamiflu 2.00g (6.4mmol), add DMAP 1.00g (8.4mmol), in system, drip chloroacetyl chloride 0.78g under the condition of ice bath; THF solution (7.6mmol), system produce a large amount of white cigarettes, after dropwising; Remove ice bath, stirring at normal temperature 3 hours.Revolve to boil off and add 40ml CH behind the THF
2Cl
2Dissolving, saturated NH
4Cl washes twice, CH
2Cl
2Layer is used anhydrous Na
2SO
4Dry 1 hour, silica gel column chromatography (ETHYLE ACETATE: methyl alcohol=10: 1) get yellowish pink solid phase prod 1.93g, productive rate 82%.m.p.175-177℃。
IR(KBr)v
max(cm
-1)3431，3279，2961，2925，2360，2341，1718，1653，1560，1384，1253，1058，668；
1H?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)
+；
Embodiment 8
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(isobutyl amine) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester (VII)
In the single neck bottle of 100ml, add (3R, 4R, 5S)-and 4-acetylaminohydroxyphenylarsonic acid 5-(2-chloracetyl amido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester 4.0g (11mmol), isobutylamine 1.3mL (13mmol), K
2CO
31.9g (14.2mmol) KI0.17g (1mmol) DMF 20mL, the 45-55 ℃ of about 3h of reaction.After the TLC detection reaction finishes, reaction solution is poured in the water, merged organic layer, anhydrous Na SO behind the 70mL ethyl acetate extraction 3 times
4Dry.Silica gel column chromatography (ETHYLE ACETATE: methyl alcohol=10: 1) get yellow oil product 3.90g, productive rate 88%.
m.p.238-240℃。
IR(KBr)v
max(cm
-1)433，2958，2926，2361，2344，1718，1654，1648，1560，1459，1384，1248，669；
1H?NMR(CDCl
3)0.85-0.93(12H，m)，1.27-1.32(4H，q，J＝15.0Hz)，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)
+；
Embodiment 9
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(isobutyl amine) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-39)
Add (3R in the single neck bottle of 100mL; 4R; 5S)-and 4-acetylaminohydroxyphenylarsonic acid 5-(2-(isobutyl amine) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester 3.9g (9.7mmol), add 30mLTHF dissolving back again and add 1mol/L LiOH35mL, stirring at room 4h.After the TLC detection reaction finishes, revolve and boil off THF.Drip concentrated hydrochloric acid under the condition of ice bath and regulate pH to 3-4.System is separated out brown solid.Suction filtration, filter cake dry product 3.63g, productive rate 85%.m.p.198-201℃。
IR(KBr)v
max(cm
-1)3426，2968，1639，1566，1383，1064，1016，609；
1H?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
20H
36N
3O
5：398.2649，found：m/z?398.2656[M+H]
+。
Embodiment 10
3-chloro-N-(4-chloro-2-aminomethyl phenyl) propionic acid amide (II)
Experimental implementation is with instance 1, and adjacent methyl p-Chlorobenzoic acid amide (1.42g, 10mmol), triethylamine 2ml, (1.10g, 12mmol) reaction obtains taupe solid 1.8g to chlorpromazine chloride.Productive rate 78.3%.m.p.128-129℃。
MS(EI)m/e：231(M)
+；
Embodiment 11
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloro-2-aminotoluene base)-2-oxopropyl is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester (III)
Experimental implementation is with instance 2, Tamiflu 3.1g (10mmol), and 3-chloro-N-(4-chloro-2-aminomethyl phenyl) propionic acid amide 2.6g (12mmol), KI0.17 (1mmol) DMF 20mL reaction obtains brown oil 3.54g.Productive rate 70%.
IR(KBr)v
max(cm
-1)3650，3629，3448，1655，1648，1384；
1H?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)
+
Embodiment 12
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(4-chloro-2-aminotoluene base)-3-oxopropyl is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-2)
Experimental implementation is with instance 3; (3R; 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloro-2-aminotoluene base)-2-oxopropyl is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester 1.0g (2mmol), 1mol/LliOH 8ml reaction obtains brown solid product 0.56g.Productive rate 51%, m.p.192-196 ℃.
IR(KBr)v
max(cm
-1)3488，2958，2925，2871，2361，2344，1718，1655，1534，1458，1399，1383，1124，1096，621；
1H?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＝15.0Hz)，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
24H
34ClN
3O
5：480.226，found：m/z 480.2275[M+H]
+
Embodiment 13
2-(3-chloropropyl sulfydryl) benzoxazoles (IV)
In the single neck bottle of 100ml, add the 2-mercaptobenzoxazole (1.0g, 6.61mmol), 1-bromo-3-chloropropane (1.0g, 6.61mmol), K2CO3 (1.82g, 13.22mmol) and KI (0.11g, 0.66mmol) and the 20ml acetonitrile.Reacting by heating was poured reaction solution in the 100ml frozen water into after refluxing 24 hours, and system is separated out yellow mercury oxide.Suction filtration, filter cake dry product.Yellow solid 1.46g, productive rate 97.5%.
MS(EI)m/e：227(M)
+
Embodiment 14
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(2-mercaptobenzoxazole base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester (III)
Experimental implementation is with instance 2, Tamiflu 3.1g (10mmol), and 2-(3-chloropropyl sulfydryl) benzoxazoles 2.7g (12mmol), KI0.17 (1mmol) DMF 20mL reaction obtains yellow oil 3.60g.Productive rate 72%.
IR(KBr)v
max(cm
-1)3650，3629，3588，3422，2924，1685，1655，1637，1629，1577，1384；
1H?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)
+
Embodiment 15
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(2-mercaptobenzoxazole base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-33)
Experimental implementation is with instance 3; (3R; 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(2-mercaptobenzoxazole base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester 1.0g (2mmol), 1mol/LliOH 8ml reaction obtains brown solid product 0.88g.Productive rate 94%, m.p.215-219 ℃.
IR(KBr)v
max(cm
-1)3415，2926，2360，2342，1701，1655，1638，1560，1454，1384，1238，1131，1098，747；
1H?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
24H
33N
3O
4S
2：492.1985，found：m/z?492.1979[M+H]
+
Embodiment 16
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(diethylin) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester (VI)
Experimental implementation is with instance 8, (3R, 4R, 5S)-and 4-acetylaminohydroxyphenylarsonic acid 5-(2-chloracetyl amido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester 4.0g (11mmol), DIETHANOL AMINE 1g (13mmol), K
2CO
31.9g (14.2mmol) KI0.17g (1mmol) DMF 20mL, the 45-55 ℃ of about 3h of reaction.After the TLC detection reaction finishes, reaction solution is poured in the water, merged organic layer, anhydrous Na SO behind the 70mL ethyl acetate extraction 3 times
4Dry.Silica gel column chromatography (ETHYLE ACETATE: methyl alcohol=10: 1) get yellow oil product 4.00g, productive rate 90.9%.
IR(KBr)v
max(cm
-1)3650，3629，3448，2959，2925，2360，2343，1654，1648，1384；
1H?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)
+；
Embodiment 17
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(diethylin) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-42)
Experimental implementation is with instance 9, (3R, 4R, 5S)-and 4-acetylaminohydroxyphenylarsonic acid 5-(2-(diethylin) acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester 4.2g (10mmol), the 1mol/LLiOH40m reaction obtains white powder 2.8g.Productive rate 70.5%.m.p.135-137℃。
IR(KBr)v
max(cm
-1)3426，2968，1639，1566，1383，1064，1016，609；
1H?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
20H
35N
3O
5：398.2649，found：m/z 398.2656[M+H]
+
Embodiment 18
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-morpholino acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester (VI)
Experimental implementation is with instance 8, (3R, 4R, 5S)-and 4-acetylaminohydroxyphenylarsonic acid 5-(2-chloracetyl amido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester 4.0g (11mmol), morpholine 1g (13mmol), K
2CO
31.9g (14.2mmol) KI0.17g (1mmol) DMF 20mL, the 45-55 ℃ of about 3h of reaction.After the TLC detection reaction finishes, reaction solution is poured in the water, merged organic layer, anhydrous Na SO behind the 70mL ethyl acetate extraction 3 times
4Dry.Silica gel column chromatography (ETHYLE ACETATE: methyl alcohol=10: 1) get yellow oil product 4.50g, productive rate 93.2%.
IR(KBr)v
max(cm
-1)3650，3629，3448，2959，2925，1718，1685，1648，1560，1384，1116，1059；
1H?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)
+
Embodiment 19
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-morpholino acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-44)
Experimental implementation is with instance 9, (3R, 4R, 5S)-and 4-acetylaminohydroxyphenylarsonic acid 5-(2-morpholino acetamido)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester 4.2g (10mmol), the 1mol/LLiOH40m reaction obtains yellow powder 3.7g.Productive rate 90.3%.m.p.109-112℃。
IR(KBr)v
max(cm
-1)3426，2967，2360，1640，1565，1383，1123，1084，1018，869，613；
1H?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
20H
34N
3O
6：412.2442，found：m/z 412.2448[M+H]
+
Embodiment 20
3-chloro-N-(3-chloropropyl)-2-aminotoluene (IV)
Experimental implementation is with instance 1, and 4-chloro-2-aminotoluene (1.42g, 10mmol), triethylamine 2ml, (2.04g, 13mmol) reaction obtains red-brown oily matter 1.21g to 1-bromo-3-chloropropane.Productive rate 55.6%.
1H?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；
Embodiment 21
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(3-chloro-2-aminotoluene base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester (III)
Experimental implementation is with instance 2, Tamiflu 3.1g (10mmol), and 3-chloro-N-(3-chloropropyl)-2-aminotoluene 3.8g (12mmol), KI0.17 (1mmol) DMF 20mL reaction obtains yellow oil 4.40g.Productive rate 55.7%.
IR(KBr)v
max(cm
-1)3676，3650，3629，3416，1655，1637，1384，762；
1H?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＝6.0Hz)，6.78(1H，s)，6.99-7.04(1H，t，J＝15.0Hz)ppm；
MS(EI)m/e：493(M)
+
Embodiment 22
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(3-chloro-2-aminotoluene base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-20)
Experimental implementation is with instance 3; (3R; 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(3-(3-chloro-2-aminotoluene base) propyl group is amino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester 0.98g (2mmol), 1mol/LliOH 8ml reaction obtains brown solid product 0.73g.Productive rate 78%, m.p.108-110 ℃.
IR(KBr)v
max(cm
-1)3432，2961，2926，2874，2360，2342，1701，1655，1577，1560，1459，1383，1126，648，616；
1H?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
24H
36ClN
3O
4：466.2467，found：m/z 466.2473[M+H]
+
Embodiment 23
4-chloro-N-(2-chloroethyl)-3-monomethylaniline (IV)
Experimental implementation is with instance 1, and 4-chloro-3-monomethylaniline (1.42g, 10mmol), triethylamine 2ml, (1.83g, 13mmol) reaction obtains yellow oil 0.75g to 1-bromo-2-monochloroethane.Productive rate 37%.
1H?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；
Embodiment 24
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloro-3-toluidine) ethylamino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester (III)
Experimental implementation is with instance 2, Tamiflu 3.1g (10mmol), and 4-chloro-N-(2-chloroethyl)-3-monomethylaniline 3.6g (12mmol), KI0.17 (1mmol) DMF 20mL reaction obtains brown oil 6.00g.Productive rate 79%.
IR(KBr)v
max(cm
-1)3676，3670，3650，3629，3421，2955，2924，2851，2361，1685，1654，1648，1637，1629，1384；
1H?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)
+
Embodiment 25
(3R, 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloro-3-toluidine) ethylamino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid (I-28)
Experimental implementation is with instance 3; (3R; 4R, 5S)-4-acetylaminohydroxyphenylarsonic acid 5-(2-(4-chloro-3-toluidine) ethylamino)-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester 0.96g (2mmol), 1mol/LliOH 8ml reaction obtains brown solid product 0.76g.Productive rate 86%, m.p.196-200 ℃.
IR(KBr)v
max(cm
-1)3421，2926，2360，2342，1701，1685，1654，1648，1560，1458，1384，1127，669，617；
1H?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＝9.0Hz)，9.29(1H，s)ppm；
ESI-HRMS?calcd?for?C
23H
34ClN
3O
4：452.2311，found：m/z?452.2311[M+H]
+
Claims (8)
1. the compound or the pharmacy acceptable salt of general formula (I):
R wherein
1The aliphatic amide of alkyl, the C1～C6 of expression C1～C6,1～4 Y substituting group be substituted to be contained 0 ~ 2 and is selected from that nitrogen-atoms, sulphur atom or Sauerstoffatom five yuan or hexa-atomic aromatic nucleus or 1～4 Y substituting group are substituted to contain 0～2 benzheterocycle that is selected from the 8-10 unit of nitrogen-atoms, sulphur atom or Sauerstoffatom, and wherein substituting group Y is H, halogen, NH
2, OH, NO
2, CN, OCH
3Or OCF
3
R
2Expression H or C
2H
5
L representes-(CH
2) n-, n=1-3 ,-(CH
2CH
2C=O)-,-(CH
2C=O)-,-(O=CCH
2CH
2)-or-(O=CCH
2)-;
X representes CH
2, O, S or NH.
2. the compound of claim 1 or pharmacy acceptable salt, wherein R
1Expression pyridine ring or pyrazine ring.
3. the compound of claim 1 or pharmacy acceptable salt, wherein R
1Expression Pyrrolidine base, imidazolyl, piperidyl, 4-oxo-piperidine base, morphine quinoline base, piperidone base, piperazinyl, N methyl piperazine base, N-Phenylpiperazinyl or N-benzyl diethylenediamine base.
4. the compound of claim 1 or pharmacy acceptable salt, wherein R
1Expression normal-butyl, n-propyl, isobutyl-, the tertiary butyl, isopentyl, cyclopropyl, cyclopentyl, cyclohexyl, dimethylamino, dipropyl amino, isobutyl amine, cyclopropylamino, NSC 32389 base or cyclohexylamino.
5. the compound of claim 1 or pharmacy acceptable salt, wherein L representes CH
2
6. pharmaceutical composition wherein contains in the claim 1 to 5 each compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
7. the compound of claim 1 is used to prepare the purposes of the medicine of treating infection.
8. the purposes in the claim 7, wherein infection is the infection that influenza virus causes.
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| CN103923060A (en) * | 2014-03-27 | 2014-07-16 | 山东大学 | Oseltamivir derivative as well as preparation method and application thereof |
| CN106117077A (en) * | 2016-06-13 | 2016-11-16 | 上海应用技术学院 | A kind of neuraminidase inhibitor and preparation method thereof |
| CN107056636A (en) * | 2017-01-19 | 2017-08-18 | 山东大学 | A kind of Oseltamivir derivative and its preparation method and application |
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| CN109553554A (en) * | 2017-09-26 | 2019-04-02 | 沈阳药科大学 | Neuraminidase inhibitor and its medical usage containing urea groups |
| CN110015979A (en) * | 2018-01-09 | 2019-07-16 | 沈阳药科大学 | Neuraminidase inhibitor and its medical usage containing sulfoamido |
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