CN110066273A - A kind of single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole and the preparation method and application thereof - Google Patents
A kind of single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole and the preparation method and application thereof Download PDFInfo
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- CN110066273A CN110066273A CN201910486939.6A CN201910486939A CN110066273A CN 110066273 A CN110066273 A CN 110066273A CN 201910486939 A CN201910486939 A CN 201910486939A CN 110066273 A CN110066273 A CN 110066273A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Abstract
The present invention relates to single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole and its preparation method and application.The compound has structure shown in Formulas I or II.The invention further relates to the pharmaceutical compositions containing Formulas I or II structural compounds.Composition the present invention also provides above compound and containing one or more such compounds is preparing the application in anti-AIDS drug.
Description
Technical field
The invention belongs to organic compound synthesis and medical applications technical field, and in particular to a kind of list of the ring containing triazole
Arylpyrimidines HIV-1 reverse transcriptase inhibitor and the preparation method and application thereof.
Background technique
AIDS (Acquired Immune Deficiency Syndrome, AIDS), full name is acquired immunodeficiency
Syndrome is a kind of destruction human body caused by human immunodeficiency virus (Human Immunodeficiency Virus, HIV)
The chronic infectious disease of immune system.Since AIDS in 1981 is found, people try to explore related methods for the treatment of, Duo Zhongshang
The use in conjunction of the anti-AIDS drug in city can control the HIV-1 virus load of AIDS patient following in detection limit.I.e.
Just in this way, global AIDS preventing and controlling situation is still severe.It is shown according to the World Health Organization (WHO) data statistics in 2018, by
In the end of the year 2017, there are about 36,900,000 inhibition of HIV carrier, the AIDS patient in 1,800,000,2017 of new infections person in 2017 is dead in the whole world
The number of dying is up to 940,000.In addition, types of drugs of the China for clinical treatment AIDS is less, mostly external drug patent is expired
Imitation medicine afterwards, toxic side effect are larger, it is difficult to meet most of patient the needs of taking medicine throughout one's life.
Reverse transcriptase plays a crucial role in HIV-1 virus replicative cycle, and it is same that it is not present in human body
Source enzyme, thus have selection specificity using reverse transcriptase as the anti-HIV-1 medicines of target spot, clinically have huge exploitation valence
Value.According to mechanism of action difference, efabirenz can be divided by the anti-HIV-1 medicines of target spot of reverse transcriptase
(NRTIs) and non-nucleoside reverse transcriptase inhibitor (NNRTIs).Wherein, NNRTIs is as a kind of noncompetitive inhibitor, energy
It is enough specific recognition NNRTIs hydrophobic binding pocket (NNRTIs binding pocket, NNIBP) and in combination, so should
Class inhibitor has preferable selectivity, so that it becomes clinically efficient anti-reverse transcription therapy (Highly Active
Antiretroviral Therapy, HAART) important component.But with the clinical application of NNRTIs, such suppression
Preparation occur drug resistance, poor solubility, toxic side effect the problems such as also gradually cause people concern.
Therefore, HIV-1 reverse transcriptase is focused, the NNRTIs for researching and developing high-efficiency low-toxicity overriding resistance researches and develops field in current AIDS
Still it is of great significance.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of single arylpyrimidines HIV-1 of ring containing triazole reverses
Transcriptase inhibitors and preparation method thereof, the activity sieve the present invention also provides above compound as HIV-1 reverse transcriptase inhibitor
Select result and its application.
Technical scheme is as follows:
1. single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole
A kind of single arylpyrimidines HIV-1 reverse transcriptase inhibitor or its pharmaceutically acceptable salt of the ring containing triazole
Or ester, there is structure shown in general formula I or II:
Wherein,
N is 1 or 2；
X are as follows: O or NH；
R are as follows: CH3, CN or CH=CHCN；
R1Are as follows: phenyl or pyridyl group；Or halogen, CH3、SO2NH2、SO2CH3、CONH2、NO2、CN、NH2、CF3、NHCH3、OH、
COOH、CH2OH、CO2Me、OCH3、B(OH)2、NHCOCH3Substituted phenyl, substituent group is o-, m-, contraposition is monosubstituted or takes more
Generation；Or COOR2；Or CONR2；Or (CH2)nCOOR2, or (CH2)nCONR2, five-ring heterocycles, hexa-member heterocycle；
R2Are as follows: CH3, CH2CH3, cyclopropyl, five-ring heterocycles, hexa-member heterocycle.
Preferred according to the present invention, n 2, the five-ring heterocycles, hexa-member heterocycle are preferably pyrroles, furans, thiophene, four
Hydrogen furans, pyrazoles, imidazoles, oxazole, thiazole, isoxazole, pyridine, pyridazine, pyrimidine, pyrazine, piperazine and morpholine ring.
According to the present invention it is further preferred that single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole is
One of following compounds:
Heretofore described " pharmaceutically acceptable salt " refer in reliable medicine range of value, the salt of compound
Class is suitable for being in contact with people or compared with the tissue of lower animal without unsuitable toxicity, stimulation and allergic reaction etc., has suitable
Reasonable income and risk ratio, usually water or oil are soluble or dispersible, and are effectively used for its expected purposes.
Including pharmaceutically acceptable acid-addition salts and pharmaceutically acceptable base addition salts, be herein can do expected purposes and with
The chemical property of compound of formula I is compatible.The list of suitable salt is referring to S.M.Birge etc., J.Pharm.Sci., 1977, and 66,
1-19 pages.
2. the preparation method of single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole
The preparation method of single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole, step includes: with 2,4-
Dichloro pyrimidine is initial feed, is generated respectively with fortified phenol or aniline nucleo philic substitution reaction under alkaline condition first intermediate
Body 2；Then intermediate 2 and N-Boc-4- amino piperidine or aminobutyne hydrochloride nucleo philic substitution reaction generate intermediate 3 or
6；Then, intermediate 3 sloughs Boc in trifluoroacetic acid and protects to obtain intermediate 4；Then 4 react generation intermediate with propargyl bromide
5；Nitrine-end alkynes cycloaddition reaction (CuAAC of monovalence copper catalysis occurs with azide substitution base respectively for last intermediate 5 and 6
Click target product I or II) are obtained；Synthetic route is as follows:
Reagent and condition: (i) fortified phenol or aniline, n,N-Dimethylformamide, potassium carbonate, room temperature；(ii)N-Boc-
4- amino piperidine or aminobutyne hydrochloride, n,N-Dimethylformamide, potassium carbonate, 110 DEG C；(iii) methylene chloride, trifluoro second
Acid, room temperature；(iv) propargyl bromide, n,N-Dimethylformamide, potassium carbonate, room temperature；(v) vitamine C sodium, cupric sulfate pentahydrate, volume
Tetrahydrofuran/water than 1:1, azide substitution base, room temperature；
n、X、R、R1With shown in above-mentioned general formula I or II；
The fortified phenol or aniline are as follows: mesitylene phenol, 2,6- dimethyl -4- cyanophenol, 2,6- dimethyl -
4- (E)-vinyl phenol, trimethyl aniline, 2,6- dimethyl -4- cyano-aniline, 2,6- dimethyl -4- (E)-cyano
Vinyl aniline；
The azide substitution base are as follows: adjacent methylbenzyl nitrine, methylbenzyl nitrine, to methylbenzyl nitrine, adjacent chlorine
Benzyl azide, m-chloro benzyl azide, p-chlorobenzyl nitrine, adjacent bromobenzyl nitrine, bromobenzyl nitrine, to bromobenzyl nitrine, neighbour
Luorobenzyl nitrine, luorobenzyl nitrine, to luorobenzyl nitrine, 2,4- difluorobenzyl nitrine, 3,4- difluorobenzyl nitrine, adjacent cyano
Benzyl azide, cyanobenzyls nitrine, to cyanobenzyls nitrine, adjacent nitro benzyl azide, nitrobenzyl nitrine, to nitrobenzyl
Base nitrine, O-methoxy benzyl azide, meta-methoxy benzyl azide, to methoxy-benzyl nitrine, to methanesulfonylbenzyl nitrine,
Between methanesulfonylbenzyl nitrine, adjacent methanesulfonylbenzyl nitrine, to sulfoamido benzyl azide, sulfoamido benzyl azide,
Adjacent sulfoamido benzyl azide, to formamido benzyl azide, formamido benzyl azide, adjacent formamido benzyl azide,
2- azido -1- (pyrrolidin-1-yl) second -1- ketone, 2- azido-N- cyclopropyl-acetamide, 2- azido -1- morpholine -1- ketone,
2- ethyl triazoacetate, 2- triazoacetic acid methyl esters, 4- azido methyl butyrate, (4- (azido-methyl) phenyl) boric acid.
Preferred according to the present invention, the chemical compounds I or II preparation method of single arylpyrimidines containing triazole, step is such as
Under:
(1) 20mL N, N- diformazan are added to by initial feed 2,4- dichloro pyrimidine 1, fortified phenol or aniline, with potassium carbonate
It in base formamide solution, stirs under room temperature, reacts 8~12h；TLC monitoring reaction, to after the reaction was completed, to reaction solution
Middle addition 40mL aqueous solution simultaneously continues 20~30min of stirring, filters to obtain white solid, i.e. intermediate 2；
(2) intermediate 2, N-Boc-4- amino piperidine or aminobutyne hydrochloride and potassium carbonate are sufficiently mixed in 20mL
It in DMF solution, is stirred under the conditions of 120 DEG C of oil baths, solution is in yellow, TLC detection reaction 24-27h；100mL aqueous solution is added to quench
It goes out reaction, ethyl acetate extracts 3 times, each 20mL, merges organic layer, and saturated sodium chloride solution washs (3 × 50mL), anhydrous sulphur
Sour sodium dries, filters, concentration；Silica gel column chromatography separation；Ethyl acetate/petroleum ether or methylene chloride/n-hexane recrystallize
To intermediate 3 and 6；
(3) intermediate 3 is added in 15mL dichloromethane solution, is sufficiently stirred, trifluoroacetic acid is then added, room temperature is stirred
It mixes, reacts 6-8h；Then dichloromethane solution extraction is added in the pH=9 that reaction solution is adjusted with saturated sodium bicarbonate solution；Merge
Organic layer, saturated common salt water washing 3 times, each 50mL；Anhydrous sodium sulfate is dry；Filtering is concentrated under reduced pressure, silica gel column chromatography separation
Obtain intermediate 4；
(4) intermediate 4, propargyl bromide and potassium carbonate are mixed in 10mL DMF, are reacted at room temperature；TLC detection, wait react
Finish, add 60mL water dilute reaction solution, ethyl acetate extracts 3 times, each 20mL, merges organic layer, adds saturated common salt water washing 3
It is secondary, each 50mL, organic phase anhydrous sodium sulfate drying；Filtering, evaporated under reduced pressure solvent；The isolated intermediate of silica gel column chromatography
5；
(5) alkynyl moieties 5 and 6 are added to from different azide substitution bases to the THF/H of volume ratio 1:1 respectively2O mixing is molten
In liquid, VcNa and CuSO is then added into this mixed solution4.5H26-12h, TLC detection is stirred at room temperature in O；Then, Xiang Fanying
Suitable water is added in liquid, is extracted with ethyl acetate 3 times, each 10mL；Merging organic layer, saturated sodium chloride solution is washed 3 times,
Each 30mL, anhydrous sodium sulfate are dry；Filtering, evaporated under reduced pressure solvent；Silica gel column chromatography separation；Ethyl acetate/petroleum ether or
Single arylpyrimidines HIV-1 reverse transcriptase that methylene chloride/n-hexane is recrystallized to give target compound ring containing triazole inhibits
Agent I or II.
Room temperature of the present invention is 20-30 DEG C.
3. Anti-HIV-1 Active and the application of single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole
By enzyme-linked immunosorbent assay target compound I and II to the inhibitory activity of recombination reverse transcriptase, according to song
Wei Lin (ETV) and HIV-1 inhibitor K-5a2 is positive control.
The activity suppression result of the HIV-1 reverse transcriptase level of target compound A1-A10 is as shown in Table 1 and Table 2.It can be with
It was found that the inhibitory effect of the enzyme activity level of 10 target compounds is quite or preferable with K-5a2 and ETV.Wherein, compound A2
(IC50=0.02 μM) it is active more prominent.
Single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole of the invention can be used as non-nucleoside HIV-
1 inhibitor application.Specifically, being used to prepare anti-AIDS drug as HIV-1 inhibitor.
A kind of anti-HIV-1 medicines composition, single arylpyrimidines HIV-1 reverse transcription including the ring of the invention containing triazole
Enzyme inhibitor and one or more pharmaceutically acceptable carriers or excipient.
The present invention provides single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the completely new ring containing triazole of structure and its
Preparation method, the present invention also provides the active ingredients result of compound anti-HIV-1 enzyme activity level and its in antiviral field
Apply for the first time.In short, single Arylpyrimidines analog derivative of the ring of the invention containing triazole can be used as HIV-1 reverse transcriptase inhibition
Agent applies and has very high application value.Specifically, being used to prepare anti-AIDS drug as HIV-1 inhibitor.
Specific embodiment
Facilitate to understand the present invention by following embodiments, but the contents of the present invention cannot be limited.
Synthetic route involved in embodiment is as follows:
The preparation of embodiment 1:4- ((2- chlorine pyrimidine-4-yl) oxygroup) -3,5- xylylic acid nitrile (7)
By initial feed 2,4- dichloro pyrimidine (13.42mmol, 2.00g), 3,5- dimethyl -4- 4-hydroxy-benzonitrile
It is molten that (14.76mmol, 2.18g) and potassium carbonate (16.10mmol, 2.22g) is added to 20mL n,N-Dimethylformamide (DMF)
It in liquid, stirs under room temperature, reacts 8~12h.TLC monitoring reaction, to after the reaction was completed, 40mL be added into reaction solution
Aqueous solution simultaneously continues 20~30min of stirring, filters to obtain white solid, i.e. intermediate 7.1H NMR(400MHz,DMSO-d6)δ8.70
(d, J=5.7Hz, 1H), 7.75 (s, 2H), 7.32 (d, J=5.7Hz, 1H), 2.10 (s, 6H)；ESI-MS:m/z 259.97(M
+H)+,C13H10ClN3O(259.05).
The preparation of embodiment 2:4- ((2- chlorine pyrimidine-4-yl) amino) -3,5- dimethylbenzaldehyde (11)
Operating procedure is with the preparation of intermediate 7, except that with 3,5- dimethyl -4- hydroxy-benzaldehyde replaces 7 preparations
3,5- dimethyl -4- 4-hydroxy-benzonitrile in the process, obtains white solid.1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),
8.70 (d, J=5.7Hz, 1H), 7.77 (s, 2H), 7.30 (d, J=5.7Hz, 1H), 2.15 (s, 6H)；ESI-MS:m/z
263.10(M+H)+,C13H11ClN2O2(262.05).
Embodiment 3:(E) -3- (4- ((2- chlorine pyrimidine-4-yl) amino) -3,5- 3,5-dimethylphenyl) acrylonitrile (12) system
It is standby
Under condition of ice bath, cyanogen methyl acid phosphate diethylester (11.40mmol, 2.02g) is added to 10mL tetrahydrofuran and two
In the mixed solution (v:v=1:1) of chloromethanes, after being sufficiently mixed, in Xiang Shangshu solution be added potassium tert-butoxide (11.40mmol,
1.28g).Then, that the intermediate 11 (3.81mmol, 1.00g) for being dissolved in 5mL tetrahydrofuran is slowly dropped to above-mentioned mixing is molten
It in liquid, is added dropwise, removes ice bath, react at room temperature.It completes wait react, removed under reduced pressure solvent, is dissolved with 20mL DMF, then added
Enter 60~80mL aqueous solution, white solid is precipitated.Filtering, washes filter cake, and Gossypol recrystallized from chloroform obtains intermediate (E) -3- (4- ((2- chlorine
Pyrimidine-4-yl) amino) -3,5- 3,5-dimethylphenyl) acrylonitrile (12).Yield 64%, white solid,1H NMR(400MHz,
DMSO-d6) δ 8.67 (d, J=5.7Hz, 1H), 7.62 (d, J=16.7Hz, 1H), 7.52 (s, 2H), 7.25 (d, J=5.7Hz,
1H), 6.45 (d, J=16.7Hz, 1H), 2.07 (s, 6H), ESI-MS:m/z 286.2 (M+H)+,C15H12ClN3O(285.07).
Embodiment 4:(E) -3- (4- ((2- (butyl- 3- alkynes -1- base amino) pyrimidine-4-yl) amino) -3,5- dimethyl benzene
Base) acrylonitrile (13) preparation
By intermediate 12 (3.50mmol, 1.00g), aminobutyne hydrochloride (4.62mmol, 487.7mg) and potassium carbonate
(7.70mmol, 1.06g) is sufficiently mixed in 20mLDMF solution, is stirred under the conditions of 120 DEG C of oil baths, and solution is in yellow, reaction
24-27h (TLC detection).A large amount of aqueous solutions (100mL) quenching reaction is added, ethyl acetate extracts (3 × 20mL), merges organic
Layer, saturated sodium chloride solution wash (3 × 50mL), and anhydrous sodium sulfate dries, filters, concentration.Silica gel column chromatography separation；Acetic acid second
Ester/petroleum ether or methylene chloride/n-hexane are recrystallized to give (E) -3- (4- ((2- (butyl- 3- alkynes -1- base amino) pyrimidine -4-
Base) amino) -3,5- 3,5-dimethylphenyl) acrylonitrile (13).1H NMR(400MHz,DMSO-d6)δ8.19(s,1H),7.58(d,J
=16.7Hz, 1H), 7.45 (s, 2H), 7.29-7.07 (m, 1H), 6.40 (d, J=16.7Hz, 1H), 6.22 (s, 1H), 3.34
(s,1H),3.31(s,1H),3.02(s,1H),2.77(s,1H),2.34(s,1H),2.06(s,6H).13C NMR(100MHz,
DMSO)δ168.70,151.98,150.49,131.67,131.52,128.57,119.39,96.65,82.85,72.42,
18.79,16.55.ESI-MS:m/z 319.3(M+H)+,C19H18N4O(318.15).
Embodiment 5:4- ((4- (4- cyano -2,6- dimethyl phenoxy) pyrimidine -2-base) amino) tertiary fourth of piperidines -1- carboxylic acid
The preparation of ester (8-1)
Operating procedure with alkynyl moieties 13 preparation, except that with N-Boc-4- amino piperidine (4.23mmol,
0.85g) replace substituent group aminobutyne hydrochloride.1H NMR(400MHz,DMSO-d6) δ 8.20 (d, J=5.5Hz, 1H), 7.68
(s, 2H), 6.39-6.01 (m, 1H), 3.85 (s, 3H), 2.81 (dd, J=63.9,1.4Hz, 3H), 2.08 (s, 6H), 1.64
(d, J=80.2Hz, 2H), 1.38 (d, J=1.5Hz, 9H), 1.23 (s, 2H) .ESI-MS:m/z 446.06 (M+Na)+,
C23H29N5O3(423.23).
Embodiment 6:(E) -4- ((4- (4- (2- vinyl) -2,6- dimethyl benzene amino) pyrimidine -2-base) amino)
The preparation of piperidines -1- carboxylic acid tert-butyl ester (8-2)
Operating procedure with alkynyl moieties 13 preparation, except that with N-Boc-4- amino piperidine (4.23mmol,
0.85g) replace substituent group aminobutyne hydrochloride.1H NMR(400MHz,DMSO-d6) δ 8.17 (d, J=5.6Hz, 1H),
7.68-7.51 (m, 1H), 7.46 (d, J=4.5Hz, 2H), 6.40 (d, J=16.6Hz, 1H), 6.17 (s, 1H), 3.85 (s,
3H), 2.81 (d, J=63.8Hz, 2H), 2.06 (s, 6H), 1.91-1.52 (m, 3H), 1.41 (d, J=6.0Hz, 3H), 1.38
(s,6H),1.31–0.99(m,2H).ESI-MS:m/z 472.02(M+Na)+,C25H31N5O3(449.24).
The system of embodiment 7:3,5- dimethyl -4- ((2- (piperidin-4-yl amino) pyrimidine-4-yl) oxygroup) benzonitrile (9-1)
It is standby
Intermediate 8-1 (3.16mmol, 1.34g) is added in 15mL dichloromethane solution, is sufficiently stirred, is then added
Trifluoroacetic acid (15.82mmol, 1.80g), is stirred at room temperature, and reacts 6-8h.Then reaction solution is adjusted with saturated sodium bicarbonate solution
PH=9, be added dichloromethane solution extraction；Merge organic layer, saturated common salt water washing (3 × 50mL)；Anhydrous sodium sulfate is dry
It is dry；Filtering is concentrated under reduced pressure, the isolated key intermediate 3 of silica gel column chromatography, 5- dimethyl -4- ((2- (piperidin-4-yl amino)
Pyrimidine-4-yl) oxygroup) benzonitrile (9-1).1H NMR(400MHz,DMSO-d6) δ 8.18 (d, J=5.6Hz, 1H), 7.67 (s,
2H), 7.13 (d, J=101.9Hz, 1H), 6.22 (d, J=5.6Hz, 1H), 3.75 (s, 2H), 2.92 (s, 3H), 2.08 (s,
6H), 1.63 (d, J=82.6Hz, 2H), 1.45-1.03 (m, 3H) .ESI-MS:m/z 324.11 (M+H)+,C18H21N5O
(323.17).
Embodiment 8:(E) -3- (3,5- dimethyl -4- ((2- (piperidin-4-yl amino) pyrimidine-4-yl) amino) phenyl) third
The preparation of alkene nitrile (9-2)
Operating procedure with intermediate 9-1 preparation, except that with intermediate 8-2 (3.16mmol, 1.42g) replace in
Mesosome 8-1.1H NMR(400MHz,DMSO-d6) δ 8.17 (d, J=5.6Hz, 1H), 7.59 (d, J=16.4Hz, 1H), 7.46
(s, 1H), 7.33-6.95 (m, 1H), 6.41 (d, J=16.8Hz, 1H), 6.17 (s, 1H), 3.02 (s, 2H), 2.47 (dd, J=
7.1,1.3Hz,2H),2.06(s,6H),1.91–1.52(m,3H),1.54–1.09(m,4H).ESI-MS:m/z 350.12(M+
H)+,C20H23N5O(349.19).
Embodiment 9:3,5- dimethyl -4- ((2- ((1- (propyl- 2- alkynes -1- base) piperidin-4-yl) amino) pyrimidine-4-yl)
Oxygroup) benzonitrile (10-1) preparation
By intermediate 9-1 (0.65mmol, 0.21g), propargyl bromide (0.779mmol, 0.093g), potassium carbonate (1.30mmol,
It 0.179g) is mixed in 10mL DMF, reacts at room temperature.TLC detection, to end of reaction, increasing amount water (60mL) dilute reaction solution,
Ethyl acetate extracts (3 × 20mL), merges organic layer, adds saturated common salt water washing (3 × 50mL), organic phase anhydrous sodium sulfate
It is dry；Filtering, evaporated under reduced pressure solvent；The isolated alkynyl moieties 3,5- dimethyl -4- of silica gel column chromatography ((2- ((1- (propyl- 2-
Alkynes -1- base) piperidin-4-yl) amino) pyrimidine-4-yl) oxygroup) benzonitrile (10-1).White solid, yield 65%.1H NMR
(400MHz,DMSO-d6) δ 8.19 (d, J=5.6Hz, 1H), 7.66 (s, 2H), 7.08 (d, J=113.6Hz, 1H), 6.23 (d,
J=5.5Hz, 1H), 3.63 (s, 1H), 3.20 (s, 2H), 3.10 (s, 1H), 2.71 (t, J=15.8Hz, 2H), 2.08 (s,
7H), 1.80 (d, J=34.3Hz, 2H), 1.64-1.14 (m, 3H)13C NMR(100MHz,DMSO)δ168.28,133.13,
119.07,108.61,75.82,46.65,31.50,31.47,16.30.ESI-MS:m/z 362.4(M+H)+,C21H23N5O
(361.45).
Embodiment 10:(E) (((2- ((1- (propyl- 2- alkynes -1- base) piperidin-4-yl) amino) is phonetic by 3,5- dimethyl -4- by -3-
Pyridine -4- base) amino) phenyl) and acrylonitrile (10-2) preparation
Operating procedure with alkynyl moieties 10-1 preparation, except that replacing intermediate III A-9-1 with intermediate 9-2.
Faint yellow solid, yield 63%.1H NMR(400MHz,DMSO-d6) δ 8.16 (d, J=5.7Hz, 1H), 7.58 (d, J=
16.3Hz, 1H), 7.44 (s, 2H), 7.05 (d, J=92.4Hz, 1H), 6.39 (d, J=16.7Hz, 1H), 6.16 (d, J=
5.7Hz, 1H), 3.14 (d, J=37.2Hz, 3H), 2.67 (d, J=43.4Hz, 2H), 2.07 (d, J=9.6Hz, 7H), 1.76
(s, 3H), 1.33 (dd, J=45.6,30.9Hz, 3H)13C NMR(100MHz,DMSO)δ168.67,150.49,131.72,131.50,
119.38,96.59,75.83,51.47,51.19,46.65,31.53,16.58.ESI-MS:m/z 388.4(M+H)+,
C23H25N5O(387.49).
Embodiment 11: the preparation of target compound A1 and A2-A10
Alkynyl moieties 10-1,10-2 or 13 (1.0eq) are added to 8mL's from different azide substitution bases (1.2eq)
THF/H2In O (v:v=1:1) mixed solution, VcNa (0.3eq) and CuSO are then added into this mixed solution4.5H2O
6-12h, TLC detection is stirred at room temperature in (0.1eq.).Then, suitable water is added into reaction solution, be extracted with ethyl acetate (3 ×
10mL)；Merge organic layer, saturated sodium chloride solution washs (3 × 30mL), and anhydrous sodium sulfate is dry；Filtering, evaporated under reduced pressure are molten
Agent；Silica gel column chromatography separation；Ethyl acetate/petroleum ether or methylene chloride/n-hexane be recrystallized to give target compound A1 and
A2-A10。
Methyl (E) -2- (4- (2- ((4- (4- (2- vinyl) -2,6- dimethyl benzene amino) pyrimidine -2-base) ammonia
Base) ethyl) -1H-1,2,3 (methyl)-triazol-1-yl) methyl acetate (A1)
White crystal, 84mg, yield: 62%, mp:137-139 DEG C.1H NMR(400MHz,DMSO-d6)δ8.21(s,
1H), 7.88 (s, 1H), 7.58 (d, J=16.7Hz, 1H), 7.46 (s, 2H), 7.30-7.04 (m, 1H), 6.39 (d, J=
16.7Hz,1H),6.21(s,1H),5.35(s,2H,CH3OC=OCH2),3.72(s,3H,OCH3),3.47(s,1H),3.14
(s, 1H), 2.75 (d, J=85.9Hz, 2H, triazole-CH2),2.08(s,6H,2×CH3).13C NMR(100MHz,
DMSO)δ168.69,168.20,160.42,152.04,150.45,144.97,131.73,131.46,128.56,123.98,
119.37,96.63,55.37,52.94,50.58,41.10,25.46,16.56.
4- ((4- ((4- ((4- (4- cyano -2,6- dimethyl phenoxy) pyrimidine -2-base) amino) piperidin-1-yl) first
Base) -1H-1,2,3- triazol-1-yl) methyl) benzamide (A2)
White powder, 75mg, yield: 50%, mp:143-145 DEG C.1H NMR(400MHz,DMSO-d6)δ8.27–8.13
(m, 1H), 8.01 (d, J=24.8Hz, 2H), 7.87 (d, J=7.8Hz, 2H), 7.66 (s, 2H), 7.40 (s, 1H), 7.35 (d,
J=7.9Hz, 2H), 7.10 (d, J=113.8Hz, 1H), 6.22 (d, J=5.6Hz, 1H), 5.64 (s, 2H, NH2COPhCH2),
3.57–3.44(m,2H,triazole-CH2), 2.74 (d, J=30.7Hz, 2H), 2.08 (s, 6H, 2 × CH3),2.00–1.85
(m, 1H), 1.63 (d, J=72.1Hz, 3H), 1.48-1.17 (m, 2H), 1.01 (d, J=6.3Hz, 1H)13C NMR
(100MHz,DMSO)δ168.28,167.89,139.68,134.46,133.12,128.37,128.05,124.40,119.11,
108.58,67.73,67.66,53.10,52.78,52.33,31.55,20.46,16.29.ESI-MS:m/z 538.25(M+H)+,
C29H31N9O2(537.26).
2- (4- ((4- ((4- (4- cyano -2,6- dimethyl phenoxy) pyrimidine -2-base) amino) piperidin-1-yl) methyl) -
1H-1,2,3- triazole cyclobutane -1- base)-N- cyclopropyl-acetamide (A3)
White powder, 84mg, yield: 60%, mp:109-111 DEG C.1H NMR(400MHz,DMSO-d6)δ8.45(s,
1H), 8.19 (s, 1H), 7.89 (s, 1H), 7.67 (s, 2H), 7.10 (d, J=110.8Hz, 1H), 6.40-6.07 (m, 1H),
5.00 (s, 2H), 3.53 (s, 2H), 2.73 (d, J=52.7Hz, 3H), 2.09 (s, 7H), 1.65 (d, J=74.1Hz, 3H),
1.48-1.06 (m, 3H), 0.66 (d, J=7.4Hz, 2H), 0.46 (s, 2H)13C NMR(100MHz,DMSO)δ168.28,
166.89,133.12,125.64,119.10,108.59,55.37,53.01,52.33,51.88,31.53,22.82,16.30,
6.06.ESI-MS:m/z502.29(M+H)+,C26H31N9O2(501.26).
4- (4- ((4- ((4- (4- cyano -2,6- dimethyl phenoxy) pyrimidine -2-base) amino) piperidin-1-yl) methyl) -
1H-1,2,3- triazol-1-yl) ethyl butyrate (A4)
White solid, 99mg, yield: 70%, mp:144-146 DEG C.1H NMR(400MHz,DMSO-d6)δ8.19(s,
1H), 7.97 (s, 1H), 7.67 (s, 2H), 7.09 (d, J=109.9Hz, 1H), 6.23 (s, 1H), 4.37 (s, 2H), 3.59 (s,
4H),2.78(s,2H),2.32(s,2H),2.09(s,9H),1.88–0.50(m,7H).13C NMR(100MHz,DMSO)δ
172.95,168.28,144.05,133.12,124.11,119.10,108.59,53.11,52.32,48.89,31.54,
30.61,25.59,16.31.ESI-MS:m/z 505.18(M+H)+,C26H32N8O3(504.26).
(E) -3- (3,5- dimethyl -4- ((2- ((1- ((1- (2- morpholino -2- oxoethyl) -1H-1,2,3- triazole -
4- yl) methyl) piperidin-4-yl) amino) pyrimidine-4-yl) amino) phenyl) acrylonitrile (A5)
Faint yellow solid, 81mg, yield: 56%, mp:145-147 DEG C.1H NMR(400MHz,DMSO-d6)δ8.27–
8.05 (m, 1H), 7.83 (s, 1H), 7.71-7.52 (m, 1H), 7.44 (s, 2H), 7.07 (d, J=94.1Hz, 1H), 6.40 (d,
J=16.7Hz, 1H), 6.16 (s, 1H), 5.43 (s, 2H), 3.93-3.39 (m, 11H), 2.79 (s, 2H), 2.08 (s, 2H),
2.06 (s, 5H), 1.66 (d, J=55.4Hz, 3H), 1.32 (d, J=68.9Hz, 2H)13C NMR(100MHz,DMSO)δ
168.68,165.01,150.51,131.71,128.56,125.82,119.41,96.60,66.41,53.08,52.35,
50.90,45.19,42.37,31.59,16.59.
(E) -2- (4- ((4- ((4- (4- (2- vinyl) -2,6- 3,5-dimethylphenyl) amino) pyrimidine -2-base) ammonia
Base) piperidin-1-yl) methyl) -1H--1,2,3- triazol-1-yl)-N- cyclopropyl-acetamide (A6)
Pale yellow powder, 90mg, yield: 66%, mp:113-115 DEG C.1H NMR(400MHz,DMSO-d6)δ8.46(d,J
=4.1Hz, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.69-7.52 (m, 1H), 7.45 (s, 2H), 7.07 (d, J=
94.7Hz, 1H), 6.40 (d, J=16.7Hz, 1H), 6.16 (s, 1H), 5.00 (s, 2H), 3.53 (s, 2H), 2.92-2.58 (m,
3H), 2.07 (d, J=9.7Hz, 8H), 1.66 (d, J=55.8Hz, 3H), 1.47-1.19 (m, 3H), 0.65 (d, J=6.9Hz,
2H), 0.45 (d, J=4.2Hz, 2H)13C NMR(100MHz,DMSO)δ168.68,166.90,162.12,160.35,
152.07,150.49,148.59,143.68,131.71,131.52,131.50,128.58,125.66,119.39,118.35,
96.61,95.42,53.02,52.33,51.88,48.41,41.80,40.61,40.40,40.20,39.99,39.88,
39.78,39.57,39.36,31.56,26.92,22.82,16.58,7.79,6.06.
Ethyl (E) -2- (4- ((4- ((4- (4- (2- vinyl) -2,6- 3,5-dimethylphenyl) amino) pyrimidine -2-base)
Amino) piperidin-1-yl) methyl) -1H-1,2,3- triazol-1-yl) methyl acetate (A7)
Pale yellow powder, 57mg, yield: 43%, mp:87-89 DEG C.1H NMR(400MHz,DMSO-d6)δ8.16(s,
1H), 7.95 (s, 1H), 7.72-7.51 (m, 1H), 7.45 (s, 2H), 7.05 (d, J=89.5Hz, 1H), 6.40 (d, J=
16.6Hz, 1H), 6.16 (s, 1H), 5.36 (s, 2H), 4.18 (d, J=7.2Hz, 2H), 3.53 (s, 2H), 2.78 (s, 2H),
2.08 (d, J=9.9Hz, 7H), 1.66 (d, J=55.8Hz, 3H), 1.51-0.98 (m, 6H)13C NMR(100MHz,DMSO)δ
168.68,167.74,150.49,148.58,144.17,131.49,128.63,125.53,119.39,96.61,61.90,
53.02,52.32,50.74,31.61,16.58,14.41.
Methyl (E) -2- (4- ((4- ((4- (4- (2- vinyl) -2,6- 3,5-dimethylphenyl) amino) pyrimidine -2-base)
Amino) piperidin-1-yl) methyl) -1H-1,2,3- triazol-1-yl) methyl acetate (A8)
White powder, 63mg, yield: 49%, mp:85-87 DEG C.1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),
7.96 (s, 1H), 7.59 (d, J=14.1Hz, 1H), 7.45 (s, 2H), 7.07 (d, J=92.9Hz, 1H), 6.40 (d, J=
16.6Hz, 1H), 6.16 (s, 1H), 5.38 (s, 2H), 3.72 (s, 3H), 3.51 (d, J=20.3Hz, 2H), 2.75 (d, J=
29.1Hz, 2H), 2.07 (s, 7H), 1.67 (d, J=53.6Hz, 3H), 1.32 (d, J=65.1Hz, 3H)13C NMR
(100MHz,DMSO)δ168.69,168.26,150.49,144.21,131.71,131.49,128.53,125.51,119.39,
96.61,53.02,52.96,52.35,50.63,31.63,16.58.
Methyl (E) -4- (4- ((4- ((4- (4- (2- vinyl) -2,6- 3,5-dimethylphenyl) amino) pyrimidine -2-base)
Amino) piperidin-1-yl) methyl) -1H-1,2,3- triazol-1-yl) ethyl butyrate (A9)
Pale yellow powder, 101mg, yield: 74%, mp:87-89 DEG C.1H NMR(400MHz,DMSO-d6)δ8.17(d,J
=5.6Hz, 1H), 8.05 (s, 1H), 7.70-7.51 (m, 1H), 7.45 (s, 2H), 7.13 (d, J=91.2Hz, 1H), 6.41
(d, J=16.6Hz, 1H), 6.18 (s, 1H), 4.38 (t, J=7.0Hz, 2H), 3.83-3.67 (m, 1H), 3.59 (s, 3H),
3.06 (d, J=7.3Hz, 1H), 2.92 (d, J=17.1Hz, 2H), 2.74 (s, 1H), 2.33 (t, J=7.3Hz, 3H), 2.07
(d, J=10.4Hz, 8H), 1.64 (d, J=123.7Hz, 4H), 1.21 (dd, J=14.5,7.3Hz, 1H)13C NMR
(100MHz,DMSO)δ172.95,168.68,150.48,144.12,131.71,128.62,124.06,119.39,96.61,
53.14,52.40,51.86,48.89,31.60,30.61,25.59,16.57.
(E)-(4- ((4- ((4- ((4- (4- (2- vinyl) -2,6- 3,5-dimethylphenyl) amino) pyrimidine -2-base) ammonia
Base) piperidin-1-yl) methyl) -1H-1,2,3- triazol-1-yl) methyl) phenyl) boric acid (A10)
Pale yellow powder, 105mg, yield: 72%, mp:153-155 DEG C of1H NMR(400MHz,DMSO-d6)δ8.16(s,
1H), 8.07 (d, J=14.1Hz, 2H), 7.78 (d, J=7.7Hz, 2H), 7.66-7.51 (m, 1H), 7.44 (s, 2H), 7.25
(d, J=7.6Hz, 2H), 7.08-6.67 (m, 1H), 6.40 (d, J=16.7Hz, 1H), 6.17 (s, 1H), 5.59 (s, 2H),
3.63 (s, 3H), 3.00-2.62 (m, 2H), 2.07 (d, J=10.3Hz, 7H), 1.88-1.56 (m, 3H), 1.53-1.24 (m,
3H).13C NMR(100MHz,DMSO)δ172.95,168.68,150.48,144.12,131.71,128.62,124.06,
119.39,96.61,53.14,52.40,51.86,48.89,31.60,30.61,25.59,16.57.
Embodiment 12: the external horizontal Inhibition test of anti-HIV-1 reverse transcriptase activity of target compound
Experimental principle: untested compound surveys the inhibitory activity of recombination reverse transcriptase by enzyme linked immunosorbent assay
It is fixed.Firstly, the dNTPs that reverse transcriptase (RT) is marked with digoxin (Digoxin, DIG) and biotin (Biotin) is substrate,
Oligo (dT) 15 is primer, and Poly (A) is that template completes primer extend process.It is completed to reverse transcription, biotin and digoxin are double
The DNA of label is integrated on 96 orifice plates containing Streptavidin.Then be added be connected with peroxidase (Peroxidase,
POD DigiTAb), is allowed in conjunction with DNA.It is eventually adding peroxidase substrate 2'- hydrazine-bis- -3- ethyl benzo thiophene
Oxazoline -6- sulfonic acid (ABTS) generates different colours with peroxide enzyme interacting.Its extinction is detected with microplate reader immediately
Degree, be inhibited activity.
Experimental material: micro sample adding appliance (10 μ L, 20 μ L, 100 μ L, 200 μ L, 1000 μ L), the EP pipe of different size
(0.5mL, 1.5mL, 5mL), untested compound, HIV-1 reverse transcriptase kit (Recombinant HIV-1RT kit,
Roche), tri-distilled water, positive control etravirine and K-5a2 (structural formula is as follows).
Experimental procedure: according to the operating procedure of specification in Roche Reverse Transcriptase kit, the inverse of untested compound is carried out
The active testing of transcriptase.Firstly, 500ng HIV-1RT freeze-drying object is configured to lysis buffer and tri-distilled water
The enzyme solutions of 0.1ng/ μ L take 20 μ L to be placed in the EP pipe of 0.5mL；Then, it is added into EP pipe equally dilute with lysis buffer
The 20 μ L of untested compound that releases and reaction mixture (template, dNTP, primer) 20 μ L is incubated for 2h at 37 DEG C.To for the first time
Incubation finishes, with 60 μ L reaction solutions in micro sample adding appliance transfer EP pipe into the micropore for being coated with Streptavidin, sealed membrane envelope
It closes, continues to be incubated for 1h at 37 DEG C.It is incubated for and finishes to second, remove reaction solution, each sample-adding micropore is cleaned with the washing lotion of 250 μ L
5 times, washing lotion is removed, the DigiTAb solution 200 μ L for being connected with peroxidase is added in every hole, continues to be incubated for 1h at 37 DEG C.
It is finished to be incubated for for the third time, removes reaction solution, then equally each sample-adding micropore is cleaned 5 times with the washing lotion of 250 μ L, removing is washed
200 μ L of ABTS solution is added into each hole for liquid.It is immediately measurement wavelength with 405nm, 490nm is reference wavelength, is surveyed with microplate reader
Fixed each hole absorbance value.It is worth noting that, test all needs setting blank group (no reverse transcriptase, no inhibitor) and feminine gender every time
Control group (no inhibitor has reverse transcriptase).
As a result it calculates:
Untested compound is calculated under single concentration to the inhibiting rate of reverse transcriptase according to above-mentioned formula.And under various concentration
Untested compound 5 software of inhibiting rate combination GraphPad Prism of reverse transcriptase is handled to obtain IC50Value.
It has been carried out in vitro according to single Arylpyrimidines analog derivative of the above-mentioned experimental method to part ring containing triazole of synthesis
The screening active ingredients of anti-reverse transcription enzyme level, Activity Results are as shown in table 1, table 2.
Inhibiting effect of the 1 partial target product of table to HIV-1RT
Inhibiting effect of the 2 partial target product of table to HIV-1RT
Claims (7)
1. a kind of single arylpyrimidines HIV-1 reverse transcriptase inhibitor of ring containing triazole or its pharmaceutically acceptable salt or
Ester, which is characterized in that there is structure shown in general formula I or II:
Wherein,
N is 1 or 2；
X are as follows: O or NH；
R are as follows: CH3, CN or CH=CHCN；
R1Are as follows: phenyl or pyridyl group；Or halogen, CH3、SO2NH2、SO2CH3、CONH2、NO2、CN、NH2、CF3、NHCH3、OH、
COOH、CH2OH、CO2Me、OCH3、B(OH)2、NHCOCH3Substituted phenyl, substituent group is o-, m-, contraposition is monosubstituted or takes more
Generation；Or COOR2；Or CONR2；Or (CH2)nCOOR2, or (CH2)nCONR2, five-ring heterocycles, hexa-member heterocycle；
R2Are as follows: CH3, CH2CH3, cyclopropyl, five-ring heterocycles, hexa-member heterocycle.
2. single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole, feature exist as described in claim 1
In, n 2, the five-ring heterocycles, hexa-member heterocycle be pyrroles, furans, thiophene, tetrahydrofuran, pyrazoles, imidazoles, oxazole, thiazole,
Isoxazole, pyridine, pyridazine, pyrimidine, pyrazine, piperazine and morpholine ring.
3. single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole as claimed in claim 1 or 2, feature
It is that one of following compounds:
4. the preparation method of single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole as described in claim 1,
Step includes: with 2,4- dichloro pyrimidine for initial feed, first under alkaline condition respectively with fortified phenol or aniline through nucleophilic
Substitution reaction generates intermediate 2；Then intermediate 2 and N-Boc-4- amino piperidine or aminobutyne hydrochloride are anti-through nucleophilic displacement of fluorine
Intermediate 3 or 6 should be generated；Then, intermediate 3 sloughs Boc in trifluoroacetic acid and protects to obtain intermediate 4；Then 4 and propargyl bromide
Reaction generates intermediate 5；Nitrine-end alkynes ring that the catalysis of monovalence copper occurs with azide substitution base respectively for last intermediate 5 and 6 adds
Target product I or II are obtained at reaction (CuAAC Click)；Synthetic route is as follows:
Reagent and condition: (i) fortified phenol or aniline, n,N-Dimethylformamide, potassium carbonate, room temperature；(ii) N-Boc-4- ammonia
Phenylpiperidines or aminobutyne hydrochloride, n,N-Dimethylformamide, potassium carbonate, 110 DEG C；(iii) methylene chloride, trifluoroacetic acid,
Room temperature；(iv) propargyl bromide, n,N-Dimethylformamide, potassium carbonate, room temperature；(v) vitamine C sodium, cupric sulfate pentahydrate, volume ratio 1:
1 tetrahydrofuran/water, azide substitution base, room temperature；
n、X、R、R1With shown in above-mentioned general formula I or II；
The fortified phenol or aniline are as follows: mesitylene phenol, 2,6- dimethyl -4- cyanophenol, 2,6- dimethyl -4-
(E)-vinyl phenol, trimethyl aniline, 2,6- dimethyl -4- cyano-aniline, 2,6- dimethyl -4- (E)-cyano second
Alkenyl aniline；
The azide substitution base are as follows: adjacent methylbenzyl nitrine, methylbenzyl nitrine, to methylbenzyl nitrine, o-chlorobenzyl
Nitrine, m-chloro benzyl azide, p-chlorobenzyl nitrine, adjacent bromobenzyl nitrine, bromobenzyl nitrine, to bromobenzyl nitrine, adjacent fluorine benzyl
Base nitrine, luorobenzyl nitrine, to luorobenzyl nitrine, 2,4- difluorobenzyl nitrine, 3,4- difluorobenzyl nitrine, o-cyanobenzyl
Nitrine, cyanobenzyls nitrine, to cyanobenzyls nitrine, adjacent nitro benzyl azide, nitrobenzyl nitrine, folded to nitrobenzyl
Nitrogen, O-methoxy benzyl azide, meta-methoxy benzyl azide, to methoxy-benzyl nitrine, to methanesulfonylbenzyl nitrine, first
Sulphonylbenzyl nitrine, adjacent methanesulfonylbenzyl nitrine, to sulfoamido benzyl azide, sulfoamido benzyl azide, adjacent sulphur
Amide groups benzyl azide folds formamido benzyl azide, formamido benzyl azide, adjacent formamido benzyl azide, 2-
Nitrogen base -1- (pyrrolidin-1-yl) second -1- ketone, 2- azido-N- cyclopropyl-acetamide, 2- azido -1- morpholine -1- ketone, 2- are folded
Nitrogen ethyl, 2- triazoacetic acid methyl esters, 4- azido methyl butyrate, (4- (azido-methyl) phenyl) boric acid.
5. the preparation method of single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole as claimed in claim 4,
Steps are as follows:
(1) 20mL N, N- dimethyl methyl are added to by initial feed 2,4- dichloro pyrimidine 1, fortified phenol or aniline, with potassium carbonate
It in amide solution, stirs under room temperature, reacts 8~12h；TLC monitoring reaction, to after the reaction was completed, add into reaction solution
Enter 40mL aqueous solution and continue 20~30min of stirring, filters to obtain white solid, i.e. intermediate 2；
(2) intermediate 2, N-Boc-4- amino piperidine or aminobutyne hydrochloride and potassium carbonate are sufficiently mixed molten in 20mL DMF
It in liquid, is stirred under the conditions of 120 DEG C of oil baths, solution is in yellow, TLC detection reaction 24-27h；100mL aqueous solution is added to be quenched instead
It answers, ethyl acetate extracts 3 times, each 20mL, merges organic layer, and saturated sodium chloride solution washs (3 × 50mL), anhydrous sodium sulfate
It dries, filters, is concentrated；Silica gel column chromatography separation；During ethyl acetate/petroleum ether or methylene chloride/n-hexane are recrystallized to give
Mesosome 3 and 6；
(3) intermediate 3 is added in 15mL dichloromethane solution, is sufficiently stirred, trifluoroacetic acid is then added, be stirred at room temperature,
React 6-8h；Then dichloromethane solution extraction is added in the pH=9 that reaction solution is adjusted with saturated sodium bicarbonate solution；It is associated with
Machine layer, saturated common salt water washing 3 times, each 50mL；Anhydrous sodium sulfate is dry；Filtering, is concentrated under reduced pressure, and silica gel column chromatography separates
To intermediate 4；
(4) intermediate 4, propargyl bromide and potassium carbonate are mixed in 10mL DMF, are reacted at room temperature；TLC detection, to end of reaction,
Add 60mL water dilute reaction solution, ethyl acetate extracts 3 times, each 20mL, merges organic layer, adds saturated common salt water washing 3 times, often
Secondary 50mL, organic phase are dry with anhydrous sodium sulfate；Filtering, evaporated under reduced pressure solvent；The isolated intermediate 5 of silica gel column chromatography；
(5) alkynyl moieties 5 and 6 are added to from different azide substitution bases to the THF/H of volume ratio 1:1 respectively2In O mixed solution,
Then VcNa and CuSO is added into this mixed solution4·5H26-12h, TLC detection is stirred at room temperature in O；Then, into reaction solution
Suitable water is added, is extracted with ethyl acetate 3 times, each 10mL；Merging organic layer, saturated sodium chloride solution washing 3 times, every time
30mL, anhydrous sodium sulfate are dry；Filtering, evaporated under reduced pressure solvent；Silica gel column chromatography separation；Ethyl acetate/petroleum ether or dichloro
Methane/n-hexane be recrystallized to give target compound ring containing triazole single arylpyrimidines HIV-1 reverse transcriptase inhibitor I or
II。
6. single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole as described in claim any one of 1-3 is being made
Application in standby anti-AIDS drug.
7. a kind of pharmaceutical composition, single arylpyrimidines HIV-1 comprising the ring containing triazole described in claim any one of 1-3 is inverse
Transcripting enzyme inhibitor and one or more pharmaceutically acceptable carriers or excipient.
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| CN111675661A (en) * | 2020-06-28 | 2020-09-18 | 山东大学 | Diaryl pyrimidine HIV-1 reverse transcriptase inhibitor containing trans double bond and preparation method and application thereof |
| CN115636817A (en) * | 2022-06-20 | 2023-01-24 | 山东大学 | Isatin derivative containing triazole ring and preparation method and application thereof |
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| CN111675661B (en) * | 2020-06-28 | 2021-08-24 | 山东大学 | Diaryl pyrimidine HIV-1 reverse transcriptase inhibitor containing trans double bond and preparation method and application thereof |
| CN115636817A (en) * | 2022-06-20 | 2023-01-24 | 山东大学 | Isatin derivative containing triazole ring and preparation method and application thereof |
| CN115636817B (en) * | 2022-06-20 | 2023-11-24 | 山东大学 | Isatin derivative containing triazole ring, and preparation method and application thereof |
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