CN1548413A - Beta-diketoacid as dimer compound and its prepn and use - Google Patents
Beta-diketoacid as dimer compound and its prepn and use Download PDFInfo
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Abstract
The beta-diketo acid dimer compound is prepared through coupling 4-aryl-4-oxy-2-hydroxy-2-butenic acid and diamine in different structure under the activation of coupling reagent to obtain diketo acid diamide, or reacting toluene dibromide and 3-hydroxy acetophenone under alkali condition to obtain benzyloxy radical connected diphenyl ethyl ketone; oxalylation and hydrolysis to obtain corresponding diaryl beta-diketo acid dimer. Pharmacological experiment shows that the compound of the present invention has very high HIV-1 integrase inhibiting activity.
Description
Technical field
The present invention relates to have beta-diketon acid dimer synthetic of symmetrical structure, more particularly for containing 3-aryl-1, the dimer compounds of 3-diketone acid mono is as the synthetic purposes that reaches of efficient HIV-1 integrase inhibitor.
Background technology
HIV-1 is the virus that causes acquired immune deficiency syndrome (AIDS), its three kinds of enzyme of encoding: reversed transcriptive enzyme (reversetranscriptase, RT), proteolytic enzyme (protease, PR) and intergrase (integrase, IN).These three kinds of enzymes are that HIV duplicates and infects necessary basic enzyme.The medicine that is used for the treatment of at present acquired immune deficiency syndrome (AIDS) clinically all is reverse transcriptase inhibitors and proteinase inhibitor, but this two classes medicine all can not be eradicated HIV, and side effects such as toxicity, patient's complication and multiple drug resistance have appearred, therefore, integrase inhibitor with novel mechanism of action is expected to improve curative effect, and can act synergistically with existing anti-acquired immunodeficiency syndrome drug deposits yields, form new effective conjoint therapy.HIV-1 intergrase (IN) is one of virus replication necessary three big basic enzyme, and retrovirus DNA inserts in the host chromosome under the catalysis of intergrase, and then duplicating and infecting of HIV taken place; And the HIV-1 intergrase might limit HIV the integrase inhibitor medicine is developed immunity to drugs with single reactive site and virus and two kinds of the hosts DNA substrate-function of isomorphic map not; Intergrase only is present in the virus in addition, and Mammals does not all have this fermentoid, thus the HIV-1 intergrase become big promising inverase design novel target protein (Curr.Opin.Drug Discov.Devel.2001,4,402-410).
Present many synthetic compounds have the effect that suppresses the HIV-1 intergrase, but (Science 2000 to have only the beta-diketon acid compounds to show effective intracellular antiviral activity, 287,646-650), its biological isostere beta-diketon tetrazolium S-1360 has entered the clinical II phase as the HIV-1 integrase inhibitor and has studied.Because the HIV-1 intergrase shows with dimerization or tetramer form and plays katalysis, therefore, we are from the diketone acid compound, the beta-diketon acid dimer that synthesizes different structure by the connection plate of different lengths, orientation, shape, further improve active, increase selectivity, exploitation has the Me Too medicine of antiviral activity.
Summary of the invention
The objective of the invention is to seek the beta-diketon acids dimer compound that a class has the efficient HIV-1 integrase inhibitor of antiviral activity.
Another object of the present invention provides the preparation method of a class beta-diketon acids dimer compound.
A further object of the present invention provides and contains 3-aryl-1, and the dimer compounds of 3-two ketone acids is in medically purposes.
The present invention's design is based on HIV-1 intergrase and interactional crystalline structure of its inhibitor and structure activity relationship, because the HIV-1 intergrase shows with dimerization or tetramer form and plays katalysis (Proc.Natl.Acad.Sci.USA, 1999,96,13040-13043), but the precise nature of oligomer is still unknown, therefore, we are from having the beta-diketon acid compounds of antiviral activity, connection plate by different lengths, orientation, shape synthesizes the beta-diketon acid dimer, to obtain highly active antiviral agent.
The present invention is with 3-aryl-1,3-two ketone acids are monomer, by different tie points be connected the beta-diketon acid dimer (the compound general formula is shown in 1 and 2) that plate synthesizes different structure, measured simultaneously the HIV-1 integrase inhibiting activities of each compound at molecular level.
A class of the present invention contains 3-aryl-1, and the symmetrical dimer compounds of 3-diketone has following structure 1 and 2:
Wherein, X is N, O, heteroatomss such as S
R is C
2-C
6Alkyl or replacement aromatic ring
R
1Be C
2-C
6Alkyl or replacement aromatic ring
Such structural general formula 1 and 2 total basic frameworks are 4-aryl-4-oxygen-2-hydroxyl-2-butylene acid, shown in their the synthetic following reaction formula:
Corresponding aryl methyl ketone and dimethyl oxalate or oxalic acid tert-butyl ester methyl esters react under the alkali condition, and after the condensation, the two ketone acid methyl esters that obtain get 4-aryl-4-oxygen-2-hydroxyl-2-butylene acid through basic hydrolysis.
Two diketone acid dimers of general formula 1 are by following prepared in reaction:
Wherein, the monomer 5 in the general formula 1 is according to document J.Med.Chem.2000, and 43 (26), 4923 method is synthetic.The phenyl aldehyde and the 3-bromo-1-phenyl lithiumbromide that are about to replace react, and obtain (3-bromo-phenyl)-(phenyl of replacement)-methyl alcohol (compound 3), obtain corresponding 3-benzyl phenyl bromine (compound 4) through the triethyl silicane reduction.This bromide by after the lithium saltsization with the effect of acylating reagent N,N-dimethylacetamide, obtain corresponding aryl ketones.Aryl methyl ketone according to method oxalylization recited above again hydrolysis just obtain corresponding monomer 4-aryl-4-oxygen-2-hydroxyl-2-butylene acid.
With the diamines of the corresponding 4-aryl-4-oxygen-2-hydroxyl of above-mentioned gained-2-butylene acid and different structure at coupling reagent I-hydroxybenzotriazole (HOBT) and 1-[3-(dimethylamino) propyl group]-activation of 3-ethyl carbodiimide (EDCI) under coupling become to have two ketone acid diamide of the different carbon chain of symmetrical structure.
Two diketone acid dimers of general formula 2 obtain by following reaction:
At first dimethylbenzene generates dibromomethylbenzene as starting raw material through N-bromo-succinimide bromination, the different positions of gained replace (adjacent-,-or right-) dibromomethylbenzene and 3-hydroxy acetophenone under alkaline condition, react two phenyl ethyl ketones of being connected of benzyloxy.Two phenyl ethyl ketones of above-mentioned gained are after oxalylization, and hydrolysis gets two accordingly aryl diketone acid dimers again.
The methyl that replaces with phenyl is from (3-bromine phenylbenzene)-(substituted-phenyl)-methyl alcohol as the diketone acid dimer of the connection plate of two (4-aryl-4-oxygen-2-hydroxyl-2-butylene acid), by following reaction acquisition:
Earlier by (3-bromo-phenyl)-(substituted-phenyl)-methyl alcohol through the Jones reagent oxidation get corresponding ketone (compound 11) again with the phenyl lithiumbromide that replaces react the tertiary alcohol (compound 12) that replaces of triaryl, the above-mentioned tertiary alcohol through dichlorodimethylsilane reduce two-(3-bromophenyl)-arylmethane (compound 13) accordingly, compound 13 after lithium saltsization with N-methoxyl group-N-methylacetamide react corresponding diaryl ketone-aryl-methane (compound 14).Compound 14 through oxalic acid tert-butyl ester methyl esters in the presence of sodium methylate, carry out oxalylization react compound 15, to separate and be able to the methane that aryl replaces be two aryl diketone acid dimers of connector element to caustic liquor then.
Pharmacological datum shows that this class contains 3-aryl-1, and the symmetrical dimer of 3-diketone has very high HIV-1 integrase inhibiting activities, the 503nhibiting concentration IC of and chain transfer disconnected for 3 ' end-grain cutting of substrate
50All in 6.0-0.02 μ M scope, the inhibition activity of wherein best compound is higher than monomeric compound.
The HIV-1 integrase inhibiting activities
The mechanism of action of HIV-1 intergrase is a two-step reaction: 1) 3 ' end processing (3 ' Processing): intergrase forms stabilized complex in conjunction with the particular sequence in the terminal repetition zone of the length of proviral DNA (LTR), carry out the inscribe nucleosides acidolysis processing of nucleosides 3 ' end then, cut away sequence specifically ... the GT dinucleotides that CAGT-3 ' is terminal, expose 3 ' recessed hydroxyl; 2) chain transfer (Strand Transfer): finished DNA/ intergrase is integrated mixture in advance and is passed nuclear membrane and enter the nucleon center, combine with host's DNA, 3 ' recessed hydroxyl of intergrase catalysis viral DNA embeds in the karyomit(e) of host cell by transesterification reaction then, becomes sophisticated provirus.Therefore, the activity of integrase inhibitor shows to the inhibition of 3 ' tip cut-off of viral DNA or the inhibition of chain transfer, with 503nhibiting concentration IC
50Characterize.
Recombinant protein HIV-1 intergrase is used in the test of external intergrase, according to the method operation of document description (Methods Enzymol.2001,340,624-633 and J.Med.Chem.1997,40,942-951).In 30 ℃ of pre-down cultivations 30 minutes, the ultimate density of the intergrase that control is added is 200nM in reaction buffer for intergrase and inhibitor.Then, add 5 ' of 20nM-end
32The linear oligomer Nucleotide substrate of P-mark continues to cultivate 1 hour.Reaction is by the cancellation of the isopyknic sex change loading dye of adding institute.One five equilibrium sample is loaded in the gel (0.09M Tris-borate, pH8.3,2mM EDTA, 20% polyacrylamide, 8M urea) of 20% denaturing polyacrylamide and goes up through electrophoretic separation.Behind the gel drying, place in the box of the dynamic phosphorus developing of a part device and expose, analyze by molecule dynamic phosphorus developing device then.
Suppressing per-cent is calculated by following formula:
％I＝100×[1-(D-C)/(N-C)]
It is the mark of 19 Nucleotide (3 '-end-grain cutting stopping pregnancy thing) or chain transfer product that C in the formula, N and D represent 21 Nucleotide substrate conversion under the different condition respectively.C wherein, the condition at N and D place is respectively: dna single solely exists, and DNA adds intergrase, and DNA adds that intergrase adds inhibitor.503nhibiting concentration IC
50Measure the pairing concentration of generation 50% inhibition and determine suppressing the per-cent mapping by inhibitor concentration.
Consisting of of reaction buffer: 25mM MOPS, pH7.2,50mM NaCl, 1mM HEPES, pH7.5,50 μ M EDTA, 50 μ M dithiothreitol (DTT), 7.5mM MnCl
2, 0.1mg/mL bovine serum albumin (BSA), 10.0mM 2 mercapto ethanol, 10% methyl-sulphoxide.
Table 1. has the inhibition activity of the dimer beta-diketon amides 1a-1e of symmetrical structure to wild shape HIV-1 intergrase
IC
50，μM
Compound R R
13 '-cut-out chain transfer
21 nucleosides DNA, 19 nucleosides DNA
At Mn
2+Ion exists down
1a
3.0 0.03 0.8
1b
10.0 0.04，0.175 3.0
1c
7.0 0.045，0.37 2.0
1d
6.5 0.1，1.0 0.37
1e
7-OH (monomer) 3.0 0.37 0.8
Table 2. has the inhibition activity of the dimer beta-diketon amides 1a-1e of symmetrical structure to the HIV-1 intergrase of fixed point variation
IC
50，μM(C-65-S?IN) IC
50，μM(C-56-S?IN)
Compound R R
1
3 '-cut-out chain transfer 3 '-cut-out chain transfer
At Mn
2+Ion exists down
1a
1.25，3.0 0.12，0.08 1.1，2.0 0.2，0.04
1b
3.0，4.0 0.45，0.08 4.5，3.0 0.25，0.1
1c
5.0，＞4.0 0.25，0.05 ＞3.3，4.0 0.85，2.0
1d
3.0，＞3.3 1.0，1.0 2.5，3.3 0.3，0.1
1e
7-OH (monomer) 0.45,＞1.0 0.02, and 0.08 2.0,2.0 0.2,0.04
Table 3. has the inhibition activity of the beta-diketon acid dimer compounds 2a-2d of symmetrical structure to the HIV-1 intergrase of wild shape and fixed point variation
IC
50，μM(WT?IN) IC
50，μM(C-65-S?IN)
Compound R
3 '-cut-out chain transfer 3 '-cut-out chain transfer
At Mn
2+Ion exists down
2a
1.1 1.5 2.5 0.5
2b
6.0，6.0 5.5 10 0.37
2c
1.33，2.0 2.0 1.75 1.75
2d
1.1 2.5 2.5 0.3
7
3.0 0.8 0.45，1.0 0.02，0.08
Embodiment
Below in conjunction with embodiment the present invention is further described, but does not limit the present invention.
Example 1 4-[3-(2-fluoro-benzyl)-phenyl]-2-hydroxyl-4-oxygen-but-2-ene acyl piperazine diamines 1a
Step 1:(3-bromo-phenyl)-(2-fluoro-phenyl)-methyl alcohol (compound 3)
Under nitrogen protection; hexane solution (the 6.5mL that in a dry reaction bottle, adds the n-Butyl Lithium of 1.6M; 10.4mmol) and the 20mL anhydrous tetrahydro furan, be chilled to-78 ℃, with 1; 3-dibromobenzene (1.2mL; 10.0mmol) slowly drop in the system ,-78 ℃～-50 ℃ were stirred 2.5 hours down, then with adjacent fluorobenzaldehyde (1.06mL; 10.4mmol) slowly drop in the system, keep system temperature to be lower than-50 ℃.-78 ℃～-50 ℃ were stirred 0.5 hour, were warming up to room temperature naturally, continued to stir the saturated NH of system 3 hours
4The cancellation of Cl solution, extracted with diethyl ether merges organic layer, uses saturated NaHCO successively
3Solution, saturated common salt water washing, anhydrous Na
2SO
4Dry.Concentrate, column chromatography (petroleum ether/ethyl ether=15: 1) purifying gets 2.82g yellow oil 3, productive rate 95%.
1HNMR(400MHz，CDCl
3)：δ7.59(s，1H)；7.39-7.53(m，2H)；7.20-7.27(m，2H)；7.10-7.19(m，2H)；6.95-7.03(m，1H)；6.02(d，1H)；2.83(d，1H).
Step 2:(3-bromo-phenyl)-(2-fluoro-phenyl)-methane (compound 4)
Under nitrogen protection, (1.183g, 4.21mmol), (0.81mL 5.05mmol) and the 15mL anhydrous methylene chloride, is chilled to 0 ℃, with BF to triethyl silicane to add compound 3 in a dry reaction bottle
3Et
2(0.64mL 5.05mmol) slowly drops in the system O, is warming up to stirred overnight at room temperature naturally, and system is with saturated NaHCO
3The solution cancellation, extracted with diethyl ether merges organic phase, with saturated salt washing, anhydrous Na
2SO
4Dry.Concentrate, column chromatography (100% sherwood oil) purifying gets 0.971g yellow oil 4, productive rate 84%.
1HNMR(400MHz，CDCl
3)：δ7.30-7.35(m，2H)；7.00-7.20(m，6H)；3.95(s，2H).
Step 3:1-[3-(2-fluoro-benzyl)-phenyl] ethyl ketone (compound 5)
With compound 4 (0.67g; 2.53mmol) be dissolved in the 10mL anhydrous tetrahydro furan; be chilled to-78 ℃; under nitrogen protection; the n-Butyl Lithium hexane solution of slow dropping 1.6M in system (1.9mL, 3.0mmol) ,-78 ℃ were stirred 2 hours down; with N; (0.35mL 3.8mmol) slowly drops in the system N-N,N-DIMETHYLACETAMIDE, and temperature of reaction is controlled at below-50 ℃; stirred 0.5 hour down in-78 ℃～-50 ℃; the system HCl solution cancellation of 1N, the water extracted with diethyl ether merges organic phase; the saturated common salt water washing, anhydrous Na
2SO
4Dry.Concentrate, resistates gets 0.288g yellow oil 5, productive rate 63% with column chromatography (petrol ether/ethyl acetate=10: 1) purifying.
1HNMR(400MHz，CDCl
3)：δ7.77-7.83(m，2H)；7.19-7.37(m，2H)；7.15-7.19(m，2H)；7.03-7.14(m，2H)；4.04(s，2H)；2.57(s，3H).
EI-MS(M/Z，％)：228(M
+，39.0)，213(100)，185(10.0)，165(26.0).
Step 4:4-[3-(2-fluoro-benzyl)-phenyl]-2,4-dioxy-methyl-butyrate (compound 6)
Under nitrogen protection, in a dry reaction bottle, add sodium methylate (2.91g, 53.95mmol) and the 45mL dry toluene; be chilled to 0 ℃, will (3.18g, 26.97mmol) dimethyl oxalate reaches (2.461g; 10.79mmol) the ethylene glycol dimethyl ether solution 45mL of compound 5 slowly drops in the system, 0 ℃ was stirred 0.5 hour, and was warming up to 60 ℃ gradually; stirring is spent the night; the system HCl solution cancellation of 1N, the water ethyl acetate extraction merges organic phase; saturated salt washing, anhydrous Na
2SO
4Dry.Concentrate yellow oil 6, not purifiedly directly carry out next step reaction.
EI-MS(M/Z，％)：314(M
+，8.0)，255(100)，213(58.0)，185(10.0)，165(18.0)，109(40.0).
Step 5:4-[3-(2-fluoro-benzyl)-phenyl]-2-hydroxyl-4-oxygen-but-2-ene acid (compound 7)
Previous step gained crude product compound 6 is dissolved in 40mL tetrahydrofuran (THF)/methyl alcohol (1: 1) mixed solvent, under the room temperature condition, drip the sodium hydroxide solution 40mL of 1N, stirring at room 1 hour, the system extracted with diethyl ether, water is transferred pH value to 1～2 with the HCl solution of 2N, uses ethyl acetate extraction then, merge organic phase, use saturated NaHCO successively
3Solution is washed, saturated salt washing, anhydrous Na
2SO
4Dry.Concentrate, residue gets faint yellow cotton-shaped 7, two step of the solid chemical compound yield 53.35% of 1.179g with sherwood oil/methylene dichloride recrystallization purifying.mp117～118℃。
1HNMR(400MHz，CDCl
3)：δ7.88-7.84(m，2H)；7.49-7.42(m，2H)；7.25-7.17(m，2H)；7.15(s，1H)，7.10-7.04(m，2H)；4.08(s，2H).
EI-MS(M/Z，％)：300(M
+，12.5)，255(100)，213(30.0)，183(18.0)，165(26.0)，109(70.0).
Step 6:4-[3-(2-fluoro-benzyl)-phenyl]-2-hydroxyl-4-oxygen-but-2-ene acyl piperazine diamines (compound 1a)
Monomer two ketone acid 4-[3-(2-fluoro-benzyl)-phenyl]-2-hydroxyl-4-oxygen-but-2-ene acid, compound 7 (0.15g, 0.2mmol) and EDCI (0.101g, 0.525mmol), (0.071g 0.525mmol) is dissolved in the 1.5mL anhydrous tetrahydro furan to HOBT, and 0 ℃ was stirred 15 minutes, in system, drip piperazine (0.02g, 0.25mmol) N, dinethylformamide solution 1mL is warming up to room temperature naturally, stir after 2.5 hours, reaction mixture is poured in the frozen water, and the water dichloromethane extraction merges organic phase, with saturated brine washing, anhydrous Na
2SO
4Dry.Concentrate, residue gets brown thickness compound 1a 56mg, productive rate 40% through column chromatography (methylene chloride=60: 1) purifying.
1HNMR(400MHz，CDCl
3)：δ7.79-7.76(m，4H)；7.44-7.38(m，4H)；7.25-7.19(m，2H)；7.17-7.13(m，2H)，7.09-7.03(m，4H)；4.05(s，4H)，3.73-3.78(m，8H).
ESI-MS：651.1(M+H
+，100)，674.2(M+Na
+，12.0).
Target compound 1b-1e makes with similar approach:
Embodiment 2:4-[3-(2-fluoro-benzyl)-phenyl]-2-carboxyl-4-oxygen-but-2-ene acyl quadrol 1b
Pale yellow powder, yield 65%.
1H?NMR(400MHz，CDCl
3)：δ7.87-7.83(m，6H)；7.75-7.42(m，4H)；7.19(s，2H)；7.26-7.02(m，6H)，4.05(s，4H)；3.64(m，4H).
EI-MS(M/Z，％)：323(100)，254(38.0)，213(70.0)，165(26.0)，109(14.0).
Embodiment 3:4-[3-(2-fluoro-benzyl)-phenyl]-2-hydroxyl-4-oxygen-but-2-ene acyl propylene diamine 1c
Pale yellow powder, yield 68%.
1H?NMR(400MHz，CDCl
3)：δ7.88-7.84(m，6H)；7.44-7.38(m，4H)；7.21(s，1H)；7.24-7.13(m，3H)，7.09-7.02(m，3H)；4.06(s，4H)；3.47(q，4H，J＝6.42Hz)；1.8(m，2H).ESI-MS：661.4(M+Na
+，100).
Embodiment 4:4-[3-(2-fluoro-benzyl)-phenyl]-2-hydroxyl-4-oxygen-but-2-ene acyl pentamethylene diamine 1d
Pale yellow powder, yield 70%.
1H?NMR(400MHz，CDCl
3)：δ7.87-7.82(m，4H)；7.44-7.38(m，4H)；7.28-7.25(m，4H)；7.19(s，1H)；7.24-7.13(m，3H)，7.09-7.02(m，3H)；4.06(s，4H)；3.41(q，4H，J＝6.86Hz)；1.69-1.62(m，4H)；1.48-1.40(m，2H).
ESI-MS(M/Z，％)：667.2(M+H
+，96.5)，689.3(M+Na
+，100).
Embodiment 5:4-[3-(2-fluoro-benzyl)-phenyl] 2-hydroxyl-4-oxygen-but-2-ene acyl hexanediamine 1e
Pale yellow powder, yield 70%.mp134～135℃.
1H?NMR(400MHz，CDCl
3)：δ7.87-7.82(m，4H)；7.44-7.38(m，4H)；7.19(s，2H)；7.27-7.13(m，5H)，7.09-7.02(m，3H)，4.06(s，4H)；3.39(q，4H，J＝6.73)，1.63-1.60(m，4H)，1.43-1.40(m，4H).ESI-MS(M/Z，％)：681.3(M+H+，9.0)，703.4(M+Na
+，100).
Embodiment 6:1,2-pair-[3-(1,3-dioxy 3-carboxyl)-Phenoxymethyl]-benzene 2a
Step 1:1,2-pair-brooethyl-benzene (compound 8a)
In an exsiccant list neck bottle, add NBS (6.6g, 37.5mmol), (1.85mL, 15.0mmol) and the 100mL tetracol phenixin, agitation condition adds benzoyl peroxide (18mg) down to o-Xylol.System refluxed 36 hours under intense agitation, during room temperature the sedimentation and filtration that generates in the reaction process was fallen, and filtrate concentrates the back column chromatography, and 100% sherwood oil is made eluent, obtains 1.5g white solid compound 8a, productive rate 33.5%.
1HNMR(400MHz，CDCl
3)：δ4.67(s，4H)，7.30-7.33(m，2H)，7.36-7.39(m，2H)
Step 2:1,2-pair-(3-acetyl Phenoxymethyl)-benzene (compound 9a)
Under nitrogen protection, (0.34g 2.5mmol) is dissolved in the anhydrous N of 4mL, and dinethylformamide is with K with the 3-hydroxy acetophenone
2CO
3(0.71g, 5.14mmol) and compound 8a (0.26g 1.0mmol) adds in the system, system 60 ℃ the reaction 4 hours, behind the system dilute with water, the water ethyl acetate extraction, the merging organic phase, use NaOH solution and the saturated common salt water washing of 2N successively, anhydrous Na
2SO
4Dry.After organic phase concentrated, (PE: EtOAc=3: 1) purifying obtained 0.34g white solid 9a, productive rate 90.9% to the resistates column chromatography.
1HNMR(400MHz，CDCl
3)：δ7.56-7.53(m，6H)，7.42-7.34(m，4H)，7.17-7.15(m，2H)，5.23(s，4H)，2.56(s，6H).
Step 3:1,2-pair-[3-(1,3-dioxy-4 butyric acid methyl esters)-Phenoxymethyl]-benzene (compound 10a)
In the single neck bottle of exsiccant 25mL, add CH
3ONa (167mg, 7.59mmol) and the 1.5mL dry toluene, cryosel is bathed cooling, slowly drip 9a (116mg, 0.31mmol) and MeOOCCOOtBu (198mg 1.24mmol) is dissolved in the solution of THF/DME (3.0mL/3.0mL), 0 ℃ is stirred after 0.5 hour down, under the intense agitation, reaction mixture is poured in the frozen water of HCl solution (1N) into the water dichloromethane extraction, merge organic phase, use the HCl solution of 1N successively, salt washing, anhydrous Na
2SO
4Dry.Organic phase concentrates back resistates column chromatography (CHCl
3/ CH
3OH=10: 1) purifying obtains 0.158g oily compound 10a, productive rate 93.5%.
1HNMR(400MHz，CDCl
3)：δ7.58-7.52(m，6H)，7.44-7.37(m，4H)，7.21-7.18(m，2H)，7.03(s，2H)，5.26(s，4H)，3.94(s，6H).
Step 4:1,2-pair-[3-(1,3-dioxy-3-carboxyl)-Phenoxymethyl]-benzene (compound 2a)
With compound 1,2-is two-and (0.164g 0.30mmol) is dissolved in the mixed solvent (2.0mL: 2.0mL) of tetrahydrofuran (THF) and methyl alcohol to [3-(1,3-dioxy-3-carboxylate methyl ester)-Phenoxymethyl]-benzene 10a, NaOH solution with 3.2mL 1N under the room temperature slowly drops in the system, stir after 1 hour, the reaction system extracted with diethyl ether, water uses the HCl adjust pH of 2N to 1-2, use ethyl acetate extraction then, merge organic phase, salt washing, anhydrous Na
2SO
4Drying.After organic phase concentrated, resistates obtained 0.109g yellow solid 2a, productive rate 70.0%. with sherwood oil/methylene dichloride recrystallization
1HNMR(400MHz，CDCl
3)：δ7.64-7.61(m，3H)；7.59-7.55(m，3H)；7.49-7.45(m，2H)；7.41-7.39(q，2H，J＝13.40)；7.06(s，2H)，5.36(s，4H).
ESI-MS：517.1(M-H
+，38.0)；445.1(100)
Embodiment 7:1,3-pair-[3-(1,3-dioxy-3-carboxyl)-Phenoxymethyl]-benzene 2b
Step 1:1,3-pair-brooethyl-benzene (compound 8b)
In an exsiccant list neck bottle, add NBS (6.68g, 37.5mmol), (1.85mL, 15.0mmol) and the 30mL tetracol phenixin, agitation condition adds benzoyl peroxide (23mg) down to m-xylene.System refluxed 36 hours under intense agitation, during room temperature the sedimentation and filtration that generates in the reaction process was fallen, and filtrate concentrates the back column chromatography, and 100% sherwood oil is made eluent, obtains 1.88g white solid compound 8b, productive rate 47.4%.
1HNMR(600MHz，CDCl
3)：δ4.46(s，4H)，7.40(s，1H)，7.31(m，3H)
Step 2:1,3-pair-(3-acetyl Phenoxymethyl)-benzene (compound 9b)
Under nitrogen protection, (0.5g 3.7mmol) is dissolved in the anhydrous N of 8mL, and dinethylformamide is with K with the 3-hydroxy acetophenone
2CO
3(1.1g, 7.6mmol) and compound 8b (0.40g 1.5mmol) adds in the system, system 60 ℃ the reaction 4 hours, behind the system dilute with water, the water ethyl acetate extraction, the merging organic phase, use NaOH solution and the saturated common salt water washing of 2N successively, anhydrous Na
2SO
4Dry.After organic phase concentrated, (PE: EtOAc=4: 1) purifying obtained 0.41g white solid 9b, productive rate 74.0% to the resistates column chromatography.
1HNMR(400MHz，CDCl
3)：δ2.595(s，6H)，5.14(s，4H)，7.17-7.20(m，2H)，7.36-7.43(m，5H)，7.54-7.58(m，5H).
Step 3:1,3-pair-[3-(1,3-dioxy-4 butyric acid methyl esters)-Phenoxymethyl]-benzene (compound 10b)
In the single neck bottle of exsiccant 25mL, add CH
3ONa (343mg, 6.36mmol) and the 2mL dry toluene, cryosel is bathed cooling, slowly drip 9b (238mg, 0.636mmol) and MeOOCCOOtBu (407mg 2.54mmol) is dissolved in the solution of THF/DME (2.0mL/2.0mL), 0 ℃ is stirred after 0.5 hour down, under the intense agitation, reaction mixture is poured in the frozen water of HCl solution (1N) into the water dichloromethane extraction, merge organic phase, use the HCl solution of 1N successively, salt washing, anhydrous Na
2SO
4Dry.Organic phase concentrates back resistates column chromatography (CHCl
3/ CH
3OH=10: 1) purifying obtains 0.343g oily compound 10b, productive rate 98.7%.
1H?NMR(400MHz，CDCl
3)：δ7.61-7.58(m，4H)，7.56(s，1H)，7.45-7.39(m，5H)，7.24-7.21(m，2H)，7.06(s，2H)，5.16(s，4H)，3.95(s，6H).
Step 4:1,2-pair-[3-(1,3-dioxy-3-carboxyl)-Phenoxymethyl]-benzene (compound 2b)
With compound 1,2-is two-and (0.174g 0.32mmol) is dissolved in the mixed solvent (2.0mL: 2.0mL) of tetrahydrofuran (THF) and methyl alcohol to [3-(1,3-dioxy-3-carboxylate methyl ester)-Phenoxymethyl]-benzene 10b, NaOH solution with 3.2mL1N under the room temperature slowly drops in the system, stir after 1 hour, the reaction system extracted with diethyl ether, water uses the HCl adjust pH of 2N to 1-2, use ethyl acetate extraction then, merge organic phase, salt washing, anhydrous Na
2SO
4Drying.After organic phase concentrated, resistates obtained 0.122g yellow solid 2b, productive rate 73.5% with sherwood oil/methylene dichloride recrystallization.
1HNMR(400MHz，CDCl
3)：δ7.68-7.63(m，4H)，7.51-7.48(m，6H)，7.36-7.33(dd，2H)，7.09(S，2H)，5.23(s，4H).ESI-MS：517.1(M-H
+，100)
Embodiment 8:1,4-pair-[3-(1,3-dioxy-3-carboxyl)-Phenoxymethyl]-benzene 2c
Step 1:1,4-pair-brooethyl-benzene (compound 8c)
In an exsiccant list neck bottle, add NBS (20.1g, 112.36mmol), (5.56mL, 45.0mmol) and the 100mL tetracol phenixin, agitation condition adds benzoyl peroxide (18mg) down to p-Xylol.System refluxed 36 hours under vigorous stirring, during room temperature the sedimentation and filtration that generates in the reaction process was fallen, and filtrate concentrates the back column chromatography, and 100% sherwood oil is made eluent, obtains 6.12g white solid compound 8c, productive rate 51.0%.
1HNMR(400MHz，CDCl
3)：δ7.37(m，4H)；4.48(s，4H).
Step 2:1,4-pair-(3-acetyl Phenoxymethyl)-benzene (compound 9c)
Under nitrogen protection, (1.36g 10.0mmol) is dissolved in the anhydrous N of 15mL, and dinethylformamide is with K with the 3-hydroxy acetophenone
2CO
3(2.76g, 20.0mmol) and compound 8c (1.056g 4.0mmol) adds in the system, system was reacted 4 hours at 60 ℃, behind the system dilute with water, and the water ethyl acetate extraction, merge organic phase, use NaOH solution and the saturated common salt water washing of 2N successively, anhydrous Na
2SO
4Dry.After organic phase concentrated, (PE: EtOAc=3: 1) purifying obtained 0.54g white solid 9c, productive rate 36.1% to the resistates column chromatography.
1HNMR(400MHz，CDCl
3)：δ7.57-7.54(m，4H)；7.47(s，4H)；7.39-7.35(t，2H)，7.19-7.16(m，2H)；5.12(s，4H)，2.58(s，6H).EI-MS(M/Z，％)：239(100)，197(18.0)，104(58.0).
Step 3:1,4-pair-[3-(1,3-dioxy-4 butyric acid methyl esters)-Phenoxymethyl]-benzene (compound 10c)
In the single neck bottle of exsiccant 25mL, add CH
3ONa (410mg, 7.59mmol) and the 4mL dry toluene, cryosel is bathed cooling, slowly drip 9c (284mg, 0.76mmol) and MeOOCCOOtBu (486mg 3.03mmol) is dissolved in the solution of THF/DME (3.0mL/3.0mLL), 0 ℃ is stirred after 0.5 hour down, under the intense agitation, reaction mixture is poured in the frozen water of HCl solution (1N) into the water dichloromethane extraction, merge organic phase, use the HCl solution of 1N successively, salt washing, anhydrous Na
2SO
4Dry.Organic phase concentrates back resistates column chromatography (CHCl
3/ CH
3OH=10: 1) purifying obtains 0.414g oily compound 10c, productive rate 100%.
1HNMR(400MHz，CDCl
3)：δ7.67-7.62(m，4H)；7.51-7.47(m，6H)；7.36-7.34(m，2H)；7.08(s，2H)；5.23(s，4H)，3.85(s，6H).
Step 4:1,4-pair-[3-(1,3-dioxy-3-carboxyl)-Phenoxymethyl]-benzene (compound 2c)
With compound 1,4-is two-and (0.163g 0.298mmol) is dissolved in the mixed solvent (1.0mL: 1.0mL) of tetrahydrofuran (THF) and methyl alcohol to [3-(1,3-dioxy-3-carboxylate methyl ester)-Phenoxymethyl]-benzene 10c, NaOH solution with 3.0mL 1N under the room temperature slowly drops in the system, stir after 1 hour, the reaction system extracted with diethyl ether, water uses the HCl adjust pH of 2N to 1-2, use ethyl acetate extraction then, merge organic phase, salt washing, anhydrous Na
2SO
4Drying.After organic phase concentrated, resistates obtained 0.107g yellow solid 2c, productive rate 69.2%. with sherwood oil/methylene dichloride recrystallization
1HNMR(400MHz，CDCl
3)：δ7.66-7.61(m，3H)；7.50-7.46(m，5H)；7.34-7.31(m，3H)；7.08(s，2H)，5.21(s，4H).ESI-MS：517.1(M-H
+，100)
Embodiment 9:1-(1,1-two [3-(1,3-dioxy-3-carboxyl)-phenyl]) methyl-2-fluoro-benzene 2d
Step 1:(3-bromo-phenyl)-(2-fluoro-phenyl)-ketone (compound 11)
With (3-bromo-phenyl)-(2-fluoro-phenyl)-methyl alcohol (compound 3) (3.84g, 13.6mmol) be dissolved in 40mL acetone, under 0 ℃ of agitation condition, slowly drop to 10.21mL Jones oxidation agent in the system, 0 ℃ was reacted 25 minutes down, the 10mL Virahol is slowly dropped in the system, remove ice bath, room temperature condition stirred 10 minutes down, the pad diatomite filtration, concentrate back column chromatography (sherwood oil: ethyl acetate=8: 1), obtain 3.757g white solid 11, productive rate 98.6%.
1HNMR(300MHz，CDCl
3)：δ7.96-7.98(m，1H)；7.71-7.76(m，2H)；7.53-7.59(m，2H)；7.29-7.38(m，2H)；7.15-7.21(m，1H).EI-MS(M/Z，％)：281(M
++3，8.0)；280(M
++2，48.0)；279(M
++1，8.0)；278(M
+，48.0)；183(28.0)；
185(23.0)；123(100).IR(film)：1658，1608，1563，1480，1453，1297，734cm
-1.
Step 2: two-(3-bromo-phenyl)-(2-fluoro-phenyl)-methyl alcohol (compound 12)
Under nitrogen protection; n-Butyl Lithium hexane solution (the 6.5mL that in a dry reaction bottle, adds 1.6M; 10.4mmol) and the 35mL anhydrous tetrahydro furan, be chilled to-78 ℃, with 1; 3-dibromobenzene (2.28mL; 18.85mmol) slowly drop in the system ,-78 ℃～-50 ℃ were stirred after 3.5 hours, will be dissolved in the compound 11 (3.757g of 5mL anhydrous tetrahydro furan; 13.46mmol) slowly drop in the system, make system temperature be lower than-50 ℃.-78 ℃～-50 ℃ were stirred 0.5 hour, were warming up to room temperature naturally and continued reaction after 3 hours, the saturated NH of system
4The cancellation of Cl solution, the water extracted with diethyl ether merges organic layer, uses saturated NaHCO successively
3Solution is washed, saturated salt washing, anhydrous Na
2SO
4Dry.After concentrating, column chromatography (petrol ether/ethyl acetate=40: 1) purifying gets 5.58g white solid 12, productive rate 95%.
1HNMR(300MHz，CDCl
3)：δ7.50-7.67(m，4H)；7.25-7.34(m，4H)；6.96-7.08(m，3H)；6.67-6.68(m，1H).EI-MS(M/Z，％)：436(M
+，8.43)；281(39.40)；279(40.35)；185(17.84)；183(22.30)；123(100)；95(21.70)；57(15.23).IR(film)：υ
max3481，3419，1610，1580，1564，1550，1485，1452，1420，1227，760cm
-1.
Step 3:1-[1,1-two (3-bromo-phenyl)]-methyl-2-fluoro-benzene (compound 13)
With compound 12 (5.58g, 12.79mmol) and sodium iodide (7.67g, 51.16mmol) be dissolved in the 35mL acetonitrile, after the stirring and dissolving, and slow dropping dimethylchlorosilane in system (3.08mL, 25.59mmol), stirring at room 2 hours, system washes saturated NaHCO with water after diluting with ethyl acetate successively
3Solution, 10% Na
2S
2O
3Solution and salt washing, anhydrous Na
2SO
4Drying.After concentrating, column chromatography (100% sherwood oil) gets 5.37g white solid 13, productive rate 100%.
1HNMR(400MHz，CDCl
3)：δ7.39-7.36(m，2H)；7.35-7.13(m，5H)；7.12-7.01(m，4H)；6.91-6.86(m，1H)；5.74(s，1H)；EI-MS(M/Z，％)：418(M
+，30.0)；420(M
++2，55.7)；422(M
++4，29.8)；341(76.0)；339(72.4)；183(100)；165(55.0).
Step 4:1-[1,1-two (3-acetyl phenyl)]-methyl-2-fluoro-benzene (compound 14)
With compound 13 (1.049g, 2.497mmol) be dissolved in the 10mL anhydrous tetrahydro furan, be chilled to-78 ℃, n-Butyl Lithium hexane solution (3.9mL with 1.6M, 6.244mmol) slowly drop in the system ,-78 ℃ were stirred 45 minutes, with N-methyl-N-methoxyl group ethanamide (0.7mL, 6.244mmol) slowly drop in the system, make system temperature be lower than-50 ℃.-78 ℃～-50 ℃ were stirred 0.5 hour, were warming up to room temperature naturally and continued reaction after 2 hours, the saturated NH of reaction
4The cancellation of Cl solution, extracted with diethyl ether merges organic layer, uses saturated NaHCO successively
3Solution is washed, saturated salt washing, anhydrous Na
2SO
4Drying.After concentrating, column chromatography (petrol ether/ethyl acetate=10: 1) gets 0.522g white solid 14, productive rate 40.2%.
1HNMR(400MHz，CDCl
3)：δ7.86-7.83(dt，2H)；7.74-7.73(m，2H)；7.43-7.40(t，2H)；7.30-7.24(m，3H)；7.10-7.04(m，2H)；6.91-6.87(td，1H)；5.94(s，1H)；2.55(s，6H).
Step 5:1-(1,1-two [3-(1,3-dioxy-3-carboxyl)-phenyl]) methyl-2-fluoro-benzene 2d
In the single neck bottle of exsiccant 25mL, add CH
3ONa (146mg, 2.7mmol) and 2mL dry toluene, will be dissolved in the time of 0 ℃ 2.0mL/2.0mL (THF/DME) compound 14 (94mg, 0.27mmol) and MeOOCCOOtBu (173mg, 1.08mmol) slowly drop in the system, 0 ℃ is stirred after 0.5 hour, under the intense agitation, reaction mixture is poured in cold HCl (1N) solution, the water dichloromethane extraction, merge organic phase, wash anhydrous Na with HCl solution, the salt of 1N successively
2SO
4Drying.Organic phase obtains oily compound 15 after concentrating, and without purification, continues next step reaction.Compound 15 is dissolved in 2.0mL/2.0mL (THF/CH
3OH), (5.0mL 5.0mmol) slowly drops in the system, and stirring at room is after 1 hour with the NaOH solution of 1N during room temperature, system extracted with diethyl ether, water use the HCl solution adjust pH of 2N to 1-2, use ethyl acetate extraction then, merge organic phase, salt washing, anhydrous Na
2SO
4Drying.After organic phase concentrated, resistates obtained yellow compound 2d (86mg, two step yields 65%) with sherwood oil/methylene dichloride recrystallization.
1HNMR(400MHz，CDCl
3)：δ7.92-7.80(m，4H)；7.49-7.45(m，3H)；7.35-7.35(m，5H)；7.12-6091(m，3H)；7.00(s，1H)；6.09(s，1H).
ESI-MS：489.1(M-H
+，100).
Claims (8)
1, the beta-diketon acid dimer compound that has following structure
Wherein, X is N, O, S heteroatoms;
R is C
2-C
6Alkyl, C
2-C
6Substituted aryl;
R
1Be C
2-C
6Alkyl, C
2-C
6Substituted aryl;
2, beta-diketon acid dimer compound according to claim 1 is characterized in that when structure during as the beta-diketon acid dimer compound of (1) formula, wherein
X is N, O, S heteroatoms;
R is C
2-C
6Alkyl, C
2-C
6Substituted aryl;
R
1Be C
2-C
6Alkyl, C
2-C
6Substituted aryl;
3, beta-diketon acid dimer compound according to claim 1 is characterized in that when structure during as the beta-diketon acid dimer compound of (2) formula, wherein
X is N, O, S heteroatoms;
R is C
2-C
6Alkyl, C
2-C
6Substituted aryl;
R
1Be C
2-C
6Alkyl, C
2-C
6Substituted aryl;
4, beta-diketon acid dimer compounds process for production thereof according to claim 1, it is characterized in that (1) formula by
A, corresponding aryl methyl ketone and dimethyl oxalate or oxalic acid tert-butyl ester methyl esters react under the alkali condition, and condenses caustic liquor again solves 4-aryl-4 oxygen-2-hydroxyl-2 butenoic acid;
B, with the diamines of the butenoic acid of above-mentioned gained and different structure in the presence of coupling reagent, coupling becomes to have the different carbon chain lengths or the difform two ketone acid diamide of symmetrical structure.
5, beta-diketon acid dimer compounds process for production thereof according to claim 1, it is characterized in that (2) formula by
To be starting raw material generate dibromomethylbenzene through N-bromo-succinimide bromination for a, dimethylbenzene, dibromomethylbenzene and 3-hydroxy acetophenone under alkaline condition, react two phenyl ethyl ketones of benzyloxy connection;
B, with two phenyl ethyl ketones of above-mentioned gained after oxalylization, hydrolysis gets two accordingly aryl diketone acid dimers again.
6, beta-diketon acid dimer compounds process for production thereof according to claim 1, it is characterized in that (2) formula by
A, (3-bromo-phenyl)-(substituted-phenyl)-methyl alcohol are oxidized to corresponding ketone through Jones reagent;
B, corresponding ketone and substituted-phenyl lithiumbromide react the trimethyl carbinol of triaryl replacement;
C, the above-mentioned and trimethyl carbinol through dichlorodimethylsilane reduce two-(3-bromophenyl)-arylmethane accordingly;
D, corresponding diaryl ketone-aryl-methane carry out oxalylization react reactant separate with caustic liquor that to be able to the methane that aryl replaces be two aryl two ketone dimers of connector element.
7, beta-diketon acid dimer compounds process for production thereof according to claim 4 is characterized in that coupling reagent is I-hydroxybenzotriazole (HOBT), 1-[3-(dimethylamino) propyl group]-3-ethyl carbodiimide (EDCI).
8, the purposes of beta-diketon acid dimer compound as claimed in claim 1 is characterized in that it uses in the prevent and treat AIDS-treating medicine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102234231A (en) * | 2010-04-26 | 2011-11-09 | 中国科学院上海药物研究所 | 1-substituted-2-substituted-4- aryl substituted-butyl-2-alkene 1, 4-diketone compound, its preparation method and application |
| CN102406634A (en) * | 2010-09-21 | 2012-04-11 | 中国医学科学院医药生物技术研究所 | Human immunodeficiency virus (HIV)-1 integrase inhibitor |
| CN111253223A (en) * | 2020-03-20 | 2020-06-09 | 重庆医科大学 | Triarylmethane derivatives with large steric hindrance and synthesis method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR0111570A (en) * | 2000-06-16 | 2003-09-09 | Bristol Myers Squibb Co | Hiv integrase inhibitors |
-
2003
- 2003-05-06 CN CN 03116758 patent/CN1548413B/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102234231A (en) * | 2010-04-26 | 2011-11-09 | 中国科学院上海药物研究所 | 1-substituted-2-substituted-4- aryl substituted-butyl-2-alkene 1, 4-diketone compound, its preparation method and application |
| CN102234231B (en) * | 2010-04-26 | 2015-01-07 | 中国科学院上海药物研究所 | 1-substituted-2-substituted-4- aryl substituted-butyl-2-alkene 1, 4-diketone compound, its preparation method and application |
| CN102406634A (en) * | 2010-09-21 | 2012-04-11 | 中国医学科学院医药生物技术研究所 | Human immunodeficiency virus (HIV)-1 integrase inhibitor |
| CN102406634B (en) * | 2010-09-21 | 2015-09-30 | 中国医学科学院医药生物技术研究所 | Hiv-1 integrase inhibitor |
| CN111253223A (en) * | 2020-03-20 | 2020-06-09 | 重庆医科大学 | Triarylmethane derivatives with large steric hindrance and synthesis method thereof |
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