CN103588731B - Salicylamide derivatives and preparation method - Google Patents
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Abstract
The invention discloses preparation with the method for following formula 1 compound.Comprise step: 2,5-dimethoxyaniline is dissolved in organic solvent and obtains N-(2-alkanoyloxy benzoyl)-2,5-dimethoxyanilines with the acetic acid ethyl reaction of O-alkyloyl bigcatkin willow acyl chlorides; Then iodobenzene diacetate exist under with R
3oH is obtained by reacting 3-(O-alkyloyl salicylyl is amino)-4,4-dialkoxy-2,5-cyclohexadienones; Then at organic solvent (such as tetrahydrofuran (THF), methyl alcohol, dimethyl formamide, particularly such as dimethyl formamide) in, 5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene is obtained by reacting under aqueous hydrogen peroxide solution and mineral alkali exist; Then under boron trifluoride ethyl ether complex exists, generation 5,6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone is reacted; 5, the 6-epoxy-4-hydroxyls-3-salicylyl amino-2-cyclonene (DHM2EQ) that formula (1) represents are obtained finally by reduction.The invention still further relates to the method for preparation 5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene.
Description
Technical field
The present invention relates to salicylamide derivatives and pharmacy acceptable salt thereof shown in formula 1, with and preparation method thereof.This salicylamide derivatives can supply Therapeutic cancer, inflammation, autoimmune disease, diabetes and diabetic complication, infection, cardiovascular disorder and defect reperfusion injury.
Background technology
Nuclear factor kappa B (NF-κ B, Nuclear factor-kappa B) the various disease of activation participation, comprise cancer, diabetes, cardiovascular disorder, autoimmune disease, virus replication, septic shock, neurodegenerative disease, ataxia telangiectasia (AT), sacroiliitis, asthma, inflammatory bowel and other inflammatory conditions.Such as, gram negative bacterium lipopolysaccharides (LPS) activates NF-κ B can produce septic shock, because transcribing of the many cytokines of NF-κ B excessive activation and modifying enzyme, their expression extends and adversely can affect critical organ, the function of such as heart and liver (Arcaroli etc., 2006; Niu etc., 2008).
Similarly, autoimmune disease, such as systemic lupus erythematosus also may relate to the activation of NF-κ B.NF-κ B transcription factor is most important for suitable dendritic cell maturation, its lose be systemic lupus erythematosus mark (Kalergis etc., 2008; Kurylowicz and Nauman, 2008), in addition, in chronic alzheimer's disease, amyloid beta peptide causes the generation of reactivity keto intermediate, by NF-kB site indirect activation genetic expression (Giri etc., 2005).
The destructiveness of bone corrodes or osteolysis is inflammatory conditions, the such as major complications of rheumatoid arthritis (RA), periodontopathy and periprosthetic osteolysis.RA is the autoimmune disease affecting about 1.0% U.S. adults, the ratio of women and the male sex be 2.5 to l (Lawrence etc., 1998).Its mark is the progressive joint destruction causing main morbid state.Periodontopathy is very general, the impact whole world up to 90% population.Well-known its be grownup's loss of tooth major cause (Pihlstrom etc., 2005).Although very general, the mechanism of periodontal bone erosion is still unclear, although it seems it is that the reaction of host to the pathogenic micro-organism existed in oral cavity triggers this process.Chronic bone resorption around exotic implants device causes periprosthetic osteolysis, until lose fixed action (Harris, 1995), it is believed that it is caused by the innate immune response for wear debris particle, acquired immune system affects not quite (Goldring etc., 1986).
Although these illnesss are caused by different reason, be in progress by all means, the important common factor in the pathophysiological processes of these illnesss is that the pro-inflammatory cytokine that the composing type activation of NF-kB pathway in Inflamed tissue drives excessively produces.With the bone pathological condition of general, hormone regulating and controlling, such as osteoporosis is different, and the bone erosion found in these illnesss is positioned the tissue of inflammation mostly.Find in these diseases many, these Inflamed tissues also produce pro-inflammatory cytokine, that is, TNF-α, IL-1 and IL-6, these pro-inflammatory cytokines and then participate in differentiation of osteoclast intracellular signaling and bone-resorbing activity.Therefore, inflammatory osteolysis is that the osteoclast that in Inflamed tissue, NF-κ B drives pro-inflammatory cytokine to promote is raised and activated caused by enhancing.
Inflammatory bowel (IBD) comprises and relates to GI many chronic recurrent inflammatory diseasess.Two kinds of modal forms of IBD are Crohn's disease and ulcerative colitis, the two difference be unique histopathological characteristics and immunne response (Atreya etc., 2008; Bouma and Strober, 2003).Current treatment offer limited effectiveness, also may have side effect to make patient and doctor thirst for controlling the new therapy of the chronic recurrent inflammation character of these diseases.
Although cause the definite cause of disease of Crohn's disease and ulcerative colitis not yet to be known, be commonly referred to be mucomembranous immune system to the improper of Bacteria fecal flora and the activation just carried out cause (Tilg etc., 2008).Therefore, resident macrophage, dendritic cell and T cell activation start Major Secretory NF-κ B-dependency chemokine and cytokine.The excessive generation that NF-κ B mediates crucial pro-inflammatory mediator cause the startup of people IBD and colitis animal model and progress (Neurath etc., 1998; Wirtz and Neurath, 2007).Specifically, the scavenger cell of IBD patient show high-caliber NF-κ B DNA binding activity and generation with interleukin (IL) l, IL6 and TNF (Tumor Necrosis Factor) alpha increase (Neurath etc., 1998).In addition, NF-κ B plays a key effect in activated T helper l (Thl) and t helper cell 2 (Th2) cytokine, and the two is that disease required (Barnes, 1997) is processed in promotion and maintenance.Due to the central role that NF-κ B plays in IBD, people pay the therapy making great efforts in a large number to attempt to develop this approach of target.
NF-κ B be presented at constitutive expression in the many cancer derived cell systems from mammary gland, ovary, colon, pancreas, Tiroidina, prostate gland, lung, neck, bladder and dermatoma (Calzado etc., 2007).B-cell lymphoma, Hodgkin's disease, T-cell lymphoma, adult T cell leukemia, also observe in acute lymphoblastic leukemia, multiple myeloma, lymphocytic leukemia and acute myelogenous leukemia.NF-κ B is the critical mediator of normal inflammation as the part that defense is replied; But chronic inflammatory diseases can cause cancer, diabetes and many above-mentioned Other diseases.Oneself identifies several pro-inflammation genes product and occurs at oncogenic process, blood vessel, attack and mediate keying action in Nasopharyngeal neoplasms.These gene products have the member of TNF-α and superfamily thereof, IL-1 α, IL-1D, IL-6, IL-8, IL-18, chemokine, MMP-9, VEGF, COX-2 and 5-LOX.The expression of all these genes regulates and controls primarily of transcription factor NF-KB, its in most of tumour, have constitutive activity and by carcinogens (cigarette of such as cigarette), tumor promoter, oncovirus albumen (HIV-tat, KHSV, EBV-LMP1, HTLVl-tax, HPV, HCV and HBV), chemotherapeutics and gamma-rays induce (Aggarwal etc., 2006).These observationss hint suppresses the anti-inflammatory agent of NF-κ B should be used for prevention and therapy cancer.
Influenza virus protein hemagglutinin also activates NF-κ B, this activation can cause the virus induction of cytokine and some influenza related symptoms (Flory etc., 2000; Pahl and BaeueR
1e, 1995).
The lipid oxide activation NF-κ B of the low-density lipoprotein that atherosclerosis is correlated with, then activates other gene, such as inflammatory cytokine (Liao etc., 1994).In addition, atherosclerosis susceptible mouse shows NF-kB activation when feeding atherogenicity diet, because they to lipid peroxidation product accumulation, Atheromatosis disfigurement that proinflammatory gene induction is relevant with NF-κ B transcription factor activator becomes sensitivity (Liao etc., 1994).Another major reason atherosclerotic is zymoplasm, its by NF-kB activation and stimulated vascular smooth muscle cell propagation (Maruyama etc., 1997).Clipped form (the I κ B α) display of I κ B aporepressor is the reason of ionizing rays hypersensitivity, composing type horizontal NF-κ B-activate ataxia telangiectasia (AT) cell in its to DNA synthesis regulation defectiveness (Jung etc., 1995).This sudden change in the I κ B α of AT cell shows the aporepressor deactivation causing NF-kB pathway composing type to activate.In view of all these sorcerers, abnormal activation or the expression of NF-κ B are obviously relevant to various pathological conditions.
In person monocytic cell, the infection of HIV-1 is closely connected with NF-kB pathway with life cycle.Virus infection causes NF-kB activation, thus produces the significant T cell overstimulation of AIDS and finally exhaust that (summary is shown in (Argyropoulos and Mouzaki, 2006).Such as, NF-κ B regulates the CCR as HIV-1 key receptor
5expression (Liu etc., 1998).The deletion analysis of CCR-5 promotor prove the forfeiture in 3 '-far-end NF-κ B/AP-l site make to transcribe reduce >95% (Liu etc., 1998).The constitutive expression of these research promptings NF-κ B causes CCR-5 acceptor information sharply to reduce.Due to CCR on target T-cell surface
5expression level affect HIV-1 enter dynamics (Ketas etc., 2007; Platt etc., 1998; Reeves etc., 2002), lower CCR
5a large amount of cells infected group diffusion producing virus base can be retrained.Also it was reported that NF-κ B affects CXCR
4express (Helbig etc., 2003), X4-tropism's isolate that prompting NF-kB inhibitor may occur during same effective anti-infective later stage.Before the DNA-integrated-the transcribing and need NF-κ B (Baba, 2006 of virus; Iordanskiy etc., 2002; Mukerjee etc., 2006; Palmieri etc., 2004; Rizzi etc., 2004; Sui etc., 2006; Williams etc., 2007).In fact, lack the cell mass that NF-kB activation causes having latent virus and produce, this be the virus eliminating infected patient major obstacle (Williams etc., 2006).
NF-κ B promotes react to inflammatory stimulus thing more than 150 kinds of target genes and express.These genes comprise il-1 ,-2 ,-6 and Tumor Necrosis Factor Receptors (TNF-R) (these receptor-mediated apoptosis also play the effect of inflammation modulators) and encoding immune acceptor, inadequate intercellular adhesion molecule and enzyme, such as cyclo-oxygenase-II and the gene (Karin, 2006 that induce type-nitrogen oxide ribozyme (iNOS); Tergaonkar, 2006).It is also at virus infection, such as, plays a crucial role in the progress of HCV and HIV-1 relative disease.
The member of NF-κ B family comprises RelA/p65, RelB, c-Rel, p50/p105 (NF-κ Bl) and p52/pl00 (NF-κ B2) (Hayden and Ghosh, 2004; Hayden etc., 2006a; Hayden etc., 2006b).Rel family member is worked as homodimer or heterodimer, to be positioned at NF-κ B-regulatory gene promoter structure territory cis binding member specificity difference (Bosisio etc., 2006; Natoli etc., 2005; Saccani etc., 2004).Classical NF-κ B-is made up of RelAlp65 and p50 heterodimer, is that NF-κ B studies to obtain the most clearly form (Burstein and Duckett, 2003; Hayden and Ghosh, 2004) reference and wherein).Before cytositimulation, classical NF-κ B resides in tenuigenin as the non-activity mixture be combined with I κ B α arrestin.The inductor of NF-κ B, such as bacteria lipopolysaccharide, inflammatory cytokine or HIV-1Vpr albumen discharge active NF-κ B (Greten and Karin, 2004 by I κ B-kinase complex (IKK) of the part phosphorylation I κ B α that lives from cytoplasmic complex; Hacker and Karin, 2006; Israel, 2000; Karin, 1999; Scheidereit, 2006).The phosphoric acid of I κ B is ubiquitination subsequently and provides mark by 26S proteasomal degradation.Free NF-κ B dimer displacement enters core, transcribes at their target gene of core moderate stimulation.
The molecular designing of racemize dehydroxylation methyl epoxy quinomycin (DHMEQ) is according to from the microbiotic epoxy Quinomycin C intending being separated without mycolic acids bacterium (Amycolatopsis) .2002 such as () Chaicharoenpong.DHMEQ is the racemoid that employing five step is synthesized from 2,5-dimethoxyaniline.Chiral column enantiomer separation is utilized to produce (+) and (-) enantiomorph.The display of (-)-enantiomorph suppresses NF-κ B to be better than (+)-enantiomorph .2004 such as () Umezawa.DHMEQ suppresses NF-κ B to be shifted into core .2002 such as () Ariga through being accredited as specificity.Specifically, it is with specific cysteine residues .2008 such as () Yammamoto in the stoichiometric ratio covalent modification p65 of 1:1 and other Rel homologous protein.As NF-kB inhibitor, extensive testing DHMEQ in the animal model of various disease, proves to comprise broad spectrum effects .2006 such as () Watanabe of being in harmony and treating solid tumor, hematologic malignancies, sacroiliitis, intestinal ischemia and atherosclerosis.Therefore, DHMEQ can be used as the treatment (.2003 such as Takeuchi) of cancer and inflammation.CN1368954A (Chinese Patent Application No. 00811487.0) discloses DHMEQ (i.e. DHM2EQ wherein, both DHM2EQ and DHMEQ have identical implication in this article, be used interchangeably, also can be described as formula 1 compound or formula I in the present invention) synthetic method, wherein in step 3, in solvents tetrahydrofurane, under the existence of hydrogen peroxide and sodium hydroxide, 3-(O-acetylsalicyclic amido)-4, 4-dimethoxy-2, 5-cyclohexadiene reactive ketone generates 5, 6-epoxy-4, 4-dimethoxy-3-salicylyl amino-2-cyclonene, reactant needs by numerous and diverse treatment process and products therefrom inferior quality.For its subsequent technique adds obstacle.
Therefore, those skilled in the art still expect to have a kind of with the novel method with good process feature to prepare DHMEQ.
Summary of the invention
The object of the invention is to provide a kind of novel method with good process feature to prepare DHMEQ (that is: 5,6-epoxy-4-hydroxyl-3-salicylyl amino-2-cyclonenes).The present inventor finds to use specific processing condition to obtain very useful technology characteristics in the process of formation 5,6-epoxy hexane ketone, and such as yield is high, product qualities is high and/or be easy to aftertreatment etc.The present invention is based on this find and must complete.
For this reason, a first aspect of the present invention provides preparation with the method for following formula 1 compound:
The method comprises the following steps:
Step a: make 2,5-dimethoxyaniline be dissolved in organic solvent (such as pyridine), at the temperature of-78 ~ 50 DEG C (such as under ice-cooling), adds the O-alkyloyl bigcatkin willow acyl chlorides with following formula (7) wherein
ethyl acetate solution, make reaction carry out under stirring; Then; add water and reaction is stopped; add ethyl acetate again; after reaction solution uses hydrochloric acid, water, sodium bicarbonate aqueous solution and water washing successively; drying, concentrating under reduced pressure, then vacuum-drying; obtain N-(2-alkanoyloxy benzoyl)-2, the 5-dimethoxyanilines represented with following formula (2):
Wherein, R
1represent hydrogen atom or C
2 ~ 4alkyloyl, such as ethanoyl;
Step b: make the compound of the formula of above acquisition (2) be dissolved in solvent such as R
3in the solvent that OH represents, at the temperature of-20 ~ 50 DEG C (such as under ice-cooling), add iodobenzene diacetate wherein, stirred at ambient temperature makes reaction carry out; Then concentrating under reduced pressure; add ethyl acetate wherein; after reaction solution uses sodium bicarbonate aqueous solution and brine It respectively; concentrating under reduced pressure solvent; residue is refined; obtain 3-(O-alkyloyl salicylyl is amino)-4,4-dialkoxy-2, the 5-cyclohexadienones represented with following formula (3):
Wherein R
3represent C
1 ~ 4alkyl, such as methyl;
Step c: make formula (3) compound be dissolved in organic solvent (such as tetrahydrofuran (THF), methyl alcohol, dimethyl formamide, particularly such as dimethyl formamide); At the temperature of-20 ~ 50 DEG C (such as under ice-cooling), add aqueous hydrogen peroxide solution and mineral alkali (such as sodium hydroxide, sodium carbonate, sodium bicarbonate, particularly such as sodium carbonate) wherein, stir and reaction is carried out; Then in reaction solution, add ethyl acetate, reaction solution is dry after using hydrochloric acid soln, sodium thiosulfate solution and brine It successively, then carries out vacuum-drying; Dry gained material is made to be dissolved in the mixed solvent of acetone-petroleum ether (the two volume ratio is 6 ~ 10:1), add isopyknic saturated aqueous common salt extraction (re-extract 2 ~ 3 times), abandon water layer, organic layer drying (such as using saltcake drying), concentrating under reduced pressure, vacuum-drying, obtains represent with following formula (4) 5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene:
Steps d: make formula (4) compound be dissolved in solvent such as methylene dichloride; Under ice-cooling, add mineral acid or organic acid (such as boron trifluoride ethyl ether complex etc.) wherein, under stirring, make reaction carry out; Then in reaction solution, add organic solvent (such as ethyl acetate), wash with water, after organic layer is concentrated, residue obtained methanol wash, obtain 5, the 6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone represented with following formula (5):
Step e: make formula (5) compound be suspended in solvent (such as methyl alcohol, ethanol, THF); At the temperature of-78 ~ 50 DEG C (such as under ice-cooling), add reductive agent (such as sodium borohydride) wherein and reaction is carried out; After completion of the reaction, solvent (such as ethyl acetate, methylene dichloride etc.) is added in reaction solution, reaction solution uses hydrochloric acid and water washing successively, drying and concentrating under reduced pressure are carried out to solvent layer, enriched material is made to be suspended in agitator treating after methyl alcohol, drying, obtains 5, the 6-epoxy-4-hydroxyls-3-salicylyl amino-2-cyclonene (DHM2EQ) represented with following formula (1)
Method according to a first aspect of the invention, it comprises the following steps:
The preparation of step a:N-(2-alkanoyloxy benzoyl)-2,5-dimethoxyanilines
Make 2,5-dimethoxyaniline is dissolved in organic solvent (such as pyridine), at the temperature of-78 ~ 50 DEG C (such as under ice-cooling), the ethyl acetate solution of the O-alkyloyl bigcatkin willow acyl chlorides of adding type (7), makes reaction carry out under stirring wherein; Then, add water and reaction is stopped, add ethyl acetate again, after reaction solution uses hydrochloric acid, water, sodium bicarbonate aqueous solution and water washing successively, drying, concentrating under reduced pressure, then vacuum-drying, N-(2-alkanoyloxy benzoyl)-2, the 5-dimethoxyanilines that acquisition formula (2) represents; Wherein R
1represent hydrogen atom or C
2 ~ 4alkyloyl, such as ethanoyl;
The preparation of step b:3-(O-alkyloyl salicylyl is amino)-4,4-dialkoxy-2,5-cyclohexadienones
The compound of the formula of above acquisition (2) is made to be dissolved in solvent such as R
3in the solvent that OH represents, at the temperature of-20 ~ 50 DEG C (such as under ice-cooling), add iodobenzene diacetate wherein, stirred at ambient temperature makes reaction carry out; Then concentrating under reduced pressure, add ethyl acetate wherein, after reaction solution uses sodium bicarbonate aqueous solution and brine It respectively, concentrating under reduced pressure solvent, residue is refined, 3-(O-alkyloyl salicylyl is amino)-4,4-dialkoxy-2, the 5-cyclohexadienones that acquisition formula (3) represents; Wherein R
3represent C
1 ~ 4alkyl, such as methyl;
The preparation of step c:5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene
The 3-(O-alkyloyl salicylyl is amino)-4 that formula (3) is represented, 4-dialkoxy-2,5-cyclohexadienone is dissolved in organic solvent (such as tetrahydrofuran (THF), methyl alcohol, dimethyl formamide, particularly such as dimethyl formamide); At the temperature of-20 ~ 50 DEG C (such as under ice-cooling), add aqueous hydrogen peroxide solution and mineral alkali (such as sodium hydroxide, sodium carbonate, sodium bicarbonate, particularly such as sodium carbonate) wherein, stir and reaction is carried out; Then in reaction solution, add ethyl acetate, reaction solution is dry after using hydrochloric acid soln, sodium thiosulfate solution and brine It successively, then carries out vacuum-drying; Dry gained material is made to be dissolved in the mixed solvent of acetone-petroleum ether (the two volume ratio is 6 ~ 10:1), add isopyknic saturated aqueous common salt extraction (re-extract 2 ~ 3 times), abandon water layer, organic layer drying (such as using saltcake drying), concentrating under reduced pressure, vacuum-drying, obtain formula (4) represent 5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene.
Steps d: the preparation of 5,6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone
5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonenes of formula (4) are made to be dissolved in solvent such as methylene dichloride; Under ice-cooling, add mineral acid or organic acid (such as boron trifluoride ethyl ether complex etc.) wherein, under stirring, make reaction carry out; Then in reaction solution, add organic solvent (such as ethyl acetate), wash with water, after organic layer is concentrated, residue obtained methanol wash, obtains 5,6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone that formula (5) represents;
The preparation of step e:5,6-epoxy-4-hydroxyl-3-salicylyl amino-2-cyclonene (DHM2EQ)
5,6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone that formula (5) is represented are suspended in solvent (such as methyl alcohol, ethanol, THF); At the temperature of-78 ~ 50 DEG C (such as under ice-cooling), add reductive agent (such as sodium borohydride) wherein and reaction is carried out; After completion of the reaction, in reaction solution, add solvent (such as ethyl acetate, methylene dichloride etc.), reaction solution uses hydrochloric acid and water washing successively.Then drying and concentrating under reduced pressure are carried out to solvent layer, make enriched material be suspended in agitator treating after methyl alcohol, dry, obtain 5, the 6-epoxy-4-hydroxyls-3-salicylyl amino-2-cyclonene (DHM2EQ) that formula (1) represents.
Method according to a first aspect of the invention, it comprises the following steps:
The preparation of step a:N-(2-alkanoyloxy benzoyl)-2,5-dimethoxyanilines
Make 2,5-dimethoxyaniline is dissolved in organic solvent (such as pyridine), at the temperature of-78 ~ 50 DEG C (such as under ice-cooling), the ethyl acetate solution of the O-alkyloyl bigcatkin willow acyl chlorides of adding type (7), makes reaction carry out under stirring wherein; Then; add water and reaction is stopped; add ethyl acetate again; after reaction solution uses hydrochloric acid, water, sodium bicarbonate aqueous solution and water washing successively; drying, concentrating under reduced pressure, then vacuum-drying; N-(2-alkanoyloxy benzoyl)-2, the 5-dimethoxyanilines that acquisition formula (2) represents.Do not carry out refining to this compound and directly use it for following steps;
Wherein R
1represent hydrogen atom or C
2 ~ 4alkyloyl, such as ethanoyl;
The preparation of step b:3-(O-alkyloyl salicylyl is amino)-4,4-dialkoxy-2,5-cyclohexadienones
The compound of the formula of above acquisition (2) is made to be dissolved in solvent such as R
3in the solvent that OH represents, at the temperature of-20 ~ 50 DEG C (such as under ice-cooling), add iodobenzene diacetate wherein, stirred at ambient temperature makes reaction carry out; Then concentrating under reduced pressure, add ethyl acetate wherein, after reaction solution uses sodium bicarbonate aqueous solution and brine It respectively, concentrating under reduced pressure solvent, by column chromatography, residue is refined, 3-(O-alkyloyl salicylyl is amino)-4,4-dialkoxy-2, the 5-cyclohexadienones that acquisition formula (3) represents;
Wherein R
3represent C
1 ~ 4alkyl, such as methyl;
The preparation of step c:5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene
The 3-(O-alkyloyl salicylyl is amino)-4 that formula (3) is represented, 4-dialkoxy-2,5-cyclohexadienone is dissolved in organic solvent (such as tetrahydrofuran (THF), methyl alcohol, dimethyl formamide, particularly such as dimethyl formamide); At the temperature of-20 ~ 50 DEG C (such as under ice-cooling), add aqueous hydrogen peroxide solution and mineral alkali (such as sodium hydroxide, sodium carbonate, sodium bicarbonate, particularly such as sodium carbonate) wherein, stir and reaction is carried out; Then in reaction solution, add ethyl acetate, reaction solution is dry after using hydrochloric acid soln, sodium thiosulfate solution and brine It successively, then carries out vacuum-drying; Dry gained material is made to be dissolved in the mixed solvent of acetone-petroleum ether (the two volume ratio is 6 ~ 10:1), add isopyknic saturated aqueous common salt extraction (3 times), abandon water layer, organic layer drying (such as using saltcake), concentrating under reduced pressure, vacuum-drying, obtain formula (4) represent 5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene;
Steps d: the preparation of 5,6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone
5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonenes of formula (4) are made to be dissolved in solvent such as methylene dichloride; Under ice-cooling, add mineral acid or organic acid (such as boron trifluoride ethyl ether complex etc.) wherein, under stirring, make reaction carry out; Then in reaction solution, add solvent (such as ethyl acetate), wash with water, after ethyl acetate layer is concentrated, residue obtained methanol wash, obtains 5,6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone that formula (5) represents;
The preparation of step e:5,6-epoxy-4-hydroxyl-3-salicylyl amino-2-cyclonene (DHM2EQ)
5,6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone that formula (5) is represented are suspended in solvent (such as methyl alcohol, ethanol, THF).At the temperature of-78 ~ 50 DEG C (such as under ice-cooling), add reductive agent (such as sodium borohydride) wherein and reaction is carried out; After completion of the reaction, in reaction solution, add solvent (such as ethyl acetate, methylene dichloride etc.), reaction solution uses hydrochloric acid and water washing successively.Then drying and concentrating under reduced pressure are carried out to solvent layer, make enriched material be suspended in agitator treating after methyl alcohol, dry, obtain 5, the 6-epoxy-4-hydroxyls-3-salicylyl amino-2-cyclonene (DHM2EQ) that formula (1) represents.
A second aspect of the present invention provides preparation with the method for following formula 1 compound:
The method comprises the following steps:
Step c: make formula (3) compound
be dissolved in organic solvent (such as tetrahydrofuran (THF), methyl alcohol, dimethyl formamide, particularly such as dimethyl formamide); At the temperature of-20 ~ 50 DEG C (such as under ice-cooling), add aqueous hydrogen peroxide solution and mineral alkali (such as sodium hydroxide, sodium carbonate, sodium bicarbonate, particularly such as sodium carbonate) wherein, stir and reaction is carried out; Then in reaction solution, add ethyl acetate, reaction solution is dry after using hydrochloric acid soln, sodium thiosulfate solution and brine It successively, then carries out vacuum-drying; Dry gained material is made to be dissolved in the mixed solvent of acetone-petroleum ether (the two volume ratio is 6 ~ 10:1), add isopyknic saturated aqueous common salt extraction (re-extract 2 ~ 3 times), abandon water layer, organic layer drying (such as using saltcake drying), concentrating under reduced pressure, vacuum-drying, obtains represent with following formula (4) 5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene:
Wherein, R
1represent hydrogen atom or C
2 ~ 4alkyloyl, such as ethanoyl; R
3represent C
1 ~ 4alkyl, such as methyl;
Steps d: make formula (4) compound be dissolved in solvent such as methylene dichloride; Under ice-cooling, add mineral acid or organic acid (such as boron trifluoride ethyl ether complex etc.) wherein, under stirring, make reaction carry out; Then in reaction solution, add organic solvent (such as ethyl acetate), wash with water, after organic layer is concentrated, residue obtained methanol wash, obtain 5, the 6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone represented with following formula (5):
Step e: make formula (5) compound be suspended in solvent (such as methyl alcohol, ethanol, THF); At the temperature of-78 ~ 50 DEG C (such as under ice-cooling), add reductive agent (such as sodium borohydride) wherein and reaction is carried out; After completion of the reaction, solvent (such as ethyl acetate, methylene dichloride etc.) is added in reaction solution, reaction solution uses hydrochloric acid and water washing successively, drying and concentrating under reduced pressure are carried out to solvent layer, enriched material is made to be suspended in agitator treating after methyl alcohol, drying, obtains 5, the 6-epoxy-4-hydroxyls-3-salicylyl amino-2-cyclonene (DHM2EQ) represented with following formula (1)
Method according to a second aspect of the invention, it comprises the following steps:
The preparation of step c:5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene
Wherein, R
1represent hydrogen atom or C
2 ~ 4alkyloyl, such as ethanoyl; R
3represent C
1 ~ 4alkyl, such as methyl;
The 3-(O-alkyloyl salicylyl is amino)-4 that formula (3) is represented, 4-dialkoxy-2,5-cyclohexadienone is dissolved in organic solvent (such as tetrahydrofuran (THF), methyl alcohol, dimethyl formamide, particularly such as dimethyl formamide); At the temperature of-20 ~ 50 DEG C (such as under ice-cooling), add aqueous hydrogen peroxide solution and mineral alkali (such as sodium hydroxide, sodium carbonate, sodium bicarbonate, particularly such as sodium carbonate) wherein, stir and reaction is carried out; Then in reaction solution, add ethyl acetate, reaction solution is dry after using hydrochloric acid soln, sodium thiosulfate solution and brine It successively, then carries out vacuum-drying; Dry gained material is made to be dissolved in the mixed solvent of acetone-petroleum ether (the two volume ratio is 6 ~ 10:1), add isopyknic saturated aqueous common salt extraction (re-extract 2 ~ 3 times), abandon water layer, organic layer drying (such as using saltcake drying), concentrating under reduced pressure, vacuum-drying, obtain formula (4) represent 5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene;
Steps d: the preparation of 5,6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone
5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonenes of formula (4) are made to be dissolved in solvent such as methylene dichloride; Under ice-cooling, add mineral acid or organic acid (such as boron trifluoride ethyl ether complex etc.) wherein, under stirring, make reaction carry out; Then in reaction solution, add organic solvent (such as ethyl acetate), wash with water, after organic layer is concentrated, residue obtained methanol wash, obtains 5,6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone that formula (5) represents;
The preparation of step e:5,6-epoxy-4-hydroxyl-3-salicylyl amino-2-cyclonene (DHM2EQ)
5,6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone that formula (5) is represented are suspended in solvent (such as methyl alcohol, ethanol, THF); At the temperature of-78 ~ 50 DEG C (such as under ice-cooling), add reductive agent (such as sodium borohydride) wherein and reaction is carried out; After completion of the reaction, in reaction solution, add solvent (such as ethyl acetate, methylene dichloride etc.), reaction solution uses hydrochloric acid and water washing successively.Then drying and concentrating under reduced pressure are carried out to solvent layer, make enriched material be suspended in agitator treating after methyl alcohol, dry, obtain 5, the 6-epoxy-4-hydroxyls-3-salicylyl amino-2-cyclonene (DHM2EQ) that formula (1) represents.
Method according to a second aspect of the invention, it comprises the following steps:
The preparation of step c:5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene
Wherein, R
1represent hydrogen atom or C
2 ~ 4alkyloyl, such as ethanoyl; R
3represent C
1 ~ 4alkyl, such as methyl;
The 3-(O-alkyloyl salicylyl is amino)-4 that formula (3) is represented, 4-dialkoxy-2,5-cyclohexadienone is dissolved in organic solvent (such as tetrahydrofuran (THF), methyl alcohol, dimethyl formamide, particularly such as dimethyl formamide); At the temperature of-20 ~ 50 DEG C (such as under ice-cooling), add aqueous hydrogen peroxide solution and mineral alkali (such as sodium hydroxide, sodium carbonate, sodium bicarbonate, particularly such as sodium carbonate) wherein, stir and reaction is carried out; Then in reaction solution, add ethyl acetate, reaction solution is dry after using hydrochloric acid soln, sodium thiosulfate solution and brine It successively, then carries out vacuum-drying; Dry gained material is made to be dissolved in the mixed solvent of acetone-petroleum ether (the two volume ratio is 6 ~ 10:1), add isopyknic saturated aqueous common salt extraction (3 times), abandon water layer, organic layer drying (such as using saltcake), concentrating under reduced pressure, vacuum-drying, obtain formula (4) represent 5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene;
Steps d: the preparation of 5,6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone
5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonenes of formula (4) are made to be dissolved in solvent such as methylene dichloride; Under ice-cooling, add mineral acid or organic acid (such as boron trifluoride ethyl ether complex etc.) wherein, under stirring, make reaction carry out; Then in reaction solution, add solvent (such as ethyl acetate), wash with water, after ethyl acetate layer is concentrated, residue obtained methanol wash, obtains 5,6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone that formula (5) represents;
The preparation of step e:5,6-epoxy-4-hydroxyl-3-salicylyl amino-2-cyclonene (DHM2EQ)
5,6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone that formula (5) is represented are suspended in solvent (such as methyl alcohol, ethanol, THF).At the temperature of-78 ~ 50 DEG C (such as under ice-cooling), add reductive agent (such as sodium borohydride) wherein and reaction is carried out; After completion of the reaction, in reaction solution, add solvent (such as ethyl acetate, methylene dichloride etc.), reaction solution uses hydrochloric acid and water washing successively.Then drying and concentrating under reduced pressure are carried out to solvent layer, make enriched material be suspended in agitator treating after methyl alcohol, dry, obtain 5, the 6-epoxy-4-hydroxyls-3-salicylyl amino-2-cyclonene (DHM2EQ) that formula (1) represents.
A third aspect of the present invention provides preparation with the method for following formula 4 compound:
The method comprises the following steps:
Make formula (3) compound
Be dissolved in organic solvent (such as tetrahydrofuran (THF), methyl alcohol, dimethyl formamide, particularly such as dimethyl formamide);
At the temperature of-20 ~ 50 DEG C (such as under ice-cooling), add aqueous hydrogen peroxide solution and mineral alkali (such as sodium hydroxide, sodium carbonate, sodium bicarbonate, particularly such as sodium carbonate) wherein, stir and reaction is carried out;
Then in reaction solution, add ethyl acetate, reaction solution is dry after using hydrochloric acid soln, sodium thiosulfate solution and brine It successively, then carries out vacuum-drying;
Dry gained material is made to be dissolved in the mixed solvent of acetone-petroleum ether (the two volume ratio is 6 ~ 10:1), add isopyknic saturated aqueous common salt extraction (re-extract 2 ~ 3 times), abandon water layer, organic layer drying (such as using saltcake drying), concentrating under reduced pressure, vacuum-drying, obtains represent with following formula (4) 5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene:
Wherein, wherein R
1represent hydrogen atom or C
2 ~ 4alkyloyl, such as ethanoyl;
R
3represent C
1 ~ 4alkyl, such as methyl.
Method according to a third aspect of the invention we, it comprises the following steps:
The 3-(O-alkyloyl salicylyl is amino)-4 that formula (3) is represented, 4-dialkoxy-2,5-cyclohexadienone is dissolved in organic solvent (such as tetrahydrofuran (THF), methyl alcohol, dimethyl formamide, particularly such as dimethyl formamide);
At the temperature of-20 ~ 50 DEG C (such as under ice-cooling), add aqueous hydrogen peroxide solution and mineral alkali (such as sodium hydroxide, sodium carbonate, sodium bicarbonate, particularly such as sodium carbonate) wherein, stir and reaction is carried out;
Then in reaction solution, add ethyl acetate, reaction solution is dry after using hydrochloric acid soln, sodium thiosulfate solution and brine It successively, then carries out vacuum-drying;
Dry gained material is made to be dissolved in the mixed solvent of acetone-petroleum ether (the two volume ratio is 6 ~ 10:1), add isopyknic saturated aqueous common salt extraction (re-extract 2 ~ 3 times), abandon water layer, organic layer drying (such as using saltcake drying), concentrating under reduced pressure, vacuum-drying, obtain formula (4) represent 5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene.
Method according to a third aspect of the invention we, it comprises the following steps:
The 3-(O-alkyloyl salicylyl is amino)-4 that formula (3) is represented, 4-dialkoxy-2,5-cyclohexadienone is dissolved in organic solvent (such as tetrahydrofuran (THF), methyl alcohol, dimethyl formamide, particularly such as dimethyl formamide);
At the temperature of-20 ~ 50 DEG C (such as under ice-cooling), add aqueous hydrogen peroxide solution and mineral alkali (such as sodium hydroxide, sodium carbonate, sodium bicarbonate, particularly such as sodium carbonate) wherein, stir and reaction is carried out;
Then in reaction solution, add ethyl acetate, reaction solution is dry after using hydrochloric acid soln, sodium thiosulfate solution and brine It successively, then carries out vacuum-drying;
Dry gained material is made to be dissolved in the mixed solvent of acetone-petroleum ether (the two volume ratio is 6 ~ 10:1), add isopyknic saturated aqueous common salt and extract 3 times, abandon water layer, organic layer drying (such as using saltcake), concentrating under reduced pressure, vacuum-drying, obtain formula (4) represent 5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene.
According to either side of the present invention; wherein in preparation 5; 6-epoxy-4; in the process of 4-dialkoxy-3-salicylyl amino-2-cyclonene; the consumption of hydrogen peroxide is formula 3 compound and 3-(O-acetylsalicyclic amido)-4; 8 ~ 12 times (mole) of 4-dimethoxy-2,5-cyclohexadienone consumption.Comparatively speaking, in the embodiment 3 of CN1368954A, the consumption of hydrogen peroxide is 16 times (mole) of formula 3 compound, but its yield and product purity are far away from the inventive method, and aftertreatment is more complicated than the inventive method thereafter.
The invention still further relates to a kind of pharmaceutical composition, wherein contained 1 compound or its pharmacy acceptable salt, solvate, ester, prodrug, isomer, and pharmaceutically acceptable carrier.
The invention still further relates to compound shown in formula 1 or its pharmacy acceptable salt, solvate, ester, prodrug, the isomer purposes in the medicine for the treatment of or preventing cancer, inflammation, autoimmune disease, diabetes and diabetic complication, infection, cardiovascular disorder and ischemia reperfusion injury.
The invention still further relates to the method for the treatment of or preventing cancer, inflammation, autoimmune disease, diabetes and diabetic complication, infection, cardiovascular disorder and ischemia reperfusion injury, comprise the Mammals needing this type of to treat, such as, shown in the formula 1 of human therapy significant quantity compound or its pharmacy acceptable salt, solvate, ester, prodrug, isomer.
Arbitrary technical characteristic that arbitrary embodiment of either side of the present invention or this either side has is suitable for arbitrary embodiment of other arbitrary embodiment or other either side equally, as long as they can not be conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
For describing term of the present invention, there is following meaning.Compound of the present invention and intermediate can according to IUPAC (International Union of Pure and Applied Chemistry) or the names of CAS (Chemical Abstract Services) naming system.
Phrase " treatment significant quantity " refers to (i) treatment or prevention specified disease, the state of an illness or illness, (ii) weaken, alleviate or eliminate one or more symptoms of specified disease, the state of an illness or illness, or (iii) prevents or delays the compound amount of one or more paresthesia epilepsies of specified disease, the state of an illness.
Phrase " pharmaceutically acceptable " represents that carrier, vehicle, thinner, vehicle and/or the salt of specifying are compatible with other Components Chemical and/or physics of forming preparation generally, and compatible in a physiologically with its receptor.
Term " Mammals " refers to as each animal into taxonomy Mammalia member, and mammiferous example includes but not limited to: people, dog, cat, horse and ox etc.In the present invention, preferred Mammals is people.
Pharmaceutical composition of the present invention comprises formula 1 compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier, vehicle, thinner or vehicle for the treatment of significant quantity.Preferred pharmaceutical composition of the present invention comprises formula 1 compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier, vehicle, thinner or vehicle for the treatment of significant quantity.The pharmaceutical composition formed by mixing the compounds of this invention and pharmaceutically acceptable carrier, vehicle or thinner of various formulation is given, such as tablet, powder agent, lozenge, syrup, Injectable solution etc. although be not difficult.If needed, these pharmaceutical compositions contain supplementary component, such as seasonings, tackiness agent, vehicle etc.
Therefore, for oral administration, containing various vehicle, the tablet of such as Trisodium Citrate, calcium carbonate and/or calcium phosphate can with various disintegrating agent, such as starch, alginic acid and/or some composition silicate and tackiness agent, such as polyvinylpyrrolidone, sucrose, gelatin and/or gum arabic use together.In addition, lubricant, such as Magnesium Stearate, Sodium Lauryl Sulphate BP/USP and talcum powder are usually used in compressing tablet object.The solids composition of similar type also can be used as the weighting agent in soft hard-filled gelatin capsule.Preferred material for this reason comprises lactose and high molecular weight polyethylene glycol.If need the oral aqueous suspension giving elixir, active pharmaceutical agent wherein can with various sweeting agent or seasonings, coloring material or dyestuff, such as, with tenderizer or suspension agent (if necessary) and thinner, water, ethanol, propylene glycol, glycerine and/or their combined hybrid.
For parenteral admin, the compounds of this invention of sesame oil or the preparation of peanut oil, aqueous propylene glycol or aseptic aqueous solution or the solution of composition can be utilized.If needed, can suitably cushion this type of aqueous solution, first the liquid diluent containing sufficient salt solution or glucose gives isotonicity.These specific aqueous solutions are especially applicable to intravenously, intramuscular, subcutaneous and Intraperitoneal medication.Thus, the standard technique that oneself knows by those skilled in the art is not difficult to obtain sterile aqueous media used.
In an exemplary embodiment, pharmaceutical preparation is unit dosage.In this type of formulation, said preparation is divided into unitary dose again, the activeconstituents wherein containing appropriate amount.Unit dosage can be the preparation of packaging, such as, package troche in bottle or ampoule, capsule and powder.Unit dosage can also be capsule, cachet or tablet itself, or it can be these packaged forms any of proper amt.
Those skilled in the art oneself know the method for various pharmaceutical compositions of preparation containing a certain amount of activeconstituents.The example of the method for pharmaceutical compositions can see by " Lei Mingdun: pharmaceutical science and put into practice " (Remington:The Scienceand Practice of Pharmacy) .Lippincott, Williams and Wilkins, 21st edition. (2005), it is incorporated by reference in this text examines.
Embodiment
Further illustrate the present invention below by specific embodiment/experimental example, but should be understood to, these embodiments and experimental example are only used for the use specifically described more in detail, and should not be construed as limiting the present invention in any form.
The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and working method are well known in the art.
the preparation of embodiment 1:5,6-epoxy-4-hydroxyl-3-salicylyl amino-2-cyclonene (DHM2EQ)
the synthesis of step 1:N-(2-acetoxy benzoyl)-2,5-dimethoxyanilines
2,5-dimethoxyaniline (10.0g, 65.3mmol) is dissolved in pyridine (100ml).Under ice-cooling, add ethyl acetate (50ml) solution of O-acetylsalicyclic acyl chlorides (13.0g, 65.3mmol) wherein, last 15 minutes, then stir 15 minutes at the same temperature.Add in reaction solution water (10ml) make reaction stop after, add ethyl acetate (500ml), then use 3 equivalent hydrochloric acid (500ml), water (500ml), 2% sodium bicarbonate aqueous solution (500ml) and water (500ml) to wash successively.Ethyl acetate layer is with after saltcake drying, and concentrating under reduced pressure vacuum-drying, obtain in faint yellow melicera title compound (19.8g).Do not carry out refining to this compound and be directly used in following steps.Through the separation refining title compound of tlc, its infrared absorption spectrum, ultra-violet absorption spectrum, FAB mass spectrum and
1the data of the embodiment 1 of H-NMR spectroscopic data CN1368954A are identical.
the synthesis of step 2:3-(O-acetylsalicyclic amido)-4,4-dimethoxy-2,5-cyclohexadienone
The N-(2-acetoxy benzoyl)-2,5-dimethoxyanilines (19.8g) that step 1 is obtained is dissolved in methyl alcohol (400ml).Under ice-cooling, add iodobenzene diacetate (27.3g, 84.9mmol) wherein, stirring at room temperature 1 hour.Add ethyl acetate (1L) in the dark brown syrupy shape residue obtained at concentrating under reduced pressure reaction solution, reaction solution uses 5% sodium bicarbonate aqueous solution (1L), 10% salt solution (1L) to wash successively.Then by ethyl acetate layer concentrating under reduced pressure, with silica gel column chromatography (1kg, hexane/ethyl acetate=2/1), the dark brown syrupy shape residue of gained is refined, obtain 12.6g decorating film.Be suspended in 30ml methyl alcohol, agitator treating, obtain 10.3g be the title compound of white solid, its infrared absorption spectrum, ultra-violet absorption spectrum, FAB mass spectrum and
1the data of the embodiment 2 of H-NMR spectroscopic data CN1368954A are identical.
the synthesis of step 3:5,6-epoxy-4,4-dimethoxy-3-salicylyl amino-2-cyclonene
3-(O-acetylsalicyclic amido)-4,4-dimethoxys-2,5-cyclohexadienone (10.9g, 33.0mmol) are made to be dissolved in dimethyl formamide (200ml);
Under ice-cooling, the sodium carbonate (165ml) of 264mmol hydrogen peroxide (adding with 30% aqueous hydrogen peroxide solution form) and 1mol/L is added wherein, stirring reaction 2 hours at the same temperature;
Ethyl acetate (500ml) is added in reaction solution, after using the hydrochloric acid (300ml) of 1 equivalent, 10% sodium thiosulfate solution (300ml × 2), 10% salt solution (300ml) to wash successively, ethyl acetate layer is dry with saltcake, then vacuum-drying, obtains in faint yellow solid powder;
Make dry gained faint yellow solid powder dissolution in the mixed solvent of acetone-petroleum ether (the two volume ratio is 10:1), add isopyknic saturated aqueous common salt and extract 3 times, abandon water layer, organic layer is dry with saltcake, concentrating under reduced pressure, vacuum-drying, 5 of the white powder that acquisition formula (4) represents, 6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene (yield of this step is 76%, HPLC purity is 97.3%).The fusing point of gained formula (4) compound, infrared absorption spectrum, ultra-violet absorption spectrum, FAB mass spectrum and
1the data of the embodiment 3 of H-NMR spectroscopic data CN1368954A are identical.
The chromatographic condition of above-mentioned HPLC method is: octadecylsilane chemically bonded silica is weighting agent; Use triethylamine adjust ph to 3.0 ± 0.2 for moving phase with acetonitrile-0.12% glacial acetic acid (90:410); Determined wavelength is 225nm.This HPLC method also can be used for the purity detecting of the product of other step.
In supplementary test of the present invention, repeat the method for the embodiment 3 of CN1368954A, result: the yield of the method is 54%, HPLC purity is 88.7%.
the synthesis of step 4:5,6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone
5,6-epoxy-4,4-dimethoxy-3-salicylyl amino-2-cyclonene (1.0g, 3.27mmol) is dissolved in 25ml methylene dichloride.Under ice-cooling, add boron trifluoride ethyl ether complex (1ml) wherein, stir 30 minutes under uniform temp.Then, in reaction solution, add ethyl acetate (300ml), wash with water (200ml).Ethyl acetate layer is with after saltcake drying, vacuum-drying, with methyl alcohol (5ml), the dark brown decorating film of gained is washed, obtains in the title compound (404mg) of Sandy solid, its infrared absorption spectrum, ultra-violet absorption spectrum, FAB mass spectrum and
1the data of the embodiment 4 of H-NMR spectroscopic data CN1368954A are identical.
the synthesis of step 5:5,6-epoxy-4-hydroxyl-3-salicylyl amino-2-cyclonene (DHM2EQ)
5,6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone (81.8mg, 0.316mmol) is suspended in methyl alcohol (10ml).Under ice-cooling, add sodium borohydride (11.9mg, 0.316mmol) wherein, stir 10 minutes under uniform temp.Then, in reaction solution, add ethyl acetate (50ml), reaction solution uses hydrochloric acid (50ml) and water (50ml) washing of 1 equivalent successively.Ethyl acetate layer is with after saltcake drying, and concentrating under reduced pressure, makes gained Sandy solid suspension in methyl alcohol (1ml), agitator treating.Obtain in the DHM2EQ (45.7mg) of white solid, the Rf value of its outward appearance and character, fusing point, TLC, infrared absorption spectrum, ultra-violet absorption spectrum, FAB mass spectrum and
1the data of the embodiment 5 of H-NMR spectroscopic data CN1368954A are identical.
the synthesis of embodiment 2:5,6-epoxy-4,4-dimethoxy-3-salicylyl amino-2-cyclonene
3-(O-acetylsalicyclic amido)-4,4-dimethoxys-2,5-cyclohexadienone (10.9g, 33.0mmol) are made to be dissolved in dimethyl formamide (200ml); Under ice-cooling, the sodium carbonate (165ml) of 396mmol hydrogen peroxide (adding with 30% aqueous hydrogen peroxide solution form) and 1mol/L is added wherein, stirring reaction 2 hours at the same temperature;
Ethyl acetate (500ml) is added in reaction solution, after using the hydrochloric acid (300ml) of 1 equivalent, 10% sodium thiosulfate solution (300ml × 2), 10% salt solution (300ml) to wash successively, ethyl acetate layer is dry with saltcake, then vacuum-drying, obtains in faint yellow solid powder;
Make dry gained faint yellow solid powder dissolution in the mixed solvent of acetone-petroleum ether (the two volume ratio is 6:1), add isopyknic saturated aqueous common salt and extract 1 time, abandon water layer, organic layer is dry with saltcake, concentrating under reduced pressure, vacuum-drying, 5 of the white powder that acquisition formula (4) represents, 6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene (yield of this step is 79%, HPLC purity is 96.1%).The fusing point of gained formula (4) compound, infrared absorption spectrum, ultra-violet absorption spectrum, FAB mass spectrum and
1the data of the embodiment 3 of H-NMR spectroscopic data CN1368954A are identical.
Further, with reference to the method for embodiment 1 step 4, step 5, preparation DHM2EQ.
the synthesis of embodiment 3:5,6-epoxy-4,4-dimethoxy-3-salicylyl amino-2-cyclonene
3-(O-acetylsalicyclic amido)-4,4-dimethoxys-2,5-cyclohexadienone (10.9g, 33.0mmol) are made to be dissolved in dimethyl formamide (200ml); Under ice-cooling, the sodium carbonate (165ml) of 330mmol hydrogen peroxide (adding with 30% aqueous hydrogen peroxide solution form) and 1mol/L is added wherein, stirring reaction 2 hours at the same temperature;
Ethyl acetate (500ml) is added in reaction solution, after using the hydrochloric acid (300ml) of 1 equivalent, 10% sodium thiosulfate solution (300ml × 2), 10% salt solution (300ml) to wash successively, ethyl acetate layer is dry with saltcake, then vacuum-drying, obtains in faint yellow solid powder;
Make dry gained faint yellow solid powder dissolution in the mixed solvent of acetone-petroleum ether (the two volume ratio is 8:1), add isopyknic saturated aqueous common salt and extract 2 times, abandon water layer, organic layer is dry with saltcake, concentrating under reduced pressure, vacuum-drying, 5 of the white powder that acquisition formula (4) represents, 6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene (yield of this step is 81%, HPLC purity is 95.8%).The fusing point of gained formula (4) compound, infrared absorption spectrum, ultra-violet absorption spectrum, FAB mass spectrum and
1the data of the embodiment 3 of H-NMR spectroscopic data CN1368954A are identical.
Further, with reference to the method for embodiment 1 step 4, step 5, preparation DHM2EQ.
reference examples 1:the synthesis of 5,6-epoxy-4,4-dimethoxy-3-salicylyl amino-2-cyclonene
The method of reference example 3, different is only change reaction solvent dimethyl formamide into tetrahydrofuran (THF).Result: yield 44%, HPLC purity is 69.8%.
reference examples 2:the synthesis of 5,6-epoxy-4,4-dimethoxy-3-salicylyl amino-2-cyclonene
The method of reference example 3, different is only change sodium carbonate into sodium hydroxide.Result: yield 49%, HPLC purity is 62.4%.
reference examples 3:the synthesis of 5,6-epoxy-4,4-dimethoxy-3-salicylyl amino-2-cyclonene
The method of reference example 3, different is only change sodium carbonate into sodium bicarbonate.Result: yield 31%, HPLC purity is 53.1%.
reference examples 4:the synthesis of 5,6-epoxy-4,4-dimethoxy-3-salicylyl amino-2-cyclonene
The method of reference example 3, different is only change acetone-petroleum ether mixed solvent into acetone, sherwood oil or ethyl acetate respectively.Result: use three kinds of solvent treatment products therefroms, after vacuum-drying, obtains formula (4) compound powder jelly, completely not as embodiment 3 gained white powder material is suitable for industrial treatment.
Without the need to further describing, those of ordinary skill in the art believe that the above description of employing and following one exemplary embodiment can be prepared and utilize the compounds of this invention and implement the inventive method.Although describe and illustrate the present invention with reference to various concrete material, method and embodiment, it will be appreciated that the particular combination that the invention is not restricted to the materials and methods selected for this object.Those skilled in the art should know that the prompting of this type of details has multiple change.All patents that the application quotes in the whole text, patent application and other reference are included in herein by reference of text.
Claims (32)
1. preparation is with the method for following formula 1 compound:
1
The method comprises the following steps:
Step a: make 2,5-dimethoxyaniline be dissolved in pyridine, at the temperature of-78 ~ 50 DEG C, adds the O-alkyloyl bigcatkin willow acyl chlorides with following formula (7) wherein
ethyl acetate solution, make reaction carry out under stirring; Then; add water and reaction is stopped; add ethyl acetate again; after reaction solution uses hydrochloric acid, water, sodium bicarbonate aqueous solution and water washing successively; drying, concentrating under reduced pressure, then vacuum-drying; obtain N-(2-alkanoyloxy benzoyl)-2, the 5-dimethoxyanilines represented with following formula (2):
Wherein, R
1represent hydrogen atom or C
2 ~ 4alkyloyl;
Step b: make the compound of the formula of above acquisition (2) be dissolved in R
3in the solvent that OH represents, at the temperature of-20 ~ 50 DEG C, add iodobenzene diacetate wherein, stirred at ambient temperature makes reaction carry out; Then concentrating under reduced pressure; add ethyl acetate wherein; after reaction solution uses sodium bicarbonate aqueous solution and brine It respectively; concentrating under reduced pressure solvent; residue is refined; obtain 3-(O-alkyloyl salicylyl is amino)-4,4-dialkoxy-2, the 5-cyclohexadienones represented with following formula (3):
Wherein R
3represent C
1 ~ 4alkyl;
Step c: make formula (3) compound be dissolved in dimethyl formamide; At the temperature of-20 ~ 50 DEG C, add aqueous hydrogen peroxide solution and sodium carbonate wherein, stir and reaction is carried out; Then in reaction solution, add ethyl acetate, reaction solution is dry after using hydrochloric acid soln, sodium thiosulfate solution and brine It successively, then carries out vacuum-drying; Making dry gained material be dissolved in volume ratio is in the acetone-petroleum ether mixed solvent of 6 ~ 10:1, add the extraction of isopyknic saturated aqueous common salt, abandon water layer, organic layer is dry, concentrating under reduced pressure, vacuum-drying, obtains represent with following formula (4) 5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene:
Steps d: make formula (4) compound be dissolved in methylene dichloride; Under ice-cooling, add mineral acid or organic acid wherein, under stirring, make reaction carry out; Then in reaction solution, add organic solvent, wash with water, after organic layer is concentrated, residue obtained methanol wash, obtains 5, the 6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone represented with following formula (5):
Step e: make formula (5) compound be suspended in solvent; At the temperature of-78 ~ 50 DEG C, add reductive agent wherein and reaction is carried out; After completion of the reaction, solvent is added in reaction solution, reaction solution uses hydrochloric acid and water washing successively, drying and concentrating under reduced pressure are carried out to solvent layer, enriched material is made to be suspended in agitator treating after methyl alcohol, drying, obtains 5, the 6-epoxy-4-hydroxyl-3-salicylyl amino-2-cyclonenes represented with following formula (1)
。
2. method according to claim 1, wherein in step a, the ethyl acetate solution of the O-alkyloyl bigcatkin willow acyl chlorides of adding type (7) under ice-cooling.
3. method according to claim 1, wherein in step a, R
1represent ethanoyl.
4. method according to claim 1, wherein in step b, adds iodobenzene diacetate under ice-cooling.
5. method according to claim 1, wherein in step b, R
3represent methyl.
6. method according to claim 1, wherein in step c, adds aqueous hydrogen peroxide solution and sodium carbonate under ice-cooling.
7. method according to claim 1, wherein in step c, with saturated aqueous common salt re-extract 2 ~ 3 times.
8. method according to claim 1, wherein in step c, organic layer is dry with saltcake.
9. method according to claim 1, wherein in steps d, organic acid is boron trifluoride ethyl ether complex.
10. method according to claim 1, wherein in steps d, organic solvent is ethyl acetate.
11. methods according to claim 1, wherein in step e, make formula (5) compound be suspended in methyl alcohol, ethanol or THF.
12. methods according to claim 1, wherein in step e, add reductive agent under ice-cooling.
13. methods according to claim 1, wherein in step e, reductive agent is sodium borohydride.
14. methods according to claim 1, wherein in step e, after completion of the reaction, add ethyl acetate or methylene dichloride in reaction solution.
15. preparations are with the method for following formula 1 compound:
1
The method comprises the following steps:
Step c: make formula (3) compound
be dissolved in dimethyl formamide; At the temperature of-20 ~ 50 DEG C, add aqueous hydrogen peroxide solution and sodium carbonate wherein, stir and reaction is carried out; Then in reaction solution, add ethyl acetate, reaction solution is dry after using hydrochloric acid soln, sodium thiosulfate solution and brine It successively, then carries out vacuum-drying; Making dry gained material be dissolved in volume ratio is in the acetone-petroleum ether mixed solvent of 6 ~ 10:1, add the extraction of isopyknic saturated aqueous common salt, abandon water layer, organic layer is dry, concentrating under reduced pressure, vacuum-drying, obtains represent with following formula (4) 5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene:
Wherein, R
1represent hydrogen atom or C
2 ~ 4alkyloyl; R
3represent C
1 ~ 4alkyl;
Steps d: make formula (4) compound be dissolved in methylene dichloride; Under ice-cooling, add mineral acid or organic acid wherein, under stirring, make reaction carry out; Then in reaction solution, add organic solvent, wash with water, after organic layer is concentrated, residue obtained methanol wash, obtains 5, the 6-epoxy-2-salicylyl amino-2-tetrahydrobenzene-Isosorbide-5-Nitrae-diketone represented with following formula (5):
Step e: make formula (5) compound be suspended in solvent; At the temperature of-78 ~ 50 DEG C, add reductive agent wherein and reaction is carried out; After completion of the reaction, solvent is added in reaction solution, reaction solution uses hydrochloric acid and water washing successively, drying and concentrating under reduced pressure are carried out to solvent layer, enriched material is made to be suspended in agitator treating after methyl alcohol, drying, obtains 5, the 6-epoxy-4-hydroxyl-3-salicylyl amino-2-cyclonenes represented with following formula (1)
。
16. method according to claim 15, wherein R
1represent ethanoyl.
17. method according to claim 15, wherein R
3represent methyl.
18. methods according to claim 15, wherein in step c, add aqueous hydrogen peroxide solution and sodium carbonate under ice-cooling.
19. methods according to claim 15, wherein in step c, with saturated aqueous common salt re-extract 2 ~ 3 times.
20. methods according to claim 15, wherein in step c, organic layer is dry with saltcake.
21. methods according to claim 15, wherein in steps d, organic acid is boron trifluoride ethyl ether complex.
22. methods according to claim 15, wherein in steps d, organic solvent is ethyl acetate.
23. methods according to claim 15, wherein in step e, make formula (5) compound be suspended in methyl alcohol, ethanol or THF.
24. methods according to claim 15, wherein in step e, add reductive agent under ice-cooling.
25. methods according to claim 15, wherein in step e, reductive agent is sodium borohydride.
26. methods according to claim 15, wherein in step e, after completion of the reaction, add ethyl acetate or methylene dichloride in reaction solution.
27. preparations are with the method for following formula 4 compound:
The method comprises the following steps:
Make formula (3) compound
Be dissolved in dimethyl formamide;
At the temperature of-20 ~ 50 DEG C, add aqueous hydrogen peroxide solution and sodium carbonate wherein, stir and reaction is carried out;
Then in reaction solution, add ethyl acetate, reaction solution is dry after using hydrochloric acid soln, sodium thiosulfate solution and brine It successively, then carries out vacuum-drying;
Making dry gained material be dissolved in volume ratio is in the acetone-petroleum ether mixed solvent of 6 ~ 10:1, add the extraction of isopyknic saturated aqueous common salt, abandon water layer, organic layer is dry, concentrating under reduced pressure, vacuum-drying, obtains represent with following formula (4) 5,6-epoxy-4,4-dialkoxy-3-salicylyl amino-2-cyclonene:
Wherein R
1represent hydrogen atom or C
2 ~ 4alkyloyl;
R
3represent C
1 ~ 4alkyl.
28. method according to claim 27, wherein R
1represent ethanoyl.
29. method according to claim 27, wherein R
3represent methyl.
30. methods according to claim 27, wherein add aqueous hydrogen peroxide solution and sodium carbonate under ice-cooling.
31. methods according to claim 27, wherein use saturated aqueous common salt re-extract 2 ~ 3 times.
32. methods according to claim 27, wherein organic layer is dry with saltcake.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1368954A (en) * | 1999-08-11 | 2002-09-11 | 美而香株式会社 | Salicylamide derivatives |
| CN1674881A (en) * | 2002-06-26 | 2005-09-28 | 学校法人庆应义塾 | Drug composition containing NF-kappa B inhibitor |
| CN1774429A (en) * | 2003-02-14 | 2006-05-17 | 学校法人庆应义塾 | Medicinal composition |
| WO2006060819A2 (en) * | 2004-12-03 | 2006-06-08 | The Regents Of The University Of California | Dhmeq as a sensitizing agent for chemotherapy and immunotherapy of resistant cancer cells |
| CN1852709A (en) * | 2003-08-06 | 2006-10-25 | 创新信号股份有限公司 | Macrophage activation inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1368954A (en) * | 1999-08-11 | 2002-09-11 | 美而香株式会社 | Salicylamide derivatives |
| CN1674881A (en) * | 2002-06-26 | 2005-09-28 | 学校法人庆应义塾 | Drug composition containing NF-kappa B inhibitor |
| CN1774429A (en) * | 2003-02-14 | 2006-05-17 | 学校法人庆应义塾 | Medicinal composition |
| CN1852709A (en) * | 2003-08-06 | 2006-10-25 | 创新信号股份有限公司 | Macrophage activation inhibitor |
| WO2006060819A2 (en) * | 2004-12-03 | 2006-06-08 | The Regents Of The University Of California | Dhmeq as a sensitizing agent for chemotherapy and immunotherapy of resistant cancer cells |
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