CN104098513B - A kind of indazole compound derivative and preparation method thereof - Google Patents
A kind of indazole compound derivative and preparation method thereof Download PDFInfo
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- CN104098513B CN104098513B CN201410371407.5A CN201410371407A CN104098513B CN 104098513 B CN104098513 B CN 104098513B CN 201410371407 A CN201410371407 A CN 201410371407A CN 104098513 B CN104098513 B CN 104098513B
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- -1 indazole compound Chemical class 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 229940126214 compound 3 Drugs 0.000 claims abstract description 8
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims abstract description 8
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229940125782 compound 2 Drugs 0.000 claims abstract description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940125904 compound 1 Drugs 0.000 claims abstract description 4
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims abstract description 4
- 230000000694 effects Effects 0.000 claims abstract description 3
- LNAHWKUKPHEFST-UHFFFAOYSA-N 1-(6-bromo-1h-indazol-3-yl)ethanone Chemical compound BrC1=CC=C2C(C(=O)C)=NNC2=C1 LNAHWKUKPHEFST-UHFFFAOYSA-N 0.000 claims description 8
- 239000012467 final product Substances 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 abstract description 5
- 230000004054 inflammatory process Effects 0.000 abstract description 5
- 239000007795 chemical reaction product Substances 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- KXTOQWKJKBSECV-UHFFFAOYSA-N formaldehyde 1H-indazole Chemical compound C=O.N1N=CC2=CC=CC=C12 KXTOQWKJKBSECV-UHFFFAOYSA-N 0.000 abstract description 3
- MAWGHOPSCKCTPA-UHFFFAOYSA-N 6-bromo-1h-indole Chemical compound BrC1=CC=C2C=CNC2=C1 MAWGHOPSCKCTPA-UHFFFAOYSA-N 0.000 abstract 1
- LTFPRWCVUZBEHX-UHFFFAOYSA-N C(C)(=O)C1=NNC2=CC=CC=C12.[Br] Chemical compound C(C)(=O)C1=NNC2=CC=CC=C12.[Br] LTFPRWCVUZBEHX-UHFFFAOYSA-N 0.000 abstract 1
- 229940125898 compound 5 Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 206010042674 Swelling Diseases 0.000 description 7
- 230000008961 swelling Effects 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 210000005069 ears Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 240000006409 Acacia auriculiformis Species 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- ZPRQXVPYQGBZON-UHFFFAOYSA-N 2-bromo-1h-indole Chemical class C1=CC=C2NC(Br)=CC2=C1 ZPRQXVPYQGBZON-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical group CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 101001031591 Mus musculus Heart- and neural crest derivatives-expressed protein 2 Proteins 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 108010014632 NF-kappa B kinase Proteins 0.000 description 1
- 102000019148 NF-kappaB-inducing kinase activity proteins Human genes 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LCWSUVRIRMTCBK-UHFFFAOYSA-N ethanol;1h-indazole Chemical compound CCO.C1=CC=C2C=NNC2=C1 LCWSUVRIRMTCBK-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010422 painting Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
Abstract
The present invention relates to a kind of indazole compound derivative and preparation method thereof, this compound is 6 bromine 3 acetylindazol, and preparation method is as follows: (1) compound 1 (6 bromo indole) generates compound 2 under natrium nitrosum and hydrochloric acid effect；(2) compound 2 di-tert-butyl dicarbonate generates compound 3 (the indazole formaldehyde of Boc protection)；(3) methyl-magnesium-bromide and compound 3 generate compound 4；(4) compound 4 is under manganese dioxide, and indazole hydroxyl is oxidized to indazole acetyl group, obtains end product compound 5；Gained end-product has wide application prospect at aspects such as treatment inflammation relevant diseases.
Description
Technical field
The present invention relates to compou nd synthesis field, especially a kind of indazole compound derivative and
Preparation method.
Background technology
According to Preparation of heterocyclic propargylic alcohol
compounds as NF-κB inducing kinase inhibitors for treating
inflammations。U.S.Pat.Appl.Publ.(2012),US 20120214762
A1 20120823 document such as grade is recorded, and indazole compound is widely present in has bioactive medicine
In thing molecule, in terms of the diseases such as treatment inflammation, there is using value, with this compou nd synthesis
Derivative, is likely to be of other biologically active more widely.Visible, due to the medicine that it is good
Managing active and potential medical value, the present stage synthesis of indazole compound derivative receives much attention.
Summary of the invention
The technical problem to be solved is to provide a kind of indazole compound derivative.
Another technical problem to be solved by this invention is to provide above-mentioned indazole compound to derive
The preparation method of thing.
For solving above-mentioned technical problem, the technical scheme is that
A kind of indazole compound derivative, 6-bromo-3-acetylindazol, its structural formula is (I)
Shown in,
Preferably, above-mentioned indazole compound derivative, 6-bromo-3-acetylindazol is khaki
Solid, its hydrogen nuclear magnetic resonance modal data is: 2.642 (s, 3H), 7.463 (d, 1H), 7.922 (s,
1H), 8.113 (d, 1H), 13.947 (s, 1H).
The preparation method of above-mentioned indazole compound derivative, specifically comprises the following steps that
(1) compound 1 (the bromo-indoles of 6-) generates chemical combination under natrium nitrosum and hydrochloric acid effect
Thing 2 (indazole formaldehyde)；
(2) compound 2 di-tert-butyl dicarbonate generates the compound 3 (indazole of Boc protection
Formaldehyde)；
(3) methyl-magnesium-bromide generates compound with compound 3 (the indazole formaldehyde of Boc protection)
4 (indazole ethanol)；
(4) compound 4 is under manganese dioxide, and indazole hydroxyl is oxidized to indazole acetyl group,
Obtain end product compound (I) (6-bromo-3-acetylindazol), wherein,
Preferably, the preparation method of above-mentioned indazole compound derivative, the conduct of described compound 4
Intermediate product, for noval chemical compound.
The concrete reaction equation of the preparation method of above-mentioned indazole compound derivative is as follows:
The invention has the beneficial effects as follows:
The preparation method of above-mentioned indazole compound derivative, is a kind of cheaper starting materials, synthetic method
The preparation method of simple 6-bromo-3-acetylindazol, its product 6-bromo-3-acetylindazol
Can have extensively at aspects such as treatment inflammation relevant diseases as the inhibitor of NF-kB target spot
Application prospect.
Accompanying drawing explanation
Fig. 1 is the HNMR spectrogram of 6-bromo-3-acetylindazol.
Detailed description of the invention
In order to make those skilled in the art be better understood from technical scheme, knot below
Close detailed description of the invention technical scheme of the present invention is described in further detail.
Embodiment 1
The preparation method of a kind of indazole compound derivative 6-bromo-3-acetylindazol, specifically walks
Rapid as follows:
(1) in the aqueous solution of 70g natrium nitrosum, 20g compound 1 (the bromo-indoles of 6-) is added
Acetone: water (200ml:200ml) solution；Under room temperature, in system, add 2N HCl solution
It is about 2.5 to pH；After 20min, having rufous gas to release, system has dope；
After 10min, TLC detection raw material disappears, and stops reaction, adds 1.0L acetic acid second in system
Ester (EA), two-phase laminated flow, organic phase saturated sodium bicarbonate (500ml*2) washs, anhydrous
Magnesium sulfate is dried organic phase, is concentrated to give 22g compound 2, for black solid.TLC information:
Raw material Rf=0.7, product Rf=0.6；Solvent: petroleum ether: ethyl acetate (PE:EA)=
3:1；
(2) add respectively in 200ml DCM (dichloromethane) solution of 22g compound 2
Enter 15.5g triethylamine (Et3And 0.5g DMAP (DMAP) N)；Then one
Secondary property is slowly added into 22.2g di-tert-butyl dicarbonate (Boc), and system is stirred at room temperature 2h；
After 2h, TLC shows a small amount of raw material, stops reaction, concentrates, and silica gel plate sample, middle compacting is standby
Separate to obtain 3g compound 3, for yellow solid.TLC information: raw material Rf=0.05, product Rf=
0.6；Solvent: PE:EA=10:1, (1st), (2) step productivity 9%；
(3) equipped with the 90ml THF solution of 3g compound 3, argon gas in 250ml there-necked flask
Replacing three times, system is cooled to 0 DEG C；After 5min, T=-10 DEG C, it is added dropwise over 27.7ml
Methyl-magnesium-bromide, and temperature control is at about 0 DEG C, has solid to separate out during dropping；15min
After, T=-8 DEG C, drip complete, system is back to stirred overnight at room temperature naturally；After 18.5h,
LCMS (liquid chromatography mass spectrometric) detection product generates, and stops reaction, is cooled to about 0 DEG C, Xiang Ti
System is added dropwise over saturated ammonium chloride (150ml), has solid to occur, add EA (250ml) and
Water (50ml), separatory, aqueous phase EA (200ml*2) extracts, and merges organic phase, anhydrous sulphur
Acid magnesium is dried, and is concentrated to give 2.4g compound 4, for thick yellow liquid；
(4) in the 240mlDCM solution of 2.4g compound 4,8.66g manganese dioxide is added,
Stirred overnight at room temperature under argon shield；After 21h, TLC display raw material disappears, and stops reaction,
Diatomite filters, and filter cake is respectively with DCM (150ml), EA (150ml), dichloromethane: methyl alcohol
(DCM:MeOH)=10:1 (150ml) washs, and merges organic phase, is concentrated to give crude product, utilizes
MTBE:PE=2:11 recrystallizes to obtain finished product 1.9g compound (I), for khaki solid.
TLC information: raw material Rf=0.5, product Rf=0.8.Solvent: PE:EA=1:1；The
(3), (4) step productivity 86%.After measured, as it is shown in figure 1, its hydrogen modal data is: 2.642
(s, 3H), 7.463 (d, 1H), 7.922 (s, 1H), 8.113 (d, 1H), 13.947
(s, 1H).
Preparation process described in embodiment 1 is as follows:
Application test example
Kunming kind healthy male mice 30,6 weeks, quality 18.5-22.5g, it is randomly divided into 3
Group, often group 10, is divided into blank group (physiological saline gastric infusion), aspirin
Group (200mg/kg gastric infusion), test group (embodiment 1 gained final product compound (I),
20mg/kg gastric infusion), continuous 7d, 1h after the 7th day gavage, by 3 groups of mouse all mouse
Forward and backward of auris dextra uniform painting dimethylbenzene 0.02mL, prepares auricle inflammatory model.Collare after 1h
Mouse is put to death in dislocation, cuts two ears along auricle baseline, with diameter 8mm card punch respectively at two ears
Same position lay round auricle, weigh and be accurate to 0.0001g.Immediately with electronic balance respectively
Claim quality, of poor quality as swelling using left and right two ear, and calculate its swelling and inhibiting rate.
Swelling=auris dextra tablet weight left auricle weight
Inhibiting rate=(the average swelling of control group-average swelling of administration group)/control group is put down
All swellings * 100%
Result of the test shows, after causing inflammation, each group mouse right ear occurs highly red and swollen phenomenon at once.Ah
Mice ear caused by department's woods group and test group paraxylene all has obvious inhibiting effect, knot
Fruit is shown in Table 1.
Table 1
| Group | Left ear (mg) | Auris dextra (mg) | Swelling (mg) | Inhibiting rate (%) |
| Blank group | 12.5±1.1 | 24.1±2.7 | 11.7±3.3 | |
| Aspirin group | 13.9±1.5 | 18.6±2.6 | 4.7±2.1 | 59.83% |
| Test group | 12.9±0.9 | 17.8±1.6 | 4.9±1.8 | 58.12% |
Above-mentioned reference detailed description of the invention is to this one indazole compound derivative and preparation side thereof
The detailed description that method is carried out, is illustrative rather than determinate, can be according to limited scope
List several embodiments, therefore changing and modifications under without departing from present general inventive concept,
Within protection scope of the present invention should being belonged to.
Claims (2)
1. an indazole compound derivative, it is characterised in that: for 6-bromo-3-acetylindazol, its knot
Structure formula is shown in (I),
2. the preparation method of the indazole compound derivative described in claim 1, it is characterised in that: concrete
Step is as follows:
(1) compound 1 generates compound 2 under natrium nitrosum and hydrochloric acid effect；
(2) compound 2 di-tert-butyl dicarbonate generates compound 3；
(3) methyl-magnesium-bromide and compound 3 generate compound 4；
(4) compound 4 is under manganese dioxide, and indazole hydroxyl is oxidized to indazole acetyl group, obtains final
Product Compound (I), wherein,
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2465247A1 (en) * | 2001-10-26 | 2003-05-01 | Aventis Pharmaceuticals Inc. | Benzimidazoles and analogues and their use as protein kinases inhibitors |
| CN101080408A (en) * | 2004-12-17 | 2007-11-28 | 霍夫曼-拉罗奇有限公司 | Trycyclic heterocycles, their manufacture and use as pharmaceutical agents |
| CN101687808A (en) * | 2007-06-21 | 2010-03-31 | 默克专利有限公司 | indazolamide derivatives |
| CN103387565A (en) * | 2013-07-29 | 2013-11-13 | 苏州明锐医药科技有限公司 | Preparation method of Axitinib |
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| CA2812088A1 (en) * | 2010-09-14 | 2012-03-22 | Exelixis, Inc. | Phtalazine derivatives as jak1 inhibitors |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2465247A1 (en) * | 2001-10-26 | 2003-05-01 | Aventis Pharmaceuticals Inc. | Benzimidazoles and analogues and their use as protein kinases inhibitors |
| CN101080408A (en) * | 2004-12-17 | 2007-11-28 | 霍夫曼-拉罗奇有限公司 | Trycyclic heterocycles, their manufacture and use as pharmaceutical agents |
| CN101687808A (en) * | 2007-06-21 | 2010-03-31 | 默克专利有限公司 | indazolamide derivatives |
| CN103387565A (en) * | 2013-07-29 | 2013-11-13 | 苏州明锐医药科技有限公司 | Preparation method of Axitinib |
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