CN102786543A - Preparation methods for imidazole[1,2-a]pyridine-6-boric acid pinacol ester and derivatives thereof - Google Patents
Preparation methods for imidazole[1,2-a]pyridine-6-boric acid pinacol ester and derivatives thereof Download PDFInfo
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- CN102786543A CN102786543A CN2012102579382A CN201210257938A CN102786543A CN 102786543 A CN102786543 A CN 102786543A CN 2012102579382 A CN2012102579382 A CN 2012102579382A CN 201210257938 A CN201210257938 A CN 201210257938A CN 102786543 A CN102786543 A CN 102786543A
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- pyridine
- pinacol ester
- acid pinacol
- boronic acid
- imidazo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title abstract 12
- 150000002460 imidazoles Chemical class 0.000 title abstract 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- 238000005859 coupling reaction Methods 0.000 claims abstract description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 3
- 150000004820 halides Chemical class 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- BKLKKLAXVIBXDW-UHFFFAOYSA-N 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN2C=CN=C2C=C1 BKLKKLAXVIBXDW-UHFFFAOYSA-N 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- 238000000967 suction filtration Methods 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 238000001514 detection method Methods 0.000 claims description 11
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 238000004537 pulping Methods 0.000 claims description 6
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 claims description 5
- YFTAUNOLAHRUIE-UHFFFAOYSA-N 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(N)N=C1 YFTAUNOLAHRUIE-UHFFFAOYSA-N 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- 235000011056 potassium acetate Nutrition 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- ZZHAKZUFNIDWIA-UHFFFAOYSA-N 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC2=NC=CN2C=C1 ZZHAKZUFNIDWIA-UHFFFAOYSA-N 0.000 claims description 2
- ZONLLDIMAJHMLM-UHFFFAOYSA-N 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CN2C1=NC=C2 ZONLLDIMAJHMLM-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims description 2
- 238000004042 decolorization Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 2
- 238000004809 thin layer chromatography Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 7
- DCYKWKYBNWRLLZ-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=NC(N)=C1 DCYKWKYBNWRLLZ-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 4
- 150000001642 boronic acid derivatives Chemical class 0.000 description 4
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- AEDZKIACDBYJLQ-UHFFFAOYSA-N ethane-1,2-diol;hydrate Chemical compound O.OCCO AEDZKIACDBYJLQ-UHFFFAOYSA-N 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OHWSWGXNZDSHLM-UHFFFAOYSA-N 2-chloro-3-iodopyridine Chemical compound ClC1=NC=CC=C1I OHWSWGXNZDSHLM-UHFFFAOYSA-N 0.000 description 2
- PGOGTWDYLFKOHI-UHFFFAOYSA-N 5-bromo-1,3-benzoxazole Chemical compound BrC1=CC=C2OC=NC2=C1 PGOGTWDYLFKOHI-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- -1 boric acid compound Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- CVVMLRFXZPKILB-UHFFFAOYSA-N methyl 5-chloropyrazine-2-carboxylate Chemical compound COC(=O)C1=CN=C(Cl)C=N1 CVVMLRFXZPKILB-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RBCARPJOEUEZLS-UHFFFAOYSA-N 3-bromopyridin-2-amine Chemical compound NC1=NC=CC=C1Br RBCARPJOEUEZLS-UHFFFAOYSA-N 0.000 description 1
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 description 1
- BAQKUNMKVAPWGU-UHFFFAOYSA-N 4-bromopyridin-2-amine Chemical compound NC1=CC(Br)=CC=N1 BAQKUNMKVAPWGU-UHFFFAOYSA-N 0.000 description 1
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IPJIKGJKMCILGV-UHFFFAOYSA-N imidazo[1,2-a]pyridin-6-ylboronic acid Chemical class C1=C(B(O)O)C=CC2=NC=CN21 IPJIKGJKMCILGV-UHFFFAOYSA-N 0.000 description 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical group C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses preparation methods for imidazole[1,2-a]pyridine-6-boric acid pinacol ester and derivatives thereof. The preparation methods comprise a preparation method for imidazole[1,2-a]pyridine-6-boric acid pinacol ester, a preparation method for imidazole[1,2-a]pyridine-7-boric acid pinacol ester and a preparation method for imidazole[1,2-a]pyridine-8-boric acid pinacol ester. The imidazole[1,2-a]pyridine-6-boric acid pinacol ester and derivatives thereof prepared by using the preparation methods are used in the Suzuki coupling reaction for a coupling reaction with compounds like halides and TfO-R. According to a technical scheme in the invention, the preparation methods have the advantages of high reaction yield, easy purification, suitability for production, etc.
Description
Technical Field
The invention relates to a preparation method of imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester, in particular to a preparation method of imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester and derivatives thereof, belonging to the field of fine chemical engineering or pharmaceutical intermediate industrial production.
Background
Imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester is an important medical intermediate, most of documents report that a boric acid compound is synthesized by firstly synthesizing an imidazo [1,2-a ] pyridine ring and then a bromide, the cyclization reaction is basically not problematic, and the yield is relatively high. However, when the boronic acid pinacol ester is prepared, the reaction is very complicated, the yield is very low (< 10%), and products are basically unavailable, most of which are bromine-removed byproducts, such as:
route 1:
The reaction to A is very complex, essentially all bromine by-products are removed.
Route 2:
The reaction to A is very complex, essentially all bromine by-products are removed.
Route 3:
Therefore, the technical problem to be solved in the related field is to design a process route of imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester and derivatives thereof, which has high reaction yield, is easy to purify and is suitable for production.
Disclosure of Invention
The invention aims to provide a preparation method of imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester and derivatives thereof, which has high reaction yield, is easy to purify and is suitable for production, so as to solve the problems in the prior art.
The purpose of the invention can be realized by the following technical scheme:
the imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester derivative of the invention,
the general formula is as follows:
which comprises the following steps:
Ia: imidazo [1,2-a ]]Pyridine-6-boronic acid pinacol ester;
Ib: imidazo [1,2-a ]]Pyridine-7-boronic acid pinacol ester;
Ic: imidazo [1,2-a ]]Pyridine-8-boronic acid pinacol ester;
the preparation method of the imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester comprises the following preparation steps:
X=-Br，-I，-Cl or-OTf
the method comprises the following specific steps:
1) 2-amino-5-X pyridine, a compound of formula (1); dissolving 1.0eq in an organic solvent with the concentration of 0.3-0.6M, adding the organic solvent into a three-necked bottle with a thermometer, a condenser and nitrogen protection, stirring uniformly, and adding 1.1-1.5eq (1.1-1.5 equivalents, 2-amino-5-X pyridine is taken as a reference 1) of pinacol ester diboron and 2.0-3.0eq of anhydrous potassium acetate; then adding 0.01-0.1eq of palladium catalyst under the protection of nitrogen, replacing the reaction system with nitrogen for 3 times, starting to heat to 70-100 ℃, and stirring for 5-20 hours;
TLC detection (thin-layer chromatography detection) completely reacting, cooling, performing suction filtration by using a Buchner funnel, washing a filter cake for 2 times by using dichloromethane, concentrating and drying a filtrate, adding methanol and activated carbon, stirring at room temperature (15-20 hours) until decolorization is realized, performing suction filtration, performing vacuum concentration and drying on the filtrate to obtain an oily substance, adding petroleum ether and methyl tert-butyl ether solution, pulping (15-20 hours), and filtering to obtain 2-aminopyridine-5-boronic acid pinacol ester (yield: 90-95%);
wherein,
the organic solvent is selected from: 1, 4-dioxane, DMF, DMSO and toluene. 1,4 dioxane is preferred.
The palladium catalyst is selected from: PdCl2(dppf)2、Pd(PPh3)4、PdCl2(PPh3)2And Pd2(dba)3And/or tricyclohexylphosphorus. Preferably PdCl2(dppf)2。
Reaction time: 5-20 hours (according to different raw materials, catalyst and TLC detection)
2) Dissolving 1.0eq of 2-aminopyridine-5-boric acid pinacol ester in 0.3-0.6M organic solvent, adding the solution into a reaction bottle with a condenser tube, stirring, and dropwise adding 1.2-1.5eq of chloroacetaldehyde in 40% aqueous solution at normal temperature; heating and refluxing for 4-6 hours. And (3) after TLC detection reaction is finished, directly adding saturated sodium bicarbonate aqueous solution to adjust the pH to be 7.5-8.5, adding ethyl acetate under stirring, stirring for 3-5 hours to separate out a large amount of solid, performing suction filtration, pulping the solid twice by using ethyl acetate to obtain the product of imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester, wherein the yield is as follows: 60-70%.
Wherein,
the organic solvent is one of ethanol, methanol and isopropanol.
The imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester and the derivative thereof prepared by the method are applied to suzuki coupling reaction and are subjected to coupling reaction with compounds such as halogenated compounds and TfO-R.
The technical scheme of the invention has the advantages of high reaction yield, easy purification, suitability for production and the like.
Detailed Description
The technical features of the present invention will be further described with reference to the following embodiments.
Example 1: preparing imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester;
the reaction equation is as follows:
the specific operation is as follows:
1) into a 5L three-necked flask equipped with a mechanical stirrer were charged 300g of 2-amino-5-bromopyridine, 528g of pinacol ester diboron, 3L of 1, 4-dioxane, 42.4g of Pd (dppf)2Cl2593g of anhydrous potassium acetate, replacing with nitrogen for 3 times, and starting to heat to about 80 ℃ for reaction for 16 hours. TLC detection reaction is complete, cooling and suction filtration are carried out, a filter cake is washed twice by 200mL dichloromethane, filtrate is concentrated to be dry, 2L methanol and 200g activated carbon are added for decoloration, the mixture is stirred at room temperature overnight, and suction filtration is carried out. Concentrating to dry to obtain an oily substance, adding 2L of petroleum ether and 150mL of methyl tert-butyl ether, pulping overnight, and filtering to obtain 380g of 2-aminopyridine-5-boronic acid pinacol ester with the yield of 99%.
Table 1: preparation of 2-aminopyridine-5-boronic acid pinacol ester, examples under different reaction conditions:
the reaction equation is as follows:
the specific operation is as follows:
2) in a 5L three-necked flask, 380g of 2-aminopyridine-5-boronic acid pinacol ester, 496g of chloroacetaldehyde (40% aqueous solution), 3.8L of ethanol were added. Heated and refluxed for about 4 hours. And (3) TLC detection, wherein the reaction is finished, saturated sodium bicarbonate aqueous solution is directly added to adjust the pH to be about =8, 200mL of ethyl acetate is added, a large amount of solid is separated out after stirring for 3 hours, the solid is filtered, and the solid is pulped twice by using ethyl acetate to obtain 280g of the imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester, and the yield is 66.8%.
Table 2: preparation of imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester, examples under different reaction conditions:
since the solubility of the product was poor, H-NMR was dissolved with CDCl3 and CD3OD (1/1).
H-NMR：1H NMR(400MHz，CDCl3-d1and CD3OD-d4)δ1.38(s，12H)，7.49～7.58(m，3H)，7.68(s，1H)，8.63(s，1H)；
Example 2: imidazo [1,2-a ] pyridine-7-boronic acid pinacol ester;
the reaction equation is as follows:
the specific operation is as follows:
1) in a 500mL three-necked flask equipped with mechanical stirring, 30g of 2-amino-4-bromopyridine, 52.8g of pinacol ester diboron, 300mL of 1, 4-dioxane, 4.2g of Pd (dppf)2Cl259.3g of anhydrous potassium acetate, 3 times replaced by nitrogen, and then the mixture is heated to about 80 ℃ overnight. TLC detection reaction is complete, cooling and suction filtration are carried out, a filter cake is washed twice by 30mL dichloromethane, filtrate is concentrated to be dry, 200mL methanol and 20g activated carbon are added for decoloration, the mixture is stirred at room temperature overnight, and suction filtration is carried out. Concentrated to dryness to give an oil, added with 200mL petroleum ether and 15mL methyl tert-butyl ether and slurried overnight, filtered to give 35g 2-aminopyridine-4-boronic acid pinacol ester, yield 91%.
Table 3: preparation of 2-aminopyridine-4-boronic acid pinacol ester, examples under different reaction conditions:
the reaction equation is as follows:
the specific operation is as follows:
2) in a 500mL three-necked flask, 35g of 2-aminopyridine-4-boronic acid pinacol ester, 45.7g of chloroacetaldehyde (40% aqueous solution), 350mL of ethanol were added. Heated and refluxed for about 4 hours. And (3) detecting by TLC, directly adding saturated sodium bicarbonate aqueous solution to adjust the pH to be about =8, adding 20mL of ethyl acetate, stirring for 3 hours to separate out a large amount of solid, performing suction filtration, and pulping the solid twice by using ethyl acetate to obtain 26g of the imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester with the yield of 67.3%.
Table 4: preparation of imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester, examples under different reaction conditions:
example 3: imidazo [1,2-a ] pyridine-8-boronic acid pinacol ester;
the reaction equation is as follows:
the specific operation is as follows:
1) in a 500mL three-necked flask equipped with mechanical stirring, 30g of 2-amino-3-bromopyridine, 52.8g of pinacol ester diboron, 300mL of 1, 4-dioxane, 4.2g of Pd (dppf)2Cl259.3g of anhydrous potassium acetate, 3 times replaced by nitrogen, and then the mixture is heated to about 80 ℃ overnight. TLC detection reaction is complete, cooling and suction filtration are carried out, a filter cake is washed twice by 30mL dichloromethane, filtrate is concentrated to be dry, 200mL methanol and 20g activated carbon are added for decoloration, the mixture is stirred at room temperature overnight, and suction filtration is carried out. Concentrated to dryness to give an oil, slurried with 200mL of petroleum ether and 15mL of methyl t-butyl ether overnight, and filtered to give 28g of 2-aminopyridine-4-boronic acid pinacol ester, yield 72.8%.
Table 5: preparation of 2-aminopyridine-4-boronic acid pinacol ester, examples under different reaction conditions:
the reaction equation is as follows:
the specific operation is as follows:
2) in a 500mL three-necked flask, 28g of 2-aminopyridine-4-boronic acid pinacol ester, 36.6g of chloroacetaldehyde (40% aqueous solution), 280mL of ethanol were added. Heated and refluxed for about 4 hours. And (3) TLC detection, wherein the reaction is finished, saturated sodium bicarbonate aqueous solution is directly added to adjust the pH to be about =8, 20mL of ethyl acetate is added, a large amount of solid is separated out after stirring for 3 hours, the solid is filtered, and the solid is pulped twice by using ethyl acetate to obtain 18.8g of the imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester, and the yield is 60.8%.
Table 6: preparation of imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester, examples under different reaction conditions:
use of imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester in a coupling reaction:
the reaction formula is as follows:
imidazo [1,2-a ] pyridine-6-borates are typically coupled with halides or OTf compounds over palladium catalysts to form C-C bonded compounds.
The application one is as follows:
the imidazo [1,2-a ] pyridine-6-boric acid ester reacts with bromide, and the reaction is complete due to the higher activity ratio of the bromide.
Reaction with 5-bromobenzoxazole proceeds as follows:
imidazo [1,2-a ] pyridine-6-borate (1.0 eq), 5-bromobenzoxazole (1.0 eq), PdCl2(dppf)2 (3% mol) and sodium carbonate (2.0 eq) were added to a reaction flask, a mixed solvent (ethylene glycol dimethyl ether/water =5/1) was added, nitrogen was substituted, and the mixture was refluxed for 5 hours at elevated temperature. Cooling, filtering, extracting with ethyl acetate for 2 times, drying with anhydrous sodium sulfate, concentrating to obtain crude product, and purifying with silica gel column to obtain pure product (yield: 86%).
Imidazo [1,2-a ] pyridine-6-boronic acid esters can be reacted with heterocyclic chlorides.
The reaction with methyl 5-chloropyrazine-2-carboxylate was carried out as follows:
imidazo [1,2-a ] pyridine-6-borate (1.0 eq), 5-chloropyrazine-2-carboxylic acid methyl ester (1.0 eq), PdCl2(dppf)2 (3% mol) and sodium carbonate (2.0 eq) were added to a reaction flask, a mixed solvent (ethylene glycol dimethyl ether/water =5/1) was added, nitrogen was substituted, and the mixture was refluxed for 22 hours at elevated temperature. Cooling, filtering, adding 2N hydrochloric acid to adjust pH =7, extracting with ethyl acetate for 2 times, drying with anhydrous sodium sulfate, concentrating to dryness to obtain crude product, and purifying with silica gel column to obtain pure product (yield: 59%).
When the heterocyclic ring is pure in chlorine and iodine, the imidazo [1,2-a ] pyridine-6-borate reacts with iodine which is preferentially and more active, but also reacts with a small amount of chlorine to produce byproducts, so that the reaction is controlled by time and temperature.
The reaction with 2-chloro-3-iodopyridine was carried out as follows:
imidazo [1,2-a ] pyridine-6-borate (1.0 eq), 2-chloro-3-iodopyridine (1.0 eq), PdCl2(dppf)2 (3% mol) and sodium carbonate (2.0 eq) were added to a reaction flask, a mixed solvent (ethylene glycol dimethyl ether/water =5/1) was added, nitrogen was replaced, and the temperature was raised to 60 ℃ for reaction for 2 hours. Cooling, filtering, extracting with ethyl acetate for 2 times, drying with anhydrous sodium sulfate, concentrating to obtain crude product, and purifying with silica gel column to obtain pure product (yield: 72%).
Claims (7)
1. The preparation method of imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester and the derivative thereof is characterized by comprising the following steps: the preparation steps are as follows:
in preparing imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester:
1) dissolving 1.0eq of 2-amino-5-X pyridine of a compound shown in a formula (1) in an organic solvent with the concentration of 0.3-0.6M, adding the solution into a three-necked bottle with a thermometer, a condenser and nitrogen protection, uniformly stirring, and then adding 1.1-1.5eq of pinacol diboron and 2.0-3.0eq of anhydrous potassium acetate; then adding 0.01-0.1eq of palladium catalyst under the protection of nitrogen, replacing the reaction system with nitrogen for 3 times, starting to heat to 70-100 ℃, and stirring for 5-20 hours;
TLC detection reaction is complete, cooling, suction filtration is carried out by a Buchner funnel, a filter cake is washed for 2 times by dichloromethane, filtrate is concentrated and dried, methanol and activated carbon are added, stirring is carried out for 15-20 hours at room temperature until decolorization is carried out, suction filtration is carried out, filtrate is concentrated and dried under reduced pressure to obtain oily matter, petroleum ether and methyl tert-butyl ether solution are added, pulping is carried out for 15-20 hours, and the yield of 2-aminopyridine-5-boronic acid pinacol ester is obtained by filtration: 90-95%;
2) dissolving 1.0eq of 2-aminopyridine-5-boric acid pinacol ester in 0.3-0.6M organic solvent, adding the solution into a reaction bottle with a condenser tube, stirring, and dropwise adding 1.2-1.5eq of chloroacetaldehyde in 40% aqueous solution at normal temperature; heating and refluxing for 4-6 hours; and (3) after TLC detection reaction is finished, directly adding saturated sodium bicarbonate aqueous solution to adjust the pH to be 7.5-8.5, adding ethyl acetate under stirring, stirring for 3-5 hours to separate out a large amount of solid, performing suction filtration, pulping the solid twice by using ethyl acetate to obtain the product of imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester, wherein the yield is as follows: 60-70%;
when preparing imidazo [1,2-a ] pyridine-7-boronic acid pinacol ester, the compound of formula (1) is 2-amino-4-X pyridine, and the others are the same as those for preparing imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester;
when preparing imidazo [1,2-a ] pyridine-8-boronic acid pinacol ester, the compound of formula (1) is 2-amino-3-X pyridine, and the others are the same as those for preparing imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester;
and X is-Br, -I, -Cl or-OTf.
2. The method of claim 1, wherein: in the step 1), the organic solvent is selected from one of 1, 4-dioxane, DMF, DMSO and toluene.
3. The method of claim 2, wherein: in step 1), the organic solvent is selected from 1,4 dioxane.
4. The method of claim 1, wherein: in step 1), the palladium catalyst is selected from: PdCl2(dppf)2、Pd(PPh3)4、PdCl2(PPh3)2And Pd2(dba)3And/or tricyclohexylphosphorus.
5. The method of claim 1, wherein: in the step 1), the palladium catalyst is selected from PdCl2(dppf)2。
6. The method of claim 1, wherein: in the step 2), the organic solvent is one of ethanol, methanol and isopropanol.
7. The imidazo [1,2-a ] pyridine-6-boronic acid pinacol ester and the derivative thereof obtained by the preparation method according to any one of claims 1 to 6 are applied to suzuki coupling reaction and are subjected to coupling reaction with a halide, a TfO-R compound.
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| CN103601745A (en) * | 2013-11-26 | 2014-02-26 | 大连联化化学有限公司 | Preparation method of commonly used acetamidopyridine boronic acid pinacol ester |
| CN104478909A (en) * | 2014-11-19 | 2015-04-01 | 上海泰坦科技股份有限公司 | Synthetic process of heterocyclic boric acid compound |
| CN114181237A (en) * | 2021-12-01 | 2022-03-15 | 上海凌凯医药科技有限公司 | Synthesis method of 1-isopropylpyrazole-5-boronic acid pinacol ester |
| CN116283740A (en) * | 2023-03-27 | 2023-06-23 | 上海添泽生物医药有限公司 | Synthesis method of drug intermediate |
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| WO2010119285A1 (en) * | 2009-04-15 | 2010-10-21 | Astex Therapeutics Limited | Imidazo [1,2-a]pyridine derivatives as fgfr kinase inhibitors for use in therapy |
| CN102137859A (en) * | 2008-06-13 | 2011-07-27 | Astex治疗学有限公司 | Imidazolopyridine derivatives as inhibitors of receptor tyrosine kinases |
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| CN102137859A (en) * | 2008-06-13 | 2011-07-27 | Astex治疗学有限公司 | Imidazolopyridine derivatives as inhibitors of receptor tyrosine kinases |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601745A (en) * | 2013-11-26 | 2014-02-26 | 大连联化化学有限公司 | Preparation method of commonly used acetamidopyridine boronic acid pinacol ester |
| CN104478909A (en) * | 2014-11-19 | 2015-04-01 | 上海泰坦科技股份有限公司 | Synthetic process of heterocyclic boric acid compound |
| CN104478909B (en) * | 2014-11-19 | 2017-01-04 | 上海泰坦科技股份有限公司 | The synthesis technique of heterocyclic boronic acids compounds |
| CN114181237A (en) * | 2021-12-01 | 2022-03-15 | 上海凌凯医药科技有限公司 | Synthesis method of 1-isopropylpyrazole-5-boronic acid pinacol ester |
| CN114181237B (en) * | 2021-12-01 | 2024-02-23 | 上海凌凯医药科技有限公司 | Synthesis method of 1-isopropyl pyrazole-5-boric acid pinacol ester |
| CN116283740A (en) * | 2023-03-27 | 2023-06-23 | 上海添泽生物医药有限公司 | Synthesis method of drug intermediate |
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