CN102070518B - Synthesis of derivatives of substituted pyridine and azaindole - Google Patents
Synthesis of derivatives of substituted pyridine and azaindole Download PDFInfo
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- CN102070518B CN102070518B CN 201110025308 CN201110025308A CN102070518B CN 102070518 B CN102070518 B CN 102070518B CN 201110025308 CN201110025308 CN 201110025308 CN 201110025308 A CN201110025308 A CN 201110025308A CN 102070518 B CN102070518 B CN 102070518B
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- CN
- China
- Prior art keywords
- alkyl
- lithium
- butyl lithium
- azaindole
- substituted pyridine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000003222 pyridines Chemical class 0.000 title claims abstract description 8
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical class C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 title abstract 2
- 230000015572 biosynthetic process Effects 0.000 title abstract 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title abstract 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title abstract 2
- 238000003786 synthesis reaction Methods 0.000 title abstract 2
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 7
- -1 carboxylic acid halides Chemical class 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 125000002524 organometallic group Chemical group 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- BHNZEZWIUMJCGF-UHFFFAOYSA-N 1-chloro-1,1-difluoroethane Chemical compound CC(F)(F)Cl BHNZEZWIUMJCGF-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- JCIVHYBIFRUGKO-UHFFFAOYSA-N lithium;2,2,6,6-tetramethylpiperidine Chemical compound [Li].CC1(C)CCCC(C)(C)N1 JCIVHYBIFRUGKO-UHFFFAOYSA-N 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- 150000002642 lithium compounds Chemical class 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 3
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical class C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 2
- TYPVHTOETJVYIV-UHFFFAOYSA-N 2,4-dichloropyridine Chemical compound ClC1=CC=NC(Cl)=C1 TYPVHTOETJVYIV-UHFFFAOYSA-N 0.000 description 2
- IVVKBPOSXABZGQ-UHFFFAOYSA-N 4-chloro-3-iodopyridine-2-carboxamide Chemical compound NC(=O)C1=NC=CC(Cl)=C1I IVVKBPOSXABZGQ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
The invention relates to the synthesis of derivatives of substituted pyridine and azaindole. A substituted pyridine derivative is obtained by using 4-chlorin-2- pyridine carboxylic acid as an initial raw material to form 3-position carbanion under the action of a metal lithium compound and reacting the 3-position carbanion with various electrophilic reagents.
Description
Technical field
The present invention relates to the synthetic of substituted pyridines and 7-azaindole derivatives.
Background technology
Preparation 3 at present, the method for 4-dichloropyridine acid amides mainly contains following two kinds of methods: Journal of Medicinal Chemistry, 2009,52 (5), 1251-1254
The raw material 3 that Scheme 1 uses, 4-dichloropyridine and the silica-based isocyanic ester of reagent front three cost an arm and a leg, and production cost is higher; It is expensive 3 that Scheme 2 has not only used, and the 4-dichloropyridine is a raw material, and be difficult to close with product polarity of by product that generates removed.
Therefore, be necessary to select a kind of method of inexpensive, easy purifying end product newly.
Summary of the invention:
The present invention is a starting raw material with the inexpensive 4-chloro-2-VPP that has got, through the effect of metal lithiumation thing, with the electrophilic reagent reaction, forms 3 substituted pyridine compounds.
The method for preparing substituted pyridines of the present invention may further comprise the steps:
Wherein: X represents halogen, C
1-C
4Alkyl;
Said step is for being raw material with 4-chloro-2-VPP, under the effect of organo-metallic lithiumation thing, and contains halogen or C
1-C
4The electrophilic reagent reaction of alkyl obtains compound I I.
Said organo-metallic lithiumation thing is selected from n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, lithium diisopropyl amido, 2,2,6,6-tetramethyl piperidine lithium.
Said electrophilic reagent is selected from Br
2, I
2, Sesquichloratum, difluoro monochlorethane, halohydrocarbon, carboxylic acid halides, contain C
1-C
4The ester of alkyl or aldehyde ketone compound.
Said halogen refers to F, Cl, Br, I, preferred Cl, Br, I.
Beneficial effect of the present invention is:
One, route is simple, and reaction reagent is commonly used, and production cost is relatively low;
Two, product is single, and purifying is easy.
Embodiment:
Content of the present invention is done further to set forth through following embodiment and accompanying drawing, but does not limit the scope of the invention.
Embodiment 1: preparation 3,4-dichloropyridine acid amides (1)
At Ar
2Under the protection, (12g 76.2mmol) is dissolved among the anhydrous THF of 250ml, adds TMEDA (Tetramethyl Ethylene Diamine then with 4-chloro-2-VPP; 18.6g 159.9mmol), stirring at room is positioned over and stirs cooling in the cryotrap after all dissolving clearly; After temperature drops to-78 ℃, stir 0.5h, slowly drip n-BuLi (64ml, 2.5M; 159.9mmol), after dropwising, low temperature stirs 1h, drips the THF solution of Sesquichloratum (228mmol) then; Dropping time 1h drips afterreaction 1h, after temperature rises to room temperature, adds saturated aqueous ammonium chloride and Sulfothiorine cancellation reaction; 2N HCl transfers to pH=3, ethyl acetate extraction, and anhydrous sodium sulfate drying, solvent evaporated obtains compound S 2 and directly is used for next step.
S2 is joined in the single port bottle of 200ml, add thionyl chloride then, after stirring at room was dissolved clearly, elevated temperature was to refluxing; Reaction 2h boils off thionyl chloride, adds the 50ml ether; Use 50ml ammoniacal liquor, ice bath stirs 30min down, uses ethyl acetate extraction again; Anhydrous sodium sulfate drying concentrates back column chromatography (PE/EA=1/1) and obtains S2 4.6g, yield 32%.
Embodiment 2: preparation 3-iodo-4-chloro-picolinamide (2)
(12g 76.2mmol) is dissolved among the anhydrous THF of 250ml, and according to the method for embodiment 1, organo-metallic lithiumation thing is selected n-Butyl Lithium for use, and (64ml, 2.5M 159.9mmol), add I with 4-chloro-2-VPP
2(38.6g 152.4mmol), obtains 2 (4.6g, yield 31%).
Product to making is tested, and the result is following:
1H-NMR(500M，DMSO-d
6)δ8.44(d，1H)，7.95(s，2H)，7.68(d，1H)ppm。
Claims (3)
1. method for preparing substituted pyridines, its characteristic may further comprise the steps:
Wherein: X represents halogen, C
1-C
4Alkyl;
Said step is for being raw material with 4-chloro-2-VPP, under the effect of organo-metallic lithiumation thing, and contains halogen or C
1-C
4The electrophilic reagent reaction of alkyl obtains compound I I.
2. preparation method as claimed in claim 1 is characterized in that: organo-metallic lithiumation thing is selected from n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, lithium diisopropyl amido, 2,2,6,6-tetramethyl piperidine lithium.
3. preparation method as claimed in claim 1, it is characterized in that: electrophilic reagent is selected from Br
2, I
2, Sesquichloratum, difluoro monochlorethane, carboxylic acid halides, contain C
1-C
4The ester of alkyl or aldehyde ketone compound.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110025308 CN102070518B (en) | 2011-01-24 | 2011-01-24 | Synthesis of derivatives of substituted pyridine and azaindole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110025308 CN102070518B (en) | 2011-01-24 | 2011-01-24 | Synthesis of derivatives of substituted pyridine and azaindole |
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| CN102070518A CN102070518A (en) | 2011-05-25 |
| CN102070518B true CN102070518B (en) | 2012-05-02 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85107182A (en) * | 1985-09-27 | 1987-04-08 | 弗·哈夫曼-拉罗切有限公司 | Process for preparing monoamide derivatives of ethylenediamine |
| WO2008079873A3 (en) * | 2006-12-20 | 2008-10-02 | Bristol Myers Squibb Co | Thiazolyl compounds useful as kinase inhibitors |
| CN101535264A (en) * | 2006-11-08 | 2009-09-16 | 百时美施贵宝公司 | Pyridinone compounds |
-
2011
- 2011-01-24 CN CN 201110025308 patent/CN102070518B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85107182A (en) * | 1985-09-27 | 1987-04-08 | 弗·哈夫曼-拉罗切有限公司 | Process for preparing monoamide derivatives of ethylenediamine |
| CN101535264A (en) * | 2006-11-08 | 2009-09-16 | 百时美施贵宝公司 | Pyridinone compounds |
| WO2008079873A3 (en) * | 2006-12-20 | 2008-10-02 | Bristol Myers Squibb Co | Thiazolyl compounds useful as kinase inhibitors |
Non-Patent Citations (10)
| Title |
|---|
| Bieniek, Adam |
| Epsztajn, Jan |
| Epsztajn, Jan;Bieniek, Adam;Kowalska, Justyna A..Application of organolithium and related reagents in synthesis. Part 9. Synthesis and metalation of 4-chloropicolin- and 2-chloroisonicotinanilides. A useful method for preparation of 2,3,4-trisubstituted pyridines.《Tetrahedron》.1991,1697-706. * |
| Kowalska, Justyna A..Application of organolithium and related reagents in synthesis. Part 9. Synthesis and metalation of 4-chloropicolin- and 2-chloroisonicotinanilides. A useful method for preparation of 2,3,4-trisubstituted pyridines.《Tetrahedron》.1991,1697-706. |
| Mitsuhashi, Keiryo.Kinetic study on the conversion of pyridine- and quinolinecarboxylic acids to the corresponding trichloromethyl compounds.《Journal of Heterocyclic Chemistry》.1978,893-6. |
| Schroeder Gretchen M. et al.Discovery of N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4- ethoxy-1-(4-fluorophenyl)-2-oxo-1 |
| Schroeder, Gretchen M. et al.Discovery of N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4- ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a Selective and Orally Efficacious Inhibitor of the Met Kinase Superfamily.《Journal of Medicinal Chemistry》.2009,1251-1254. * |
| Takahashi, Kazuyuki |
| Takahashi, Kazuyuki;Takeda, Koichi;Mitsuhashi, Keiryo.Kinetic study on the conversion of pyridine- and quinolinecarboxylic acids to the corresponding trichloromethyl compounds.《Journal of Heterocyclic Chemistry》.1978,893-6. * |
| Takeda, Koichi |
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Address after: 210042 Xuanwu District, Xuanwu District, Jiangsu, Nanjing No. 699 -18 Applicant after: JIANGSU SIMCERE PHARMACEUTICAL R & D Co.,Ltd. Address before: 210042 -18, Xuanwu Avenue, Xuanwu District, Jiangsu, Nanjing, 669 Applicant before: JIANGSU SIMCERE PHARMACEUTICAL R & D Co.,Ltd. |
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