CN102153579B - Method for synthesizing N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester - Google Patents
Method for synthesizing N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester Download PDFInfo
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Abstract
The invention provides a novel method for synthesizing N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, which belongs to the technical field of chemical synthesis. The method comprises the following steps of: obtaining a target product, namely the N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester through a three-step reaction by taking N-(tert-butoxycarbonyl)-4-piperidone, 4-aminopyridine, trifluoromethanesulfonic anhydride, n-butyl lithium, bis(pinacolato)diboron, triethylamine, diisopropylamine and potassium acetate as raw materials, dichloromethane, tetrahydrofuran and dioxane as solvents, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) as a catalyst; and characterizing data through liquid chromatogram, nuclear magnetic spectrum and mass spectrum. By the method, the production period is short, the synthetic cost is low, a synthetic process is safe and reliable, and a post-treatment method is simple, convenient and quick; and the yield of a product is high (51 to 58 percent) and the purity of the product is high (98.2 to 99.6 percent).
Description
Technical field
The invention belongs to chemosynthesis technical field, relate to a kind of synthetic nitrogen-tertbutyloxycarbonyl-1,2,5, the novel method of 6-tetrahydropyridine-4-pinacol borate.
Background technology
Nitrogen-tertbutyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-pinacol borate are a kind of important medicine intermediates, the parent nucleus intermediate of multi-medicament, and at home and abroad be widely used in a lot of medicine intermediates synthetic, have very large market.
" biological organic and medical chemistry communication " (Bioorganic ﹠amp; Medicinal Chemistry Letters) 2008 18 phases disclosed a kind of nitrogen-tertbutyloxycarbonyl-1,2,5, the synthetic method of 6-tetrahydropyridine-4-pinacol borate, as starting raw material take nitrogen-tertbutyloxycarbonyl-4-piperidone, under the hexamethyldisilazane lithium effect, obtain 3 with two (trifluoromethane sulphonyl) imines of phenyl, 6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester, with the effect of duplex tetramethyl ethylene ketone boric acid ester, obtain nitrogen-tertbutyloxycarbonyl-1 again, 2,5,6-tetrahydropyridine-4-pinacol borate, total recovery reaches 27.2%,, purity 〉=98.1%.But two (trifluoromethane sulphonyl) imines of the phenyl that adopts in the document are that raw materials cost is higher, give nitrogen-tertbutyloxycarbonyl-1,2,5, the synthetic cost that increased of 6-tetrahydropyridine-4-pinacol borate, and yield is lower.Simultaneously, the last handling process of the method adopts the method for column chromatography, and cost is high, and the cycle is long.
Summary of the invention
The present invention seeks to provides a kind of synthetic nitrogen-tertbutyloxycarbonyl-1,2,5 in order to overcome problems of the prior art, the novel method of 6-tetrahydropyridine-4-pinacol borate.
Synthetic nitrogen-tertbutyloxycarbonyl of the present invention-1,2,5, the method for 6-tetrahydropyridine-4-pinacol borate comprises following processing step:
(1) two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine is synthetic
4-aminopyridine and the triethylamine mol ratio with 1:3 ~ 1:5 is dissolved in the methylene dichloride, in 0 ~ 5 ℃ of trifluoromethanesulfanhydride anhydride that slowly adds 2.2 ~ 3 times of 4-aminopyridine molar weights, stirring at room 1 ~ 2 hour, be cooled to 0 ~ 5 ℃, solution with water, saturated common salt water washing, the dichloromethane layer anhydrous sodium sulfate drying, evaporate to dryness obtains two (trifluoromethane sulphonyl) imines of crude product nitrogen-4-pyridine, obtains sterling with the normal hexane recrystallization.
Wherein, methylene dichloride is the dry methylene dichloride of crossing, and its consumption is 10 ~ 20 times of 4-aminopyridine quality.
(2) 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester synthetic
Two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine are dissolved in the tetrahydrofuran (THF), at-60 ~-70 ℃, this solution are joined in the tetrahydrofuran (THF) of Diisopropylamine, nitrogen-tertbutyloxycarbonyl-4-piperidone and n-Butyl Lithium, be warming up to room temperature, stir 10 ~ 16h; Add again saturated aqueous ammonium chloride, stirred layering 10 ~ 30 minutes; Organic layer saturated common salt water washing, anhydrous sodium sulfate drying filters, and boils off solvent, obtains 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester crude product; Crude product is dissolved in ethyl acetate, and uses filtered through silica gel, and evaporate to dryness obtains 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester sterling.
The consumption of Diisopropylamine is 1 ~ 1.5 times of nitrogen-tertbutyloxycarbonyl-4-piperidone molar weight.
The consumption of n-Butyl Lithium is 1 ~ 1.5 times of nitrogen-tertbutyloxycarbonyl-4-piperidone molar weight.
The consumption of two (trifluoromethane sulphonyl) the imines molar weights of nitrogen-4-pyridine is 1 ~ 1.5 times of nitrogen-tertbutyloxycarbonyl-4-piperidone molar weight.Above-mentioned solvents tetrahydrofurane is the dry tetrahydrofuran (THF) of crossing.
(3) nitrogen-tertbutyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-pinacol borate synthetic
In the environment of nitrogen protection, with 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester, duplex tetramethyl ethylene ketone boric acid ester, potassium acetate, [1, two (diphenylphosphino) ferrocene of 1'-] palladium chloride is with 1:(1 ~ 1.5): (2 ~ 3): the mixed in molar ratio of (0.05 ~ 0.1) is in dioxane, be heated to 80 ~ 100 ℃, stir 10 ~ 16h; Be cooled to room temperature, with 100 ~ 200 order filtered through silica gel, solvent evaporated obtains sterling nitrogen-tertbutyloxycarbonyl-1,2,5 with the normal hexane recrystallization, 6-tetrahydropyridine-4-pinacol borate.
Its concrete synthetic route is as follows:
Below by proton nmr spectra, mass spectrum, the methods such as high performance liquid chromatography, fusing point test characterize the compound that the present invention synthesizes.
1. the proton nmr spectra data are as follows:
H-NMR?(400MHz,?CDCl3):?
δ=6.492?(s,?1H),?3.968-3.981(d,?2H),?3.451-3.478(t,?2H),?2.248-2.261(t,?2H),?1.488(s,?9H),?1.291(s,?12H)。
Wherein chemical shift
δ=6.492 (s, 1H) be hydrogen on the two keys of piperidine ring, 3.968-3.981 (d, 2H) is that piperidine ring is near the methylene radical hydrogen of two keys, 3.451-3.478 (t, 2H) be the methylene radical hydrogen of the close N atom of piperidine ring, 2.248-2.261 (t, 2H) is that piperidine ring is near the methylene radical hydrogen of B atom, 1.488 (s, 9H) be tertiary butyl hydrogen on the Boc group, 1.291 (s, 12H) are four methyl hydrogen on the boric acid ester.The nuclear magnetic resonance hydrogen spectruming determining result is defined as nitrogen-tertbutyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-pinacol borate.
2. the mass spectrograph determination data is as follows:
EI-MS?(m/z,?%)?310,?332。
This compound molecular weight is 309, occurs 310 peak in the spectrogram, is compound hydrogenation quasi-molecular ions, and 332 peak is that compound adds the sodium ion peak.The mass spectroscopy result is defined as nitrogen-tertbutyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-pinacol borate.
3, high performance liquid chromatography:
Purity is 98.2 ~ 99. 6%.
4, fusing point analysis:
Fusing point is 100-102 ℃.
Above-mentioned, the proton nmr spectra of analysis-by-synthesis, mass spectrum, high performance liquid chromatography, fusing point test show that the finished product that the present invention synthesizes are nitrogen-tertbutyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-pinacol borate, and purity is qualified.Its structural formula is:
Product yield is 51～58%.
Synthetic method of the present invention compared with prior art has the following advantages:
1, the present invention is with nitrogen-tertbutyloxycarbonyl-4-piperidone, 4-aminopyridine, trifluoromethanesulfanhydride anhydride, n-Butyl Lithium, duplex tetramethyl ethylene ketone boric acid ester, triethylamine, Diisopropylamine, potassium acetate is raw material, with methylene dichloride, tetrahydrofuran (THF), dioxane is solvent, with [1, two (diphenylphosphino) ferrocene of 1'-] palladium chloride is catalyzer, by three-step reaction, obtains target product nitrogen-tertbutyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-pinacol borate.Its operational path section is short,, simplified synthesis technique, shortened the production cycle, reduced synthetic cost.
2, aftertreatment technology of the present invention adopts and filters, the methods such as recrystallization, and easy to operate, cost is low.
3, the yield of product of the present invention high (being 51～58%), product purity high (being 98.2 ~ 99. 6%).
Embodiment
To synthetic nitrogen-tertbutyloxycarbonyl of the present invention-1,2,5, the method for 6-tetrahydropyridine-4-pinacol borate is described further below by specific embodiment.
Embodiment one
(1) two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine is synthetic
4-aminopyridine and the triethylamine mol ratio take 1:3 is dissolved in the dry methylene dichloride (consumption is as 10 times of the 4-aminopyridine quality) of crossing, in 0 ℃ of trifluoromethanesulfanhydride anhydride that slowly is added dropwise to 2.2 times of 4-aminopyridine molar weights, time for adding is 1 hour, drip and finished rear stirring at room 1 hour, be cooled to 0 ℃, solution with water, the saturated common salt water washing, the dichloromethane layer anhydrous sodium sulfate drying, evaporate to dryness gets crude product to two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine.Crude product obtains sterling with the normal hexane recrystallization, yield 80%.
(2) 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester synthetic
Diisopropylamine is dissolved in the dry tetrahydrofuran (THF) (consumption of tetrahydrofuran (THF) is 10 times of Diisopropylamine quality) of crossing; under the environment of nitrogen protection; slowly be added dropwise to n-Butyl Lithium (consumption is 1.2 times of nitrogen-tertbutyloxycarbonyl-4-piperidone molar weight) in-60 ℃, time for adding is 1 hour.Dripping Bi Houzai-60 ℃ stirred 1 hour.
Nitrogen-tertbutyloxycarbonyl-4-piperidone is dissolved in dry tetrahydrofuran (THF) (consumption is 10 times of nitrogen-tertbutyloxycarbonyl-4-piperidone quality), at-60 ℃, this solution slowly is added dropwise in the tetrahydrofuran solution of above-mentioned Diisopropylamine, time for adding is 1 hour.Drip to finish at-60 ℃ and stirred 1 hour.
Two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine are dissolved in dry tetrahydrofuran (THF) (consumption is 10 times of two (trifluoromethane sulphonyl) the imines quality of nitrogen-4-pyridine).At-60 ℃, slowly be added dropwise in the tetrahydrofuran solution of above-mentioned Diisopropylamine and nitrogen-tertbutyloxycarbonyl-4-piperidone mixing, time for adding is 1 hour.Slowly rise to room temperature after drip finishing, stirred 10 hours.At room temperature, slowly add saturated aqueous ammonium chloride (consumption is 10 times of nitrogen-tertbutyloxycarbonyl-4-piperidone quality), stirred 10 minutes, layering, water layer is with ethyl acetate extraction three times (consumption that extracts ethyl acetate is 10 times of nitrogen-tertbutyloxycarbonyl-4-piperidone quality) at every turn, merge organic layer, and use the saturated common salt water washing, anhydrous sodium sulfate drying filters, and boils off solvent, obtain 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester crude product, dissolving crude product is in ethyl acetate, and uses filtered through silica gel, evaporate to dryness, obtain 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester sterling, yield 80%.
(3) nitrogen-tertbutyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-pinacol borate synthetic
In the environment of nitrogen protection; with 3; 6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester, duplex tetramethyl ethylene ketone boric acid ester, potassium acetate, [1; two (diphenylphosphino) ferrocene of 1'-] palladium chloride with the mixed in molar ratio of 1:1:2:0.05 in dioxane; be heated to 80 ℃, stirred 10 hours.Be cooled to room temperature, use filtered through silica gel, solvent evaporated obtains sterling nitrogen-tertbutyloxycarbonyl-1,2,5 with the normal hexane recrystallization, 6-tetrahydropyridine-4-pinacol borate, yield 80%.
Nitrogen-tertbutyloxycarbonyl-1,2,5, the total recovery of 6-tetrahydropyridine-4-pinacol borate is 53%, purity is 98.2%.
Embodiment two
(1) two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine is synthetic
4-aminopyridine and the triethylamine mol ratio take 1:3.5 is dissolved in the dry methylene dichloride (consumption is as 10 times of the 4-aminopyridine quality) of crossing, in 0 ℃ of trifluoromethanesulfanhydride anhydride that slowly is added dropwise to 2.5 times of 4-aminopyridine molar weights, time for adding is 2 hours, drips to finish rear stirring at room 1 hour; Be cooled to about 0 ℃, solution with water, the saturated common salt water washing, the dichloromethane layer anhydrous sodium sulfate drying, evaporate to dryness, get crude product to two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine, two (trifluoromethane sulphonyl) imines of crude product nitrogen-4-pyridine obtain sterling with the normal hexane recrystallization, yield 85%.
(2) 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester synthetic
Diisopropylamine is dissolved in the dry tetrahydrofuran (THF) of crossing (consumption of tetrahydrofuran (THF) is 12 times of Diisopropylamine quality); Under the environment of nitrogen protection, slowly be added dropwise to n-Butyl Lithium (the n-Butyl Lithium consumption is 1.2 times of nitrogen-tertbutyloxycarbonyl-4-piperidone molar weight) at-70 ℃, time for adding is 2 hours; Dripping Bi Houzai-60 ℃ stirred 1 hour.
Nitrogen-tertbutyloxycarbonyl-4-piperidone is dissolved in dry tetrahydrofuran (THF) (consumption of tetrahydrofuran (THF) is 10 times of nitrogen-tertbutyloxycarbonyl-4-piperidone quality), at-60 ℃, this solution slowly is added dropwise in the dry tetrahydrofuran solution of above-mentioned Diisopropylamine, time for adding is 2 hours.Drip to finish at-60 ℃ and stirred 1 hour.
Two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine are dissolved in dry tetrahydrofuran (THF) (consumption of tetrahydrofuran (THF) is 12 times of two (trifluoromethane sulphonyl) the imines quality of nitrogen-4-pyridine), slowly are added dropwise in the tetrahydrofuran solution that above-mentioned Diisopropylamine and nitrogen-tertbutyloxycarbonyl-4-piperidone mix (dropwising in 1 hour) at-60 ℃.Slowly rise to room temperature after drip finishing, stirred 12 hours.At room temperature, slowly add saturated aqueous ammonium chloride (consumption of saturated aqueous ammonium chloride is 10 times of nitrogen-tertbutyloxycarbonyl-4-piperidone quality), stirred 10 minutes, layering, water layer is with ethyl acetate extraction three times (consumption that extracts ethyl acetate is 10 times of nitrogen-tertbutyloxycarbonyl-4-piperidone quality) at every turn, merge organic layer, and use the saturated common salt water washing, anhydrous sodium sulfate drying filters, and boils off solvent, obtain 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester crude product, dissolving crude product is in ethyl acetate, and uses filtered through silica gel, evaporate to dryness, obtain 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester sterling, yield 82%.
(3) nitrogen-tertbutyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-pinacol borate synthetic
In the environment of nitrogen protection; with 3; 6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester, duplex tetramethyl ethylene ketone boric acid ester, potassium acetate, [1; two (diphenylphosphino) ferrocene of 1'-] in the mixed in molar ratio and dioxane of palladium chloride with 1:1:2:0.06; be heated to 85 ℃, stirred 12 hours.Be cooled to room temperature, use filtered through silica gel, solvent evaporated obtains sterling nitrogen-tertbutyloxycarbonyl-1,2,5 with the normal hexane recrystallization, 6-tetrahydropyridine-4-pinacol borate, yield 82%.
Nitrogen-tertbutyloxycarbonyl-1,2,5, the total recovery of 6-tetrahydropyridine-4-pinacol borate is 57%, purity is 98.9%.
Embodiment three
(1) two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine is synthetic
4-aminopyridine and the triethylamine mol ratio take 1:4 is dissolved in the dry methylene dichloride of crossing (consumption of methylene dichloride is as 13 times of the 4-aminopyridine quality), slowly be added dropwise to the trifluoromethanesulfanhydride anhydride of 2.2 times of 4-aminopyridine molar weights in about 0 ℃, time for adding is 1 hour; Drip and finished rear stirring at room 1 hour, be cooled to 5 ℃, solution with water, the saturated common salt water washing, the dichloromethane layer anhydrous sodium sulfate drying, evaporate to dryness gets crude product to two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine, two (trifluoromethane sulphonyl) imines of crude product nitrogen-4-pyridine obtain sterling with the normal hexane recrystallization, yield 81%.
(2) 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester synthetic
Diisopropylamine is dissolved in the dry tetrahydrofuran (THF) of crossing (consumption of tetrahydrofuran (THF) is 12 times of Diisopropylamine quality), under the environment of nitrogen protection, at-65 ℃, slowly be added dropwise to n-Butyl Lithium (the n-Butyl Lithium consumption is 1.2 times of nitrogen-tertbutyloxycarbonyl-4-piperidone molar weight, and time for adding is 1.5 hours); Dripping Bi Houzai-60 ℃ stirred 1.5 hours.
Nitrogen-tertbutyloxycarbonyl-4-piperidone is dissolved in dry tetrahydrofuran (THF) (consumption of tetrahydrofuran (THF) is 11 times of nitrogen-tertbutyloxycarbonyl-4-piperidone quality), at-65 ℃, this solution slowly is added dropwise in the dry tetrahydrofuran solution of above-mentioned Diisopropylamine, time for adding is 1 hour.Drip to finish at-60 ℃ and stirred 1 hour.
Two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine are dissolved in (consumption of tetrahydrofuran (THF) is 11 times of two (trifluoromethane sulphonyl) the imines quality of nitrogen-4-pyridine) in the dry tetrahydrofuran (THF),-60 ℃, this solution slowly is added dropwise in the tetrahydrofuran solution of above-mentioned Diisopropylamine and nitrogen-tertbutyloxycarbonyl-4-piperidone mixing, time for adding is 2 hours.Slowly rise to room temperature after drip finishing, stirred 10 hours.At room temperature, slowly add saturated aqueous ammonium chloride (consumption of saturated aqueous ammonium chloride is 11 times of nitrogen-tertbutyloxycarbonyl-4-piperidone quality), stirred 10 minutes, layering, water layer is with ethyl acetate extraction three times (consumption that extracts ethyl acetate is 10 times of nitrogen-tertbutyloxycarbonyl-4-piperidone quality) at every turn, merge organic layer, and use the saturated common salt water washing, anhydrous sodium sulfate drying filters, and boils off solvent, obtain 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester crude product, dissolving crude product is in ethyl acetate, and uses filtered through silica gel, evaporate to dryness, obtain 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester sterling, yield 85%.
(3) nitrogen-tertbutyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-pinacol borate synthetic
In the environment of nitrogen protection; with 3; 6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester, duplex tetramethyl ethylene ketone boric acid ester, potassium acetate, [1; two (diphenylphosphino) ferrocene of 1'-] palladium chloride with the mixed in molar ratio of 1:1.2:2:0.08 in dioxane; be heated to 90 ℃, stirred 16 hours.Be cooled to room temperature, use filtered through silica gel, solvent evaporated obtains sterling nitrogen-tertbutyloxycarbonyl-1,2,5 with the normal hexane recrystallization, 6-tetrahydropyridine-4-pinacol borate, yield 85%.
Nitrogen-tertbutyloxycarbonyl-1,2,5, the total recovery of 6-tetrahydropyridine-4-pinacol borate is 58%, purity is 98.6%.
Embodiment four
(1) two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine is synthetic
4-aminopyridine and the triethylamine mol ratio take 1:5 is dissolved in the dry methylene dichloride of crossing (consumption of methylene dichloride is as 20 times of the 4-aminopyridine quality), in 0 ℃ of trifluoromethanesulfanhydride anhydride that slowly is added dropwise to 2.5 times of 4-aminopyridine molar weights, time for adding is 2 hours; Drip and finished rear stirring at room 2 hours, be cooled to 0 ℃, solution with water, the saturated common salt water washing, dichloromethane layer anhydrous sodium sulfate drying, evaporate to dryness, get crude product to two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine, crude product obtains sterling with the normal hexane recrystallization, yield 82%.
(2) 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester synthetic
Diisopropylamine is dissolved in the dry tetrahydrofuran (THF) of crossing (consumption of tetrahydrofuran (THF) is 13 times of Diisopropylamine quality), under the environment of nitrogen protection, at-60 ℃, slowly be added dropwise to n-Butyl Lithium (the n-Butyl Lithium consumption is 1.4 times of nitrogen-tertbutyloxycarbonyl-4-piperidone molar weight, and time for adding is 2 hours); Dripping Bi Houzai-70 ℃ stirred 1 hour.
Nitrogen-tertbutyloxycarbonyl-4-piperidone is dissolved in the dry tetrahydrofuran (THF) (consumption of tetrahydrofuran (THF) is 10 times of nitrogen-tertbutyloxycarbonyl-4-piperidone quality), at-70 ℃, this solution slowly is added drop-wise in the tetrahydrofuran solution of above-mentioned Diisopropylamine, time for adding is 1 hour.Drip to finish at-70 ℃ and stirred 1 hour.
Two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine are dissolved in (consumption of tetrahydrofuran (THF) is 10 times of two (trifluoromethane sulphonyl) the imines quality of nitrogen-4-pyridine) in the dry tetrahydrofuran (THF), this solution slowly is added dropwise in the tetrahydrofuran solution that above-mentioned Diisopropylamine and nitrogen-tertbutyloxycarbonyl-4-piperidone mixes at-70 ℃, time for adding is 1 hour.Slowly rise to room temperature after drip finishing, stirred 10 hours.At room temperature, (consumption of saturated aqueous ammonium chloride is 12 times of nitrogen-tertbutyloxycarbonyl-4-piperidone quality slowly to add saturated aqueous ammonium chloride, stirred 15 minutes), layering, water layer is with ethyl acetate extraction three times (consumption that extracts ethyl acetate is 12 times of nitrogen-tertbutyloxycarbonyl-4-piperidone quality) at every turn, merge organic layer, and use the saturated common salt water washing, anhydrous sodium sulfate drying filters, and boils off solvent, obtain 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester crude product, dissolving crude product is in ethyl acetate, and uses filtered through silica gel, evaporate to dryness, obtain 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester sterling, yield 85%.
(3) nitrogen-tertbutyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-pinacol borate synthetic
In the environment of nitrogen protection; with 3; 6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester, duplex tetramethyl ethylene ketone boric acid ester, potassium acetate, [1; two (diphenylphosphino) ferrocene of 1'-] palladium chloride with the mixed in molar ratio of 1:1:2:0.09 in dioxane; be heated to 90 ℃, stirred 15 hours.Be cooled to room temperature, use filtered through silica gel, solvent evaporated obtains sterling nitrogen-tertbutyloxycarbonyl-1,2,5 with the normal hexane recrystallization, 6-tetrahydropyridine-4-pinacol borate, yield 82%.
Nitrogen-tertbutyloxycarbonyl-1,2,5, the total recovery of 6-tetrahydropyridine-4-pinacol borate is 57%, purity is 99.1%.
Embodiment five
(1) two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine is synthetic
4-aminopyridine and the triethylamine mol ratio take 1:5 is dissolved in the dry methylene dichloride of crossing (consumption of methylene dichloride is as 20 times of the 4-aminopyridine quality), in 5 ℃ of trifluoromethanesulfanhydride anhydrides that slowly are added dropwise to 3 times of 4-aminopyridine molar weights, time for adding is 2 hours, drip and finished rear stirring at room 2 hours, be cooled to 5 ℃, solution with water, the saturated common salt water washing, the dichloromethane layer anhydrous sodium sulfate drying, evaporate to dryness, get crude product to two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine, two (trifluoromethane sulphonyl) imines of crude product nitrogen-4-pyridine obtain sterling with the normal hexane recrystallization, yield 82%.
(2) 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester synthetic
Diisopropylamine is dissolved in the dry tetrahydrofuran (THF) of crossing (consumption of tetrahydrofuran (THF) is 15 times of Diisopropylamine quality), under the environment of nitrogen protection, slowly be added dropwise to n-Butyl Lithium (the n-Butyl Lithium consumption is 1.5 times of nitrogen-tertbutyloxycarbonyl-4-piperidone molar weight, and time for adding is 2 hours) at-70 ℃; Dripping Bi Houzai-70 ℃ stirred 2 hours.
Nitrogen-tertbutyloxycarbonyl-4-piperidone is dissolved in the dry tetrahydrofuran (THF) (consumption of tetrahydrofuran (THF) is 15 times of nitrogen-tertbutyloxycarbonyl-4-piperidone quality), at-70 ℃, this solution slowly is added drop-wise in the tetrahydrofuran solution of above-mentioned Diisopropylamine, time for adding is 2 hours.Drip to finish at-70 ℃ and stirred 2 hours.
Two (trifluoromethane sulphonyl) imines of nitrogen-4-pyridine are dissolved in (consumption of tetrahydrofuran (THF) is 15 times of two (trifluoromethane sulphonyl) the imines quality of nitrogen-4-pyridine) in the dry tetrahydrofuran (THF), at-70 ℃, slowly be added drop-wise in the tetrahydrofuran solution of above-mentioned Diisopropylamine and nitrogen-tertbutyloxycarbonyl-4-piperidone mixing, time for adding is 2 hours.Slowly rise to room temperature after drip finishing, stirred 16 hours.At room temperature, (consumption of saturated aqueous ammonium chloride is 15 times of nitrogen-tertbutyloxycarbonyl-4-piperidone quality slowly to add saturated aqueous ammonium chloride, stirred 30 minutes), layering, water layer is with ethyl acetate extraction three times (consumption that extracts ethyl acetate is 15 times of nitrogen-tertbutyloxycarbonyl-4-piperidone quality) at every turn, merge organic layer, and use the saturated common salt water washing, anhydrous sodium sulfate drying filters, and boils off solvent, obtain 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester crude product, dissolving crude product is in ethyl acetate, and uses filtered through silica gel, evaporate to dryness, obtain 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester sterling, yield 82%.
(3) nitrogen-tertbutyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-pinacol borate synthetic
In the environment of nitrogen protection; with 3; 6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester, duplex tetramethyl ethylene ketone boric acid ester, potassium acetate, [1; two (diphenylphosphino) ferrocene of 1'-] palladium chloride with the mixed in molar ratio of 1:1.5:3:0.1 in dioxane; be heated to 100 ℃, stirred 16 hours.Be cooled to room temperature, use filtered through silica gel, solvent evaporated obtains sterling nitrogen-tertbutyloxycarbonyl-1,2,5 with the normal hexane recrystallization, 6-tetrahydropyridine-4-pinacol borate.
Nitrogen-tertbutyloxycarbonyl-1,2,5, the total recovery of 6-tetrahydropyridine-4-pinacol borate is 55%, purity is 99.6%.
Claims (2)
1. nitrogen-tertbutyloxycarbonyl-1,2,5, the synthetic method of 6-tetrahydropyridine-4-pinacol borate comprises following processing step:
(1) two (trifluoromethane sulphonyl) amine of nitrogen-4-pyridine is synthetic
4-aminopyridine and the triethylamine mol ratio with 1:3 ~ 1:5 is dissolved in the methylene dichloride, in 0 ~ 5 ℃ of trifluoromethanesulfanhydride anhydride that slowly adds 2.2 ~ 3 times of 4-aminopyridine molar weights, stirring at room 1 ~ 2 hour, be cooled to 0 ~ 5 ℃, solution with water, saturated common salt water washing, the dichloromethane layer anhydrous sodium sulfate drying, evaporate to dryness obtains two (trifluoromethane sulphonyl) amine of crude product nitrogen-4-pyridine, obtains sterling with the normal hexane recrystallization;
The structure of two (trifluoromethane sulphonyl) amine of described nitrogen-4-pyridine is:
(2) 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester synthetic
Two (trifluoromethane sulphonyl) amine of nitrogen-4-pyridine are dissolved in the tetrahydrofuran (THF), at-60 ~-70 ℃, this solution are joined in the tetrahydrofuran solution of Diisopropylamine, nitrogen-tertbutyloxycarbonyl-4-piperidone and n-Butyl Lithium, be warming up to room temperature, stir 10 ~ 16h; Add again saturated aqueous ammonium chloride, stirred layering 10 ~ 30 minutes; Organic layer saturated common salt water washing, anhydrous sodium sulfate drying filters, and boils off solvent, obtains 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester crude product; Crude product is dissolved in ethyl acetate, and uses filtered through silica gel, and evaporate to dryness obtains 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester sterling;
The consumption of described Diisopropylamine is 1 ~ 1.5 times of nitrogen-tertbutyloxycarbonyl-4-piperidone molar weight;
The consumption of described n-Butyl Lithium is 1 ~ 1.5 times of nitrogen-tertbutyloxycarbonyl-4-piperidone molar weight;
The consumption of two (trifluoromethane sulphonyl) the amine molar weights of described nitrogen-4-pyridine is 1 ~ 1.5 times of nitrogen-tertbutyloxycarbonyl-4-piperidone molar weight;
Above-mentioned solvents tetrahydrofurane is the dry tetrahydrofuran (THF) of crossing;
Described 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base] structure of-1 (2H)-pyridine carboxylic acid tert-butyl ester is:
(3) nitrogen-tertbutyloxycarbonyl-1,2,5,6-tetrahydropyridine-4-pinacol borate synthetic
In the environment of nitrogen protection, with 3,6-dihydro-4-[[(trifluoromethyl) sulphonyl] the oxygen base]-1 (2H)-pyridine carboxylic acid tert-butyl ester, duplex tetramethyl ethylene ketone boric acid ester, potassium acetate, [1, two (diphenylphosphino) ferrocene of 1'-] palladium chloride is with 1:(1 ~ 1.5): (2 ~ 3): the mixed in molar ratio of (0.05 ~ 0.1) is in dioxane, be heated to 80 ~ 100 ℃, stir 10 ~ 16h; Be cooled to room temperature, with 100 ~ 200 order filtered through silica gel, solvent evaporated obtains sterling nitrogen-tertbutyloxycarbonyl-1,2,5 with the normal hexane recrystallization, 6-tetrahydropyridine-4-pinacol borate;
Described nitrogen-tertbutyloxycarbonyl-1,2,5, the structure of 6-tetrahydropyridine-4-pinacol borate is:
2. nitrogen-tertbutyloxycarbonyl-1,2,5 as claimed in claim 1, the synthetic method of 6-tetrahydropyridine-4-pinacol borate is characterized in that: the consumption of methylene dichloride is 10 ~ 20 times of 4-aminopyridine quality in the step (1).
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