CN104876929A - Synthesis method and application of 1,2,3,4-tetrahydronaphthyridine compound - Google Patents

Synthesis method and application of 1,2,3,4-tetrahydronaphthyridine compound Download PDF

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CN104876929A
CN104876929A CN201510253313.2A CN201510253313A CN104876929A CN 104876929 A CN104876929 A CN 104876929A CN 201510253313 A CN201510253313 A CN 201510253313A CN 104876929 A CN104876929 A CN 104876929A
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tetrahydronaphthyridderivates
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phenyl
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chloride
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CN104876929B (en
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张珉
熊彪
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South China University of Technology SCUT
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South China University of Technology SCUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention belongs to the technical field of pharmaceutical chemical synthesis and in particular relates to a synthesis method and application of a 1,2,3,4-tetrahydronaphthyridine compound. The synthesis method of the 1,2,3,4-tetrahydronaphthyridine compound comprises the following steps: in a reactor, adding a compound with adjacent methyl alcohol and amino substituted groups, alcohol, a metal catalyst, a ligand and a solvent, then adding alkali as an accelerant, introducing inert gas, stirring for reacting for 1-48 hours at the temperature of 40-150 DEG C, and then separating and purifying, so that the 1,2,3,4-tetrahydronaphthyridine compound is obtained. The synthesis method of the 1,2,3,4-tetrahydronaphthyridine compound has the advantages that the operation is safe and simple, the raw material cost is low, and the industrial production is facilitated. The 1,2,3,4-tetrahydronaphthyridine compound can be used for synthesizing 1-(2-methyl sulfydryl)-pyrimidine-4-yl)-7-phenyl-1,2,3,4-tetrahydro-1,8-naphthyridine, and further an active pharmaceutical ingredient N-phenethyl-4-(-7-phenyl-3,4-dihydro-1,8-naphthyridine-1(2H)-yl-2-amine is prepared.

Description

A kind of synthetic method of 1,2,3,4-Tetrahydronaphthyridderivates compounds and application
Technical field
The invention belongs to medication chemistry synthesis technical field, be specifically related to a kind of synthetic method and application of 1,2,3,4-Tetrahydronaphthyridderivates compounds.
Background technology
1,2,3,4-Tetrahydronaphthyridderivates compounds matter is the nitrogenous compound that a class has biological and pharmacoligical activities, is the important feature skeleton of some natural product and medicine.This compounds has very strong antagonistic action to non-peptide protein, vitronectin and integral protein acceptor, can be used as the antioxidant of lipid film and low-density lipoprotein, and to anti-inflammatory, eliminate pain, there is great utility treatment diabetes aspect.In addition, 1,2,3,4-Tetrahydronaphthyridderivates compounds is also important raw material, the intermediate of a class, has important purposes in organic synthesis.Therefore, the synthesis of 1,2,3,4-Tetrahydronaphthyridderivates is paid close attention to always widely.
The synthetic method of 1,2,3,4-traditional Tetrahydronaphthyridderivates compounds is with PA, acrylate for raw material, and by intermolecular addition, the polystep reactions such as the reductive action of polyphosphoric acid dehydration and borine carry out establishing target compound.Due to acrylate or the high malicious susceptibility-to-corrosion of polyphosphoric acid class material, and the working conditions of borine requires harsh, whole building-up process complex steps, easily cause environmental pollution, the production of serious threat people and living safety, so be extremely restricted (M.Wijtmans in industrial application, Angew.Chem.Int.Ed.2003,42,4370-4373; M.Wijtmans, J.Org.Chem.2004,69,9215-9223).
In recent years, some other synthesis 1,2, the method of 3,4-Tetrahydronaphthyridderivates is also in the news successively, mainly contains: the ammonolysis reaction of (1) 2-amino-3-picoline and Tetra hydro Phthalic anhydride, again through the condensation of NBS bromination and methyl phenyl ketone, finally use palladium carbon catalytic reduction (S.R.Nagarajan, U.S.Pat.0092538,2004 under high pressure hydrogen; H.Kroth, PCT Int.045383,2011; H.N.Nguyen, Z.J.Wang, Tetrahedron Lett, 2007,48,7460-7463; K.Leonard, Bioorg.Med.Chem.Lett.2005,15,2679-2684); (2) naphthyridines is prepared, then through palladium carbon catalytic reduction (T.-G.Nam, N.A.Porter, J.Am.Chem.Soc.2007,129,10211-10219 under high pressure hydrogen with the Freedlander reaction of aminopyridine formaldehyde and aromatic ketone; S.R.Nagarajan, U.S.Pat.0092538,2004), but still there is synthesis step complexity and the unmanageable shortcoming of condition in above technology.
Summary of the invention
In order to solve the shortcoming and defect part of above prior art, primary and foremost purpose of the present invention is the synthetic method providing a kind of 1,2,3,4-Tetrahydronaphthyridderivates compounds.
Another object of the present invention is to provide the application of a kind of 1,2,3,4-Tetrahydronaphthyridderivates compounds in Buchwald-Hartwig linked reaction (Buchwald-Hartwig reaction).
The object of the invention is achieved through the following technical solutions:
A kind of synthetic method of 1,2,3,4-Tetrahydronaphthyridderivates compounds, comprises the following steps:
In the reactor, add compound 1, alcohol, metal catalyst, part and solvent, then to add alkali be promotor, pass into rare gas element, stirring reaction 1 ~ 48 hour at 40 ~ 150 DEG C, is cooled to room temperature, dilute reaction solution after reaction terminates, filter, remove solvent under reduced pressure and obtain crude product, purifying through column chromatography obtains 1,2,3,4-Tetrahydronaphthyridderivates compounds;
Described compound 1 refers to the nitrogen heterocyclic with adjacent methyl alcohol and amino-substituent, comprises compound, 3-amino-2-4-hydroxymethylpiperidine, 4-amino-3-4-hydroxymethylpiperidine or the 2-amino-3-methylol piperazine with formula (1) structure; Described alcohol refers to alcohol, the hexalin with formula (2) structure, pyridine ethanol, 1,2,3,4-tetrahydrochysene-1-naphthols or 5,6,7,8-tetrahydrochysene-oxine;
Wherein, R 1and R 2for identical or not identical phenyl, methyl, ethyl, methoxyl group, halogenic substituent or hydrogen; R 3and R 4for identical or not identical hydrogen, methyl, ethyl, propyl group, phenyl, benzyl, 4-chloro-phenyl-or 4-trifluoromethyl.
Partial reaction equation involved by above-mentioned synthetic method is as follows:
Preferred schlenk pipe (history Ranque tube) of described reactor; Described rare gas element is nitrogen or argon gas.
Described compound 1 is 1:(1 ~ 20 with the mol ratio of alcohol); Preferred 1:1.
Described metal catalyst is one or more the mixing in neutralized verdigris, copper sulfate, iron(ic) chloride, palladium, bis-triphenylphosphipalladium palladium dichloride, cyclooctadiene iridium chloride, iridous chloride, ten dicarbapentaborane three rutheniums, two (the 4-isopropyl methyl phenyl) ruthenium of dichloro and bi triphenyl phosphine-1H-indenes ruthenium chloride; Described part is one or more the mixing in two diphenylphosphine-9,9-dimethyl xanthene (Xantphos) of triphenylphosphine, phenanthroline, Isosorbide-5-Nitrae-bis-(diphenylphosphine) butane, 2-phenylpyridine and 4,5-.
Described solvent is one or more the mixing in acetonitrile, tetrahydrofuran (THF), DMF, dimethyl sulfoxide (DMSO), toluene, methyl alcohol, tertiary amyl alcohol and water.
Described alkali is one or more the mixing in sodium carbonate, salt of wormwood, cesium carbonate, sodium methylate, potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol lithium, Tetramethyl Ethylene Diamine and triethylamine; The add-on of alkali and the mol ratio of compound 1 are (0.5 ~ 5): 1; Preferred 0.5:1.
Described column chromatography elutriant used of purifying is sherwood oil: the volume ratio of ethyl acetate is (0.5 ~ 50): the mixed solvent of 1.
Above-mentioned 1,2,3, the 4-application of Tetrahydronaphthyridderivates compounds in Buchwald-Hartwig linked reaction.
Described application comprises following applying step:
(1) add 1,2,3,4-tetrahydrochysene-7-phenyl-1,8-naphthyridines, the chloro-2-of 4-(first sulfydryl) pyrimidine, metal catalyst, part, alkali and solvent in the reactor, be filled with N 2protection, at 100 DEG C of stirring reactions after 10 hours, stops heating and stirs, be cooled to room temperature, cool to 0 DEG C, use saturated ammonium chloride solution cancellation, reaction solution removes solvent through washing, extraction, filtration and vacuum rotary steam successively, pass through column chromatographic isolation and purification again, obtain intermediate product 1-(2-first sulfydryl)-pyrimidine-4-yl)-7-phenyl-1,2,3,4-tetrahydrochysene-1,8-naphthyridines;
(2) intermediate product of step (1) is joined in methylene dichloride, be cooled to 0 DEG C, add metachloroperbenzoic acid to react, saturated sodium bicarbonate solution cancellation is added after reaction terminates, reaction solution revolves to boil off through extraction, washing, drying and vacuum successively and desolventizes, and obtains thick sulfoxide product; Thick sulfoxide product is joined and has dissolved in the N-Methyl pyrrolidone solution of phenylethylamine, pour N 2protection; at 100 DEG C of stirring reactions after 10 hours; stop heating and stir, being cooled to room temperature, dilute reaction solution; filter; vacuum rotary steam removes solvent, then by column chromatographic isolation and purification, obtains N-styroyl-4-(-7-phenyl-3; 4-dihydro-1,8-naphthyridines-1 (2H)-Ji-2-amine.
Described metal catalyst is one or more the mixing in neutralized verdigris, copper sulfate, iron(ic) chloride, palladium, bis-triphenylphosphipalladium palladium dichloride, cyclooctadiene iridium chloride, iridous chloride, ten dicarbapentaborane three rutheniums, two (the 4-isopropyl methyl phenyl) ruthenium of dichloro and bi triphenyl phosphine-1H-indenes ruthenium chloride; Described part is one or more the mixing in two diphenylphosphine-9,9-dimethyl xanthene (Xantphos) of triphenylphosphine, phenanthroline, Isosorbide-5-Nitrae-bis-(diphenylphosphine) butane, 2-phenylpyridine and 4,5-.
Preparation method of the present invention and the product tool obtained have the following advantages and beneficial effect:
The present invention take alcohol as raw material one-step synthesis 1,2,3,4-Tetrahydronaphthyridderivates compounds, has that synthesis step is simple, operational safety (without the need to using high pressure hydrogen), advantages of nontoxic raw materials and cheap and easy to get, that synthetic method is good to functional group compatibility, Atom economy is a high advantage.
Accompanying drawing explanation
Fig. 1 and Fig. 2 is respectively hydrogen spectrogram and the carbon spectrogram of embodiment 1 products therefrom;
Fig. 3 and Fig. 4 is respectively hydrogen spectrogram and the carbon spectrogram of embodiment 2 products therefrom;
Fig. 5 and Fig. 6 is respectively hydrogen spectrogram and the carbon spectrogram of embodiment 3 products therefrom;
Fig. 7 and Fig. 8 is respectively hydrogen spectrogram and the carbon spectrogram of embodiment 4 products therefrom;
Fig. 9 and Figure 10 is respectively hydrogen spectrogram and the carbon spectrogram of embodiment 5 products therefrom;
Figure 11 and Figure 12 is respectively hydrogen spectrogram and the carbon spectrogram of embodiment 6 products therefrom;
Figure 13 and Figure 14 is respectively hydrogen spectrogram and the carbon spectrogram of embodiment 7 products therefrom;
Figure 15 and Figure 16 is respectively hydrogen spectrogram and the carbon spectrogram of embodiment 8 gained intermediate product;
Figure 17 and Figure 18 is respectively hydrogen spectrogram and the carbon spectrogram of embodiment 8 gained object product.
Embodiment
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
Embodiment 1
0.5 mmole 2-amino-3-4-hydroxymethylpiperidine, 0.5 mmole 1-(p-methylphenyl) ethanol, 0.25 mmole potassium tert.-butoxide is added in schlenk pipe, 0.005 mmole ten dicarbapentaborane three ruthenium, 0.015 mmole 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene, 1.2 milliliters of tertiary amyl alcohols, be filled with N 2protection; at 130 DEG C of stirring reactions after 5 hours; stop heating and stir, being cooled to room temperature, dilute reaction solution; filter; vacuum rotary steam removes solvent, then by column chromatographic isolation and purification, obtains target product; the sherwood oil of column chromatography elutriant used to be volume ratio be 12:1: ethyl acetate mixed solvent, productive rate 90%.
Respectively as depicted in figs. 1 and 2, structural characterization data are as follows for the hydrogen spectrogram of products therefrom and carbon spectrogram:
1H NMR(400MHz,CDCl 3):δ＝7.78(d,J＝8.0Hz,2H),7.18-7.23(m,3H),6.91(d,J＝7.2Hz,1H),5.01(brs,1H),3.42(s,2H),2.75(t,J＝6.0Hz,2H),2.38(s,3H),1.90-1.95(m,2H)。
13C NMR(100MHz,CDCl 3):δ＝155.78,153.40,138.24,137.18,136.39,129.21,126.68,115.01,109.37,41.51,26.46,21.30,21.24。
IR(KBr):3235,3054,2923,2851,1602,1564,1531,1455,1281,1179,1117,792cm -1cm -1。
MS(EI,m/z):224.[M] +。
HRMS(ESI):Calcd.for C 15H 16N 2[M+H] +:225.1386；found:225.1390。
Structure according to above inferred from input data products therefrom is shown below:
Embodiment 2
0.5 mmole 2-amino-3-4-hydroxymethylpiperidine, 0.5 mmole hexalin, 0.25 mmole potassium tert.-butoxide is added in schlenk pipe, 0.005 mmole ten dicarbapentaborane three ruthenium, 0.015 mmole 4,5-two diphenylphosphine-9,9-dimethyl xanthene, 1.2 milliliters of tertiary amyl alcohols, be filled with N 2protection; at 130 DEG C of stirring reactions after 10 hours; stop heating and stir, being cooled to room temperature, dilute reaction solution; filter; vacuum rotary steam removes solvent, then by column chromatographic isolation and purification, obtains target product; the sherwood oil of column chromatography elutriant used to be volume ratio be 12:1: ethyl acetate mixed solvent, productive rate 61%.
Respectively as shown in Figure 3 and Figure 4, structural characterization data are as follows for the hydrogen spectrogram of products therefrom and carbon spectrogram:
1H NMR(400MHz,CDCl 3):δ6.86(s,1H),4.73(brs,1H),3.37(s,2H),2.66(m,4H),2.56(t,J＝6.0Hz,2H),1.89(m,2H),1.80(m,2H),1.73(m,2H)。
13C NMR(101MHz,CDCl 3):δ153.94,152.38,137.59,141.95,120.51,113.81,41.74,31.93,27.82,26.33,23.41,23.25,21.83。
IR(KBr):3253,3101,2928,2845,1617,1532,1400,1273,1125,757cm -1。
MS(EI,m/z):188[M] +。
HRMS(ESI):Calcd.for C 12H 16N 2[M+H] +:189.1386；found:189.1388。
Obtain structure according to above inferred from input data products therefrom to be shown below:
Embodiment 3
0.5 mmole 2-amino-3-4-hydroxymethylpiperidine, 0.5 mmole Pentyl alcohol, 0.25 mmole potassium tert.-butoxide is added in schlenk pipe, 0.005 mmole ten dicarbapentaborane three ruthenium, 0.015 mmole 4,5-two diphenylphosphine-9,9-dimethyl xanthene, 1.2 milliliters of tertiary amyl alcohols, be filled with N 2protection; at 130 DEG C of stirring reactions after 12 hours; stop heating and stir, being cooled to room temperature, dilute reaction solution; filter; vacuum rotary steam removes solvent, then by column chromatographic isolation and purification, obtains target product; the sherwood oil of column chromatography elutriant used to be volume ratio be 12:1: ethyl acetate mixed solvent, productive rate 58%.
Respectively as shown in Figure 5 and Figure 6, structural characterization data are as follows for the hydrogen spectrogram of products therefrom and carbon spectrogram:
1H NMR(400MHz,CDCl 3):δ7.67(s,1H),6.98(s,1H),4.81(brs,1H),3.38(s,2H),2.70(t,J＝6.0Hz,2H),2.39(t,J＝7.2Hz 2H),1.90(m,2H),1.55(m,2H),0.91(t,J＝7.2Hz,3H)。
13C NMR(101MHz,CDCl 3):δ154.65,145.20,136.75,126.44,115.75,41.68,34.25,26.65,24.70,21.56,13.67。
IR(KBr):3246,3005,2957,2854,1617,1538,1401,1266,1104,762,724cm -1。
MS(EI,m/z):176[M] +。
HRMS(ESI):Calcd.for C 11H 16N 2[M+H] +:177.1386；found:177.1387。
Obtain structure according to above inferred from input data products therefrom to be shown below:
Embodiment 4
0.5 mmole 6-methyl-2-amino-3-4-hydroxymethylpiperidine, 0.5 mmole 1-(rubigan) ethanol, 0.25 mmole potassium tert.-butoxide is added in schlenk pipe, 0.005 mmole ten dicarbapentaborane three ruthenium, 0.015 mmole 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene, 1.2 milliliters of tertiary amyl alcohols, be filled with N 2protection; at 130 DEG C of stirring reactions after 16 hours; stop heating and stir, being cooled to room temperature, dilute reaction solution; filter; vacuum rotary steam removes solvent, then by column chromatographic isolation and purification, obtains target product; the sherwood oil of column chromatography elutriant used to be volume ratio be 12:1: ethyl acetate mixed solvent, productive rate 43%.
Respectively as shown in Figure 7 and Figure 8, structural characterization data are as follows for the hydrogen spectrogram of products therefrom and carbon spectrogram:
1H NMR(400MHz,CDCl 3):δ7.84(d,J＝7.6Hz,2H),7.36(d,J＝8.4Hz,2H),7.22(d,J＝7.6Hz,1H),6.91(d,J＝7.6Hz,1H),4.86(brs,1H),3.58(s,1H),2.58-2.80(m,2H),1.96(m,1H),1.53-1.64(m,1H),1.26(d,J＝6.4Hz,3H)。
13C NMR(101MHz,CDCl 3):δ155.96,152.57,138.35,136.78,134.08,128.59,127.81,114.95,109.41,47.24,29.41,25.69,22.46。
IR(KBr):3420,2922,2843,1593,1462,1341,1273,1084,801,755cm -1。
MS(EI,m/z):258[M] +。
HRMS(ESI):Calcd.for C 15H 15ClN 2[M+H] +:259.0997；found:259.1002。
Obtain structure according to above inferred from input data products therefrom to be shown below:
Embodiment 5
0.5 mmole 3-amino-2-4-hydroxymethylpiperidine, 0.5 mmole phenylethyl alcohol, 0.5 mmole potassium tert.-butoxide is added in schlenk pipe, 0.005 mmole ten dicarbapentaborane three ruthenium, 0.015 mmole 4,5-two diphenylphosphine-9,9-dimethyl xanthene, 1.2 milliliters of tertiary amyl alcohols, be filled with N 2protection; at 130 DEG C of stirring reactions after 10 hours; stop heating and stir, being cooled to room temperature, dilute reaction solution; filter; vacuum rotary steam removes solvent, then by column chromatographic isolation and purification, obtains target product; the sherwood oil of column chromatography elutriant used to be volume ratio be 12:1: ethyl acetate mixed solvent, productive rate 46%.
Respectively as shown in Figure 9 and Figure 10, structural characterization data are as follows for the hydrogen spectrogram of products therefrom and carbon spectrogram:
1H NMR(400MHz,CDCl 3):δ8.09(s,1H),7.52(d,J＝7.2Hz,2H),7.43(t,J＝7.6Hz,2H),7.35(t,J＝7.2Hz,1H),6.91(s,1H),3.91(brs,1H),3.34(s,2H),2.97(t,J＝6.0Hz,2H),2.06(m,2H)。
13C NMR(101MHz,CDCl 3):δ141.80,140.77,138.52,136.51,135.26,128.85,127.59,126.98,118.55,41.60,30.08,21.86。
IR(KBr):3249,3019,2929,2849,1601,1532,1458,1399,1260,1188,1013,874,758,695cm -1。
MS(EI,m/z):210[M] +。
HRMS(ESI):Calcd.for C 14H 14N 2[M+H] +:211.1230；found:211.1233。
Obtain structure according to above inferred from input data products therefrom to be shown below:
Embodiment 6
0.5 mmole 2-amino-3-methylol piperazine, 0.5 mmole 1-phenylethyl alcohol, 0.25 mmole potassium tert.-butoxide is added in schlenk pipe, 0.005 mmole ten dicarbapentaborane three ruthenium, 0.015 mmole 4,5-two diphenylphosphine-9,9-dimethyl xanthene, 1.2 milliliters of tertiary amyl alcohols, be filled with N 2protection; at 130 DEG C of stirring reactions after 12 hours; stop heating and stir, being cooled to room temperature, dilute reaction solution; filter; vacuum rotary steam removes solvent, then by column chromatographic isolation and purification, obtains target product; the sherwood oil of column chromatography elutriant used to be volume ratio be 12:1: ethyl acetate mixed solvent, productive rate 63%.
Respectively as is illustrated by figs. 11 and 12, structural characterization data are as follows for the hydrogen spectrogram of products therefrom and carbon spectrogram:
1H NMR(400MHz,CDCl3):δ7.83(d,J＝7.6Hz,2H),7.37(t,J＝7.2Hz,2H),7.25(s,1H),6.91(d,J＝7.6Hz,1H),6.68(d,J＝7.6Hz,1H),5.09(brs,1H),3.49(s,2H),3.38(s,2H)。
13C NMR(101MHz,CDCl3):δ146.77,145.28,139.99,128.43,128.16,127.13,125.90,119.32,110.94,40.78,40.52。
IR(KBr):3405,3236,2921,2853,1603,1530,1505,1354,1277,1223,1127,1022,816,778,752,697cm -1。
MS(EI,m/z):211[M] +。
HRMS(ESI):Calcd.for C 13H 13N 3[M+H] +:212.1182；found:212.1187。
Obtain structure according to above inferred from input data products therefrom to be shown below:
Embodiment 7
0.5 mmole 2-amino-3-methylol-4 is added in schlenk pipe, 6-phenylbenzene pyridine, 1.5 mmole ethanol, 0.25 mmole potassium tert.-butoxide, 0.005 mmole ten dicarbapentaborane three ruthenium, 0.015 mmole 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene, 1.2 milliliters of tertiary amyl alcohols, be filled with N 2protection; at 130 DEG C of stirring reactions after 12 hours; stop heating and stir, being cooled to room temperature, dilute reaction solution; filter; vacuum rotary steam removes solvent, then by column chromatographic isolation and purification, obtains target product; the sherwood oil of column chromatography elutriant used to be volume ratio be 12:1: ethyl acetate mixed solvent, productive rate 72%.
Respectively as shown in Figure 13 and Figure 14, structural characterization data are as follows for the hydrogen spectrogram of products therefrom and carbon spectrogram:
1H NMR(400MHz,CDCl3):δ7.90-7.94(m,2H),7.30-7.46(m,8H),6.92(s,1H),5.32(brs,1H),3.37(s,2H),2.66(t,J＝6.0Hz,2H),1.83(m,2H)。
13C NMR(101MHz,CDCl3):δ156.29,153.61,149.72,140.00,139.94,128.63,128.48,128.27,128.20,127.63,126.69,112.04,111.34,41.59,25.06,21.70。
IR(KBr):3265,3021,2836,1576,1493,1450,1401,1314,1267,1191,1068,837,765,695cm -1。
MS(EI,m/z):286[M] +。
HRMS(ESI):Calcd.for C 20H 18N 2[M+H] +:287.1543；found:287.1546。
Obtain structure according to above inferred from input data products therefrom to be shown below:
Embodiment 8
(1) in schlenk pipe, 1.0 mmoles 1 are added, 2,3,4-tetrahydrochysene-7-phenyl-1,8-naphthyridines (prepare by the method for embodiment 6, raw material 2-amino-3-methylol piperazine is replaced with 2-amino-3-4-hydroxymethylpiperidine), the chloro-2-of 1.5 mmole 4-(first sulfydryl) pyrimidine, 0.05 mmole palladium, 0.05 mmole Xantphos, 2.0 mmole sodium methylates and 2.0 milliliters of toluene, be filled with N 2protection; at 100 DEG C of stirring reactions after 10 hours, stop heating and stir, being cooled to room temperature; cool to 0 DEG C; use saturated ammonium chloride solution cancellation, washing extraction is filtered, and vacuum rotary steam removes solvent; pass through column chromatographic isolation and purification again; obtain intermediate product, the sherwood oil of column chromatography elutriant used to be volume ratio be 8:1: ethyl acetate mixed solvent, productive rate 71%.
Respectively as shown in Figure 15 and Figure 16, structural characterization data are as follows for the hydrogen spectrogram of gained intermediate product and carbon spectrogram:
1H NMR(400MHz,CDCl3):δ8.18(d,J＝5.6Hz,1H),7.97(d,J＝7.2Hz,2H),7.82(d,J＝6.0Hz,1H),7.35-7.54(m,5H),4.21(t,J＝4.8Hz,2H),2.85(d,J＝6.0Hz,2H),2.57(s,3H),2.04(m,2H)。
13C NMR(101MHz,CDCl3):δ179.84,160.00,155.16,152.84,151.90,138.75,138.31,128.88,128.78,126.41,122.25,114.64,106.37,44.91,26.95,22.62,14.13。
IR(KBr):3050,3013,2924,1600,1561,1530,1467,1436,1345,1316,1232,1203,1174,976,900,811,772,745,694cm -1。
MS(EI,m/z):334[M] +。
HRMS(ESI):Calcd.for C 19H 18N 4S[M+H] +:335.1325；found:335.1319。
Structure according to above inferred from input data gained intermediate product is shown below:
(2) in 25 milliliters of round-bottomed flasks, add 1-(2-first the sulfydryl)-pyrimidine-4-yl that 0.5 mmole step (1) obtains)-7-phenyl-1,2,3,4-tetrahydrochysene-1,8-naphthyridines, 5 milliliters of methylene dichloride, cool to 0 DEG C, add 0.75 mmole metachloroperbenzoic acid, keep low-temp reaction 30 minutes; After question response terminates, add saturated sodium bicarbonate solution cancellation.Collected organic layer, and by methylene dichloride repeatedly aqueous layer extracted, merge organic layer and wash with the sodium hydroxide solution of 1mol/L.Separatory, obtains organic layer, and with anhydrous sodium sulfate drying, removes solvent obtain thick sulfoxide product with vacuum rotary evaporator.In the middle of N-Methyl pyrrolidone solution sulfoxide crude product being joined the dissolving of 1.5mL 2.5 mmole phenylethylamine, pour nitrogen, react 10 hours under mixed solution being placed in 100 DEG C of conditions, stop heating and stir, be cooled to room temperature, dilute reaction solution, filters, and vacuum rotary steam removes solvent, pass through column chromatographic isolation and purification again, obtain target product, the sherwood oil of column chromatography elutriant used to be volume ratio be 5:1: ethyl acetate mixed solvent, productive rate 91%.
Respectively as shown in Figure 17 and Figure 18, structural characterization data are as follows for the hydrogen spectrogram of gained target product and carbon spectrogram:
1H NMR(400MHz,CDCl3):δ8.00(t,J＝6.4Hz,3H),7.18-7.50(m,11H),5.10(brs,1H),4.15(s,2H),3.69(q,J＝6.4Hz,2H),2.94(t,J＝6.4Hz,2H),2.81(t,J＝6.0Hz,2H),2.00(m,2H)。
13C NMR(101MHz,CDCl3):δ162.12,161.31,156.17,152.80,152.48,139.74,139.01,138.09,128.93,128.74,128.56,126.48,126.28,122.09,114.03,101.16,44.75,42.96,36.17,27.09,22.74。
IR(KBr):3256,3026,2928,2851,1606,1558,1517,1467,1409,1312,1265,1237,1182,1127,1073,1020,913,817,748,694,641cm -1。
MS(EI,m/z):407[M] +。
HRMS(ESI):Calcd.for C 26H 25N 5[M+H] +:408.2183；found:408.2192。
Obtain structure according to above inferred from input data gained target product to be shown below:
Reaction equation involved by the present embodiment is as follows:
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.

Claims (10)

1. the synthetic method of a Tetrahydronaphthyridderivates compounds, is characterized in that: comprise following synthesis step:
In the reactor, add compound 1, alcohol, metal catalyst, part and solvent, then to add alkali be promotor, pass into rare gas element, stirring reaction 1 ~ 48 hour at 40 ~ 150 DEG C, is cooled to room temperature, dilute reaction solution after reaction terminates, filter, remove solvent under reduced pressure and obtain crude product, purifying through column chromatography obtains 1,2,3,4-Tetrahydronaphthyridderivates compounds;
Described compound 1 refers to compound, 3-amino-2-4-hydroxymethylpiperidine, 4-amino-3-4-hydroxymethylpiperidine or the 2-amino-3-methylol piperazine with formula (1) structure; Described alcohol refers to alcohol, hexalin, pyridine ethanol, 1,2,3,4-tetrahydrochysene-1-naphthols or 5,6,7, the 8-tetrahydrochysene-oxine with formula (2) structure;
Wherein, R 1and R 2for identical or not identical phenyl, methyl, ethyl, methoxyl group, halogenic substituent or hydrogen; R 3and R 4for identical or not identical hydrogen, methyl, ethyl, propyl group, phenyl, benzyl, 4-chloro-phenyl-or 4-trifluoromethyl.
2. the synthetic method of a kind of 1,2,3,4-Tetrahydronaphthyridderivates compounds according to claim 1, is characterized in that: described reactor refers to that schlenk manages; Described rare gas element is nitrogen or argon gas.
3. the synthetic method of a kind of 1,2,3,4-Tetrahydronaphthyridderivates compounds according to claim 1, is characterized in that: described compound 1 is 1:(1 ~ 20 with the mol ratio of alcohol).
4. according to claim 1 a kind of 1,2,3, the synthetic method of 4-Tetrahydronaphthyridderivates compounds, is characterized in that: described metal catalyst is one or more the mixing in neutralized verdigris, copper sulfate, iron(ic) chloride, palladium, bis-triphenylphosphipalladium palladium dichloride, cyclooctadiene iridium chloride, iridous chloride, ten dicarbapentaborane three rutheniums, two (the 4-isopropyl methyl phenyl) ruthenium of dichloro and bi triphenyl phosphine-1H-indenes ruthenium chloride; Described part is one or more the mixing in two diphenylphosphine-9, the 9-dimethyl xanthene of triphenylphosphine, phenanthroline, Isosorbide-5-Nitrae-bis-(diphenylphosphine) butane, 2-phenylpyridine and 4,5-.
5. according to claim 1 a kind of 1, the synthetic method of 2,3,4-Tetrahydronaphthyridderivates compounds, it is characterized in that: described solvent is one or more the mixing in acetonitrile, tetrahydrofuran (THF), DMF, dimethyl sulfoxide (DMSO), toluene, methyl alcohol, tertiary amyl alcohol and water.
6. according to claim 1 a kind of 1,2,3, the synthetic method of 4-Tetrahydronaphthyridderivates compounds, is characterized in that: described alkali is one or more the mixing in sodium carbonate, salt of wormwood, cesium carbonate, sodium methylate, potassium tert.-butoxide, sodium tert-butoxide, trimethyl carbinol lithium, Tetramethyl Ethylene Diamine and triethylamine; The add-on of alkali and the mol ratio of compound 1 are (0.5 ~ 5): 1.
7. according to claim 1 a kind of 1,2, the synthetic method of 3,4-Tetrahydronaphthyridderivates compounds, is characterized in that: described column chromatography elutriant used of purifying is sherwood oil: the volume ratio of ethyl acetate is (0.5 ~ 50): the mixed solvent of 1.
8. 1,2,3, the 4-application of Tetrahydronaphthyridderivates compounds in Buchwald-Hartwig linked reaction described in any one of claim 1 ~ 7.
9. 1,2,3, the 4-application of Tetrahydronaphthyridderivates compounds in Buchwald-Hartwig linked reaction according to claim 8, is characterized in that described applying step is:
(1) add 1,2,3,4-tetrahydrochysene-7-phenyl-1,8-naphthyridines, the chloro-2-of 4-(first sulfydryl) pyrimidine, metal catalyst, part, alkali and solvent in the reactor, be filled with N 2protection, at 100 DEG C of stirring reactions after 10 hours, stops heating and stirs, be cooled to room temperature, cool to 0 DEG C, use saturated ammonium chloride solution cancellation, reaction solution removes solvent through washing, extraction, filtration and vacuum rotary steam successively, pass through column chromatographic isolation and purification again, obtain intermediate product 1-(2-first sulfydryl)-pyrimidine-4-yl)-7-phenyl-1,2,3,4-tetrahydrochysene-1,8-naphthyridines;
(2) intermediate product of step (1) is joined in methylene dichloride, be cooled to 0 DEG C, add metachloroperbenzoic acid to react, saturated sodium bicarbonate solution cancellation is added after reaction terminates, reaction solution revolves to boil off through extraction, washing, drying and vacuum successively and desolventizes, and obtains thick sulfoxide product; Thick sulfoxide product is joined and has dissolved in the N-Methyl pyrrolidone solution of phenylethylamine, pour N 2protection; at 100 DEG C of stirring reactions after 10 hours; stop heating and stir, being cooled to room temperature, dilute reaction solution; filter; vacuum rotary steam removes solvent, then by column chromatographic isolation and purification, obtains N-styroyl-4-(-7-phenyl-3; 4-dihydro-1,8-naphthyridines-1 (2H)-Ji-2-amine.
10. according to claim 91,2,3, the application of 4-Tetrahydronaphthyridderivates compounds in Buchwald-Hartwig linked reaction, is characterized in that: described metal catalyst is one or more the mixing in neutralized verdigris, copper sulfate, iron(ic) chloride, palladium, bis-triphenylphosphipalladium palladium dichloride, cyclooctadiene iridium chloride, iridous chloride, ten dicarbapentaborane three rutheniums, two (the 4-isopropyl methyl phenyl) ruthenium of dichloro and bi triphenyl phosphine-1H-indenes ruthenium chloride; Described part is one or more the mixing in two diphenylphosphine-9, the 9-dimethyl xanthene of triphenylphosphine, phenanthroline, Isosorbide-5-Nitrae-bis-(diphenylphosphine) butane, 2-phenylpyridine and 4,5-.
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