CN101429160B - Synthesis method of 1-R-4-amino-1,2,3,4-tetrahydroquinoline - Google Patents
Synthesis method of 1-R-4-amino-1,2,3,4-tetrahydroquinoline Download PDFInfo
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- CN101429160B CN101429160B CN2007100942046A CN200710094204A CN101429160B CN 101429160 B CN101429160 B CN 101429160B CN 2007100942046 A CN2007100942046 A CN 2007100942046A CN 200710094204 A CN200710094204 A CN 200710094204A CN 101429160 B CN101429160 B CN 101429160B
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- 238000001308 synthesis method Methods 0.000 title abstract 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 56
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 11
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 11
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- -1 benzyl halides Chemical class 0.000 claims description 14
- 238000010189 synthetic method Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 5
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 150000002561 ketenes Chemical class 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 abstract 2
- 239000003638 chemical reducing agent Substances 0.000 abstract 2
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 abstract 2
- 230000002194 synthesizing effect Effects 0.000 abstract 2
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 abstract 1
- 238000006722 reduction reaction Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- ZBVHSAIBQRUINV-UHFFFAOYSA-N 4-azido-1-methyl-3,4-dihydro-2H-quinoline Chemical compound CN1CCC(C2=CC=CC=C12)N=[N+]=[N-] ZBVHSAIBQRUINV-UHFFFAOYSA-N 0.000 description 2
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- YHHMNHMWVVSJEA-UHFFFAOYSA-N 1-benzyl-3,4-dihydro-2h-quinolin-4-amine Chemical compound C12=CC=CC=C2C(N)CCN1CC1=CC=CC=C1 YHHMNHMWVVSJEA-UHFFFAOYSA-N 0.000 description 1
- DAPOGWRBGOPUFG-UHFFFAOYSA-N 1-ethyl-3,4-dihydro-2h-quinolin-4-amine Chemical compound C1=CC=C2N(CC)CCC(N)C2=C1 DAPOGWRBGOPUFG-UHFFFAOYSA-N 0.000 description 1
- AXAMWBAMTKYVFO-UHFFFAOYSA-N 4-azido-1-ethyl-3,4-dihydro-2H-quinoline Chemical compound C(C)N1CCC(C2=CC=CC=C12)N=[N+]=[N-] AXAMWBAMTKYVFO-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 238000006898 Intramolecular Friedel-Crafts reaction Methods 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- JVSYNDALNVTNIQ-UHFFFAOYSA-N NC(CC1)c2ccccc2N1N Chemical compound NC(CC1)c2ccccc2N1N JVSYNDALNVTNIQ-UHFFFAOYSA-N 0.000 description 1
- JRAVZISMXMYFRP-PKNBQFBNSA-N O/N=C1/c2ccccc2NCC1 Chemical compound O/N=C1/c2ccccc2NCC1 JRAVZISMXMYFRP-PKNBQFBNSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Abstract
The present invention relates to a method for synthesizing 1-R-4-amino-1, 2, 3, 4-tetrahydroquinoline, which mainly solves the technical problems that the prior synthesis method is difficult to amplify, long in route, inconvenient in reaction operation, and the like. The invention adopts a technical proposal that the method for synthesizing 1-R-4-amino-1, 2, 3, 4-tetrahydroquinoline is characterized by comprising the following steps: a. 4-hydroxyquinoline is taken as a raw material and reacts with alkyl halogenated matter or benzyl halogenated matter in solvent to form ketene; b. the ketene dissolves in the solvent, and a reducing agent is added to the solvent so as to obtain corresponding alcohol; c. corresponding alcohol of anhydrous tetrahydrofuran dissolved in the solvent is added to diphenoxyphosphinyl azide so as to be transformed into corresponding azide; and d. the obtained azide is dissolved in the solvent, and the 1-R-4-amino-1, 2, 3, 4-tetrahydroquinoline is obtained by a hydrogenation or adding triphenyl phosphine chemical reduction method.
Description
Technical field:
The present invention relates to 1-R-4-amino-1,2,3, a kind of synthetic method of 4-tetrahydroquinoline.
Background technology:
1-alkyl-4-amino-1,2,3, the 4-tetrahydroquinoline has widespread use in pharmaceutical chemistry and organic synthesis.This compounds is synthetic as WO2005/42533A2 (2005/05/12), J.Chem.Soc., 1954,403-406 at present; FR806715,1936; Chem.Abstr., 1961,3600; J.Med.Chem., 8,1965,566-569 etc.Mainly, obtain corresponding ketone, after it is converted into oxime, obtain 1-alkyl-4-amino-1,2,3 behind the hydro-reduction through intramolecular Friedel-Crafts reaction by after corresponding mono-substituted alkyl benzene amine and propylene ester or the nitrile addition, the 4-tetrahydroquinoline, route is synthetic as follows:
In the above-mentioned existing method, one step of intramolecularly Friedel-Crafts reaction cyclisation is mainly undertaken by polyphosphoric acid, and this step polyphosphoric acid consumption is big, the temperature of reaction height, and post-processing difficulty is big, is difficult for amplifying.The water-soluble big extraction that is difficult for of this class ketone of part simultaneously.Can't obtain required product fast by these class methods.
Summary of the invention:
The objective of the invention is to develop a kind of comparatively easy and general 1-R-4-amino-1,2,3, the synthetic method of 4-tetrahydroquinoline.Mainly solve the difficult amplification of raw material in the present synthetic method, route is longer, technical problems such as operation inconvenience.
Technical scheme of the present invention: a kind of 1-R-4-amino-1,2,3, the synthetic method of 4-tetrahydroquinoline is characterized in that: may further comprise the steps: a, be raw material with the 4-hydroxyquinoline, generate ketenes with halogenated alkyl thing or the reaction of benzyl halides in solvent; B, ketenes is dissolved in the solvent, add reductive agent and obtain corresponding alcohol; C, the correspondent alcohol that will be dissolved in the solvent anhydrous tetrahydro furan add two phenoxy group phosphoryl azides and change corresponding nitrine into; D, the nitrine that obtains is dissolved in the solvent, by hydrogenation or add the triphenyl phosphorus method of reducing and obtain 1-R-4-amino-1,2,3, the 4-tetrahydroquinoline; Reaction formula is as follows:
In the above-mentioned technology, R is alkyl or the benzyl of C1～C20; RX is halogenated alkyl thing or the benzyl halides of C1～C20; The first step reaction solvent is methyl alcohol, ethanol, tetrahydrofuran (THF), toluene, acetonitrile etc.; Temperature of reaction is the reflux temperature that room temperature arrives solvent; The second step reductive agent is sodium borohydride, POTASSIUM BOROHYDRIDE, lithium aluminium hydride etc., and solvent is methyl alcohol, ethanol, tetrahydrofuran (THF) etc.; The three-step reaction temperature be 0 ℃ to room temperature; The 4th step can or be added the triphenyl phosphorus method of reducing by hydrogenation, and the hydrogenation catalyst system therefor is: palladium carbon, solvent are ethyl acetate, temperature of reaction: room temperature; Adding triphenyl phosphorus method of reducing solvent is tetrahydrofuran (THF) and water, and temperature of reaction is a room temperature.
Beneficial effect of the present invention:
It is low to the invention solves in the present synthetic method yield, operation inconvenience, and the preparation method is to different 1-alkyl-1,2,3, and 4-tetrahydroquinoline-4-ketone does not have shortcomings such as general applicability.The 4-hydroxyquinoline that this synthetic method can get with industrialization is a raw material, after adding halogenated alkyl thing, benzyl halides or bromo-acetic acid tert-butyl become ketenes, directly reduction obtains corresponding alcohol, it changes corresponding nitrine under the effect of two phenoxy group phosphoryl azides, after reduction, obtain 1-R-4-amino-1,2,3, the 4-tetrahydroquinoline.Process choice is reasonable, and raw material is simple and easy to, and the yield height is easy to amplify, and is suitable for the 1-R-4-amino-1,2,3 of synthetic all kinds of replacements, the 4-tetrahydroquinoline.
Embodiment:
Embodiment 1
6.1-methyl isophthalic acid H-quinoline-4-ketone is synthetic
Under the room temperature, (11.8g 82.8mmol) slowly is added drop-wise to 4-hydroxyquinoline (4g, 27.6 mmol) and K with methyl iodide
2CO
3(7.6g is in acetonitrile solution 55.2mmol).Drip and finish, reflux is spent the night.Then reaction solution is spin-dried for, adds the 200mL ethyl acetate in the residuum, stir 0.5 hour after-filtration, filtrate being spin-dried for obtains 1-methyl isophthalic acid H-quinoline-4-ketone (2.8g, yield 64%).
1H-NMR(400MHz，DMSO)：δ?8.14(d，J＝7.6Hz，1H)，7.94(d，J＝7.6Hz，1H)，7.72(t，J＝13.2Hz，1H)，7.63(d，J＝8.4Hz，1H)，7.37(t，J＝14.4Hz，1H)，6.01(d，J＝11.6Hz，2H)，3.78(s，3H).
2.1-methyl-4-hydroxyl-1,2,3,4-tetrahydroquinoline synthetic
(1g 6.3mmol) is dissolved in methyl alcohol, adds NaBH under the ice bath cooling with 1-methyl isophthalic acid H-quinoline-4-ketone
4(1.9g, 50.3mmol), stirred overnight at room temperature then.After reaction solution is used the frozen water cancellation, revolve to steam and remove methyl alcohol, the water ethyl acetate extraction is spin-dried for after the organic phase drying, and residuum obtains 1-methyl-4-hydroxyl-1,2,3 after crossing post, 4-tetrahydroquinoline (0.87g, 85%).
1H-NMR(400MHz，CDCl3)：δ7.22(m，J＝15.6Hz，2H)，6.67(m，J＝24Hz，2H)，4.73(m，J＝7.2Hz，1H)，3.39(m，J＝26.4Hz，1H)，3.16(m，J＝19.6Hz，1H)，2.94(s，3H)，2.01(m，J＝16.4Hz，2H).
3.1-methyl-4-azido--1,2,3,4-tetrahydroquinoline synthetic
With 1-methyl-4-hydroxyl-1,2,3, the 4-tetrahydroquinoline (0.1g, 0.6mmol) and two phenoxy group phosphoryl azides (0.25g 0.9mmol) is dissolved in anhydrous tetrahydro furan (10mL), ice bath cooling add down DBU (0.14g, 0.9mmol).Stirred overnight at room temperature then.Vacuum concentration removes and desolvates, and residuum is crossed post and obtained 1-methyl-4-azido--1,2,3,4-tetrahydroquinoline (0.09g, 82%).
1H-NMR(400MHz，CDCl3)：δ7.23(t，J＝8.4Hz，1H)，7.13(d，J＝9.2Hz，1H)，6.72(d，J＝8.4Hz，1H)，6.66(t，J＝14.4Hz，1H)，4.57(m，J＝6.4Hz，1H)，3.32(m，J＝36.4Hz，1H)，3.2(m，J＝18.8Hz，1H)，2.98(s，3H)，2.01(m，J＝51.6Hz，2H).
4.1-methyl-4-amino-1,2,3,4-tetrahydroquinoline synthetic
With 1-methyl-4-azido--1,2,3, (0.05g 0.3mmol) is dissolved in ethyl acetate (5mL) to the 4-tetrahydroquinoline, adds 10% PdJC (0.05g) then, feeds hydrogen, and normal temperature and pressure stirs down and spends the night.Remove by filter catalyzer, obtain 1-methyl-4-amino-1,2,3 after mother liquor is spin-dried for, 4-tetrahydroquinoline (0.043g, 100%).
1H-NMR(400MHz，CDCl3)：δ?7.23(t，J＝8.4Hz，1H)，7.13(d，J＝9.2Hz，1H)，6.72(d，J＝8.4Hz，1H)，6.66(t，J＝14.4Hz，1H)，4.03(m，J＝8.8Hz，1H)，3.32(m，J＝36.4Hz，1H)，3.2(m，J＝18.8Hz，1H)，2.92(s，3H)，2.13(s，2H)，2.08(m，J＝27.2Hz，1H)，1.88(m，J＝27.2Hz，1H).
Embodiment 2
1.1-ethyl-1H-quinoline-4-ketone is synthetic
Under the room temperature, with iodoethane (12.9g, 82.8mmol) slowly be added drop-wise to the 4-hydroxyquinoline (4g, 27.6mmol) and K
2CO
3(7.6g is in ethanolic soln 55.2mmol).Drip and finish, reflux is spent the night.Then reaction solution is spin-dried for, adds the 200mL ethyl acetate in the residuum, stir 0.5 hour after-filtration, filtrate being spin-dried for obtains 1-ethyl-1H-quinoline-4-ketone (2.86g, yield 60%).
1H-NMR(400MHz，DMSO)：δ8.17(d，J＝8Hz，1H)，7.99(d，J＝7.6Hz，1H)，7.72(m，J＝3.6Hz，2H)，7.36(m，J＝15.6Hz，1H)，6.04(d，J＝7.6Hz，1H)，4.26(q，J＝21.2Hz，2H)，1.32(t，3H).
2.1-ethyl-4-hydroxyl-1,2,3,4-tetrahydroquinoline synthetic
(1g 5.8mmol) is dissolved in ethanol, adds KBH under the ice bath cooling with 1-ethyl-1H-quinoline-4-ketone
4(2.49g, 46.2mmol), stirred overnight at room temperature then.After the cancellation of reaction solution usefulness frozen water, revolve to steam and remove ethanol, the water ethyl acetate extraction is spin-dried for after the organic phase drying, and residuum obtains 1-ethyl-4-hydroxyl-1,2,3 after crossing post, 4-tetrahydroquinoline (0.85g, 83%).
1H-NMR(400MHz，CDCl3)：δ?7.16(m，J＝34Hz，2H)，6.62(t，J＝45.2Hz，2H)，4.72(m，J＝4.8Hz，1H)，3.48(m，J＝54.8Hz，2H)，3.32(m，J＝36.4Hz，1H)，3.2(m，J＝18.8Hz，1H)，2.01(m，J＝68.8Hz，2H)，1.26(t，J＝19.2Hz，3H).
3.1-ethyl-4-azido--1,2,3,4-tetrahydroquinoline synthetic
With 1-ethyl-4-hydroxyl-1,2,3, the 4-tetrahydroquinoline (0.11g, 0.6mmol) and two phenoxy group phosphoryl azides (0.25g 0.9mmol) is dissolved in anhydrous tetrahydro furan (10mL), ice bath cooling add down DBU (0.14g, 0.9mmol).Stirred overnight at room temperature then.Vacuum concentration removes and desolvates, and residuum is crossed post and obtained 1-ethyl-4-azido--1,2,3,4-tetrahydroquinoline (0.1g, 80%).
1H-NMR(400MHz，CDCl3)：δ7.23(t，J＝8.4Hz，1H)，7.13(d，J＝9.2Hz，1H)，6.72(d，J＝8.4Hz，1H)，6.66(t，J＝14.4Hz，1H)，4.57(m，J＝6.4Hz，1H)，3.47(m，J＝54.8Hz，2H)，3.32(m，J＝36.4Hz，1H)，3.2(m，J＝18.8Hz，1H)，2.01(m，J＝51.6Hz，2H)，1.16(t，J＝21.6Hz，3H).
4.1-ethyl-4-amino-1,2,3,4-tetrahydroquinoline synthetic
With 1-ethyl-4-azido--1,2,3, the 4-tetrahydroquinoline (0.08g, 0.4mmol) and triphenyl phosphorus (0.42g 1.6mmol) is dissolved in anhydrous tetrahydro furan (5mL), adds 0.25mL water then, stirs under the room temperature and spends the night.Reaction solution is spin-dried for the back post of crossing obtains 1-ethyl-4-amino-1,2,3,4-tetrahydroquinoline (0.06g, 88%).
1H-NMR(400?MHz，CDCl3)：δ7.18(d，J＝7.2Hz，1H)，7.11(t，J＝16.8Hz，1H)，6.62(m，J＝16.8Hz，2H)，3.97(m，1H)，3.45-3.29(m，J＝64.8Hz，3H)，3.2(m，J＝21.2Hz，1H)，2.01(m，J＝31.6Hz，1H)，1.85(m，J＝26.8Hz，1H)，1.78(br，2H)，1.15(t，J＝14Hz，1H).
Embodiment 3
1.1-benzyl-1H-quinoline-4-ketone is synthetic
Under the room temperature, with the benzyl bromine (7g, 41.3mmol) slowly be added drop-wise to the 4-hydroxyquinoline (2g, 13.8mmol) and K
2CO
3(3.8g is in tetrahydrofuran solution 27.6mmol).Drip and finish, reflux is spent the night.Then reaction solution is spin-dried for, adds the 200mL ethyl acetate in the residuum, stir 0.5 hour after-filtration, filtrate being spin-dried for obtains 1-benzyl-1H-quinoline-4-ketone (1g, yield 31%).
1H-NMR(400MHz，DMSO)：δ8.21(q，J＝41.6Hz，2H)，7.59(m，J＝31.2Hz，2H)，7.35-7.20(m，6H)，6.14(d，J＝7.6Hz，1H)，5.52(s，2H).
2.1-benzyl-4-hydroxyl-1,2,3,4-tetrahydroquinoline synthetic
With 1-benzyl-1H-quinoline-4-ketone (1g 4.3mmol) is dissolved in anhydrous tetrahydro furan, under ice bath cooling, add lithium aluminium hydride (0.65g, 17mmol), stirred overnight at room temperature then.After the cancellation of reaction solution usefulness frozen water, revolve to steam and remove tetrahydrofuran (THF), the water ethyl acetate extraction is spin-dried for after the organic phase drying, and residuum obtains 1-benzyl-4-hydroxyl-1,2,3 after crossing post, 4-tetrahydroquinoline (0.86g, 85%).
1H-NMR(400MHz，CDCl3)：δ7.27-7.15(m，J＝46Hz，6H)，6.99(t，J＝21.6Hz，1H)，6.57(t，J＝14.8Hz，1H)，6.49(d，J＝8.4Hz，1H)，4.74(m，1H)，4.47(m，J＝38.4Hz，2H)，3.52(m，J＝27.2Hz，1H)，3.20(m，J＝20.4Hz，1H)，2.0(m，J＝44.4Hz，2H)，1.68(s，1H).
3.1-benzyl-4-azido--1,2,3,4-tetrahydroquinoline synthetic
With 1-benzyl-4-hydroxyl-1,2,3, the 4-tetrahydroquinoline (0.3g, 1.3mmol) and two phenoxy group phosphoryl azides (1.39g 5.0mmol) is dissolved in anhydrous tetrahydro furan (10mL), ice bath cooling add down DBU (0.77g, 5.0mmol).Stirred overnight at room temperature then.Vacuum concentration removes and desolvates, and residuum is crossed post and obtained 1-methyl-4-azido--1,2,3,4-tetrahydroquinoline (0.3g, 91%).
1H-NMR(400MHz，CDCl3)：δ?7.35(m，J＝14.8Hz，2H)，7.28(m，J＝12.8Hz，3H)，7.14(m，J＝18Hz，2H)，6.69(t，J＝14.4Hz，1H)，6.63(d，J＝8.4Hz，1H)，4.67(m，J＝6.4Hz，1H)，4.55(m，J＝38.4Hz，2H)，3.58(m，J＝27.6Hz，1H)，3.32(m，J＝19.2Hz，1H)，2.12(m，J＝57.6Hz，2H).
4.1-benzyl-4-amino-1,2,3,4-tetrahydroquinoline synthetic
With 1-benzyl-4-azido--1,2,3, the 4-tetrahydroquinoline (0.2g, 0.8mmol) and triphenyl phosphorus (0.8g 3.0mmol) is dissolved in anhydrous tetrahydro furan (5mL), adds 0.25mL water then, stirs under the room temperature and spends the night.Reaction solution is spin-dried for, crosses post and obtain 1-benzyl-4-amino-1,2,3,4-tetrahydroquinoline (0.16g, 90%).
1H-NMR(400MHz，CDCl3)：δ7.27-7.15(m，J＝46Hz，6H)，6.98(t，J＝24Hz，1H)，6.56(t，J＝23.2Hz，1H)，6.46(d，J＝8.0Hz，1H)，4.41(m，J＝46.8Hz，2H)，4.03(m，J＝9.2Hz，1H)，3.45(m，J＝26Hz，1H)，3.26(m，J＝30Hz，1H)，2.38(br，2H)，2.05(m，J＝39.6Hz，1H)，1.9(m，J＝28Hz，1H).
Embodiment 4
1.1-tert.-butyl acetate base-1H-quinoline-4-ketone is synthetic
Under the room temperature, with bromo-acetic acid tert-butyl (16g, 82.5mmol) slowly be added drop-wise to the 4-hydroxyquinoline (4g, 27.6mmol) and K
2CO
3(7.6g is in acetonitrile 55.2mmol) (40mL) solution.Drip and finish, reflux is spent the night.Then reaction solution is spin-dried for, adds the 200mL ethyl acetate in the residuum, stir 0.5 hour after-filtration, filtrate being spin-dried for obtains 1-tert.-butyl acetate base-1H-quinoline-4-ketone (5.0g, yield 70%).
1H-NMR(400MHz，DMSO)：δ8.46(d，J＝9.2Hz，1H)，7.67(t，J＝17.2Hz，1H)，7.54(d，J＝7.6Hz，1H)，7.4(t，J＝14.8Hz，1H)，7.23(d，J＝8.4Hz，1H)，6.34(d，J＝7.6Hz，1H)，4.72(s，2H)，1.44(s，9H).
2.1-tert.-butyl acetate base-4-hydroxyl-1,2,3,4-tetrahydroquinoline synthetic
(2g 7.7mmol) is dissolved in methyl alcohol, adds NaBH under the ice bath cooling with 1-tert.-butyl acetate base-1H-quinoline-4-ketone
4(1.2g, 31mmol), stirred overnight at room temperature then.After the cancellation of reaction solution usefulness frozen water, revolve to steam and remove methyl alcohol, the water ethyl acetate extraction is spin-dried for after the organic phase drying, and residuum obtains 1-tert.-butyl acetate base-4-hydroxyl-1,2,3 after crossing post, 4-tetrahydroquinoline (0.3g, 15%).
1H-NMR(400MHz，CDCl3)：δ7.25(d，J＝7.6Hz，1H)，7.16(t，J＝15.6Hz，1H)，6.7(t，J＝14.8Hz，1H)，6.5(d，J＝8.4Hz，1H)，4.76(m，1H)，4.1(d，J＝18Hz，1H)，3.8(d，J＝18Hz，1H)，3.67(m，J?＝26.4Hz，1H)，3.24(m，J＝11.2Hz，1H)，2.05(m，J＝26.4Hz，1H)，1.63(s，1H)，1.44(s，9H).
5.1-tert.-butyl acetate base-4-azido--1,2,3,4-tetrahydroquinoline synthetic
With 1-tert.-butyl acetate base-4-hydroxyl-1,2,3, the 4-tetrahydroquinoline (0.1g, 0.38mmol) and two phenoxy group phosphoryl azides (0.16g 0.57mmol) is dissolved in anhydrous tetrahydro furan (10mL), ice bath cooling add down DBU (0.09g, 0.57mmol).Stirred overnight at room temperature then.Vacuum concentration removes and desolvates, and residuum is crossed post and obtained 1-tert.-butyl acetate base-4-azido--1,2,3,4-tetrahydroquinoline (0.05g, 43%).
1H-NMR(400MHz，CDCl3)：δ7.18(t，J＝15.6Hz，1H)，7.12(d，J＝8.4Hz，1H)，6.7(t，J＝14.8Hz，1H)，6.51(d，J＝8.4Hz，1H)，4.60(m，J＝6.8Hz，1H)，4.0(d，J＝18Hz，1H)，3.8(d，J＝18Hz，1H)，3.63(m，J＝12Hz，1H)，3.23(m，J＝11.6Hz，1H)，2.03(m，J＝28.4Hz，2H)，1.41(s，9H).
6.1-tert.-butyl acetate base-4-amino-1,2,3,4-tetrahydroquinoline synthetic
With 1-tert.-butyl acetate base-4-azido--1,2,3, the 4-tetrahydroquinoline (0.05g, 0.17mmol) and triphenyl phosphorus (0.18g 0.69mmol) is dissolved in anhydrous tetrahydro furan (5mL), adds 0.25mL water then, stirs under the room temperature and spends the night.Reaction solution is spin-dried for, crosses post and obtain 1-tert.-butyl acetate base-4-amino-1,2,3,4-tetrahydroquinoline (0.04g, 91%).
1H-NMR(400MHz，CDCl3)：δ7.18(t，J＝15.6Hz，1H)，7.12(d，J＝8.4Hz，1H)，6.7(t，J＝14.8Hz，1H)，6.51(d，J＝8.4Hz，1H)，4.0(d，J＝18Hz，1H)，3.97(m，1H)，3.45(m，J＝26Hz，1H)，3.26(m，J＝30Hz，1H)，2.03(m，J＝28.4Hz，2H)，1.41(s，9H).
Claims (7)
1. 1-R-4-amino-1,2,3, the synthetic method of 4-tetrahydroquinoline is characterized in that: may further comprise the steps: a, be raw material with the 4-hydroxyquinoline, generate ketenes with halogenated alkyl thing or the reaction of benzyl halides in solvent; B, ketenes is dissolved in the solvent, add reductive agent and obtain corresponding alcohol; C, the correspondent alcohol that will be dissolved in the solvent anhydrous tetrahydro furan add two phenoxy group phosphoryl azides and change corresponding nitrine into; D, the nitrine that obtains is dissolved in the solvent, by hydrogenation or add the triphenyl phosphorus method of reducing and obtain 1-R-4-amino-1,2,3, the 4-tetrahydroquinoline; Reaction formula is as follows:
R is alkyl or the benzyl of C1～C20; RX is halogenated alkyl thing or the benzyl halides of C1～C20.
2. a kind of 1-R-4-amino-1 according to claim 1,2,3, the synthetic method of 4-tetrahydroquinoline, it is characterized in that: the first step reaction solvent is a kind of in methyl alcohol, ethanol, tetrahydrofuran (THF), toluene, the acetonitrile, and temperature of reaction is the reflux temperature that room temperature arrives solvent.
3. a kind of 1-R-4-amino-1 according to claim 1,2,3, the synthetic method of 4-tetrahydroquinoline, it is characterized in that: the second step reductive agent is a kind of in sodium borohydride, POTASSIUM BOROHYDRIDE, the lithium aluminium hydride, and solvent is a kind of in methyl alcohol, ethanol, the tetrahydrofuran (THF).
4. a kind of 1-R-4-amino-1,2,3 according to claim 1, the synthetic method of 4-tetrahydroquinoline is characterized in that: the three-step reaction temperature be 0 ℃ to room temperature.
5. a kind of 1-R-4-amino-1,2,3 according to claim 1, the synthetic method of 4-tetrahydroquinoline is characterized in that: the 4th step, the hydrogenation catalyst system therefor is: palladium carbon, solvent were ethyl acetate when being hydrogenation, and temperature of reaction is a room temperature.
6. a kind of 1-R-4-amino-1,2,3 according to claim 1, the synthetic method of 4-tetrahydroquinoline is characterized in that: the 4th step was that solvent is tetrahydrofuran (THF) and water when adding the triphenyl phosphorus method of reducing, and temperature of reaction is a room temperature.
7. 1-tert.-butyl acetate base-4-amino-1,2,3, the synthetic method of 4-tetrahydroquinoline, it is characterized in that: may further comprise the steps: under a, the room temperature, 16g, 82.5mmol bromo-acetic acid tert-butyl slowly are added drop-wise to 4g, 27.6mmol 4-hydroxyquinoline and 7.6g, 55.2mmol K
2C0
3The 40mL acetonitrile solution in, drip to finish, reflux is spent the night, and then reaction solution is spin-dried for, and adds the 200mL ethyl acetate in the residuum, stirs 0.5 hour after-filtration, filtrate being spin-dried for obtains 5.0g1-tert.-butyl acetate base-1H-quinoline-4-ketone, yield 70%; B, 2g, 7.7mmol 1-tert.-butyl acetate base-1H-quinoline-4-ketone are dissolved in methyl alcohol, under the ice bath cooling, add 1.2g, 31mmol NaBH
4, stirred overnight at room temperature after the cancellation of reaction solution usefulness frozen water, is revolved to steam and is removed methyl alcohol then, and the water ethyl acetate extraction is spin-dried for after the organic phase drying, and residuum obtains 0.3g1-tert.-butyl acetate base-4-hydroxyl-1,2,3 after crossing post, 4-tetrahydroquinoline, yield 15%; C, with 0.1g, 0.38mmol 1-tert.-butyl acetate base-4-hydroxyl-1,2,3,4-tetrahydroquinoline and 0.16g, 0.57mmol two phenoxy group phosphoryl azides are dissolved in the 10mL anhydrous tetrahydro furan, the ice bath cooling adds 0.09g, 0.57mmol DBU down, stirred overnight at room temperature then, vacuum concentration removes and desolvates, and residuum is crossed post and is obtained 0.05g1-tert.-butyl acetate base-4-azido--1,2,3,4-tetrahydroquinoline, yield 43%; D, with 0.05g, 0.17mmol 1-tert.-butyl acetate base-4-azido--1,2,3,4-tetrahydroquinoline and 0.18g, 0.69mmol triphenyl phosphorus are dissolved in the 5mL anhydrous tetrahydro furan, add 0.25mL water then, stir under the room temperature and spend the night, reaction solution is spin-dried for, cross post and obtain 0.04g1-tert.-butyl acetate base-4-amino-1,2,3,4-tetrahydroquinoline, yield 91%.
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Non-Patent Citations (2)
| Title |
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| M.S.Atwal等.Analgesics, some substituted 2,3-dihydro-4-quinolones.《J.Med.Chem》.1965,第8卷第566-571页. * |
| 张磊.STN检索报告.《STN检索报告》.2010, * |
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