CN110015985B - 2- (alpha-deuterium-alpha-hydroxy-alpha-aryl/alkyl) aza-aromatic hydrocarbon compound and preparation method and application thereof - Google Patents
2- (alpha-deuterium-alpha-hydroxy-alpha-aryl/alkyl) aza-aromatic hydrocarbon compound and preparation method and application thereof Download PDFInfo
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- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention provides a preparation method of a 2- (alpha-deuterium-alpha-hydroxy-alpha-aryl/alkyl) aza aromatic hydrocarbon compound, which comprises the steps of dispersing 2-aryl/alkyl formyl aza aromatic hydrocarbon, a photosensitizer DPZ, Hans ester HEH, a chiral catalyst CPA, a deuterium source and sodium chloride in an organic solvent, degassing at the temperature of not higher than-78 ℃, placing at the temperature of-2 to-8 ℃, irradiating by using a 3-10W blue lamp, reacting for 3-14 hours, and separating and purifying after the reaction is finished to obtain the 2- (alpha-deuterium-alpha-hydroxy-alpha-aryl/alkyl) aza aromatic hydrocarbon compound; the obtained product has the advantages of about 90 percent of enantiomeric excess, more than 90 percent of deuteration rate, high yield of part of target products up to 99 percent, mild reaction condition, environmental protection, no metal participation, less photocatalyst dosage and short reaction time, and lays a good foundation for future large-scale production.
Description
Technical Field
The invention belongs to the technical field of deuterated compounds, and particularly relates to a 2- (alpha-deuterium-alpha-hydroxy-alpha-aryl/alkyl) nitrogen heteroaromatic hydrocarbon compound as well as a preparation method and application thereof.
Background
The deuterium-substituted drug is prepared by replacing partial hydrogen atoms in a molecule with deuterium atoms on the basis of the original drug. As the C-D bond is more stable than the C-H bond, and the C-H bond breakage is involved in the metabolic clearance mechanism of a plurality of medicines in a body, deuterium atoms are introduced into the metabolic sites of the medicines, so that the C-D bond breakage can be slowed down or prevented, and the aim of changing the metabolic rate or the metabolic pathway of the medicines is fulfilled. Compared with non-deuterated drugs, the deuterated drugs have the effects of slowing down drug metabolism, improving pharmacokinetics, reducing toxic metabolites and the like, so that the deuterated technology is also considered to be a simple and effective drug development mode. Currently, hundreds of patents for deuterated drugs have been filed by the united states trademark office (PTO) and the patent office, and a number of deuterated drugs have entered clinical trials. It can be said that the deuterated drug technology has become a new trend for the development of new drugs.
At present, few people are exploring the synthesis of the chiral deuterium-carrying compound, which greatly limits the application range of the chiral deuterium-carrying compound in the research and development of medicines.
Disclosure of Invention
One of the purposes of the invention is to solve the problem of low stereoselectivity in the synthesis of chiral deuterated compounds in the prior art and provide a preparation method of 2- (alpha-deuterium-alpha-hydroxy-alpha-aryl/alkyl) nitrogen heteroaromatic compound.
The invention also aims to provide a 2- (alpha-deuterium-alpha-hydroxy-alpha-aryl/alkyl) nitrogen heteroaromatic hydrocarbon compound aiming at the blank field of deuteration of nitrogen heteroaromatic compound, and a preparation method and application thereof.
The invention adopts the following technical scheme:
2- (α -deuterium- α -hydroxy- α -aryl/alkyl) azaarene compounds, which are compounds having the following structural formula (I):
wherein, the nitrogen heteroaryl is pyridyl, quinolyl, 6-fluorine quinolyl, 7-methyl quinolyl, benzimidazolyl, benzothiazolyl and phenanthridinyl; r is phenyl, 4-methylphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 3-methylphenyl, 2-
Methylphenyl, 2-furyl, 2-thienyl, methyl and 3-butenyl.
The preparation method of the 2- (alpha-deuterium-alpha-hydroxy-alpha-aryl/alkyl) azaarene compound comprises the steps of dispersing 2-aryl/alkyl formyl azaarene shown in a formula II, a photosensitizer DPZ, Hans ester HEH, a chiral catalyst CPA, a deuterium source and sodium chloride in an organic solvent, degassing at the temperature of not higher than-78 ℃, placing at the temperature of-2 to-8 ℃, irradiating by using a 3-10W blue lamp, reacting for 3-14 hours, and separating and purifying after the reaction is finished to obtain the 2- (alpha-deuterium-alpha-hydroxy-alpha-aryl/alkyl) azaarene compound; wherein, the sodium chloride has the function of lowering the freezing point of the heavy water;
preferably, the amount of the photosensitizer DPZ is 0.2-2% of the molar amount of the 2-aryl/alkyl formyl azaarene.
Preferably, the amount of the hans-esters HEH is 120-250% of the molar amount of the 2-aryl/alkyl formyl azaarene.
Preferably, the chiral catalyst CPA is named as (R) -2,2',3,3' -tetrahydro-1, 1 '-spirobi [ 1H-indene ] -7,7' -diol derived spiro phosphoric acid, and the dosage of the spiro phosphoric acid is 8-20% of the molar amount of the 2-aryl/alkyl formyl azaarene.
Preferably, the deuterium source is heavy water, and the dosage of the deuterium source is 150-300 times of the molar weight of the 2-aryl/alkyl formyl aza-arene.
Preferably, the amount of the sodium chloride is 20-100% of the molar amount of the 2-aryl/alkyl formyl azaarene.
The 2- (alpha-deuterium-alpha-hydroxy-alpha-aryl/alkyl) aza-arene compound is applied to the preparation of anti-cancer drugs.
The invention has the following beneficial effects:
(1) the 2- (alpha-deuterium-alpha-hydroxy-alpha-aryl/alkyl) aza-aromatic hydrocarbon compound provided by the invention has about 90% of enantiomeric excess and has great application potential in anticancer drugs.
(2) The synthesis method provided by the invention has the deuteration rate of more than 90 percent, the yield of part of target products is up to 99 percent, the reaction condition is mild, the environment is friendly, no metal is involved, the dosage of the photocatalyst is less, the reaction time is short, and a good foundation is laid for future large-scale production.
Detailed Description
In order to make the technical purpose, technical solutions and advantageous effects of the present invention more clear, the technical solutions of the present invention are further described below with reference to specific embodiments.
In the following examples, the photosensitizer used was 5, 6-bis- (2- (5-methoxy) thienyl) -2, 3-Dicyanopyrazine (DPZ), the synthesis of which is referenced in the following documents: zhao, c.zhang, k.f.chi, o.pytela, g.wei, h.liu, F.
Z.Jiang,Dicyanopyrazine-derived push–pull chromophores for highly efficient photoredox catalysis RSC Adv.2014,4,30062.。
The chiral catalyst is spiro phosphoric acid (CPA) substituted by 2-trifluoromethyl phenyl group at the 3 and 3' positions, and the synthesis of the chiral catalyst is referred to the following documents: xu, D.Huang, C.Han, W.Shen, X.Lin, Y.Wang, SPINOL-Derived phosphorus Acids Synthesis and Application in organic selected Friedel-Crafts Reaction of industries with imines.J.org.chem.2010,75,8677.
Example 5 starting material 1-tert-butoxycarbonyl-2-benzoyl-benzimidazole, the synthesis of which is described in the following references: sultan, s.; rizvi, m.a.; kumar, j.; shah, B.A., Acyl Radicals from Terminal alkyls of Photoredox-Catalyzed Acylation of heterocyclic. chemistry-A European Journal 2018,24(42), 10617-;
for the synthesis of the starting materials used in the remaining examples, reference may be made to the following documents: wu, x.; geng, x.; zhao, p.; zhang, j.; gong, x.; wu, y. -d.; wu, A. -X., I2-Promoted Povarov-Type Reaction Using 1,4-Dithane-2,5-diol as an Ethylene Surrogate:Formal[4+2]Synthesis of Quinolines.Org.Lett.2017,19(7),1550-1553.
Example 1: preparation of 2- (alpha-deuterium-alpha-hydroxy-alpha-phenyl) pyridine
The preparation process comprises the following steps: weighing 2-benzoylpyridine (0.055g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans ester (0.11g,0.45mmol), chiral spiro-phosphate catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol), sodium chloride (0.0035-0.0175 g,0.06mmol) in a dry 25mL schlenk tube, continuously adding 5mL cyclopentyl methyl ether, degassing 2-3 times by a vacuum pump at the temperature of not higher than-78 ℃ for 5-10 min each time, placing at-2 to-8 ℃, irradiating by a 3W blue lamp, reacting for 3 hours, after the reaction is finished, separating by column chromatography (petroleum ether/ethyl acetate: 20-4: 1, volume ratio), rotary evaporation concentration, vacuum drying for 1 hour at 25 ℃ to obtain 2- (alpha-deuterium-alpha-hydroxy-phenyl) pyridine (0.056g,0.3mmol), yield 96%, deuteration rate 91%.1H NMR(400MHz,CDCl3)δ8.60(d,J＝4.8Hz,1H),7.65(td,J1＝7.6Hz,J2＝1.6Hz,1H),7.44-7.36(m,4H),7.34-7.30(m,1H),7.25-7.19(m,2H),5.80(s,0.09H),5.40(brs,1H)ppm；13C NMR(100MHz,CDCl3)δ160.9,147.8,143.2,136.9,128.6,127.8,127.1,122.4,121.4,75.0。
Example 2: preparation of 2- (alpha-deuterium-alpha-hydroxy-alpha-phenyl) quinolines
The preparation process comprises the following steps: weighing 2-benzoyl quinoline (0.070g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans ester (0.11g,0.45mmol), chiral spiro phosphoric acid catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol), sodium chloride (0.0035-0.0175 g,0.06mmol) in a dry 25mL schlenk tube, continuously adding 5mL of cyclopentyl methyl ether, degassing 2-3 times by a vacuum pump at the temperature of not higher than-78 ℃ for 5-10 min each time, then placing at-2 to-8 ℃, irradiating by a 3W blue lamp, reacting for 3 hours, after the reaction is finished, separating by column chromatography (petroleum ether/ethyl acetate is 20-4: 1, volume ratio), rotary evaporation concentration, vacuum drying for 1 hour at 25 ℃) to obtain optically pure 2- (alpha-hydroxy-alpha-phenyl) quinoline (0.070g, 0.8 mmol), 0.279mmol), yield 96%, enantiomeric excess 91%, deuteration rate 91%.1H NMR(300MHz,CDCl3)δ8.18(d,J＝8.4Hz,1H),8.08(d,J＝8.5Hz,1H),7.78(dd,J＝16.1,8.0Hz,2H),7.57(t,J＝7.5Hz,1H),7.42(d,J＝6.9Hz,2H),7.33(dd,J＝16.2,8.7Hz,3H),7.20(d,J＝8.5Hz,1H),6.09(s,1H),5.90(s,0.09H)；13C NMR(75MHz,CDCl3)δ160.4,145.9,142.7,137.0,129.9,128.8,128.6,128.0,127.6,127.4,126.6,119.2,75.1。
Example 3: preparation of 6-fluoro-2- (alpha-deuterium-alpha-hydroxy-alpha-phenyl) quinoline
The preparation process comprises the following steps: weigh 6-fluoro-2-benzoyl into a dry 25mL schlenk tubeQuinoline (0.075g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans ester (0.11g,0.45mmol), chiral spiro-phosphate catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol), sodium chloride (0.0035-0.0175 g,0.06mmol), continuously adding 5mL of cyclopentyl methyl ether, degassing by a vacuum pump for 2-3 times at a temperature not higher than-78 ℃ for 5-10 min each time, then placing at-2 to-8 ℃, irradiating by a 3W blue lamp for 5 hours, after the reaction is finished, performing column chromatography separation (petroleum ether/ethyl acetate is 20-4: 1 in volume ratio), rotary concentration, vacuum drying (at 25 ℃ for 1 hour) to obtain optically pure 6-fluoro-2- (alpha-deuterium-alpha-hydroxy-alpha-phenyl) quinoline (0.195 mmol), the yield is 65%, the enantiomeric excess is 90%, and the deuteration rate is 92%.1H NMR(300MHz,CDCl3)δ8.16(dd,J＝9.2,5.3Hz,1H),8.02(d,J＝8.6Hz,1H),7.53(m,1H),7.37(m,6H),7.22(d,J＝8.6Hz,1H),5.88(s,1H),5.88(s,0.08H)；19F NMR(376MHz,CDCl3)δ-112.87.13C NMR(75MHz,CDCl3)δ159.4,146.7,146.0,137.4,130.1,130.1(q,J＝32.4Hz),128.7,127.6,127.6,127.5,126.9,125.6(q,J＝3.8Hz),124.0(q,J＝272.1Hz),118.9,74.6；19F NMR(376MHz,CDCl3)δ-112.87。
Example 4: preparation of 7-methyl-2- (alpha-deuterium-alpha-hydroxy-alpha-phenyl) quinoline
The preparation process comprises the following steps: weighing 7-methyl-2-benzoylquinoline (0.074g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans' ester (0.11g,0.45mmol), chiral spiro-phosphate catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol), sodium chloride (0.0035-0.0175 g,0.06mmol) in a dry 25mL schlenk tube, adding 5mL cyclopentyl methyl ether continuously, degassing for 2-3 times by a vacuum pump under the condition of not higher than-78 ℃, each time for 5-10 min, then placing at-2 to-8 ℃, irradiating by a 3W blue lamp, reacting for 3 hours, after the reaction is finished, performing column chromatography separation (petroleum ether/ethyl acetate is 20-4: 1, volume ratio), performing rotary evaporation concentration, and performing vacuum drying (drying at 25 ℃ for 1 hour) to obtain the optically pure 7-methyl-2- (alpha-deuterium).- α -hydroxy- α -phenyl) quinoline (0.062g,0.246mmol), yield 82%, enantiomeric excess 94%, deuteration 92%.1H NMR(300MHz,CDCl3)δ7.99(m,2H),7.69(d,J＝8.3Hz,1H),7.34(m,2H),7.12(d,J＝8.4Hz,1H),6.11(s,0.08H),5.87(s,1H),2.57(d,J＝13.3Hz,3H)；13C NMR(75MHz,CDCl3)δ160.9,144.4,142.4,136.1,132.4,130.8,130.4,128.7,128.1,128.1,127.4,126.3,120.2,75.2。
Example 5: preparation of 2- (alpha-deuterium-alpha-hydroxy-alpha-phenyl) benzimidazole
The preparation process comprises the following steps: weighing 1-tert-butoxycarbonyl-2-benzoylbenzimidazole (0.097g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans ester (0.11g,0.45mmol), chiral spiro phosphoric acid catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol), sodium chloride (0.0035-0.0175 g,0.06mmol) in a dry 25mL schlenk tube, adding 5mL of cyclopentyl methyl ether, degassing 2-3 times with a vacuum pump at a temperature not higher than-78 ℃ for 5-10 min each time, placing at-2 to-8 ℃, irradiating with a 3W blue lamp, reacting for 11 hours, performing column chromatography (petroleum ether/ethyl acetate ratio: 20-4: 1, volume ratio), concentrating by evaporation, drying at 25 ℃ for 1 hour) to obtain optically pure 2- (alpha-hydroxy-phenyl) benzimidazole (0.087g ), 0.249mmol), yield 83%, enantiomeric excess 95%, deuteration rate 96%.1H NMR(300MHz,CDCl3)δ7.88(m,1H),7.75(dd,J＝5.5,3.2Hz,1H),7.33(ddd,J＝15.3,7.4,4.7Hz,7H),7.06(s,0.04H),4.69(s,1H),1.54(s,9H)；13C NMR(75MHz,CDCl3)δ152.1,151.5,136.7,128.9,128.8,127.0,122.9,83.6,74.6,27.6。
Example 6: preparation of 2- (alpha-deuterium-alpha-hydroxy-alpha-phenyl) benzothiazole
The preparation process comprises the following steps:weighing 2-benzoyl benzothiazole (0.072g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans ester (0.11g,0.45mmol), chiral spiro-phosphate catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol) and sodium chloride (0.0035-0.0175 g,0.06mmol) in a dry 25mL schlenk tube, continuously adding 5mL of cyclopentyl methyl ether, degassing 2-3 times by a vacuum pump at the temperature of not higher than-78 ℃ for 5-10 min each time, then placing at-2 to-8 ℃, irradiating by a 3W blue lamp, reacting for 14 h, after the reaction is finished, carrying out column chromatography separation (petroleum ether/ethyl acetate is 20-4: 1, volume ratio), rotary concentration and vacuum drying for 1h at the temperature of 25 ℃) to obtain optically pure 2- (alpha-06-hydroxy-alpha-phenyl) benzothiazole (0.8 g,0.279mmol), 93% yield, 95% enantiomeric excess and 89% deuteration.1H NMR(300MHz,CDCl3)δ7.99(d,J＝8.1Hz,1H),7.84(d,J＝7.8Hz,1H),7.44(m,7H),6.15(s,0.11H),3.66(s,1H)；13C NMR(75MHz,CDCl3)δ175.0,152.4,140.9,135.2,128.8,128.7,126.7,126.2,125.2,123.0,121.8,74.4。
Example 7: preparation of 2- (alpha-deuterium-alpha-hydroxy-alpha-phenyl) phenanthridine
Weighing 2-benzoylphenanthridine (0.085g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans ester (0.11g,0.45mmol), chiral spiro phosphoric acid catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol), sodium chloride (0.0035-0.0175 g,0.06mmol) in a 50 mL-dry Hirangiaceae reaction flask, continuously adding 5mL of cyclopentyl methyl ether, degassing 2-3 times by using a vacuum pump at the temperature of not higher than-78 ℃ for 5-10 min each time, then placing at-2 to-8 ℃, irradiating by using a 3W blue lamp, reacting for 14 hours, after the reaction is finished, carrying out column chromatography separation (petroleum ether/ethyl acetate is 20-4: 1, volume ratio), steam-rotary concentration, vacuum drying for 1 hour at the temperature of 25 ℃ to obtain optically pure 2- (alpha-hydroxy-alpha-phenyl) phenanthridine (0.085g, 0.085 h), 0.297mmol), yield 99%, enantiomeric excess 91%, deuteration rate 91%.1H NMR(300MHz,CDCl3)δ8.64(dd,J＝13.2,8.3Hz,2H),8.33(d,J＝7.6Hz,1H),8.07(d,J＝8.2Hz,1H),7.80(m,3H),7.59(t,J＝7.6Hz,1H),7.44(d,J＝6.7Hz,2H),7.33(td,J＝8.7,4.2Hz,3H),6.64(s,1H),6.46(s,0.09H)；13C NMR(75MHz,CDCl3)δ159.0,142.9,141.6,133.4,130.9,129.5,129.0,128.8,128.0,127.8,127.4,127.3,126.0,124.4,123.4,122.5,122.1,72.7。
Example 8: preparation of 2- (alpha-deuterium-alpha-hydroxy-4-methyl-alpha-phenyl) quinoline
The preparation process comprises the following steps: weighing 2- (4-methylphenyl) -formylquinoline (0.074g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans ester (0.11g,0.45mmol), chiral spiro-phosphate catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol), sodium chloride (0.0035-0.0175 g,0.06mmol) in a dry 25mL schlenk tube, continuously adding 5mL of cyclopentyl methyl ether, degassing 2-3 times by a vacuum pump at the temperature of not higher than-78 ℃ for 5-10 min each time, placing at-2 to-8 ℃, irradiating by a 3W blue lamp, reacting for 3 hours, separating after the reaction is finished (petroleum ether/ethyl acetate is 20-4: 1 in volume ratio), rotary evaporating for concentration, drying in vacuum (drying for 1 hour at 25 ℃) to obtain optical pure 2- (alpha-hydroxyphenyl) -formylquinoline (alpha-hydroxy-4-methyl-4-alpha-074 g) deuterium (0.074. alpha. -methyl-phenyl) quinoline, 0.297mmol), yield 99%, enantiomeric excess 97%, deuteration rate 91%.1H NMR(300MHz,CDCl3)δ8.16(d,J＝8.4Hz,1H),8.06(d,J＝8.5Hz,1H),7.77(dd,J＝16.3,7.9Hz,2H),7.56(t,J＝7.4Hz,1H),7.29(d,J＝7.9Hz,2H),7.17(dd,J＝12.2,8.2Hz,3H),6.02(s,1H),5.86(s,0.09H),2.33(s,3H)；13C NMR(75MHz,CDCl3)δ160.4,145.9,142.6,138.3,137.0,129.9,128.8,128.5,128.0,127.6,126.6,124.6,119.3,75.1,21.4。
Example 9: preparation of 2- (alpha-deuterium-alpha-hydroxy-4-fluoro-alpha-phenyl) quinoline
The preparation process comprises the following steps: in a trunkDrying 25mL schlenk tube, weighing 2- (4-fluorophenyl) -formylquinoline (0.074g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans ester (0.11g,0.45mmol), chiral spiro-phosphate catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol), sodium chloride (0.0035-0.0175 g,0.06mmol), adding 5mL cyclopentyl methyl ether, degassing 2-3 times by using a vacuum pump at the temperature of not higher than-78 ℃ for 5-10 min each time, placing at-2 to-8 ℃, irradiating by using a 3W blue lamp, reacting for 3 hours, after the reaction is finished, carrying out column chromatography separation (petroleum ether/ethyl acetate is 20-4: 1, volume ratio), rotary concentration, and vacuum drying (drying for 1 hour at 25 ℃) to obtain optically pure 2- (alpha-hydroxy-4-fluoro-phenyl) quinoline (0.074g, 4-fluoro-phenyl) deuterium, 0.297mmol), yield 99%, enantiomeric excess 97%, deuteration rate 91%.1H NMR(300MHz,CDCl3)δ8.21(dd,J＝22.8,8.5Hz,2H),7.83(dd,J＝18.7,7.9Hz,2H),7.62(t,J＝7.6Hz,1H),7.45(dd,J＝8.4,5.5Hz,2H),7.28(s,1H),7.05(t,J＝8.6Hz,2H),6.15(s,1H),6.01(s,0.1H)；19F NMR(376MHz,CDCl3)δ-105.11；13C NMR(75MHz,CDCl3)δ162.3(d,J＝246.1Hz),160.3,145.8,138.5(d,J＝3.1Hz),137.0,129.8,128.9(d,J＝8.2Hz),128.6,127.5,127.3,126.6,118.9,115.3(d,J＝21.5Hz),74.4。
Example 10: preparation of 2- (alpha-deuterium-alpha-hydroxy-4-trifluoromethyl-alpha-phenyl) quinoline
The preparation process comprises the following steps: weighing 2- (4-trifluoromethylphenyl) -formylquinoline (0.090g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans ester (0.11g,0.45mmol), chiral spiro-phosphate catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol), sodium chloride (0.0035-0.0175 g,0.06mmol) in a dry 25mL schlenk tube, continuously adding 5mL of cyclopentyl methyl ether, degassing 2-3 times by a vacuum pump at the temperature of not higher than-78 ℃ for 5-10 min, placing at-2 to-8 ℃, irradiating by a 3W blue lamp, reacting for 3 hours, separating after the reaction is finished (petroleum ether/ethyl acetate is 20-4: 1 in volume ratio), concentrating by rotary evaporation, and drying in vacuum (2-column chromatography)Drying at 5 ℃ for 1 hour) to obtain the optically pure 2- (alpha-deuterium-alpha-hydroxy-4-trifluoromethyl-alpha-phenyl) quinoline (0.075g,0.246mmol), with 82% yield, 94% enantiomeric excess and 91% deuteration rate.1H NMR(300MHz,CDCl3)δ8.21(d,J＝8.6Hz,1H),8.15(d,J＝8.5Hz,1H),7.82(dd,J＝16.6,8.0Hz,2H),7.60(m,5H),7.23(s,1H),6.17(s,1H),6.03(s,0.09H)；13C NMR(75MHz,CDCl3)δ159.4,146.7,146.0,137.4,130.1,130.1(q,J＝32.4Hz),128.7,127.6,127.6,127.5,126.9,125.6(q,J＝3.8Hz),124.0(q,J＝272.1Hz),118.9,74.6；19F NMR(376MHz,CDCl3)δ-63.07。
Example 11: preparation of 2- (alpha-deuterium-alpha-hydroxy-3-methyl-alpha-phenyl) quinoline
The preparation process comprises the following steps: weighing 2- (3-methylphenyl) -formylquinoline (0.074g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans ester (0.11g,0.45mmol), chiral spiro-phosphate catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol), sodium chloride (0.0035-0.0175 g,0.06mmol) in a drying 25mL schlenk tube, continuously adding 5mL of cyclopentyl methyl ether, degassing 2-3 times by a vacuum pump at the temperature of not higher than-78 ℃ for 5-10 min each time, placing at-2 to-8 ℃, irradiating by a 3W blue lamp, reacting for 5 hours, separating after the reaction is finished (petroleum ether/ethyl acetate is 20-4: 1 in volume ratio), concentrating by rotary evaporation, drying at the temperature of 25 ℃ for 1 hour to obtain optical pure 2- (alpha-063-hydroxyphenyl) -formylquinoline (alpha-3-methyl-deuterium) (0.8 g), 0.273mmol), yield 91%, enantiomeric excess 99%, deuteration rate 90%.1H NMR(300MHz,CDCl3)δ8.17(d,J＝8.4Hz,1H),8.07(d,J＝8.5Hz,1H),7.78(dd,J＝16.5,7.9Hz,2H),7.57(t,J＝7.5Hz,1H),7.21(m,4H),7.10(d,J＝6.2Hz,1H),6.07(s,1H),5.86(s,0.1H),2.32(s,3H)；13C NMR(75MHz,CDCl3)δ160.6,145.8,139.8,137.7,137.0,129.9,129.3,128.7,127.6,127.4,127.4,126.6,119.3,74.9,21.1。
Example 12: preparation of 2- (alpha-deuterium-alpha-hydroxy-2-methyl-alpha-phenyl) quinoline
The preparation process comprises the following steps: weighing 2- (2-methylphenyl) -formylquinoline (0.074g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans ester (0.11g,0.45mmol), chiral spiro-phosphate catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol), sodium chloride (0.0035-0.0175 g,0.06mmol) in a drying 25mL schlenk tube, continuously adding 5mL of cyclopentyl methyl ether, degassing 2-3 times by a vacuum pump at the temperature of not higher than-78 ℃ for 5-10 min each time, placing at-2 to-8 ℃, irradiating by a 3W blue lamp, reacting for 8 hours, separating after the reaction is finished (petroleum ether/ethyl acetate is 20-4: 1 in volume ratio), rotary evaporating and concentrating, drying in vacuum (drying at the temperature of 25 ℃ for 1 hour) to obtain optically pure 2- (alpha-hydroxyphenyl) -formylquinoline (alpha-2-hydroxy-phenyl) deuterium (0620.0620.0620 g), 0.249mmol), yield 83%, enantiomeric excess 97%, deuteration rate 93%.1H NMR(300MHz,CDCl3)δ8.17(d,J＝8.5Hz,1H),8.06(d,J＝8.5Hz,1H),7.79(dd,J＝17.4,7.9Hz,2H),7.57(t,J＝7.6Hz,1H),7.17(m,4H),7.08(d,J＝8.5Hz,1H),6.11(s,0.07H),5.92(s,1H),2.40(s,3H)；13C NMR(75MHz,CDCl3)δ160.4(d,J＝246.2Hz),159.7,145.9,137.4,130.0,129.8,δ129.4(d,J＝8.3Hz),128.8(d,J＝4.0Hz),128.7,127.6,127.6,126.7,124.5(d,J＝3.5Hz),118.9(d,J＝3.1Hz),115.5(d,J＝21.9Hz),68.1(d,J＝4.0Hz)。
Example 13: preparation of 2- (alpha-deuterium-alpha-hydroxy-2-furyl) quinoline
The preparation process comprises the following steps: weighing 2- (2-furyl) -formylquinoline (0.067g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans' ester (0.11g,0.45mmol), chiral spiro-phosphate catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol), sodium chloride (0.0035-0.0175 g,0.06mmol) in a dry 25mL schlenk tube, adding cyclopentyl methyl ether continuously for 5mL, adding cyclopentyl methyl ether continuously until the concentration is not higher than that of cyclopentyl methyl etherDegassing for 2-3 times by using a vacuum pump at the temperature of minus 78 ℃, each time for 5-10 min, then placing at the temperature of minus 2-minus 8 ℃, irradiating by using a 3W blue lamp, reacting for 3 hours, after the reaction is finished, carrying out column chromatography separation (petroleum ether/ethyl acetate is 20-4: 1, volume ratio), rotary evaporation concentration and vacuum drying (drying for 1 hour at the temperature of 25 ℃) to obtain the optically pure 2- (alpha-deuterium-alpha-hydroxy-2-furyl) quinoline (0.049g,0.216mmol), wherein the yield is 72%, the enantiomeric excess is 97%, and the deuterium substitution rate is 97%>95％。1H NMR(300MHz,CDCl3)δ8.15(d,J＝8.4Hz,2H),7.84(d,J＝8.0Hz,1H),7.76(t,J＝7.6Hz,1H),7.58(t,J＝7.5Hz,1H),7.35(m,2H),6.34(s,2H),5.96(s,0.01H),5.81(s,1H)；13C NMR(75MHz,CDCl3)δ157.6,154.7,146.1,142.8,137.2,130.0,128.8,127.7,127.6,126.8,118.9,110.3,108.0,68.6。
Example 14: preparation of 2- (alpha-deuterium-alpha-hydroxy-2-thienyl) quinolines
The preparation process comprises the following steps: weighing 2- (2-thienyl) -formylquinoline (0.072g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans ester (0.11g,0.45mmol), chiral spiro-phosphate catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol), sodium chloride (0.0035-0.0175 g,0.06mmol), continuously adding 5mL of cyclopentyl methyl ether, degassing 2-3 times by a vacuum pump at the temperature of not higher than-78 ℃ for 5-10 min each time, then placing at-2 to-8 ℃ and irradiating by a 3W blue lamp, reacting for 3 hours, separating after the reaction is finished (petroleum ether/ethyl acetate is 20-4: 1 in volume ratio), rotary evaporation and concentration, drying for 1 hour at the temperature of 25 ℃ to obtain optical pure 2- (alpha-thienyl-2-hydroxyquinoline (072-alpha-thienyl-2-hydroxyl) deuterium (0.072 g), 0.297mmol), yield 99%, enantiomeric excess 96%, deuteration rate 95%.1H NMR(300MHz,CDCl3)δ8.14(dd,J＝8.3,3.7Hz,2H),7.83(d,J＝8.1Hz,1H),7.77(t,J＝7.6Hz,1H),7.57(t,J＝7.4Hz,1H),7.33(d,J＝8.5Hz,1H),7.27(d,J＝5.0Hz,1H),7.12(d,J＝2.6Hz,1H),6.98(m,1H),6.17(s,0.05H),6.02(s,1H)；13C NMR(75MHz,CDCl3)δ159.5,146.7,145.8,137.4,130.1,128.7,127.6,127.6,126.9,126.6,125.9,125.6,119.0,70.8。
Example 15: preparation of 2- (alpha-deuterium-alpha-hydroxy-alpha-methyl) quinoline
The preparation process comprises the following steps: weighing 2-formylquinoline (0.051g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans ester (0.11g,0.45mmol), chiral spiro-phosphate catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol), sodium chloride (0.0035-0.0175 g,0.06mmol), continuously adding 5mL of cyclopentyl methyl ether, degassing 2-3 times by a vacuum pump at the temperature of not higher than-78 ℃ for 5-10 min each time, then placing at-2 to-8 ℃, irradiating by a 3W blue lamp, reacting for 14 h, after the reaction is finished, separating by column chromatography (petroleum ether/ethyl acetate is 20-4: 1, volume ratio), rotary evaporation concentration, vacuum drying for 1h at the temperature of 25 ℃) to obtain optically pure 2- (alpha-hydroxy-alpha-methyl) quinoline (0.051g, 0.048 mmol), 0.273mmol), yield 91%, enantiomeric excess 80%, deuteration rate>95％。1H NMR(300MHz,CDCl3)δ8.17(d,J＝8.5Hz,1H),8.09(d,J＝8.4Hz,1H),7.83(d,J＝8.1Hz,1H),7.74(t,J＝7.6Hz,1H),7.55(t,J＝7.5Hz,1H),7.36(d,J＝8.5Hz,1H),5.03(s,1H),1.58(s,3H)；13C NMR(75MHz,CDCl3)δ162.8,146.3,137.0,129.8,128.7,127.6,127.4,126.4,118.0,68.7,24.1。
Example 16: preparation of 2- (. alpha. -deuterium-. alpha. -hydroxy-2- (3-butenyl)) quinoline
The preparation process comprises the following steps: weighing 2- (3-butenyl) -formylquinoline (0.063g,0.3mmol), DPZ (0.00053g,0.0015mmol), hans ester (0.11g,0.45mmol), chiral spirocyclic phosphoric acid catalyst (0.018g,0.003mmol), heavy water (0.8-1.6 mL, 45-90 mmol), sodium chloride (0.0035-0.0175 g,0.06mmol) in a dry 25mL schlenk tube, adding cyclopentyl methyl ether continuously for 5mL, heating to a temperature of not higher than-78 deg.CDegassing for 2-3 times by using a vacuum pump under the condition of 5-10 min each time, then placing at-2-8 ℃, irradiating by using a 3W blue lamp, reacting for 3 hours, after the reaction is finished, performing column chromatography separation (petroleum ether/ethyl acetate is 20-4: 1 in volume ratio), performing rotary evaporation concentration and vacuum drying (drying for 1 hour at 25 ℃) to obtain the optically pure 2- (alpha-deuterium-alpha-hydroxy-2- (3-butenyl)) quinoline (0.064g,0.297mmol), wherein the yield is 99%, the enantiomeric excess is 88%, and the deuterium substitution rate is 88%>95％。1H NMR(300MHz,CDCl3)δ8.16(d,J＝8.5Hz,1H),8.08(d,J＝8.4Hz,1H),7.83(d,J＝8.0Hz,1H),7.73(t,J＝7.6Hz,1H),7.55(t,J＝7.5Hz,1H),7.34(d,J＝8.5Hz,1H),5.87(ddt,J＝16.9,10.2,6.6Hz,1H),4.99(m,3H),2.26(m,2H),2.04(ddd,J＝15.9,9.6,6.4Hz,1H),1.81(m,1H)；13C NMR(75MHz,CDCl3)δ161.9,146.3,138.2,137.0,129.8,128.6,127.6,127.4,126.4,118.3,114.8,72.0,37.4,29.4。
Evaluation of biological Activity
1. Cellular level
Four cell strains of breast cancer MCF-7, MAB-MB-231, liver cancer H beta G2 and cervical cancer Hela are taken, and 6000-8000 cells per well are inoculated on a 96-well cell culture plate. ZZX (target products prepared in examples 1 to 7) with corresponding concentration is respectively added 24h after cell spotting, supernatant is discarded after 48h of action, 50 mu L of 1mg/mL MTT solution is added into each hole, 100 mu L of dimethyl sulfoxide is added into each hole after continuous culture for 4h, and the OD value is measured at 490nm wavelength by using a full-wavelength microplate reader after 30min of oscillation by using a formula: the cell inhibition rate is (1-absorbance value of experimental group/absorbance value of control group) × 100% (the invention sets up control group at the same time, the control group is not added with any corresponding compound group, the experimental group is added with corresponding compound group), the cell inhibition rate is calculated, and the statistics are as following table 1:
as can be seen from table 1, the 2- (α -deuterium- α -hydroxy- α -aryl/alkyl) azaarene compounds prepared in embodiments 1 to 15 of the present invention exhibit certain activities on cancer cells of the four types, i.e., breast cancer MCF-7, MAB-MB-231, liver cancer H β G2, and cervical cancer Hela, and are expected to be applied to the preparation of anticancer drugs.
Finally, it should be noted that: the above embodiments are merely illustrative and not restrictive of the technical solutions of the present invention, and any equivalent substitutions and modifications or partial substitutions made without departing from the spirit and scope of the present invention should be included in the scope of the claims of the present invention.
Claims (7)
- A process for the preparation of 2- (α -deuterium- α -hydroxy- α -aryl/alkyl) azaaromatic compounds characterized by: dispersing 2-aryl/alkyl formyl azaarene shown in a formula II, a photosensitizer DPZ, a hans ester HEH, a chiral catalyst CPA, a deuterium source and sodium chloride in an organic solvent, degassing at the temperature of not higher than-78 ℃, then placing at the temperature of-2 to-8 ℃, irradiating by using a 3-10W blue lamp, reacting for 3-14 hours, and after the reaction is finished, separating and purifying to obtain a 2- (alpha-deuterium-alpha-hydroxy-alpha-aryl/alkyl) azaarene compound;
Ⅱ；
the 2- (alpha-deuterium-alpha-hydroxy-alpha-aryl/alkyl) aza-aromatic hydrocarbon compound is a compound with the following structural general formula (I):（I），
wherein, the nitrogen heteroaryl is pyridyl, quinolyl, 6-fluorine quinolyl, 7-methyl quinolyl, benzimidazolyl, benzothiazolyl and phenanthridinyl; r is phenyl, 4-methylphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 3-methylphenyl, 2-furyl, 2-thienyl, methyl and 3-butenyl. - 2. The process for the preparation of 2- (α -deuterium- α -hydroxy- α -aryl/alkyl) azaarene compounds according to claim 1, wherein: the dosage of the photosensitizer DPZ is 0.2-2% of the molar weight of the 2-aryl/alkyl formyl azaarene.
- 3. The process for the preparation of 2- (α -deuterium- α -hydroxy- α -aryl/alkyl) azaarene compounds according to claim 1, wherein: the amount of the Hans ester HEH is 120-250% of the molar amount of the 2-aryl/alkyl formyl azaarene.
- 4. The process for the preparation of 2- (α -deuterium- α -hydroxy- α -aryl/alkyl) azaarene compounds according to claim 1, wherein: the dosage of the chiral catalyst CPA is 8-20% of the molar quantity of the 2-aryl/alkyl formyl aza-arene.
- 5. The process for the preparation of 2- (α -deuterium- α -hydroxy- α -aryl/alkyl) azaarene compounds according to claim 1, wherein: the deuterium source is heavy water, and the dosage of the deuterium source is 150-300 times of the molar weight of the 2-aryl/alkyl formyl aza-arene.
- 6. The process for the preparation of 2- (α -deuterium- α -hydroxy- α -aryl/alkyl) azaarene compounds according to claim 1, wherein: the using amount of the sodium chloride is 20-100% of the molar amount of the 2-aryl/alkyl formyl azaarene.
- 7. Use of 2- (α -deuterium- α -hydroxy- α -aryl/alkyl) azaarene compounds prepared by the method of claim 1 in the preparation of anti-cancer drugs.
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