CN110563649A - high-selectivity deuteration method of 2-methyl nitrogen heterocyclic compound - Google Patents
high-selectivity deuteration method of 2-methyl nitrogen heterocyclic compound Download PDFInfo
- Publication number
- CN110563649A CN110563649A CN201910798544.XA CN201910798544A CN110563649A CN 110563649 A CN110563649 A CN 110563649A CN 201910798544 A CN201910798544 A CN 201910798544A CN 110563649 A CN110563649 A CN 110563649A
- Authority
- CN
- China
- Prior art keywords
- formula
- reaction
- nitrogen
- methyl
- reaction tube
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—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
- C07D215/16—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—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
- C07D215/16—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
- C07D221/12—Phenanthridines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
The invention discloses a high-selectivity deuteration method of a 2-methyl nitrogen heterocyclic compound, which comprises the following steps: adding a 2-methyl nitrogen-containing heterocyclic compound shown in a formula I, a formula II or a formula III, an oxidant and an additive into a dried Schlenk reaction tube, adding deuterium water and an organic solvent into the reaction tube under the condition of protective gas, stirring and reacting for 2-12 hours at 50-100 ℃, and obtaining reaction liquid, and respectively obtaining the deuterated nitrogen-containing heterocyclic shown in a formula IV, a formula V or a formula VI after post-treatment. The method is based on a free radical process, is high-efficiency, can synthesize the methyl-d 3 substituted nitrogen heterocyclic compounds which are difficult to prepare by the existing method, and has high reaction deuteration rate; the method is carried out under a neutral condition, and the requirement on equipment is low; the catalytic amount of the oxidant is used, and the additive is cheap and easy to obtain; the reaction conditions are mild, and the energy consumption is saved; high yield, strong substrate universality, simple and convenient operation and the like.
Description
(I) technical field
The invention relates to a synthesis method of an organic compound, in particular to a high-selectivity deuteration method of a 2-methyl nitrogen heterocyclic compound.
(II) background of the invention
Deuterated compounds are an important high-value-added chemical. It can be widely used in the field of nuclear magnetic resonance spectroscopy as a solvent, and can also be used for revealing the mechanism of organic reaction. More importantly, in the field of pharmaceutical chemistry, deuterium atoms are used to replace hydrogen atoms, which is an ideal method for modifying drugs. On one hand, deuterium is introduced into non-metabolic sites and non-action sites of the drug molecules, so that the in vivo dynamics of the drug molecules can be tracked, and the absorption, distribution, metabolism, excretion and the like of the drug molecules can be researched under the condition of not influencing the drug action. On the other hand, the carbon-deuterium bond is stabilized by about 6 to 9 times compared with the carbon-hydrogen bond, and the C-H bond is broken in the metabolic clearance mechanism of a plurality of medicines in a human body, so that the half-life period of the medicine can be prolonged by carrying out deuteration on the active site of the medicine. For example, in 4 months of 2017, the first example of deuterated drugs Austedo (Scheme 1a) approved by the Food and Drug Administration (FDA) is to replace hydrogen atoms in methoxy groups at positions 9 and 10 in the tetrabenazine skeleton with deuterium atoms, and the pharmacokinetic characteristics of deuterated tetrabenazine are found to be obviously improved. From this, the synthetic chemistry raises the wave of deuteration. For example, in 2018, the MacMillan group achieved highly selective deuterium/tritium generation reactions at the alpha position of tertiary amines in a variety of bioactive molecules or drugs through a photocatalytic hydrogen atom transfer strategy. Almost simultaneously, the Renaud task group takes deuterium water as a deuterium source, and realizes the de-iodination and deuteration reaction of iodoalkane through a free radical process. Furthermore, the professor of Suchenlian of Shenzhen university takes CdSe as a photocatalyst, and realizes the highly selective deuteration of halogenated hydrocarbon through a photoredox pathway. Recently, the Bandar group achieved selective deuteration of the alpha position of styrene by reversible addition of methanol to styrene. Although some practical selective deuteration methods have been reported, it is still far from meeting the synthesis requirement of the deuterated drugs, so that it is of great significance to explore efficient deuteration methods of various molecular frameworks.
Nitrogen-containing heterocycles are the core backbones of a wide variety of biologically active molecules, such as Papaverine, Cinchonine, Loratadine, and others (Scheme 1 b-d.). In consideration of the remarkable methyl effect in clinical medicines, the development of a highly selective deuteration method of methyl in nitrogen-containing heterocycle is of great significance. The method reported at present uses deuterium water as a deuterium source, and realizes deuteration of 2-methyl nitrogen-containing heterocyclic ring by high-temperature heating (more than 160 ℃) under the action of strong alkali, and the reaction condition of the method is very severe (see chem. In 2017, the Yin topic group reported a deuteration method of 2-methyl nitrogen-containing heterocycles under relatively mild conditions (80-120 ℃), however, this method not only requires an acid as a catalyst, but also the chemoselectivity of the reaction is general (e.g. there is no selectivity between the methyl group at the 2-position and the methyl group at the 4-position of quinoline, see org. biomol. chem.,2017,15, 2507.). If the reaction temperature of the deuteration reaction of the 2-methyl nitrogen-containing heterocycle is further reduced, a metal catalyst is added or DMSO-d6 is used as a deuteration reagent, however, the use of expensive metal catalyst and deuteration reagent limits the application of the deuteration reaction in drug development (see Angew. chem. int. Ed.2017,56,1634. and J.org. chem.2017,82,4289.)
Disclosure of the invention
Aiming at the defects in the prior art, the invention aims to provide a high-selectivity deuteration method of a 2-methyl nitrogen heterocyclic compound.
a high-selectivity deuteration method of a 2-methyl nitrogen heterocyclic compound specifically comprises the following steps:
Adding a 2-methyl nitrogen-containing heterocyclic compound shown in a formula I, a formula II or a formula III, an oxidant and an additive into a dried Schlenk reaction tube, adding deuterium water and an organic solvent into the reaction tube under the condition of protective gas, stirring and reacting for 2-12 hours (preferably 12 hours) at 50-100 ℃ (preferably 100 ℃), and obtaining reaction liquid which is subjected to post-treatment to respectively obtain a deuterated nitrogen-containing heterocyclic ring shown in a formula IV, a formula V or a formula VI; the amount ratio of the 2-methyl nitrogen-containing heterocycle shown in the formula I, the formula II or the formula III, the oxidant, the additive and the deuterium oxide substance is 1: 0.02-1.5: 0.5: 10-50;
Formula I or formula IV:
R1H, F, tert-butyl;
R2Is H, OMe, F, Cl, Br, I, OCF3One of (1);
Formula II or formula V: r3is one of H, F, Br and OMe;
Formula III or formula VI: r4Is one of H, phenyl and 4-bromophenyl.
Further, the oxidant is one of iodobenzene diacetate, potassium persulfate, ammonium ceric nitrate and 2, 3-dichloro-5, 6-dinitrile benzoquinone, and is preferably iodobenzene diacetate.
Further, the additive is azobisisobutyronitrile.
Further, the protective gas of the present invention is nitrogen or argon, preferably nitrogen.
Further, the organic solvent is dry N, N-dimethylformamide.
Further, the total amount of the organic solvent added is 10mL/mmol based on the amount of the substance of the alkyne compound shown in formula I, formula II or formula III.
further, the post-treatment method of the reaction solution comprises the following steps: and after the reaction is finished, adding water into the obtained reaction liquid, extracting with diethyl ether, collecting an organic layer, drying with anhydrous sodium sulfate, filtering, taking a filtrate, and evaporating to remove the solvent to obtain the deuterated nitrogen-containing heterocyclic compound shown in the formula IV, the formula V or the formula VI.
Compared with the prior art, the invention has the beneficial effects that:
The method is based on a free radical process, is high-efficiency, can synthesize the methyl-d 3 substituted nitrogen heterocyclic compounds which are difficult to prepare by the existing method, and has high reaction deuteration rate; the method is carried out under a neutral condition, and the requirement on equipment is low; the catalytic amount of the oxidant is used, and the additive is cheap and easy to obtain; the reaction conditions are mild, and the energy consumption is saved; high yield, strong substrate universality, simple and convenient operation and the like.
(IV) detailed description of the preferred embodiment
The invention will be further illustrated by the following examples, without limiting the scope of the invention:
The general synthesis method of the 6-methyl phenanthridine comprises the following steps:
2-bromoaniline (10mmol), phenylboronic acid (12mmol), palladium acetate (0.25mmol) and sodium carbonate (10mmol) were placed in a three-necked flask, nitrogen was purged three times and DMF/H was added2O2: 1 mixed solvent (30 mL). And (3) stirring the reaction at room temperature overnight, adding water for dilution after the reaction is finished, extracting with ethyl acetate, taking an organic layer, removing the solvent in vacuum, carrying out silica gel column chromatography separation on the obtained crude product, carrying out elution by using petroleum ether/ethyl acetate (5/1) as an eluent, tracking the elution process by TLC (thin layer chromatography), collecting eluent containing the target product, combining the eluent, and evaporating the solvent to obtain a pure product. The yield was 78%.
A solution of o-phenylaniline (10mmol) and acetic anhydride (20mmol) in dichloromethane (10mL) was added to a round-bottomed flask, the reaction solution was stirred at room temperature, and the progress of the reaction was checked by TLC. After the reaction is finished, extracting with dichloromethane, taking an organic phase, adding 100-200 meshes of column chromatography silica gel into the organic phase, decompressing and distilling to remove the solvent, carrying out silica gel column chromatography separation on the obtained crude product, eluting by using petroleum ether/ethyl acetate (3/1) as an eluent, tracking the elution process by TLC, collecting eluent containing a target product, combining the eluent and distilling off the solvent to obtain a pure product. The material was a white solid in 89% yield.
a solution of the N-acetyl-2-phenylaniline (10mmol) and triphenylphosphine oxide (30mmol) in methylene chloride (80mL) obtained above was placed in a round-bottomed flask, and the reaction system was left at 0 ℃ to which trifluoromethanesulfonic anhydride (15mmol) was added dropwise. The reaction was stirred at room temperature for 5 h. After the reaction is finished, adding 100-200 meshes of column chromatography silica gel into the obtained reaction liquid, distilling under reduced pressure to remove the solvent, carrying out silica gel column chromatography separation on the obtained crude product, eluting by using petroleum ether/ethyl acetate (10/1) as an eluent, tracking the elution process by TLC, collecting eluent containing the target product, combining the eluents, and distilling off the solvent to obtain the pure product. The material was a white solid in 80% yield.
The 2-methylquinoline and 2-methylquinoxaline of the present invention are directly available from Annage reagent.
Example 1
6-Methylphenidine (0.3mmol,58mg), iodobenzene diacetate (0.45mmol,144.9mg), and azobisisobutyronitrile (0.15mmol,24.6mg) were charged into a dry Schlenk reaction tube, vacuum-pumped and nitrogen-purged three times, and deuterium oxide (300. mu.L) and N, N-dimethylformamide (3mL) were added to the above reaction tube under nitrogen protection, and the reaction tube was stirred at 100 ℃ for 12 hours. After the reaction, 10mL of water was added to the obtained reaction solution, extraction was performed with ether, an organic layer was collected, dried over anhydrous sodium sulfate, and filtered, and the filtrate was taken out, and the solvent was evaporated to obtain 6- (methyl-d 3) phenanthridine with a yield of 65% and a deuteration rate of 79%.
characterization data:1H NMR(500MHz,CDCl3)δ8.54-8.51(m,1H),8.47-8.44(m,1H), 8.14-8.10(m,1H),8.09(dd,J1＝8.1Hz,J2＝1.0Hz,3H),7.75(m,3H),7.70-7.66 (m,1H),7.63-7.60(m,1H),7.59-7.55(m,1H),2.97(m,0.3H).13C NMR(125 MHz,CDCl3)δ158.75,143.60,132.46,130.40,129.27,128.56,127.22,126.44, 126.26,125.83,123.71,122.22,121.89,23.04-22.43(m).
Example 2
8-fluoro-6-methylphenanthridine (0.3mmol,63.3mg), potassium persulfate (0.45mmol,121.6mg), azobisisobutyronitrile (0.15mmol,24.6mg) were added to a dried Schlenk reaction tube, vacuum was applied three times with nitrogen, deuterium water (300. mu.L) and N, N-dimethylformamide (3mL) were added to the reaction tube under nitrogen protection, and the reaction tube was stirred at 100 ℃ for 12 hours. After the reaction, 10mL of water was added to the obtained reaction solution, extraction was performed with diethyl ether, the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was taken, and the solvent was evaporated to obtain 8-fluoro-6- (methyl-d 3) phenanthridine with a yield of 75% and a deuteration rate of 34%.
characterization data:1H NMR(500MHz,CDCl3)δ8.57(dd,J1＝9.1Hz,J2＝5.3Hz,1H), 8.44(d,J＝8.2Hz,1H),8.09(dd,J1＝8.2Hz,J2＝1.1Hz,1H),7.78(dd,J1＝9.6 Hz,J2＝2.5Hz,1H),7.72-7.66(m,1H),7.64-7.58(m,1H),7.58-7.52(m,1H), 2.96-2.94(m,0.13H).13C NMR(125MHz,CDCl3)δ161.34(d,1JC-F＝246.5Hz), 157.89,143.38,129.53,129.24,128.51,127.19(d,3JC-F＝7.8Hz),126.72,124.88(d, 3JC-F＝8.2Hz),123.29,121.70,119.52(d,2JC-F＝23.4Hz),111.10(d,2JC-F＝20.9 Hz).
Example 3
9-tert-butyl-6-methylphenanthridine (0.3mmol,74.8mg), ceric ammonium nitrate (0.45mmol,246.7 mg), azobisisobutyronitrile (0.15mmol,24.6mg) were added to a dry Schlenk reaction tube, vacuum was applied three times with nitrogen replaced, and deuterium water (300. mu.L) and N, N-dimethylformamide (3mL) were added to the reaction tube at 100 ℃ under nitrogen protectionthe reaction was stirred for 12 hours. After the reaction, 10mL of water was added to the obtained reaction solution, extraction was performed with diethyl ether, the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was taken, and the solvent was evaporated to obtain 9-tert-butyl-6- (methyl-d 3) phenanthridine with a yield of 69% and a deuteration rate of 84%. Characterization data:1H NMR(500MHz,CDCl3)δ8.57-8.50(m,2H),8.18(d,J＝1.9Hz,1 H),8.13(dd,J1＝8.2Hz,J2＝1.0Hz,1H),7.93(dd,J1＝8.7Hz,J2＝2.0Hz,1H), 7.72-7.69(m,1H),7.65-7.58(m,1H),3.09-3.06(m,0.18H),1.51(s,9H).13C NMR(125MHz,CDCl3)δ158.87,150.35,143.43,130.35,129.20,128.81,128.17, 126.18,125.81,123.77,122.12,121.90,121.80,35.07,31.33.
Example 4
1-methoxy-6-methylphenanthridine (0.3mmol,67mg), 2, 3-dichloro-4, 5-dicyano-1, 4-benzoquinone (0.45mmol,102.15mg), azobisisobutyronitrile (0.15mmol,24.6mg) were added to a dried Schlenk reaction tube, vacuum-pumping was performed three times with nitrogen gas, deuterium water (300. mu.L) and N, N-dimethylformamide (3mL) were added to the reaction tube under nitrogen gas protection, and the reaction tube was stirred at 100 ℃ for 12 hours. After the reaction, 10mL of water was added to the obtained reaction solution, extraction was performed with diethyl ether, the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was taken, and the solvent was evaporated to obtain 1-methoxy-6- (methyl-d 3) phenanthridine with a yield of 80% and a deuteration rate of 49%.
characterization data:1H NMR(500MHz,CDCl3)δ9.58(d,J＝8.5Hz,1H),8.23(dd,J1＝8.1 Hz,J2＝0.8Hz,1H),7.84-7.81(m,1H),7.77(dd,J＝8.1,1.0Hz,1H),7.70-7.66 (m,1H),7.64(t,J＝8.1Hz,1H),7.13(d,J＝8.0Hz,1H),3.03-3.00(m,0.15H), 4.14(s,3H).13C NMR(125MHz,CDCl3)δ159.36,158.14,145.71,132.57,130.38, 128.20,128.13,126.61,126.27,126.01,122.19,114.50,107.67,55.84.
Example 5
3-chloro-6-methylphenanthridine (0.3mmol,68.3mg), iodobenzene diacetate (0.36mmol,115.9mg), azobisisobutyronitrile (0.15mmol,24.6mg) were added to a dried Schlenk reaction tube, vacuum was applied three times with nitrogen exchange, deuterium water (300. mu.L) and N, N-dimethylformamide (3mL) were added to the above reaction tube under nitrogen protection, and the reaction tube was stirred at 100 ℃ for 12 hours. After the reaction, 10mL of water was added to the obtained reaction solution, and extraction was performed with ether, and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was taken, and the solvent was evaporated to obtain 3-chloro-6- (methyl-d 3) phenanthridine with a yield of 87% and a deuteration rate of 87%.
Characterization data:1H NMR(500MHz,CDCl3)δ8.34(d,J＝8.2Hz,1H),8.30(d,J＝2.2 Hz,1H),8.08(dd,J1＝8.1Hz,J2＝0.6Hz,1H),7.93(d,J＝8.7Hz,1H), 7.75-7.72(m,1H),7.65-7.61(m,1H),7.56(dd,J1＝8.7Hz,J2＝2.3Hz,1H), 2.94-2.90(m,0.14H).13C NMR(125MHz,CDCl3)δ158.95,141.90,131.95,131.28, 130.6,130.52,128.89,127.78,126.38,125.79,124.63,122.12,121.44,22.80-22.14 (m).
Example 6
3-bromo-6-methylphenanthridine (0.3mmol,81.6mg), iodobenzene diacetate (0.3mmol,96.6mg), azobisisobutyronitrile (0.15mmol,24.6mg) were added to a dry Schlenk reaction tube, vacuum was applied three times with nitrogen, deuterium water (300. mu.L) and N, N-dimethylformamide (3mL) were added to the reaction tube under nitrogen, and the reaction tube was stirred at 100 ℃ for 12 hours. After the reaction, 10mL of water was added to the obtained reaction solution, extraction was performed with ether, an organic layer was collected, dried with anhydrous sodium sulfate, filtered, and the filtrate was taken, and the solvent was evaporated to obtain 3-bromo-6- (methyl-d 3) phenanthridine with a yield of 93% and a deuteration rate of 95%.
Characterization data:1H NMR(500MHz,CDCl3)δ8.55(d,J＝2.1Hz,1H),8.43(d,J＝8.2 Hz,1H),8.16-8.11(m,1H),7.90(d,J＝8.7Hz,1H),7.83-7.77(m,1H),7.73(dd, J1＝8.7Hz,J2＝2.1Hz,1H),7.69-7.65(m,1H),2.87-2.93(m,0.14H).13C NMR (125MHz,CDCl3)δ159.23,142.26,131.69,131.26,130.94,130.66,127.89,126.47, 125.88,125.18,124.72,122.21,120.18,22.68-22.37(m).
example 7
3-methoxy-6-methylphenanthridine (0.3mmol,66.9mg), iodobenzene diacetate (0.15mmol,48.3 mg), azobisisobutyronitrile (0.15mmol,24.6mg) were added to a dried Schlenk reaction tube, vacuum was applied three times with nitrogen exchange, deuterium water (300. mu.L) and N, N-dimethylformamide (3mL) were added to the above reaction tube under nitrogen protection, and the reaction tube was stirred at 100 ℃ for 12 hours. After the reaction, 10mL of water was added to the obtained reaction solution, extraction was performed with diethyl ether, the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was taken, and the solvent was evaporated to obtain 3-methoxy 6- (methyl-d 3) phenanthridine with a yield of 85% and a deuteration rate of 87%. Characterization data:1H NMR(500MHz,CDCl3)δ8.47(d,J＝8.3Hz,1H),8.38(d,J＝9.0 Hz,1H),8.14(d,J＝8.2Hz,1H),7.78-7.75(m,1H),7.60-7.57(m,1H),7.50(d,J ＝2.7Hz,1H),7.23(dd,J1＝9.0Hz,J2＝2.7Hz,1H),3.96(s,3H),3.01-2.97(m, 0.28H).13C NMR(125MHz,CDCl3)δ160.53,149.10,144.42,131.94,130.92, 127.68,126.65,125.83,123.66,122.25,121.66,120.06,119.49,,22.80-2.29(m).
Example 8
3-trifluoromethoxy-6-methylphenanthridine (0.3mmol,83.1mg), iodobenzene diacetate (0.03mmol, 9.66mg), azobisisobutyronitrile (0.15mmol,24.6mg) were added to a dry Schlenk reaction tube, vacuum was applied three times to exchange nitrogen, deuterium water (300. mu.L) and N, N-dimethylformamide (3mL) were added to the above reaction tube under nitrogen protection, and the reaction tube was stirred at 100 ℃ for 12 hours. After the reaction, 10mL of water was added to the obtained reaction solution, extraction was performed with ether, an organic layer was collected, dried with anhydrous sodium sulfate, filtered, and the filtrate was taken, and the solvent was evaporated to obtain 3-trifluoromethoxy-6- (methyl-d 3) phenanthridine with a yield of 95% and a deuteration rate of 96%.
Characterization data:1H NMR(500MHz,CDCl3)δ8.53(dd,J1＝14.0,J2＝8.6Hz,2H), 8.24-8.19(m,1H),7.97(d,J＝1.1Hz,1H),7.89-7.83(m,1H),7.74-7.70(m,1H), 7.47(dd,J1＝8.9Hz,J2＝1.8Hz,1H),3.03-3.00(m,0.10H).13C NMR(125MHz, CDCl3)δ160.53,149.10,144.42,131.94,130.92,127.68,126.65,125.83,123.69(d, J＝6.0Hz),122.25,120.64(q,JCF3＝256.3Hz),120.06,117.58,22.69-22.41(m).
Example 9
2-methylquinoline (0.3mmol,43mg), iodobenzene diacetate (0.006mmol,1.9mg), azobisisobutyronitrile (0.15mmol,24.6mg) were added to a dried Schlenk reaction tube, vacuum was applied three times with nitrogen exchange, deuterium oxide (300. mu.L) and N, N-dimethylformamide (3mL) were added to the above reaction tube under nitrogen protection, and the reaction tube was stirred at 100 ℃ for 12 hours. After the reaction, 10mL of water was added to the obtained reaction solution, extraction was performed with diethyl ether, the organic layer was collected, dried over anhydrous sodium sulfate, and filtered to obtain a filtrate, and the solvent was evaporated to obtain 2-methylquinoline with a yield of 96% and a deuteration rate of 39%.
Characterization data:1H NMR(500MHz,CDCl3)δ8.03(d,J＝8.5Hz,1H),7.98(d,J＝8.4 Hz,1H),7.72(d,J＝8.1Hz,1H),7.67-7.63(m,1H),7.44(t,J＝7.5Hz,1H),7.22 (d,J＝8.4Hz,1H),2.71-2.28(m,0.24H).13C NMR(125MHz,CDCl3)δ158.80, 147.75,136.05,129.30,128.50,127.38,126.39,125.55,121.87,24.85-23.26(m).
example 10
7-fluoro-2-methylquinoline (0.3mmol,48.4mg), iodobenzene diacetate (0.03mmol,9.7mg), azobisisobutyronitrile (0.15mmol,24.6mg) were added to a dried Schlenk reaction tube, vacuum was applied three times with nitrogen exchange, and deuterium water (240. mu.L) and N, N-dimethylformamide (3mL) were added to the above reaction tube under nitrogen protection, and the reaction tube was stirred at 100 ℃ for 12 hours. After the reaction, 10mL of water was added to the obtained reaction solution, extraction was performed with diethyl ether, the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate to obtain 7-fluoro-2- (methyl-d 3) quinoline in 95% yield and 89% deuteration rate.
Characterization data:1H NMR(500MHz,CDCl3)δ8.01(d,J＝8.4Hz,1H),7.74(dd,J1＝8.9 Hz,J2＝6.1Hz,1H),7.64(dd,J1＝10.4Hz,J2＝2.5Hz,1H),7.28-7.22(m,2H), 2.73-2.69(m,0.11H).13C NMR(125MHz,CDCl3)δ163.08(d,J＝247.6Hz), 160.12,148.83(d,J＝12.6Hz),135.96,129.41(d,J＝10.1Hz),123.45,121.31, 116.02(d,J＝25.1Hz),112.38(d,J＝20.1Hz),24.81-24.19(m).
Example 11
6-bromo-2-methylquinoline (0.3mmol,66.6mg), iodobenzene diacetate (0.03mmol,9.7mg), azobisisobutyronitrile (0.15mmol,24.6mg) were added to a dried Schlenk reaction tube, vacuum was applied three times with nitrogen replaced, and deuterium water (120. mu.L) and N, N-dimethylformamide (3mL) were added to the above reaction tube under nitrogen protection, and the reaction tube was stirred at 100 ℃ for 12 hours. After the reaction, 10mL of water was added to the obtained reaction solution, extraction was performed with diethyl ether, the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain 6-bromo-2- (methyl-d 3) quinoline in 96% yield and 78% deuteration rate.
Characterization data:1H NMR(500MHz,CDCl3)δ7.77-7.73(m,3H),7.59(dd,J1＝9.0,J2＝ 2.1Hz,1H),7.12(d,J＝8.4Hz,1H),2.59-2.55(m,0.13H).13C NMR(125MHz, CDCl3)δ159.25,146.26,134.88,132.59,130.26,129.33,127.43,122.63,119.19, 24.57-24.10(m).
Example 12
6-methoxy-2-methylquinoline (0.3mmol,52mg), iodobenzene diacetate (0.03mmol,9.7mg), azobisisobutyronitrile (0.15mmol,24.6mg) were added to a dried Schlenk reaction tube, vacuum-pumping was performed three times with nitrogen gas, and deuterium water (60. mu.L) and N, N-dimethylformamide (3mL) were added to the above reaction tube under nitrogen gas protection, and the reaction tube was stirred at 100 ℃ for 12 hours. After the reaction, 10mL of water was added to the obtained reaction solution, and extraction was performed with diethyl ether, and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate to obtain 6-methoxy-2- (methyl-d 3) quinoline in 96% yield and 61% deuteration rate.
characterization data:1H NMR(500MHz,CDCl3)δ7.92(d,J＝8.7Hz,2H),7.33(dd,J1＝9.2 Hz,J2＝2.8Hz,1H),7.22(d,J＝8.3Hz,1H),7.02(d,J＝2.8Hz,1H),3.89(s,3 H),2.68-2.66(m,0.12H).13C NMR(125MHz,CDCl3)δ157.10,156.2,143.82, 134.97,129.93,127.28,122.15,121.79,105.20,22.42-23.81(m).
Example 13
2-methylquinoxaline (0.3mmol,43.2mg), iodobenzene diacetate (0.03mmol,9.7mg), azobisisobutyronitrile (0.15mmol,24.6mg) were added to a dried Schlenk reaction tube, vacuum was applied three times with nitrogen gas, deuterium water (300. mu.L) and N, N-dimethylformamide (3mL) were added to the above reaction tube under nitrogen gas protection, and the reaction tube was stirred at 80 ℃ for 12 hours. After the reaction is finished, 10mL of water is added into the obtained reaction liquid, ether is used for extraction, an organic layer is collected, anhydrous sodium sulfate is used for drying, filtration is carried out, filtrate is obtained, the solvent is evaporated, and the 2- (methyl-d 3) quinoxaline is obtained, wherein the yield is 97%, and the deuteration rate is 80%.
Characterization data1H NMR(500MHz,CDCl3)δ8.74(s,1H),8.08-8.06(m,1H),8.03-8.00 (m,1H),7.75-7.68(m,2H),2.76-2.73(m,0.2H).13C NMR(125MHz,CDCl3)δ 153.68,145.97,142.07,140.98,129.95,129.15,128.88,128.65,22.01-21.46(m).
example 14
2- (4-bromophenyl) -3-methylquinoxaline (0.3mmol,90mg), iodobenzene diacetate (0.03mmol,9.7mg), azobisisobutyronitrile (0.15mmol,24.6mg) were added to a dried Schlenk reaction tube, vacuum was applied three times with nitrogen gas, deuterium water (300. mu.L) and N, N-dimethylformamide (3mL) were added to the above reaction tube under nitrogen gas protection, and the reaction tube was stirred at 50 ℃ for 12 hours. After the reaction is finished, 10mL of water is added into the obtained reaction liquid, ether is used for extraction, an organic layer is collected, anhydrous sodium sulfate is used for drying, filtration is carried out, filtrate is obtained, the solvent is evaporated to obtain the 2- (4-bromophenyl) -3- (methyl-d 3) quinoxaline, the yield is 94%, and the deuteration rate is 28%.
Characterization data:1H NMR(500MHz,CDCl3)δ8.11-8.08(m,1H),8.07-8.04(m,1H), 7.77-7.71(m,2H),7.68-7.66(m,2H),7.57-7.54(m,2H),2.77-2.74(m,0.05H).13C NMR(125MHz,CDCl3)δ153.66,152.05,141.34,140.99,137.93,131.76,130.67, 129.97,129.40,129.21,128.39,123.54.
example 15
2- (4-bromophenyl) -3-methylquinoxaline (0.3mmol,90mg), iodobenzene diacetate (0.03mmol,9.7mg), azobisisobutyronitrile (0.15mmol,24.6mg) were added to a dried Schlenk reaction tube, vacuum was applied three times with nitrogen gas, deuterium water (300. mu.L) and N, N-dimethylformamide (3mL) were added to the above reaction tube under nitrogen gas protection, and the reaction tube was stirred at 100 ℃ for 5 hours. After the reaction is finished, 10mL of water is added into the obtained reaction liquid, ether is used for extraction, an organic layer is collected, anhydrous sodium sulfate is used for drying, filtration is carried out, filtrate is obtained, the solvent is evaporated to obtain the 2- (4-bromophenyl) -3- (methyl-d 3) quinoxaline, the yield is 98%, and the deuteration rate is 55%.
Characterization data:1H NMR(500MHz,CDCl3)δ8.11-8.08(m,1H),8.07-8.04(m,1H), 7.77-7.71(m,2H),7.68-7.66(m,2H),7.57-7.54(m,2H),2.77-2.74(m,0.05H).13C NMR(125MHz,CDCl3)δ153.66,152.05,141.34,140.99,137.93,131.76,130.67, 129.97,129.40,129.21,128.39,123.54.
example 16
2- (4-bromophenyl) -3-methylquinoxaline (0.3mmol,90mg), iodobenzene diacetate (0.03mmol,9.7mg), azobisisobutyronitrile (0.15mmol,24.6mg) were added to a dried Schlenk reaction tube, vacuum was applied three times with nitrogen gas, deuterium water (300. mu.L) and N, N-dimethylformamide (3mL) were added to the above reaction tube under nitrogen gas protection, and the reaction tube was stirred at 100 ℃ for 2 hours. After the reaction is finished, 10mL of water is added into the obtained reaction liquid, ether is used for extraction, an organic layer is collected, anhydrous sodium sulfate is used for drying, filtration is carried out, filtrate is obtained, the solvent is evaporated to obtain the 2- (4-bromophenyl) -3- (methyl-d 3) quinoxaline, the yield is 98%, and the deuteration rate is 40%.
characterization data:1H NMR(500MHz,CDCl3)δ8.11-8.08(m,1H),8.07-8.04(m,1H), 7.77-7.71(m,2H),7.68-7.66(m,2H),7.57-7.54(m,2H),2.77-2.74(m,0.05H).13C NMR(125MHz,CDCl3)δ153.66,152.05,141.34,140.99,137.93,131.76,130.67, 129.97,129.40,129.21,128.39,123.54。
Claims (8)
1. A high-selectivity deuteration method of 2-methyl nitrogen heterocyclic compounds is characterized in that: the method comprises the following steps:
adding a 2-methyl nitrogen-containing heterocyclic compound shown in a formula I, a formula II or a formula III, an oxidant and an additive into a dried Schlenk reaction tube, adding deuterium water and an organic solvent into the reaction tube under the condition of protective gas, stirring and reacting for 2-12 hours at 50-100 ℃, and obtaining reaction liquid, and respectively obtaining a deuterated nitrogen-containing heterocyclic ring shown in a formula IV, a formula V or a formula VI after post-treatment; the amount ratio of the 2-methyl nitrogen-containing heterocycle shown in the formula I, the formula II or the formula III, the oxidant, the additive and the deuterium oxide substance is 1: 0.02-1.5: 0.5: 10-50;
Formula I or formula IV:
R1H, F, tert-butyl;
R2is H, OMe, F, Cl, Br, I, OCF3one of (1);
Formula II or formula V: r3is one of H, F, Br and OMe;
formula III or formula VI: r4Is one of H, phenyl and 4-bromophenyl.
2. The method of claim 1, wherein: the oxidant is one of iodobenzene diacetate, potassium persulfate, ammonium ceric nitrate and 2, 3-dichloro-5, 6-dicyan benzoquinone.
3. the method of claim 1, wherein: the additive is azobisisobutyronitrile.
4. the method of claim 1, wherein: the protective gas is nitrogen or argon.
5. the method of claim 1, wherein: the organic solvent is dry N, N-dimethylformamide.
6. the method of claim 1, wherein: the total amount of the organic solvent added is 10mL/mmol based on the amount of the substance of the alkyne compound shown in the formula I, the formula II or the formula III.
7. the method of claim 1, wherein: the reaction temperature is 100 ℃, and the reaction time is 12 hours.
8. The method of claim 1, wherein: the post-treatment method of the reaction solution comprises the following steps: and after the reaction is finished, adding water into the obtained reaction liquid, extracting with diethyl ether, collecting an organic layer, drying with anhydrous sodium sulfate, filtering, taking a filtrate, and evaporating to remove the solvent to obtain the deuterated nitrogen-containing heterocyclic compound shown in the formula IV, the formula V or the formula VI.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910798544.XA CN110563649B (en) | 2019-08-27 | 2019-08-27 | High-selectivity deuteration method of 2-methyl nitrogen heterocyclic compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910798544.XA CN110563649B (en) | 2019-08-27 | 2019-08-27 | High-selectivity deuteration method of 2-methyl nitrogen heterocyclic compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110563649A true CN110563649A (en) | 2019-12-13 |
| CN110563649B CN110563649B (en) | 2021-07-27 |
Family
ID=68776403
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910798544.XA Active CN110563649B (en) | 2019-08-27 | 2019-08-27 | High-selectivity deuteration method of 2-methyl nitrogen heterocyclic compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110563649B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111039796A (en) * | 2019-12-12 | 2020-04-21 | 德州学院 | Novel synthesis method of 4' -chloro-2-aminobiphenyl |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565600A (en) * | 2016-10-28 | 2017-04-19 | 湖南大学 | Deuterated aza aromatic compound and synthesis method thereof |
| CN110156766A (en) * | 2019-06-04 | 2019-08-23 | 南京工业大学 | A kind of preparation method of the deuterated five-membered aromatic heterocyclic compounds of silver catalysis |
-
2019
- 2019-08-27 CN CN201910798544.XA patent/CN110563649B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565600A (en) * | 2016-10-28 | 2017-04-19 | 湖南大学 | Deuterated aza aromatic compound and synthesis method thereof |
| CN110156766A (en) * | 2019-06-04 | 2019-08-23 | 南京工业大学 | A kind of preparation method of the deuterated five-membered aromatic heterocyclic compounds of silver catalysis |
Non-Patent Citations (1)
| Title |
|---|
| ALAGESAN MUTHUKUMAR，ET AL.: "Zinc-catalyzed chemoselective alkylation of α-keto amides with 2-alkylazaarenes", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111039796A (en) * | 2019-12-12 | 2020-04-21 | 德州学院 | Novel synthesis method of 4' -chloro-2-aminobiphenyl |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110563649B (en) | 2021-07-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110563649B (en) | High-selectivity deuteration method of 2-methyl nitrogen heterocyclic compound | |
| CN104844399A (en) | Method for synthetizing 2-fluoro phenol compound | |
| CN108892601B (en) | Preparation method of polycyclic aromatic hydrocarbon with benzofluorene structure | |
| Guo et al. | Synthesis of 3 or 3, 3′-substituted BINOL ligands and their application in the asymmetric addition of diethylzinc to aromatic aldehydes | |
| CN109608394A (en) | The synthetic method and azepine aromatic amine compounds of azepine aromatic amine compounds | |
| CN114044751B (en) | Deuterated difluoromethylthio reagent, preparation method thereof and introduction of SCF (SCF) into drug molecules 2 Method for preparing D group | |
| CN110305122B (en) | Pyridine ring C4 site sulfonyl and phosphorus oxygen group functionalized Pybox ligand and synthesis method and application thereof | |
| CN103724319B (en) | The preparation method of a kind of benzothiophenes and purification method thereof | |
| CN104876929A (en) | Synthesis method and application of 1,2,3,4-tetrahydronaphthyridine compound | |
| CN113845509B (en) | Synthetic method of indolyl-substituted spiro [ cyclobutane-1,1' -indene ] compound | |
| CN111217847B (en) | Thiosilane ligand, preparation method thereof and application thereof in aryl boronization catalytic reaction | |
| WO2020177347A1 (en) | Oxygen-guided synthesis method for 7-alkynyl indole compound | |
| CN106366069B (en) | A kind of preparation method of N- heteroaryl carbazole compound | |
| CN109897039B (en) | Method for preparing pyrrolo [3,2,1-ij ] quinolinone compound | |
| CN108358923B (en) | Sophoridine pyrrole and indole derivatives, and preparation method and application thereof | |
| CN108164397B (en) | Catechol derivative and its preparation method | |
| CN114621218A (en) | Zolpidem intermediate compound | |
| CN111217654A (en) | Palladium-catalyzed meta-arylation reaction and application thereof in synthesis of vemurafenib analogue | |
| CN111004164A (en) | Preparation method of polysubstituted 2-aryl indole derivative | |
| CN108530445A (en) | A kind of synthetic method of 3- cyanoimidazoles simultaneously [1,5-a] quinoline compound | |
| CN110563658A (en) | synthesis method of 1, 5-benzodiazepine compound | |
| CN105085275A (en) | O-nitrophenol and its derivative synthesis method | |
| CN103254065B (en) | 2,4,4',6-tetracarboxylic acid biphenyl silver complex and preparation method and application thereof | |
| CN113024604B (en) | Preparation method of C3-alkenylated 2-pyridone derivative | |
| CN110483502B (en) | Pyrido [1,2-a ] [1,2,4] triazole carbene ligand and synthetic method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |