CN106565600A - Deuterated aza aromatic compound and synthesis method thereof - Google Patents
Deuterated aza aromatic compound and synthesis method thereof Download PDFInfo
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Abstract
The invention provides a synthetic method for preparing a deuterated aza aromatic compound, which has the advantages of simple reaction condition, high selectivity and high deuterated ratio. The method is carried out in an inert gas atmosphere or in an air atmosphere, and an acid reagent is used as one only catalyst for synthesis of the deuterated aza aromatic compound directly from an aza aromatic compound and a deuterated reagent. The method does not need the reaction conditions such as a ligand, microwave radiation, a high pressure, an organic reaction solvent and the like. The substrate is cheap, easily-available, and rich in the nature, does not need prefunctionalization, and has the advantages of wide adaptability and simple experiment operation. At the same time, the method has good chemical and regioselectivity, and can effectively realize the deuteration of the aza aromatic compound. The method has a very important application prospect in the organic synthesis and medicinal chemistry-related isotope labelling field.
Description
【Technical field】
The present invention relates to organic synthesis, the isotope marks field of pharmaceutical chemistry correlation, and in particular to a kind of deuterated azepine
Aromatic and its synthetic method.
【Background technology】
Isotope-labelling method is a kind of highly important technological means in methodology of organic synthesis research, is widely used in
In exploring the study mechanism of organic chemical reactionses course, for vitochemical depth development important theory support is provided.Azepine
Aromatic is a kind of highly important basic building block in organic synthesis, pharmaceutical chemistry and natural product chemistry,
Rich and varied sense dough can be realized.Dynamics research, medicine of the deuterated azepine aromatic in the hydrocarbon activation of organic synthesis
The very important roles of aspect performer such as spike application, the natural product chemistry isotope marks tracking in thing chemical research.
The method report for synthesizing deuterated azepine aromatic at present is extremely limited, and general synthesis path is 1, transition metal
The hydrogen deuterium of catalysis is exchanged, and the method is less efficient, and selective poor, deuterated rate is not ideal enough, is post-processed not easy to operate and is lacked
Economy；2nd, the hydrogen deuterium exchange reaction that base reagent promotes, the approach reaction condition is very harsh, needs high temperature, high pressure, microwave
Support, and substrate practicality is very limited.
【Bibliography：(a)D.Cagli,M.C.Krutein,K.M.Bompiani,D.J.Barlow,G.Benoni,
J.C.Pelletier,A.B.Reitz,L.L.Lairson,K.L.Houseknecht,G.R.Smith and
T.J.Dickerson,J.Med.Chem.2014,57,669-676；(b)Eric M.Simmons and John
F.Hartwig,Angew.Chem.Int.Ed.,2012,51,3066–3072；(c)J.Atzrodt,V.Derdau,T.Fey,
and J.Zimmermann,Angew.Chem.Int.Ed.,2007,46,7744–7765；(d)M.Benedetti,
C.R.Barone,C.R.Girelli,F.P.Fanizzi,G.Natile and L.Maresca,Dalton Trans.,2014,
43,3669-3675；(e)Y.Ito and M.Yoshimatsu,Org.Chem.Front.,2015,2,201-205.】.
For the deficiency of said method, a kind of reaction condition of exploitation is simple, high selectivity, high deuterated rate prepare deuterated azepine
The synthetic method of aromatic is particularly important.
【The content of the invention】
The purpose of the present invention is under a kind of nitrogen of exploitation, atmosphere of inert gases or air atmosphere, using acid catalyst, with nitrogen
Heteroaryl aroma compounds are raw material with deuterated reagent, and high selectivity, high productivity synthesize the synthesis side of deuterated azepine aromatic
Method.
The goal of the invention of the present invention is achieved by the following technical solution：
A kind of deuterated azepine aromatic and its synthetic method, comprise the steps of：
Take azepine aromatic, deuterated reagent, acid catalyst to be placed in reaction vessel, mix；In nitrogen, inert gas
Or under air atmosphere, reaction temperature is 40 DEG C～130 DEG C, continues stirring reaction 0.5h～24h, reaction is cooled to room after terminating
Temperature, is washed with aqueous slkali, is then extracted with organic solvent, is dried；Vacuum distillation removes extractant, obtains final product target compound.
In above-mentioned synthetic method, described methyl substituted azepine aromatic is selected from 2- methylquinolines, 2,6- bis-
Methylquinoline, 2- methyl -6- methoxy quinolines, 2- methyl -8- methoxy quinolines, 2- methyl -6- chloroquinolines, 2- methyl -6- fluorine
Quinoline, 2- methyl -6- bromoquinolines, 7-Chloroquinaldine, 2- methyl -6- nitroquinolines, 2- methylquinoline -6- methyl formates,
2- methyl -8-hydroxyquinoline, 2- methyl -8-hydroxyquinoline, the chloro- 8- hydroxyls quinaldines of 5,7- bis-, the iodo- 8- hydroxyls quinolines of the chloro- 7- of 5-
Which pyridine, 4- methylquinolines, 2,4- dimethyl quinolines, 2,9- dimethyl -1,10- ferrosins, 2,4- lutidines, 4- methyl pyrrole
Pyridine, 2- picolines, 4- ethylpyridines, 4- benzyl pyridines, 2- isopropyl quinolines, 2- ethyl quinoliniums, 2- vinylquinolines, 1- benzyls
Base -2 methyl indole, 2,3,3- trimethyl -3H- indoles, 2- methylbenzothiazoles, 2- Jia base benzoxazoles, papaverine, support pyrrole
Card amine or Irinotecan.
In above-mentioned synthetic method, described deuterated reagent is selected from d6-DMSO、d7-DMF、d6-Acetone、CD3OD、D2O、
CD3CN、C6D6In at least one.
In above-mentioned synthetic method, described acid catalyst is selected from copper acetate, ferric trichloride, alchlor, zinc chloride, vinegar
Acid, acetic anhydride, trifluoroacetic acid, TFAA, trifluoromethayl sulfonic acid, benzoic acid, p-methylbenzoic acid, paranitrobenzoic acid,
P-methoxybenzoic acid, 3,5- dinitrobenzoic acids, diphenylphosphoric acid, phenyl phosphinic acid, phosphoric acid, hypophosphorous acid, phenylacetic acid, phenylpropyl alcohol
In acid, trimethylace tonitric, benzene sulfonic acid, p-methyl benzenesulfonic acid, mandelic acid, salicylic at least one.
In above-mentioned synthetic method, the acid catalyst levels for calculation in the molar ratio for azacyclo- aromatic 1～
20%.
In above-mentioned synthetic method, the aqueous slkali for washing is selected from sodium bicarbonate solution, sodium carbonate liquor, carbonic acid
At least one in potassium solution or sodium hydroxide solution
In above-mentioned synthetic method, the organic solvent in described extraction step is ethyl acetate, chloroform or dichloromethane
At least one in alkane.
Present invention also offers a kind of deuterated azepine aromatic by prepared by above-mentioned any means, with structure
Formula：
I：Or II：
In the structure Formulas I or II：
N=1,2,3；R1Be hydrogen, alkyl, alkoxyl, fluorine, chlorine, bromine, iodine, hydroxyl, ester group, aldehyde radical, amide groups, carboxyl or
Nitro；R2It is deuterium, alkyl, alkoxyl, halogen, hydroxyl, ether, ester group, amino or ketone group；CD wherein in structure Formulas InR2 (3-n)
It is located at least one of 2-, 3- or 4- position position；X in formula II is CH (CH3)2、CH2, O or S.
The present invention is directly raw material by azepine aromatic and deuterated reagent, and a step prepares deuterated azepine aromatic
Method.According to experimental result, the method have catalyst and raw material is cheap and easy to get, the easily separated purifying of gained target product, choosing
The features such as selecting property is high, deuterated yield is high, operation is simple, substrate applicability is wide.In this method solving other synthetic methods
Existing economy is low, selective low, relatively low deuterated yield, complex operation, narrow substrate adaptability the problems such as.
【Specific embodiment】
Synthetic method of the present invention is described further with reference to the synthesis example of the present invention, needs explanation
It is that embodiment does not constitute the restriction to the claimed scope of the invention.
What the present invention was provided prepares deuterated azepine aromatics by azacyclo- fragrance methyl compound with the step of deuterated reagent one
Thing, its synthesis path is：
Correspondingly, synthesis step is：By azepine aromatic, deuterated reagent, the acid catalyst (base of mol ratio 1～20%
In azepine aromatic) reaction vessel is placed in, mixing；Under nitrogen, inert gas or air atmosphere, reaction temperature is 40
DEG C～130 DEG C, continuing stirring reaction 0.5h～24h, reaction is cooled to room temperature, is washed with aqueous slkali after terminating, then with organic
Solvent extraction, is dried, and vacuum distillation removes solvent and obtains final product deuterated azepine aromatic.
Synthesis example 1
d3The synthesis of -2- methylquinolines
0.20mmol 2- methylquinolines, 0.2mL D are added in the reactor2O, 0.015mmol benzoic acid.In nitrogen/sky
Under atmosphere is enclosed, 80 DEG C are heated to, persistently stir 4h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate solution washing,
With ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield 96%.1H NMR
(400MHz,CDCl3) δ 8.03 (d, J=8.4Hz, 2H), 7.76 (d, J=8.4Hz, 1H), 7.66-7.69 (t, J=7.6Hz,
1H), 7.45-7.49 (t, J=7.4Hz, 1H), 8.03 (d, J=8.4Hz, 1H)；13C NMR(100MHz,CDCl3)δ157.94,
146.84,135.16,128.41,127.59,126.47,125.49,124.65,120.98,23.13-23.75(quat-C).。
Synthesis example 2
d3The synthesis of -2,6- dimethyl quinolines
0.20mmol 2,6- dimethyl quinolines, 0.2mL D are added in the reactor2O, 0.02mmol benzoic acid.In nitrogen
Under gas/air atmosphere, 80 DEG C are heated to, persistently stir 4h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate solution
Washing, with ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield 97%.1H
NMR(400MHz,CDCl3) δ 7.90-7.95 (m, 2H), 7.50 (d, J=9.2Hz, 2H), 7.23 (d, J=8Hz, 1H), 2.51
(s,3H)；13C NMR(100MHz,CDCl3)δ157.93,146.44,135.54,135.38,131.64,128.29,126.51,
126.39,121.95,24.25-24.71(quat-C),21.46。
Synthesis example 3
d3The synthesis of -6- methoxyl group -2- methylquinolines
0.20mmol 6- methoxyl group -2- methylquinolines, 0.2mL D are added in the reactor2O, 0.02mmol benzoic acid.
Under nitrogen/air atmosphere, 100 DEG C are heated to, persistently stir 4h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate
Solution is washed, and with ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield
97%.1H NMR(400MHz,CDCl3) δ 7.83-7.86 (m, 2H), 7.24-7.27 (m, 1H), 7.15 (d, J=8.4Hz, 1H),
6.95 (d, J=2Hz, 1H), 3.83 (s, 3H)；13C NMR(100MHz,CDCl3)δ157.15,156.29,143.89,
135.04,130.00,127.33,122.23,121.87,105.23,55.49,23.97-24.40(quat-C)。
Synthesis example 4
d3The synthesis of -8- methoxyl group -2- methylquinolines
0.20mmol 8- methoxyl group -2- methylquinolines, 0.2mL D are added in the reactor2O, 0.02mmol benzoic acid.
Under nitrogen/air atmosphere, 100 DEG C are heated to, persistently stir 4h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate
Solution is washed, and with ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield
95%.1H NMR(400MHz,CDCl3) δ 7.93 (d, J=4.4Hz, 2H), 7.20-7.33 (m, 2H), 6.94 (d, J=7.6Hz,
1H),3.99(s,3H)；13C NMR(100MHz,CDCl3)δ158.08,154.81,139.70,136.00-136.11(quat-
C),127.58,125.69,122.60,119.42,107.59,55.98,24.25-24.71(quat-C)。
Synthesis example 5
d3The synthesis of the fluoro- 2- methylquinolines of -6-
The fluoro- 2- methylquinolines of 0.20mmol 6-, 0.2mL D are added in the reactor2O, 0.02mmol benzoic acid.In nitrogen
Under gas/air atmosphere, 80 DEG C are heated to, persistently stir 4h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate solution
Washing, with ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield 96%.1H
NMR(400MHz,CDCl3) δ 7.89-7.95 (m, 2H), 7.34-7.39 (t, J=9.8Hz, 1H), 7.30 (d, J=8.8Hz,
1H), 7.2 (d, J=8.4Hz, 1H)；13C NMR(100MHz,CDCl3)δ159.96(JF-C=245.1Hz), 158.24,
144.94,135.50(JF-C=5.2Hz), 131.02 (JF-C=9Hz), 126.98 (JF-C=9.8Hz), 122.75,119.45
(JF-C=25.4Hz), 110.51 (JF-C=21.4Hz), 24.02-24.77 (quat-C).
Synthesis example 6
d3The synthesis of -6- chloro-2-methyl quinoline
0.20mmol 6- chloro-2-methyl quinoline, 0.2mL D are added in the reactor2O, 0.02mmol benzoic acid.In nitrogen
Under gas/air atmosphere, 80 DEG C are heated to, persistently stir 4h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate solution
Washing, with ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield 91%.1H
NMR(400MHz,CDCl3) δ 7.87 (d, J=8.4Hz, 2H), 7.67 (s, 1H), 7.53 (d, J=8.8Hz, 1H), 7.19-
7.23 (t, J=7.2Hz, 1H)；13C NMR(100MHz,CDCl3)δ159.31,146.24,135.21,135.10,131.30,
130.27,127.09,126.17,122.87,24.34-24.80(quat-C)。
Synthesis example 7
d3The synthesis of -6- nitro -2- methylquinolines
0.20mmol 6- nitro -2- methylquinolines, 0.2mL D are added in the reactor2O, 0.04mmol benzoic acid.
Under nitrogen/air atmosphere, 120 DEG C are heated to, persistently stir 24h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate
Solution is washed, and with ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield
94%.1H NMR(400MHz,CDCl3) δ 8.74 (d, J=2Hz, 1H), 8.43-8.46 (m, 1H), 8.22-8.24 (t, J=
4Hz, 1H), 8.12 (d, J=9.2Hz, 1H), 7.46 (d, J=8.4Hz, 0.35H)；13C NMR(100MHz,CDCl3)δ
163.24,150.00,144.98,137.61-137.72(quat-C),130.39,125.25,124.34,123.96,
122.97,24.71-25.70(quat-C)。
Synthesis example 8
d3The synthesis of -6- methyl formate -2- methylquinolines
0.20mmol 6- methyl formate -2- methylquinolines, 0.2mL D are added in the reactor2O, 0.02mmol benzene first
Acid.Under nitrogen/air atmosphere, 80 DEG C are heated to, persistently stir 4h, stop reaction, be cooled to room temperature, add unsaturated carbonate hydrogen
Sodium solution is washed, and with ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield
97%.1H NMR(400MHz,CDCl3) δ 8.44 (s, 1H), 8.18 (d, J=8.8Hz, 1H), 8.04 (d, J=8.4Hz, 1H),
7.95 (d, J=8.8Hz, 1H), 7.25 (d, J=8.4Hz, 1H)；13C NMR(100MHz,CDCl3)δ166.73,161.54,
149.78,137.29,130.69,129.00,128.91,127.24,125.61,122.81,52.34,24.61-25.00
(quat-C)。
Synthesis example 9
d3The synthesis of -7- chloro-2-methyl quinoline
0.20mmol 7- chloro-2-methyl quinoline, 0.2mL D are added in the reactor2O, 0.02mmol benzoic acid.In nitrogen
Under gas/air atmosphere, 80 DEG C are heated to, persistently stir 4h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate solution
Washing, with ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield 97%.1H
NMR(400MHz,CDCl3) δ 7.92 (d, J=8.0Hz, 2H), 7.60 (d, J=8.0Hz, 1H), 7.34 (d, J=8.8Hz,
1H), 7.19 (d, J=8.4Hz, 1H)；13C NMR(100MHz,CDCl3)δ160.15,148.24,135.90,135.18,
128.69,127.76,126.70,124.85,122.20,24.38-25.03(quat-C)。
Synthesis example 10
d3The synthesis of -2- methylisoquinoliniums
0.20mmol 2- methylisoquinoliniums, 0.2mL D are added in the reactor2O, 0.015mmol benzoic acid.Nitrogen/
Under air atmosphere, 90 DEG C are heated to, persistently stir 4h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate solution to wash
Wash, with ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield 96%.1H
NMR(400MHz,CDCl3) δ 8.67 (s, 0.45H), 7.99 (d, J=8.0Hz, 1H), 7.94 (d, J=8.0Hz, 1H), 7.61-
7.69(m,2H)；13C NMR(100MHz,CDCl3)δ153.72,145.99,142.06,140.98,130.01,129.14,
128.94,128.64,21.39-22.04(quat-C)。
Synthesis example 11
d3The synthesis of -4- methylquinolines
0.20mmol 4- methylquinolines, 0.2mL D are added in the reactor2O, 0.02mmol benzoic acid.In nitrogen/sky
Under atmosphere is enclosed, 100 DEG C are heated to, persistently stir 4h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate solution washing,
With ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield 97%.1H NMR
(400MHz,CDCl3) δ 8.01 (d, J=8.4Hz, 1H), 7.35-7.39 (t, J=7.8Hz, 1H), 7.26-7.29 (t, J=
6.8Hz, 2H), 7.14 (d, J=7.6Hz, 1H)；13C NMR(100MHz,CDCl3)δ150.16,147.95,144.26,
129.98,129.13,128.32,126.30,123.83,121.88,17.68-18.33(quat-C)。
Synthesis example 12
D6The synthesis of -2,9- dimethyl -1,10- ferrosins
0.20mmol 2,9- dimethyl -1,10- ferrosins, 0.2mL D are added in the reactor2O, 0.03mmol benzene first
Acid.Under nitrogen/air atmosphere, 90 DEG C are heated to, persistently stir 4h, stop reaction, be cooled to room temperature, add unsaturated carbonate hydrogen
Sodium solution is washed, and with ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield
91%.1H NMR(400MHz,CDCl3) δ 8.10 (d, J=8.0Hz, 2H), 7.68 (s, 2H), 7.48 (d, J=8.0Hz,
1.6H)；13C NMR(100MHz,CDCl3)δ159.11,145.25,136.07-136.18(quat-C),126.72,125.38,
122.85-123.41(quat-C),24.58-25.49(quat-C)。
Synthesis example 13
d3The synthesis of -8- hydroxy-2-methylquinolines
0.20mmol 8- hydroxy-2-methylquinolines, 0.2mL D are added in the reactor2O, 0.02mmol benzoic acid.
Under nitrogen/air atmosphere, 120 DEG C are heated to, persistently stir 4h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate molten
Liquid is washed, and with ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield 97%.1H NMR(400MHz,CDCl3) δ 8.69 (d, J=4.4Hz, 1H), 8.03 (d, J=8.4Hz, 1H), 7.91 (d, J=8.4Hz,
1H), 7.61-7.64 (t, J=7.6Hz, 1H), 7.46-7.50 (t, J=7.4Hz, 1H), 7.14 (d, J=4.4Hz, 1H)；13C
NMR(100MHz,CDCl3)δ156.84,151.69,137.69,136.02-136.13(quat-C),126.52-126.65
(quat-C),122.72,117.58,109.80,23.93-24.32(quat-C)。
Synthesis example 14
d3The synthesis of the chloro- 2- methylquinolines of -8- hydroxyls -5,7- two
0.20mmol 8- hydroxyl -5, the chloro- 2- methylquinolines of 7- bis-, 0.2mL D are added in the reactor2O, 0.02mmol
Benzoic acid.Under nitrogen/air atmosphere, 120 DEG C are heated to, persistently stir 4h, stop reaction, be cooled to room temperature, add saturation
Sodium bicarbonate solution is washed, and with ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated
Yield 91%.1H NMR(400MHz,CDCl3) δ 8.23 (d, J=8.8Hz, 1H), 7.39 (s, 1H), 7.30 (d, J=8.8Hz,
1H)；13C NMR(100MHz,CDCl3)δ158.79,147.06,138.00,133.47,127.15,123.46,123.14,
120.62,114.99,23.86-24.40(quat-C)。
Synthesis example 15
d6The synthesis of -2,4- lutidines
0.20mmol 2,4- lutidines, 0.2mL D are added in the reactor2O, 0.04mmol benzoic acid.In nitrogen
Under gas/air atmosphere, 120 DEG C are heated to, persistently stir 24h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate molten
Liquid is washed, and with dichloromethane extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield 92%-
d4, 49%-d2。1H NMR(400MHz,CDCl3) δ 8.33 (d, J=4.8Hz, 1H), 6.98 (s, 1H), 6.91 (d, J=
7.2Hz,1H)；13C NMR(100MHz,CDCl3)δ158.00,148.78,147.22,124.20,121.77,23.66-24.19
(quat-C),19.91-20.30(quat-C)。
Synthesis example 16
d3The synthesis of -4- picolines
0.20mmol 4- picolines, 0.2mL D are added in the reactor2O, 0.04mmol benzoic acid.In nitrogen/sky
Under atmosphere is enclosed, 120 DEG C are heated to, persistently stir 24h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate solution to wash
Wash, with dichloromethane extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield 95%.1H
NMR(400MHz,CDCl3) δ 8.38 (d, J=5.2Hz, 2H), 7.03 (d, J=5.2Hz, 2H)；13C NMR(100MHz,
CDCl3)δ149.47,147.02,124.68,20.02-20.41(quat-C)。
Synthesis example 17
d3The synthesis of -4- ethylpyridines
0.20mmol 4- ethylpyridines, 0.2mL D are added in the reactor2O, 0.04mmol benzoic acid.In nitrogen/sky
Under atmosphere is enclosed, 120 DEG C are heated to, persistently stir 24h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate solution to wash
Wash, with dichloromethane extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield 95%.1H
NMR(400MHz,CDCl3) δ 8.48 (d, J=5.2Hz, 2H), 7.12 (d, J=5.2Hz, 2H), 1.24-1.28 (t, J=8Hz,
3H)；13C NMR(100MHz,CDCl3)δ152.93,149.62,123.38,27.06-27.89(quat-C),14.15。
Synthesis example 18
d3The synthesis of -4- second benzyl pyridines
0.20mmol 4- second benzyl pyridines, 0.2mL D are added in the reactor2O, 0.04mmol benzoic acid.Nitrogen/
Under air atmosphere, 120 DEG C are heated to, persistently stir 24h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate solution to wash
Wash, with ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield 95%.1H
NMR(400MHz,CDCl3) δ 8.41 (d, J=5.6Hz, 2H), 7.22-7.25 (t, J=7.2Hz, 2H), 7.14-7.18 (t, J
=7.4Hz, 1H), 7.09 (d, J=7.2Hz, 2H), 7.02 (d, J=5.6Hz, 2H)；13C NMR(100MHz,CDCl3)δ
149.99,149.82,138.81,129.02,128.75,128.70,124.21,40.21-40.78(quat-C)。
Synthesis example 19
d3The synthesis of -2,3,3- trimethyl -3H- indoles
Trimethyl -3H- the indoles of 0.20mmol 2,3,3-, 0.2mL D are added in the reactor2O, 0.02mmol benzoic acid.
Under nitrogen/air atmosphere, 80 DEG C are heated to, persistently stir 4h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate
Solution is washed, and with ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield
97%.1H NMR(400MHz,CDCl3) δ 7.46 (d, J=7.6Hz, 1H), 7.20-7.22 (t, J=5.8Hz, 2H), 7.10-
7.14 (t, J=7.2Hz, 1H), 1.23 (s, 6H)；13C NMR(100MHz,CDCl3)δ188.00,153.70,145.65,
127.57,125.08,121.28,119.89,53.60,23.07,14.52-14.90(quat-C)。
Synthesis example 20
d3The synthesis of -2- methylbenzothiazoles
0.20mmol 2- methylbenzothiazoles, 0.2mL D are added in the reactor2O, 0.03mmol benzoic acid.In nitrogen
Under gas/air atmosphere, 120 DEG C are heated to, persistently stir 8h, stop reaction, be cooled to room temperature, add saturated sodium bicarbonate solution
Washing, with ethyl acetate extraction, sodium sulphate is dried, and vacuum distillation removes solvent, obtains final product target product, deuterated yield 95%.1H
NMR(400MHz,CDCl3) δ 7.95 (d, J=8.0Hz, 1H), 7.82 (d, J=7.6Hz, 1H), 7.43-7.46 (t, J=
7.6Hz, 1H), 7.32-7.36 (t, J=7.6Hz, 1H)；13C NMR(100MHz,CDCl3)δ166.91,153.39,135.63,
125.92,124.70,122.40,121.40,19.01-19.79(quat-C)。
Claims (8)
1. a kind of synthetic method of deuterated azepine aromatic, comprising following step：
Take azepine aromatic, deuterated reagent, acid catalyst to be placed in reaction vessel, mix；In nitrogen, inert gas or sky
Under atmosphere is enclosed, reaction temperature is 40 DEG C～130 DEG C, continues stirring reaction 0.5h～24h；Reaction is cooled to room temperature after terminating, and uses
Aqueous slkali is washed, and is then extracted with organic solvent, is dried, and vacuum distillation removes extractant, obtains final product.
2. the synthetic method of deuterated azepine aromatic according to claim 1, it is characterised in that described azepine virtue
Aroma compounds are selected from 2- methylquinolines, 2,6- dimethyl quinolines, 2- methyl -6- methoxy quinolines, 2- methyl -8- methoxyl group quinolines
Quinoline, 2- methyl -6- chloroquinolines, 2- methyl -6- fluorine quinoline, 2- methyl -6- bromoquinolines, 7-Chloroquinaldine, 2- methyl -6-
Nitroquinoline, 2- methylquinoline -6- methyl formates, 2- methyl -8-hydroxyquinoline, 2- methyl -8-hydroxyquinoline, 5,7- bis- are chloro-
The iodo- 8- hydroxyls quinaldine of 8- hydroxyl quinaldines, the chloro- 7- of 5-, 4- methylquinolines, 2,4- dimethyl quinolines, 2,9- dimethyl -1,
10- ferrosins, 2,4- lutidines, 4- picolines, 2- picolines, 4- ethylpyridines, 4- benzyl pyridines, 2- isopropyls
Quinoline, 2- ethyl quinoliniums, 2- vinylquinolines, 1- benzyls -2 methyl indole, 2,3,3- trimethyl -3H- indoles, 2- methylbenzenes
And thiazole, 2- Jia base benzoxazoles, papaverine, Tropicamide or Irinotecan.
3. the synthetic method of deuterated azepine aromatic according to claim 1, it is characterised in that described deuterated examination
Agent is selected from d6-DMSO、d7-DMF、d6-Acetone、CD3OD、D2O、CD3CN、C6D6In at least one.
4. the synthetic method of deuterated azepine aromatic according to claim 1, it is characterised in that described acid catalysis
Agent is selected from copper acetate, ferric trichloride, alchlor, zinc chloride, acetic acid, acetic anhydride, trifluoroacetic acid, TFAA, trifluoro
Loprazolam, benzoic acid, p-methylbenzoic acid, paranitrobenzoic acid, P-methoxybenzoic acid, 3,5- dinitrobenzoic acids, two
In phosphenylic acid, phenyl phosphinic acid, phosphoric acid, hypophosphorous acid, phenylacetic acid, benzenpropanoic acid, trimethylace tonitric, benzene sulfonic acid, p-methyl benzenesulfonic acid,
Mandelic acid, salicylic at least one.
5. the synthetic method of deuterated azepine aromatic according to claim 1, it is characterised in that described acid catalysis
Agent consumption is for calculation in the molar ratio the 1～20% of azacyclo- aromatic.
6. the synthetic method of deuterated azepine aromatic according to claim 1, it is characterised in that described for washing
Aqueous slkali be at least one in sodium bicarbonate solution, sodium carbonate liquor, solution of potassium carbonate or the sodium hydroxide solution.
7. the synthetic method of deuterated azepine aromatic according to claim 1, it is characterised in that described for extracting
Organic solvent be at least one in ethyl acetate, chloroform or the dichloromethane.
8. it is a kind of by claim 1～7 any one synthetic method prepare deuterated azepine aromatic, it is characterised in that
With structural formula：
In the structure Formulas I or II：
N=1,2,3；
R1Be hydrogen, alkyl, alkoxyl, fluorine, chlorine, bromine, iodine, hydroxyl, ester group, aldehyde radical, amide groups,
Carboxyl or nitro；
R2It is deuterium, alkyl, alkoxyl, halogen, hydroxyl, ether, ester group, amino or ketone group；
Wherein, the CD in structure Formulas InR2 (3-n)It is located at least one of 2-, 3- or 4- position position；
X in formula II is CH (CH3)2、CH2, O or S.
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| CN110563649A (en) * | 2019-08-27 | 2019-12-13 | 浙江工业大学 | high-selectivity deuteration method of 2-methyl nitrogen heterocyclic compound |
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| CN110563649A (en) * | 2019-08-27 | 2019-12-13 | 浙江工业大学 | high-selectivity deuteration method of 2-methyl nitrogen heterocyclic compound |
| CN112876406A (en) * | 2021-01-15 | 2021-06-01 | 安徽秀朗新材料科技有限公司 | Deuterated carbazole compound, preparation method thereof, photoelectric material and medicine |
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