CN104370736B - A kind of synthetic method of 2-ethoxy benzonitrile acid compounds - Google Patents
A kind of synthetic method of 2-ethoxy benzonitrile acid compounds Download PDFInfo
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Abstract
The invention discloses the synthetic method of a kind of 2-ethoxy benzonitrile acid compounds, step is for being sequentially added into fragrance acylamino-class pyridine-1-oxide, stannous chloride and organic solvent in reaction vessel, it is placed under room temperature condition stirring 25 ~ 35 minutes, potassium carbonate is added after complex compound sediment to appear, reaction system is warming up to 125 ~ 135 DEG C react 10 ~ 15 hours, reaction extracts after terminating, is dried, concentrates and chromatographic isolation obtains ethoxylated product, then alkaline hydrolysis is passed through, acidifying, finally gives 2-ethoxy benzonitrile acid compounds.This method, raw material is easy to get, and catalyst is cheap, and reaction system is gentle, easy and simple to handle, has good productivity and substrate universality, productivity up to 87% and guiding base and can be removed by gentle condition.
Description
Technical field
Present document relates to the synthetic method of a kind of 2-ethoxy benzonitrile acid compounds.The method is with benzoic acid for initial former
Material introduces N-O bidentate and guides base, efficiently obtains 2-ethyoxyl compounds under the catalysis of stannous chloride, is finally directed to base and moves
Except obtaining 2-ethoxy benzonitrile acid compounds.
Background technology
2-ethoxy benzonitrile acid compounds is the medical material that a class is important, has easing pain and diminishing inflammation in medical experiment
Among effect, and the synthesis of the antagonist being widely used in 'Xiduofeng ' and arginine vasopressin acceptor V1A and V2, the highest
Effect synthesis 2-ethoxy benzonitrile acid compounds causes the extensive concern of people.Owing to the direct sense dough of c h bond is not required to
The plurality of advantages such as wanting the pre-sense dough of raw material, synthesis step is brief, environmentally friendly, and atom utilization is high, therefore pass through C-H
The method of the direct sense dough of key introduces ethyoxyl and achieves quickly development (Jiang, T.-S. at the ortho position of aromatic ring;
Wang, G.-W. J. Org. Chem. 2012,77,9504.；Bhadra, S.; Matheis, C.; Katayev,
D.; Gooßen, L. J. Angew. Chem. Int. Ed. 2013, 52, 9279.；Shi, S.；Kuang, C.J.
Org. Chem. 2014, 79, 6105;).But examples detailed above has obvious shortcoming, it is mainly manifested in (1) reaction bar
Part is harsh, needs to use expensive catalyst or additive.(2) reaction afterproduct homing device is difficult to depart from (such as, conventional
In 2-phenylpyridine compounds, guiding group can not depart from).Then greatly limit the application of reaction system, therefore
Develop a class cheap metal catalysis, the most efficiently, turn to the synthesis 2-ethoxy benzonitrile of means with the direct functional group of c h bond
The synthetic method of acid has broad application prospects.
Summary of the invention
The technical problem to be solved is combined to 2-ethoxybenzoic acid for the direct functional group of c h bond
Synthesising method reacting condition is harsh, reaction afterproduct homing device is difficult to the problems such as disengaging, it is provided that a kind of 2-ethoxybenzoic acid
The synthetic method of compounds, the method is with cheap metal as catalyst and the most efficient.
For solve above-mentioned technical problem, the present invention by the following technical solutions:
A kind of synthetic method of 2-ethoxy benzonitrile acid compounds, step is as follows:
(1) in reaction vessel, it is sequentially added into fragrance acylamino-class pyridine-1-oxide, stannous chloride and organic solvent,
It is placed under room temperature condition stirring 25 ~ 35 minutes, after complex compound sediment to appear, adds potassium carbonate, reaction system is warming up to 125 ~
135 DEG C are reacted 10 ~ 15 hours, and reaction extracts after terminating, is dried, concentrates and chromatographic isolation obtains ethoxylated product；Wherein virtue
Fragrant acylamino-class pyridine-1-oxide, stannous chloride, the ratio of amount of material of potassium carbonate be 0.8 ~ 1.2:0.8 ~ 1.2:0.3 ~
0.6, the consumption of organic solvent is on the basis of stannous chloride, and needed for 1mmol stannous chloride, organic solvent is 5 ~ 10mmL；
The chemical formula of fragrance acylamino-class pyridine-1-oxide is
, wherein R is in phenyl ring C2-C4 position, and R is hydrogen atom, trifluoromethyl, methyl, the tert-butyl group, methoxy
Base, phenyl, fluorine, bromine, iodine, first sulfonyl or ester group (CO2Me).
(2) ethoxylated product obtained is dissolved in the ethanol solution of NaOH, reacts under conditions of 75 ~ 85 DEG C
6 ~ 10 hours, after reaction terminates, reduced pressure removing ethanol, adds in watery hydrochloric acid and unnecessary alkali, then through extraction, dry, concentration
2-ethoxy benzonitrile acid compounds is obtained with chromatographic isolation；
Reaction equation is as follows:
。
The mixture that organic solvent is ethanol and pyridine in described step (1), and the volume ratio of ethanol and pyridine is 1:
1。
In described step (1), extraction uses and adds watery hydrochloric acid cancellation reaction, and then reactant liquor dichloromethane extracts, and uses
Anhydrous sodium sulfate is dried, and uses decompression distillation to concentrate, uses the method for TLC separation to carry out chromatographic isolation, solvent
For dichloromethane/acetone.
In described step (2), the consumption of the ethanol solution of NaOH is on the basis of stannous chloride, 1mmol stannous chloride institute
The ethanol solution needing NaOH is 5 ~ 10mL.
Concentration in described step (2) is 1.5 ~ 3mol/L.
In described step (2), extraction uses dichloromethane extraction, uses sodium sulphate to be dried, and uses decompression distillation to carry out dense
Contracting, uses the method chromatographic isolation of pillar layer separation, and flowing is methylene chloride/methanol mutually.
Beneficial effects of the present invention: the innovative point of the present invention is the side by c h bond direct sense dough of creativeness
Method is directly realized by the ethoxylation of aromatic ring thus has started a kind of synthetic method synthesizing 2-ethoxy benzonitrile acid compounds.Instead
Answering system simple, easy and simple to handle, it is not necessary to additive, catalyst low cost, substrate universality is good, and productivity is up to 87% and guides
Base can be removed by gentle condition.
Detailed description of the invention
In order to make the mesh of the present invention obtain, technical scheme and advantage clearer, the present invention enters with following instantiation
Row explanation.It is clear that the invention is not restricted to above embodiment, it is also possible to there are many deformation, it is adaptable to all kinds of substrates and all kinds of
Level alcohol, secondary alcohol.All deformation that those of ordinary skill in the art can directly derive from the disclosure of invention or associate,
All it is considered as protection scope of the present invention.
Embodiment 1
The synthetic method step of the 2-ethoxybenzoic acid of the present embodiment is as follows:
(1) preparation of 2-ethoxy benzonitrile amidopyridine-1-oxide: by benzene carbon amide yl pyridines-1-oxide
(0.2 mmol, 42.8 mg), anhydrous CuCl (0.2 mmol, 19.6 mg), add in high-pressure-resistant sealed pipe, be then injected into
0.75 mL ethanol and 0.75 mL pyridine, stir 30 minutes under room temperature, adds K after complex compound sediment to appear2CO3 (0.1
Mmol, 13.8 mg), reaction system is warming up to 130 DEG C reaction 12 h. reaction terminate after, add watery hydrochloric acid (5 mL,
2N) cancellation reaction, then reactant liquor CH2Cl2(10 × 3 mL) extracts, and anhydrous sodium sulfate is dried, TLC separation
(CH2Cl2/ acetone) obtain 2-ethyoxyl amide-type product 43 mg, productivity 84%, fusing point 140-141 DEG C.1H NMR (400
MHz, CDCl3) δ 12.30 (s, 1H), 8.73 (d, J = 8.4 Hz, 1H), 8.31-8.28 (m, 2H),
7.55-7.51 (m, 1H), 7.38-7.34 (m, 1H), 7.13-7.09 (m, 1H),7.07 (d, J = 8.4 Hz,
1H), 7.02-6.98 (m, 1H), 4.35 (q, J = 7.0 Hz, 2H), 1.72 (t, J = 7.0 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 164.0, 157.5, 145.4, 137.4, 134.3, 132.7, 127.8,
121.1, 120.5, 118.5, 115.9, 112.4, 65.4, 14.8. HRMS (ESI) Calcd. For
C14H15N2O3: [M+H]+, 259.1083, Found: 259.1081；
(2) preparation of 2-ethoxybenzoic acid: the ortho position ethoxylated product (0.2 mmol, 52 mg) that will obtain,
NaOH (3 mmol, 120 mg) is placed in Shrek pipe, adds 1.5 mL ethanol, and confined reaction 8 h at 80 DEG C, reaction terminates
Rear decompression removes ethanol, adds watery hydrochloric acid (5 mL, 2N) and neutralizes unnecessary alkali, then mixed liquor CH2Cl2(5 × 4 mL) extracts
Taking, anhydrous sodium sulfate is dried, pillar layer separation (CH2Cl2/CH3OH) 2-ethoxybenzoic acid 27 mg, productivity 80% are obtained.1H
NMR (400 MHz, CDCl3) δ 10.97 (bs, 1H), 8.18 (dd, J = 7.8 Hz, J = 1.8 Hz, 1H),
7.58-7.54 (m, 1H), 7.15-7.11 (m, 1H), 7.05 (d, J = 8.3 Hz, 1H), 4.34 (q, J =
7.0 Hz, 2H), 1.57 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 165.6,
157.4, 135.1, 133.7, 122.2, 117.7, 112.6, 66.0, 14.7。
Embodiment 2
The synthetic method of the 4-methyl benzoic acid of the present embodiment is as follows:
(1) preparation of 2-(4-methyl-2-ethoxy benzamide base) pyridine-1-oxide: as described in embodiment 1
Method, except for the difference that substrate used and reagent are: 2-(4-methyl-benzoyl amido) pyridine-1-oxide (0.2 mmol,
45.6 mg), CuCl (0.2 mmol, 19.6 mg), K2CO3 (0.1 mmol, 13.8 mg), EtOH 0.75 mL,
Pyridine 0.75 mL, reacts 12 h. and obtains 2-(4-methyl-2-ethoxy benzamide base) pyridine-1-oxygen at temperature 130 DEG C
Compound 46 mg, solid, productivity 85%.Fusing point 162-163 DEG C.1H NMR (400 MHz, CDCl3) δ 12.16 (s,
1H), 8.66 (d, J = 8.4 Hz, 1H), 8.20-8.18 (m, 1H), 8.09-8.07 (d, J = 8.0 Hz,
1H), 7.26-7.23 (m, 1H), 6.91-6.88 (m, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.77 (s,
1H), 4.24 (q, J = 7.0 Hz, 2H), 2.32 (s, 3H), 1.63 (t, J = 7.0 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 164.0, 157.4, 145.5, 137.4, 132.5, 127.9, 122.0, 118.3,
117.8, 115.7, 113.0, 65.2, 21.9, 14.8. HRMS (ESI) Calcd. For C15H17N2O3: [M+H
]+, 273.1239, Found: 273.1234；
(2) preparation of 4-methyl benzoic acid: step with the step (2) of embodiment 1, except for the difference that substrate used and reagent
For: 2-(4-methyl-2-ethoxy benzamide base) pyridine-1-oxide (0.2 mmol, 45.6 mg), NaOH (3
Mmol, 120 mg), EtOH 1.5 mL, reacts 8h, HCl (2N) and is acidified to obtain 4-methyl benzoic acid at temperature 80 DEG C.
Embodiment 3
The preparation method of the 4-p t butylbenzoic acid of the present embodiment is as follows:
(1) preparation of 2-(the 4-tert-butyl group-2-ethoxy benzamide base) pyridine-1-oxide: by embodiment 1 step
(1) method described in, except for the difference that substrate used and reagent are: 2-(4-t-butyl-benzamide base) pyridine-1-oxide
(0.2 mmol, 54.0 mg), CuCl (0.2 mmol, 19.6 mg), K2CO3 (0.1 mmol, 13.8 mg), EtOH
0.75 mL, pyridine 0.75 mL, react 12 h. and obtain 2-(the 4-tert-butyl group-2-ethoxy benzamide base) at temperature 130 DEG C
Pyridine-1-oxide 52 mg, solid, productivity 83%.Fusing point 127-128 DEG C.1H NMR (400 MHz, CDCl3) δ
12.27 (s, 1H), 8.75 (dd, J = 8.5 Hz, J = 1.7 Hz, 1H), 8.29 (dd, J = 6.5 Hz, J
= 1.0 Hz, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.37-7.33 (m, 1H), 7.14 (dd, J = 8.4
Hz, J = 1.7 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 7.00-6.96(m, 1H), 4.37 (q, J =
7.0 Hz, 2H), 1.73 (t, J = 7.0 Hz, 3H). 1.36 (s, 9H). 13C NMR (100 MHz, CDCl3)
δ 164.0, 158.6, 157.3, 145.5, 137.3, 132.3, 127.8, 118.4, 118.3, 117.8,
115.8, 109.4, 65.1, 35.4, 31.1, 14.8. HRMS (ESI) Calcd. For C18H23N2O3: [M+H]+,
315.1709, Found: 315.1705；
(2) preparation of 4-p t butylbenzoic acid: step with the step (2) of embodiment 1, except for the difference that substrate used and reagent
For: 2-(the 4-tert-butyl group-2-ethoxy benzamide base) pyridine-1-oxide (0.2 mmol, 54.0 mg), NaOH (3
Mmol, 120 mg), EtOH 1.5 mL, reacts 8h, HCl (2N) and is acidified to obtain 4-p t butylbenzoic acid at temperature 80 DEG C.
Embodiment 4
The synthetic method of the present embodiment m-methoxybenzoic acid is as follows:
(1) preparation of 2-(5-methoxyl group-2-ethoxy benzamide base) pyridine-1-oxide: by embodiment 1 step
(1) method described in, except for the difference that substrate used and reagent are: 2-(5-methoxy-b enzamide base) pyridine-1-oxide
(0.2 mmol, 48.8 mg), CuCl (0.2 mmol, 19.6 mg), K2CO3 (0.1 mmol, 13.8 mg), EtOH
0.75 mL, pyridine 0.75 mL, react 12 h. and obtain 2-(5-methoxyl group-2-ethoxy benzamide base) at temperature 130 DEG C
Pyridine-1-oxide 35 mg, solid, productivity 61%, fusing point 179-180 DEG C.1H NMR (400 MHz, CDCl3) δ
12.40 (s, 1H), 8.73 (dd, J = 8.5 Hz, J = 1.7 Hz, 1H), 8.30-8.29 (m, 1H), 7.81
(d, J = 3.2 Hz, 1H), 7.38-7.34 (m, 1H), 7.11-7.08 (m, 1H), 7.02-7.00 (m, 2H),
4.31 (q, J = 7.0 Hz, 2H), 3.85 (s, 3H), 1.69 (t, J = 7.0 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 163.8, 153.6, 151.9, 145.4, 137.4, 127.8, 121.3, 120.8, 118.6,
115.8, 115.4, 114.0, 65.8, 55.9, 14.8. HRMS (ESI) Calcd. For C15H17N2O4: [M+H
]+, 289.1188, Found: 289.1185；
(2) preparation of m-methoxybenzoic acid: step with the step (2) of embodiment 1, except for the difference that substrate used and reagent
For: 2-(5-methoxyl group-2-ethoxy benzamide base) pyridine-1-oxide (0.2 mmol, 48.8 mg), NaOH (3
Mmol, 120 mg), EtOH 1.5 mL, reacts 8h, HCl (2N) and is acidified to obtain m-methoxybenzoic acid at temperature 80 DEG C.
Embodiment 5
The synthetic method of the m-methyl benzoic acid of the present embodiment is as follows:
(1) preparation of 2-(5-methyl-2-ethoxy benzamide base) pyridine-1-oxide: by embodiment 1 step
(1) method described in, except for the difference that substrate used and reagent are: 2-(5-methyl-benzoyl amido) pyridine-1-oxide (0.2
mmol, 45.6 mg), CuCl (0.2 mmol, 19.6 mg), K2CO3 (0.1 mmol, 13.8 mg), EtOH 0.75
ML, pyridine 0.75 mL, react 12 h. and obtain 2-(5-methyl-2-ethoxy benzamide base) pyridine-1-at temperature 130 DEG C
Oxide 35 mg, solid, productivity 64%, fusing point 191-192 DEG C.1H NMR (400 MHz, CDCl3) δ 12.32 (s,
1H), 8.74 (dd, J = 8.5 Hz, J = 1.8 Hz, 1H), 8.30-8.28(m, 1H), 8.08 (d, J =
2.2 Hz, 1H), 7.38-7.31 (m, 2H), 7.01-6.97 (m, 1H), 6.96 (d, J = 8.6 Hz, 1H),
4.31 (q, J = 7.0 Hz, 2H), 2.36 (s, 3H), 1.70 (t, J = 7.0 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 164.1, 155.5, 145.5, 137.3, 134.9, 132.7, 130.4, 127.8, 120.0,
118.4, 115.9, 112.4, 65.3, 20.4, 14.8. HRMS (ESI) Calcd. For C15H17N2O3: [M+H
]+, 273.1239, Found: 273.1236；
(2) preparation of m-methyl benzoic acid: step with the step (2) of embodiment 1, except for the difference that substrate used and reagent
For: 2-(5-methyl-2-ethoxy benzamide base) pyridine-1-oxide (0.2 mmol, 45.6 mg), NaOH (3
Mmol, 120 mg), EtOH 1.5 mL, reacts 8h, HCl (2N) and is acidified to obtain m-methyl benzoic acid at temperature 80 DEG C.
Embodiment 6
The synthetic method of the p-phenyl benzoic acid of the present embodiment is as follows:
(1) preparation of 2-(4-phenyl-2-ethoxy benzamide base) pyridine-1-oxide: by embodiment 1 step
(1) method described in, except for the difference that substrate used and reagent are: 2-(4-methyl-benzoyl amido) pyridine-1-oxide (0.2
mmol, 58.0 mg), CuCl (0.2 mmol, 19.6 mg), K2CO3 (0.1 mmol, 13.8 mg), EtOH 0.75
ML, pyridine 0.75 mL, react 12 h. and obtain 2-(4-phenyl-2-ethoxy benzamide base) pyridine-1-at temperature 130 DEG C
Oxide 39 mg, solid, productivity 59%, fusing point 174-175 DEG C.1H NMR (400 MHz, CDCl3) δ 12.32 (s,
1H), 8.76 (dd, J = 8.6 Hz, J = 1.7 Hz, 1H), 8.34 (d, J = 8.2 Hz, 1H), 8.31-
8.29 (m, 1H), 7.64-7.62 (m, 2H), 7.50-7.46 (m, 2H), 7.43-7.41 (m, 1H), 7.36-
7.32 (m, 2H), 7.25-7.24 (m, 1H), 7.02-6.98 (m, 1H), 4.43 (q, J = 7.0 Hz, 2H),
1.75 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 163.8, 157.7, 147.4,
145.4, 139.9, 137.3, 133.2, 129.0, 128.4, 127.9, 127.3, 119.9, 119.2, 118.5,
115.9, 111.1, 65.5, 14.8. HRMS (ESI) Calcd. For C20H19N2O3: [M+H]+, 335.1396,
Found: 335.1392；
(2) preparation of p-phenyl benzoic acid: step with the step (2) of embodiment 1, except for the difference that substrate used and reagent
For: 2-(4-phenyl-2-ethoxy benzamide base) pyridine-1-oxide (0.2 mmol, 58.0 mg), NaOH (3
Mmol, 120 mg), EtOH 1.5 mL, reacts 8h, HCl (2N) and is acidified to obtain p-phenyl benzoic acid at temperature 80 DEG C.
Embodiment 7
The synthetic method of the parachlorobenzoic-acid of the present embodiment is as follows:
(1) preparation of 2-(4-chloro-2-ethoxy benzamido) pyridine-1-oxide: by embodiment 1 step (1)
Described method, except for the difference that substrate used and reagent are: 2-(the chloro-benzamido of 4-) pyridine-1-oxide (0.2
mmol, 49.6 mg), CuCl (0.2 mmol, 19.6 mg), K2CO3 (0.1 mmol, 13.8 mg), EtOH 0.75
ML, pyridine 0.75 mL, react 12 h. and obtain 2-(4-chloro-2-ethoxy benzamido) pyridine-1-oxygen at temperature 130 DEG C
Compound 29 mg, solid, productivity 50%, fusing point 210-211 DEG C.1H NMR (400 MHz, CDCl3) δ 12.19 (s,
1H), 8.71 (dd, J = 8.5 Hz, J = 1.4 Hz, 1H), 8.30-8.28 (m, 1H), 8.23 (d, J =
8.5 Hz, 1H), 7.38-7.34 (m, 1H), 7.10 (dd, J = 8.5 Hz, J = 1.8 Hz, 1H), 7.06
(d, J = 1.8 Hz, 1H), 7.03-6.99 (m, 1H), 4.34 (q, J = 7.0 Hz, 2H), 1.73 (t, J
= 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 163.0, 157.8, 145.2, 140.2, 137.4,
133.8, 128.0, 121.5, 119.1, 118.7, 115.9, 113.1, 66.0, 14.6. HRMS (ESI)
Calcd. For C14H14ClN2O3: [M+H]+, 293.0693, Found: 293.0690；
(2) preparation of parachlorobenzoic-acid: step is with the step (2) of embodiment 1, and except for the difference that substrate used and reagent are:
2-(4-chloro-2-ethoxy benzamido) pyridine-1-oxide (0.2 mmol, 49.6 mg), NaOH (3 mmol,
120 mg), EtOH 1.5 mL, reacts 8h, HCl (2N) and is acidified to obtain parachlorobenzoic-acid at temperature 80 DEG C.
Embodiment 8
The synthetic method of the parabromobenzoic acid of the present embodiment is as follows:
(1) preparation of 2-(4-bromo-2-ethoxy benzamide base) pyridine-1-oxide: by embodiment 1 step (1)
Described method, except for the difference that substrate used and reagent are: 2-(the bromo-benzamido of 4-) pyridine-1-oxide (0.2
mmol, 58.6 mg), CuCl (0.2 mmol, 19.6 mg), K2CO3 (0.1 mmol, 13.8 mg), EtOH 0.75
ML, pyridine 0.75 mL, react 12 h. and obtain 2-(4-bromo-2-ethoxy benzamide base) pyridine-1-oxygen at temperature 130 DEG C
Compound 36 mg, solid, productivity 53%, fusing point 195-196 DEG C.1H NMR (400 MHz, CDCl3) δ 12.18 (s,
1H), 8.72-8.70 (m, 1H), 8.30-8.28 (m, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.38-
7.34 (m, 1H), 7.26 (dd, J = 8.5 Hz, J = 1.7 Hz, 1H), 7.22 (d, J = 1.6 Hz,
1H), 7.03-6.99 (m, 1H), 4.34 (q, J = 7.0 Hz, 2H), 1.73 (t, J = 7.0 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 163.1, 157.7, 145.2, 137.4, 133.9, 128.6, 128.0,
124.5, 119.5, 118.7, 116.0, 115.8, 66.0, 14.6. HRMS (ESI) Calcd. For
C14H14BrN2O3: [M+H]+, 337.0188, Found: 337.0184；
(2) preparation of parabromobenzoic acid: step is with the step (2) of embodiment 1, and except for the difference that substrate used and reagent are:
2-(4-bromo-2-ethoxy benzamide base) pyridine-1-oxide (0.2 mmol, 58.2 mg), NaOH (3 mmol,
120 mg), EtOH 1.5 mL, reacts 8h, HCl (2N) and is acidified to obtain parabromobenzoic acid at temperature 80 DEG C.
Embodiment 9
The synthetic method processed of the 4-Iodobenzoic acid of the present embodiment is as follows:
(1) preparation of 2-(4-iodo-2-ethoxy benzamide base) pyridine-1-oxide: by embodiment 1 step (1)
Described method, except for the difference that substrate used and reagent are: 2-(the iodo-benzamido of 4-) pyridine-1-oxide (0.2
mmol, 68.0 mg), CuCl (0.2 mmol, 19.6 mg), K2CO3 (0.1 mmol, 13.8 mg), EtOH 0.75
ML, pyridine 0.75 mL, react 12 h. and obtain 2-(4-iodo-2-ethoxy benzamide base) pyridine-1-oxygen at temperature 130 DEG C
Compound 45 mg, solid, productivity 58%.Fusing point 163-164 DEG C.1H NMR (400 MHz, CDCl3) δ 12.17 (s,
1H), 8.72-8.69 (m, 1H), 8.29-8.28 (m, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.47
(dd, J = 8.3 Hz, J = 1.3Hz, 1H), 7.40 (d, J = 1.1 Hz, 1H), 7.37-7.33 (m, 1H),
7.03-6.99 (m, 1H), 4.33 (q, J = 7.0 Hz, 2H), 1.72 (t, J = 7.0 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 163.3, 157.3, 145.2, 137.4, 133.8, 130.6, 127.9, 121.9,
120.2, 118.7, 115.8, 101.1, 66.0, 14.7. HRMS (ESI) Calcd. For C14H14IN2O3: [M+
H]+, 385.0049, Found: 385.0044；
(2) preparation of 4-Iodobenzoic acid: step is with the step (2) of embodiment 1, and except for the difference that substrate used and reagent are:
2-(4-iodo-2-ethoxy benzamide base) pyridine-1-oxide (0.2 mmol, 68.0 mg), NaOH (3 mmol,
120 mg), EtOH 1.5 mL, reacts 8h, HCl (2N) and is acidified to obtain 4-Iodobenzoic acid at temperature 80 DEG C.
Embodiment 10
The synthetic method of the m-trifluoromethylbenzoic acid of the present embodiment is as follows:
(1) preparation of 2-(5-trifluoromethyl-2-ethoxy benzamide base) pyridine-1-oxide: by embodiment 1 step
Suddenly the method described in (1), except for the difference that substrate used and reagent are: 2-(5-triflooromethyl-benzamide base) pyridine-1-aoxidizes
Thing (0.2 mmol, 56.4 mg), CuCl (0.2 mmol, 19.6 mg), K2CO3 (0.1 mmol, 13.8 mg),
EtOH 0.75 mL, pyridine 0.75 mL, react 12 h. and obtain 2-(5-trifluoromethyl-2-ethoxy benzonitrile at temperature 130 DEG C
Amide groups) pyridine-1-oxide 38 mg, solid, productivity 59%.Fusing point 190-191 DEG C.1H NMR (400 MHz, CDCl3)
δ 12.25 (s, 1H), 8.73-8.71 (m,1H), 8.59-8.58 (m, 1H), 8.30-8.29 (m, 1H), 7.77
(dd, J = 8.7 Hz, J = 2.2Hz, 1H), 7.40-7.36 (m, 1H), 7.17 (d, J = 8.7 Hz, 1H),
7.05-7.02 (m, 1H), 4.41 (q, J = 7.0 Hz, 2H), 1.75 (t, J = 7.0 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 161.5,158.5,144.0,136.3,130.0 (q, JC-F = 3.4 Hz), 129.3
(q, JC-F = 3.7 Hz), 127.0, 122.8 (q, JC-F = 269.9 Hz), 122.5 (q, JC-F = 33.3
Hz), 119.8, 117.9, 114.9, 111.8, 65.1, 13.6. 19F NMR (376 MHz, CDCl3) δ -
61.92. HRMS (ESI) Calcd. For C15H14F3N2O3: [M+H]+, 327.0957, Found: 327.0953；
(2) preparation of m-trifluoromethylbenzoic acid: step with the step (2) of embodiment 1, except for the difference that substrate used and examination
Agent is: 2-(5-trifluoromethyl-2-ethoxy benzamide base) pyridine-1-oxide (0.2 mmol, 56.4 mg), NaOH
(3 mmol, 120 mg), EtOH 1.5 mL, reacts 8h, HCl (2N) and is acidified to obtain m-trifluoromethyl benzene at temperature 80 DEG C
Formic acid.
Embodiment 11
The synthetic method of the P-methoxybenzoic acid of the present embodiment is as follows:
(1) preparation of 2-(4-methoxyl group-2-ethoxy benzamide base) pyridine-1-oxide: by embodiment 1 step
(1) method described in, except for the difference that substrate used and reagent are: 2-(4-methoxy-b enzamide base) pyridine-1-oxide
(0.2 mmol, 48.8 mg), CuCl (0.2 mmol, 19.6 mg), K2CO3 (0.1 mmol, 13.8 mg), EtOH
0.75 mL, pyridine 0.75 mL, react 12 h. and obtain 2-(4-methoxyl group-2-ethoxy benzamide base) at temperature 130 DEG C
Pyridine-1-oxide 50 mg, solid, productivity 87%, fusing point 196-197 DEG C.1H NMR (400 MHz, CDCl3) δ
12.16 (s, 1H), 8.74 (dd, J = 8.5 Hz, J = 1.3 Hz, 1H), 8.29-8.27(m, 1H), 8.24
(d, J = 8.9 Hz, 1H), 7.36-7.32 (m, 1H), 6.99-6.96 (m, 1H), 6.63 (dd, J = 8.8
Hz, J = 2.2 Hz, 1H), 6.54 (d, J = 2.2 Hz, 1H), 4.31 (q, J = 7.0 Hz, 2H), 3.83
(s, 3H), 1.72 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 164.6, 163.7,
159.0, 145.6, 137.3, 134.4, 128.1, 118.1, 115.7, 113.5, 105.7, 99.1, 65.4,
55.6, 14.7. HRMS (ESI) Calcd. For C15H17N2O4: [M+H]+, 289.1188, Found:
289.1185；
(2) preparation of P-methoxybenzoic acid: step with the step (2) of embodiment 1, except for the difference that substrate used and reagent
For: 2-(4-methoxyl group-2-ethoxy benzamide base) pyridine-1-oxide (0.2 mmol, 48.8 mg), NaOH (3
Mmol, 120 mg), EtOH 1.5 mL, reacts 8h, HCl (2N) and is acidified to obtain P-methoxybenzoic acid at temperature 80 DEG C.
Embodiment 12
A kind of synthetic method of 2-ethoxybenzoic acid, step is as follows:
(1) in reaction vessel, it is sequentially added into benzene carbon amide yl pyridines-1-oxide, stannous chloride and organic solvent, puts
Stir 25 minutes under room temperature condition, add potassium carbonate after complex compound sediment to appear, reaction system is warming up to 125 DEG C of reactions
15 hours, reaction extracted after terminating, is dried, concentrates and chromatographic isolation obtains ethoxylated product；Wherein benzene carbon amide yl pyridines-
1-oxide, stannous chloride, the ratio of amount of material of potassium carbonate are 0.8:1.2:0.6, and organic solvent is the mixed of ethanol and pyridine
Compound, and the volume ratio of ethanol and pyridine is 1:1, the consumption of organic solvent on the basis of stannous chloride, 1mmol stannous chloride institute
Needing organic solvent is 5mmL；Extraction uses and adds watery hydrochloric acid cancellation reaction, and then reactant liquor dichloromethane extracts, and uses anhydrous
Sodium sulphate is dried, and uses decompression distillation to concentrate, uses the method for TLC separation to carry out chromatographic isolation, and solvent is two
Chloromethanes/acetone；
(2) ethoxylated product obtained is dissolved in the ethanol solution (naoh concentration is 1.5mol/L) of NaOH
In, on the basis of stannous chloride, needed for 1mmol stannous chloride, the ethanol solution of NaOH is 5mL, anti-under conditions of 75 DEG C
Answer 10 hours, after reaction terminates, reduce pressure and remove ethanol, add in watery hydrochloric acid and unnecessary alkali, then use dichloromethane to extract,
Sodium sulphate is dried, the distillation and concentration that reduces pressure obtains 2-ethoxybenzene with column chromatography (flowing is mutually for methylene chloride/methanol) chromatographic isolation
Carboxylic acid compounds.
Embodiment 13
A kind of synthetic method of 4-methyl benzoic acid, step is as follows:
(1) be sequentially added in reaction vessel 2-(4-methyl-benzoyl amido) pyridine-1-oxide, stannous chloride and
Organic solvent, is placed under room temperature condition stirring 35 minutes, adds potassium carbonate, reaction system heated up after complex compound sediment to appear
Reacting 10 hours to 135 DEG C, reaction extracts after terminating, is dried, concentrates and chromatographic isolation obtains ethoxylated product；Wherein 2-
(4-methyl-benzoyl amido) pyridine-1-oxide, stannous chloride, the ratio of amount of material of potassium carbonate are 1.2:0.8:0.3,
Organic solvent is the mixture of ethanol and pyridine, and the volume ratio of ethanol and pyridine is 1:1, and the consumption of organic solvent is with protochloride
On the basis of copper, needed for 1mmol stannous chloride, organic solvent is 10mmL；Extraction uses and adds watery hydrochloric acid cancellation reaction, then reacts
Liquid dichloromethane extracts, and uses anhydrous sodium sulfate to be dried, and uses decompression distillation to concentrate, uses the side of TLC separation
Method carries out chromatographic isolation, and solvent is dichloromethane/acetone；
(2) ethoxylated product obtained is dissolved in the ethanol solution (naoh concentration is 3mol/L) of NaOH
In, on the basis of stannous chloride, needed for 1mmol stannous chloride, the ethanol solution of NaOH is 10mL, under conditions of 85 DEG C
Reacting 6 hours, after reaction terminates, decompression removes ethanol, adds in watery hydrochloric acid and unnecessary alkali, then uses dichloromethane extraction
Take, sodium sulphate is dried, the distillation and concentration that reduces pressure obtains 4-methylbenzene with column chromatography (flowing is mutually for methylene chloride/methanol) chromatographic isolation
Formic acid.
Embodiment 14
A kind of synthetic method of 4-p t butylbenzoic acid, step is as follows:
(1) in reaction vessel, it is sequentially added into 2-(4-t-butyl-benzamide base) pyridine-1-oxide, stannous chloride
And organic solvent, it is placed under room temperature condition stirring 30 minutes, adds potassium carbonate after complex compound sediment to appear, by reaction system liter
Temperature is reacted 12 hours to 130 DEG C, and reaction extracts after terminating, is dried, concentrates and chromatographic isolation obtains ethoxylated product；Wherein 2-
(4-t-butyl-benzamide base) pyridine-1-oxide, stannous chloride, the ratio of amount of material of potassium carbonate are 1.0:1.0:
0.5, organic solvent is the mixture of ethanol and pyridine, and the volume ratio of ethanol and pyridine is 1:1, and the consumption of organic solvent is with chlorine
Change cuprous on the basis of, needed for 1mmol stannous chloride, organic solvent is 8mmL；Extraction uses and adds watery hydrochloric acid cancellation reaction, then
Reactant liquor dichloromethane extracts, and uses anhydrous sodium sulfate to be dried, and uses decompression distillation to concentrate, uses TLC separation
Method carry out chromatographic isolation, solvent is dichloromethane/acetone；
(2) ethoxylated product obtained is dissolved in the ethanol solution (naoh concentration is 2mol/L) of NaOH
In, on the basis of stannous chloride, needed for 1mmol stannous chloride, the ethanol solution of NaOH is 8mL, anti-under conditions of 80 DEG C
Answer 8 hours, after reaction terminates, reduce pressure and remove ethanol, add in watery hydrochloric acid and unnecessary alkali, then use dichloromethane to extract,
Sodium sulphate is dried, the distillation and concentration that reduces pressure obtains 4-tert-butyl benzene with column chromatography (flowing is mutually for methylene chloride/methanol) chromatographic isolation
Formic acid.
Claims (5)
1. the synthetic method of a 2-ethoxy benzonitrile acid compounds, it is characterised in that step is as follows:
(1) in reaction vessel, it is sequentially added into fragrance acylamino-class pyridine-1-oxide, stannous chloride and organic solvent, is placed in
Stir 25 ~ 35 minutes under room temperature condition, add potassium carbonate after complex compound sediment to appear, reaction system is warming up to 125 ~ 135
DEG C reaction 10 ~ 15 hours, reaction extracts after terminating, is dried, concentrates and chromatographic isolation obtains ethoxylated product；Wherein fragrance
Acylamino-class pyridine-1-oxide, stannous chloride, the ratio of amount of material of potassium carbonate be 0.8 ~ 1.2: 0.8 ~ 1.2: 0.3 ~
0.6, the consumption of organic solvent is on the basis of stannous chloride, and needed for 1mmol stannous chloride, organic solvent is 5 ~ 10mL；Fragrance acyl
The chemical formula of amino pyridine-1-oxide is, wherein R is in phenyl ring C2-C4 position, R be hydrogen atom,
Trifluoromethyl, methyl, the tert-butyl group, methoxyl group, phenyl, fluorine, bromine, iodine, first sulfonyl or CO2Me；
(2) ethoxylated product obtained is dissolved in the ethanol solution of NaOH, under conditions of 75 ~ 85 DEG C, reacts 6 ~ 10
Hour, after reaction terminates, reduce pressure removing ethanol, adds in watery hydrochloric acid and unnecessary alkali, then through extraction, dry, concentration and look
Spectrum isolated 2-ethoxy benzonitrile acid compounds；Reaction equation is as follows:
；
The mixture that organic solvent is ethanol and pyridine in described step (1), and the volume ratio of ethanol and pyridine is 1: 1.
2. according to the synthetic method of the 2-ethoxy benzonitrile acid compounds described in claim 1, it is characterised in that: described step
Suddenly in (1), extraction uses addition watery hydrochloric acid cancellation reaction, and then reactant liquor dichloromethane extracts, and uses anhydrous sodium sulfate to do
Dry, use decompression distillation to concentrate, use the method for TLC separation to carry out chromatographic isolation.
3. according to the synthetic method of the 2-ethoxy benzonitrile acid compounds described in claim 1, it is characterised in that: described step
Suddenly in (2) consumption of the ethanol solution of NaOH on the basis of stannous chloride, NaOH needed for 1mmol stannous chloride
Ethanol solution is 5 ~ 10mL.
4. according to the synthetic method of the 2-ethoxy benzonitrile acid compounds described in claim 1, it is characterised in that: described step
Suddenly in (2), the concentration of the ethanol solution of NaOH is 1.5 ~ 3mol/L.
5. according to the synthetic method of the 2-ethoxy benzonitrile acid compounds described in claim 1, it is characterised in that: described step
Suddenly in (2), extraction uses dichloromethane extraction, uses sodium sulphate to be dried, and uses decompression distillation to concentrate, uses column chromatography to divide
From method chromatographic isolation.
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| Copper-Mediated Dehydrogenative Biaryl Coupling of Naphthylamines and 1,3-Azoles;Riko Odani, et al.;《The Journal of Organic Chemistry》;20131008;第78卷;第11045-11052页 * |
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