CN109232402A - A kind of preparation method for the nitrogenous hexa-member heterocycle class compound that 2- amino replaces - Google Patents
A kind of preparation method for the nitrogenous hexa-member heterocycle class compound that 2- amino replaces Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
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Abstract
The invention discloses a kind of preparation methods for the nitrogenous hexa-member heterocycle class compound that 2- amino replaces, the preparation method comprises the following steps: after the fluorine-substituted nitrogenous hexa-member heterocycle class compound of 2- is mixed with amidine hydrochloride salt compounds, reaction obtains the nitrogenous hexa-member heterocycle class compound of 2- amino substitution under the action of alkaline matter.Preferably, the nitrogenous hexa-member heterocycle class compound that the 2- amino replaces is 2-aminopyridine class compound, 2- amino-metadiazine compound or 2- Aminopyrazine class compound.Compared with prior art, this method synthesis condition is simple, reaction step is few, reaction condition is mild, used catalyst is cheap, waste discharge is few and functional group tolerance is good.
Description
Technical field
The present invention relates to technical field of fine, and in particular to a kind of nitrogenous hexa-member heterocycle class chemical combination that 2- amino replaces
The preparation method of object.
Background technique
The nitrogenous hexa-member heterocycle class compound that 2- amino replaces has important application, especially 2- amino pyrrole in chemical field
Pyridine and its derivative are one of structures important in drug and agricultural chemicals molecule, be widely present in natural products, drug with
And in the synthesis application of luminescent material and various fine chemicals.In the prior art, 1) method for preparing 2-aminopyridine includes:
Metal catalytic haloperidid amination the preparation method, being such as catalyzed the amination of 2- haloperidid by copper is most common method
(Adv.Syn.Catal., 2013,355,627-631；Chem Commun., 2010,46,925-927), palladium chtalyst 2- bromopyridine
(Me3Si)2The amination of NHLi obtain 2-aminopyridine product (yield 88%, Catal Lett., 2017,147,204-
214), such methods have many advantages, such as high income, and reaction condition is mild, however but there is the defects of economic cost is high；2) ammonolysis
The preparation method is such as prepared by the ammonolysis of the fluoro- pyridine of 2- and ammonia, and this method is to use ammonia as reaction raw materials at high temperature, therefore,
It needs using high pressure and the reaction vessel of sealing (J.Org.Chem., 1988,53,2740-2744.)；3) cyan-hydrolysis method or suddenly
The graceful edman degradation Edman of husband (Bioorg.Med.Chem.Lett, 2010,20,2512-2515), however, such methods are needed using a large amount of
Oxidant and toxic bromine, and it is difficult to control reactivity, be not suitable for large-scale production；4) catalytic reduction method such as uses palladium chtalyst
Obtained in the hydro-reduction of 2- nitropyridine, but this method need using high pressure hydrogen (Org.Lett., 2015,17,941-
3943)；5) other methods, although such as the Chichibabin reaction preparation 2-aminopyridine by pyridine compounds and Sodamide
With very high Atom economy, however, the substrate applicability of this method it is not high (Chem.ReV., 1937,20,413-487；
Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1914,46,1216-1236) and exist and permitted
More side reactions and the stringent anhydrous and oxygen-free reaction condition of needs.
Therefore, although the methods that a variety of synthesis 2-aminopyridine exist in the prior art, continue development is mild, reaction can
Control, high chemo-selective and the low 2-aminopyridine synthetic method of economic cost are to be of great significance and application prospect.
Summary of the invention
The technical problems to be solved by the present invention are: providing a kind of high financial profit and what the high 2- amino of yield replaced contains
The preparation method of nitrogen hexa-member heterocycle class compound.
In order to solve the above-mentioned technical problem, the technical solution adopted by the present invention are as follows: a kind of 2- amino replaces nitrogenous hexa-atomic
The preparation method of heterocycle compound, the preparation method comprises the following steps: by the fluorine-substituted nitrogenous hexa-member heterocycle class of 2-
After conjunction object is mixed with amidine hydrochloride salt compounds, reaction obtains the nitrogenous hexa-atomic miscellaneous of 2- amino substitution under the action of alkaline matter
Cyclics.
Preferably, the nitrogenous hexa-member heterocycle class compound that the 2- amino replaces is 2-aminopyridine class compound, 2- ammonia
Yl pyrimidines class compound or 2- Aminopyrazine class compound.
Preferably, shown in the general structure such as formula (I) of the fluorine-substituted nitrogenous hexa-member heterocycle class compound of the 2-:
In formula (I), A1And A2In one be N, another is CH or A1And A2
It is CH；R1For single or multiple substituent groups, the R1Selected from hydrogen, halogen, alkyl, alkoxy, nitro, aromatic radical, aldehyde radical, ester
At least one of base, carboxyl.
Further, shown in the general structure such as formula (II) of the amidine hydrochloride salt compounds:
In formula (II), R2Selected from alkyl or aromatic radical；Preferably, the R2Selected from first
Base, ethyl, isopropyl, phenyl, butyl；Preferably, the R2Selected from methyl.
Further, the alkaline matter includes inorganic base and/or organic base；Preferably, the alkaline matter includes hydrogen
Potassium oxide, sodium hydroxide, lithium hydroxide, sodium tert-butoxide and/or sodium methoxide.
Further, the molar ratio of the fluorine-substituted nitrogenous hexa-member heterocycle class compound of the 2- and amidine hydrochloride salt be 1:(1~
2), preferably 1:1.2.
Further, the dosage of the alkaline matter is the fluorine-substituted nitrogenous hexa-member heterocycle class compound amount of the 2-
1~3 times；Preferably, the dosage of the alkaline matter is the 2 of the fluorine-substituted nitrogenous hexa-member heterocycle class compound amount of the 2-
Times.
Further, reaction temperature is 100~150 DEG C, and the reaction time is 24~36 hours；Preferably 130 DEG C, reaction
24h。
Further, the reaction carries out in the solution, and solvent includes organic solvent and inorganic solvent, the organic solvent
Selected from chlorobenzene, diethylene glycol dimethyl ether, N- pyrrolidones, dimethyl sulfoxide (Dimethyl sulfoxide, DMSO), N, N- bis-
At least one of methylformamide, DMAC N,N' dimethyl acetamide, toluene, dimethylbenzene and 1,4- dioxane；Organic solvent is excellent
It is selected as dimethyl sulfoxide.
Further, the preparation method further includes progress purification processes operation after reaction, the purification processes behaviour
As ethyl acetate quenching reaction is added after reaction, saturated common salt water washing is added, isolates organic phase；
Remaining water phase after isolating organic phase is extracted with ethyl acetate again, solution extracted organic is harmonious with described
And anhydrous sodium sulfate drying is added, it include organic solvent and inorganic solvent, the organic solvent through vacuum distillation removal solvent
Afterwards, then through column chromatograph to obtain the nitrogenous hexa-member heterocycle class compound of the substitution of 2- amino after purification.
The beneficial effects of the present invention are: the present invention program reaction condition is mild, and operating procedure is few；The catalyst of use is honest and clean
Valence is easy to get, and the waste of discharge is few, and atom economy is high, economic and environment-friendly；Substrate wide adaptability, high income and chemo-selective are good,
It is easy to large-scale production.Preparation method of the present invention is without transition metal-catalyzed, with the fluorine-substituted nitrogenous hexa-member heterocycle class chemical combination of 2-
Object is raw material, and the amidine hydrochloride salt of inexpensive safety is amine source, under the action of alkaline matter, the fluorine-substituted nitrogenous hexa-member heterocycle class of 2-
The nitrogenous hexa-member heterocycle class of 2- amino substitution is made by necleophilic reaction, hydrolysis for compound and amidine hydrochloride salt compounds
Close object.
Detailed description of the invention
Fig. 1 is the nuclear magnetic resonance spectroscopy of product made from the embodiment of the present invention 1；
Fig. 2 is the carbon-13 nmr spectra of product made from the embodiment of the present invention 1.
Specific embodiment
To explain the technical content, the achieved purpose and the effect of the present invention in detail, below in conjunction with embodiment and cooperate attached
Figure is explained.
The reaction principle of preparation method of the present invention is as follows:
In above formula, A1And A2For N or CH；R1For single or multiple substituent groups, the R1Selected from hydrogen, halogen, alkyl, alcoxyl
At least one of base, nitro, aromatic radical, aldehyde radical, ester group, carboxyl；R2Selected from alkyl or aromatic radical.
The embodiment of the present invention one is the preparation of the iodo- 2-aminopyridine of 3-: the fluoro- 3- iodine of 2- being added in 25 milliliters of reaction tube
Pyridine (1mmol, 223.0mg), B amidine hydrochloric acid salt (1.2mmol, 113.4mg), NaOH (2.5mmol, 100mg), H2O
(0.5mL) and dimethyl sulfoxide (2.5mL).Reaction carries out at 130 DEG C, and the reaction time is 24 hours, to after the reaction was completed, cool down
To room temperature.
Ethyl acetate 10mL quenching reaction is added, 6mL saturated common salt water washing is added, separates organic phase, then with acetic acid second
Ester aqueous phase extracted 3 times (each ethyl acetate dosage is 6mL) merging organic phases, are added anhydrous sodium sulfate drying, through being evaporated under reduced pressure
Removing solvent includes organic solvent and inorganic solvent, the organic solvent, then obtains target product 3- iodine pyrrole through column chromatography for separation
Pyridine -2- amine, yield 95%.
By gas chromatograph-mass spectrometer (GC-MS) (Gas chromatography-mass spectrometry, GC-MS) and
Nuclear magnetic resonance spectrometer (nuclear magnetic resonance spectrometer, NMR) carries out product obtained qualitative
Analysis.
Wherein, GC-MS uses the source electron bombardment ion (electron impact ionization, EI), ionization voltage
For 70eV, m/z.220 is measured, 127,93,66.
1H NMR (400MHz, CDCl3), as shown in Figure 1, δ 8.02 (dd, J=4.8,1.5Hz, 1H), 7.86 (dd, J=
7.7,1.6Hz, 1H), 6.39 (dd, J=7.7,4.9Hz, 1H), 5.00 (s, 2H)；
13C NMR (100MHz, CDCl3), as shown in Fig. 2, δ 157.5,147.8,147.1,115.3,77.7.
The embodiment of the present invention two is the preparation of the iodo- 2-aminopyridine of 6-: the fluoro- 6- iodine of 2- being added in 25 milliliters of reaction tube
Pyridine (1mmol), B amidine hydrochloric acid salt (1.3mmol), KOH (2.5mmol), H2O (0.5mL) and dimethyl sulfoxide (2.5mL).Reaction
It is carried out at 130 DEG C, the reaction time is 24 hours, to after the reaction was completed, be cooled to room temperature.
Ethyl acetate 10mL quenching reaction is added, 6mL saturated common salt water washing is added, separates organic phase, then with acetic acid second
Ester aqueous phase extracted 3 times (each ethyl acetate dosage is 6mL) merging organic phases, are added anhydrous sodium sulfate drying, through being evaporated under reduced pressure
Removing solvent includes organic solvent and inorganic solvent, the organic solvent, then obtains target product through column chromatography for separation, and yield is
93%.
Qualitative characterization is carried out by GC-MS and NMR:
GC-MS (EI, 70eV) m/z.220,127,93,66.
1H NMR (600MHz, CDCl3) δ 7.10-6.92 (m, 2H), 6.41 (d, J=7.6Hz, 1H), 4.64 (s, 2H)；
13C NMR (150MHz, CDCl3) δ 158.5,138.9,124.3,115.7,107.3.
The embodiment of the present invention three is the preparation of the fluoro- 2-aminopyridine of the chloro- 5- of 3-: 2- is added in 25 milliliters of reaction tube
The fluoro- pyridine of the fluoro- chloro- 5- of 3- (1mmol), tertiary Butanimidamide, monohydrochloride (1mmol), sodium methoxide (2mmol), H2O (0.5mL) and N, N- bis-
Methylformamide (2.5mL).Reaction carries out at 140 DEG C, and the reaction time is 30 hours, to after the reaction was completed, be cooled to room temperature.
Ethyl acetate 10mL quenching reaction is added, 6mL saturated common salt water washing is added, separates organic phase, then with acetic acid second
Ester aqueous phase extracted 3 times (each ethyl acetate dosage is 6mL) merging organic phases, are added anhydrous sodium sulfate drying, through being evaporated under reduced pressure
Removing solvent includes organic solvent and inorganic solvent, the organic solvent, then obtains target product through column chromatography for separation, and yield is
87%.
Qualitative characterization is carried out by GC-MS and NMR:
GC-MS (EI, 70eV) m/z.146,119,111,84.
1H NMR (400MHz, CDCl3) δ 7.89 (d, J=2.6Hz, 1H), 7.34 (dd, J=7.5,2.6Hz, 1H), 4.81
(s, 2H)；
13C NMR (100MHz, CDCl3) δ 153.9 (s, 1C), 151.5 (d, JC-F=12.02Hz, 1C), 133.2 (d, JC-F
=24.04Hz, 1C), 125.0 (d, JC-F=22.83Hz, 1C), 144.4 (s, 1C).
The embodiment of the present invention four is the preparation of 3- nitro -2-aminopyridine: the fluoro- 3- of 2- being added in 25 milliliters of reaction tube
Nitro-pyridine (1mmol), the third amidine hydrochloride (2mmol), sodium tert-butoxide (3mmol), H2O (0.5mL) and N- pyrrolidones
(2.5mL).Reaction carries out at 100 DEG C, and the reaction time is 36 hours, to after the reaction was completed, be cooled to room temperature.
Ethyl acetate 10mL quenching reaction is added, 6mL saturated common salt water washing is added, separates organic phase, then with acetic acid second
Ester aqueous phase extracted 3 times (each ethyl acetate dosage is 6mL) merging organic phases, are added anhydrous sodium sulfate drying, through being evaporated under reduced pressure
Removing solvent includes organic solvent and inorganic solvent, the organic solvent, then obtains target product through column chromatography for separation, and yield is
92%.
Qualitative characterization is carried out by GC-MS and NMR:
GC-MS (EI, 70eV) m/z.139,122,93,66.
1H NMR (600MHz, acetonitrile (Acetone)) δ 8.51-8.23 (m, 2H), 7.46 (s, 2H), 6.80 (dd, J=
8.3,4.5Hz, 1H)；
13C NMR (150MHz, Acetone) δ 156.9,154.9,135.6,128.6,113.7.
The embodiment of the present invention five is the preparation of 4- methyl-5-nitro -2-aminopyridine: being added in 25 milliliters of reaction tube
Fluoro- -5 nitro-pyridine of 4- methyl (1mmol) of 2-, benzene carbon amidine hydrochloride (2mmol), sodium tert-butoxide (3mmol), H2O (0.5mL) and
Toluene (2.5mL).Reaction carries out at 130 DEG C, and the reaction time is 28 hours, to after the reaction was completed, be cooled to room temperature.
Ethyl acetate 10mL quenching reaction is added, 6mL saturated common salt water washing is added, separates organic phase, then with acetic acid second
Ester aqueous phase extracted 3 times (each ethyl acetate dosage is 6mL) merging organic phases, are added anhydrous sodium sulfate drying, through being evaporated under reduced pressure
Removing solvent includes organic solvent and inorganic solvent, the organic solvent, then obtains target product through column chromatography for separation, and yield is
95%.
Qualitative characterization is carried out by GC-MS and NMR:
GC-MS (EI, 70eV) m/z 153,136,80.
1H NMR (600MHz, CDCl3+d6- DMSO) δ 8.76 (s, 1H), 7.29 (s, 2H), 6.31 (s, 1H), 2.47 (s,
3H)；
13C NMR (150MHz, CDCl3+d6- DMSO) δ 160.5,146.5,142.2,133.6,106.9,19.2.
The embodiment of the present invention six is the preparation of the chloro- 2- aminopyrimidine of the fluoro- 5- of 4-: 2- is added in 25 milliliters of reaction tube
The chloro- pyrimidine of the fluoro- fluoro- 5- of 4- (1mmol), benzene carbon amidine hydrochloride (2mmol), sodium tert-butoxide (3mmol), H2O (0.5mL) and toluene
(2.5mL).Reaction carries out at 130 DEG C, and the reaction time is 28 hours, to after the reaction was completed, be cooled to room temperature.
Ethyl acetate 10mL quenching reaction is added, 6mL saturated common salt water washing is added, separates organic phase, then with acetic acid second
Ester aqueous phase extracted 3 times (each ethyl acetate dosage is 6mL) merging organic phases, are added anhydrous sodium sulfate drying, through being evaporated under reduced pressure
Removing solvent includes organic solvent and inorganic solvent, the organic solvent, then obtains target product through column chromatography for separation, and yield is
91%.
Qualitative characterization is carried out by GC-MS and NMR:
GC-MS (EI, 70eV) m/z.147,120,114,40.
1H NMR (600MHz, Acetone) δ 8.13 (s, 1H), 7.16 (d, J=180.3Hz, 2H)；
13CNMR (150MHz, Acetone) δ 163.5 (d, JC-F=18.6Hz, 1C), 162.1 (d, JC-F=210.65Hz,
1C), 156.5 (d, JC-F=57.08Hz, 1C), 111.2 (d, JC-F=6.49Hz, 1C).
The embodiment of the present invention seven is the preparation of the bromo- 2- amino-pyridine of 6-: the fluoro- 6- of 2- being added in 25 milliliters of reaction tube
Bromo- pyridine (1mmol), pentamidine salts hydrochlorate (2mmol), sodium tert-butoxide (3mmol), H2O (0.5mL) and diethylene glycol dimethyl ether
(2.5mL).Reaction carries out at 150 DEG C, and the reaction time is 24 hours, to after the reaction was completed, be cooled to room temperature.
Ethyl acetate 10mL quenching reaction is added, 6mL saturated common salt water washing is added, separates organic phase, then with acetic acid second
Ester aqueous phase extracted 3 times (each ethyl acetate dosage is 6mL) merging organic phases, are added anhydrous sodium sulfate drying, through being evaporated under reduced pressure
Removing solvent includes organic solvent and inorganic solvent, the organic solvent, then obtains target product through column chromatography for separation, and yield is
93%.
Qualitative characterization is carried out by GC-MS and NMR:
GC-MS (EI, 70eV) m/z.174,172,93,63.
1H NMR (600MHz, CDCl3) δ 7.21 (t, J=7.8Hz, 1H), 6.74 (d, J=7.5Hz, 1H), 6.37 (d, J
=8.1Hz, 1H), 4.93 (s, 2H)；
13C NMR (151MHz, CDCl3) δ 158.73,139.76,139.70,116.57,106.77.
The embodiment of the present invention eight is the preparation of the bromo- 2- amino-pyridine of 3-: the fluoro- 3- of 2- being added in 25 milliliters of reaction tube
Bromo- pyridine (1mmol), pentamidine salts hydrochlorate (1.2mmol), sodium tert-butoxide (3mmol), H2O (0.5mL) diethylene glycol dimethyl ether
(2.5mL).Reaction carries out at 130 DEG C, and the reaction time is 24 hours, to after the reaction was completed, be cooled to room temperature.
Ethyl acetate 10mL quenching reaction is added, 6mL saturated common salt water washing is added, separates organic phase, then with acetic acid second
Ester aqueous phase extracted 3 times (each ethyl acetate dosage is 6mL) merging organic phases, are added anhydrous sodium sulfate drying, through being evaporated under reduced pressure
Removing solvent includes organic solvent and inorganic solvent, the organic solvent, then obtains target product through column chromatography for separation, and yield is
89%.
Qualitative characterization is carried out by GC-MS and NMR:
GC-MS (EI, 70eV) m/z.174,172,145,93.
1H NMR (600MHz, CDCl3) δ 7.99 (d, J=4.8Hz, 1H), 7.68-7.56 (m, 1H), 6.51 (dd, J=
7.7,4.9Hz, 1H), 5.11 (s, 2H)；
13C NMR (150MHz, CDCl3) δ 155.60,146.88,140.26,114.82,104.38.
The embodiment of the present invention nine is the preparation of the bromo- 2- amino-pyridine of 5-: the fluoro- 5- of 2- being added in 25 milliliters of reaction tube
Bromo- pyridine (1mmol), B amidine hydrochloric acid salt (1.2mmol), sodium hydroxide (3mmol), H2O (0.5mL) dimethyl sulfoxide
(2.5mL).Reaction carries out at 130 DEG C, and the reaction time is 24 hours, to after the reaction was completed, be cooled to room temperature.
Ethyl acetate 10mL quenching reaction is added, 6mL saturated common salt water washing is added, separates organic phase, then with acetic acid second
Ester aqueous phase extracted 3 times (each ethyl acetate dosage is 6mL) merging organic phases, are added anhydrous sodium sulfate drying, through being evaporated under reduced pressure
Removing solvent includes organic solvent and inorganic solvent, the organic solvent, then obtains target product through column chromatography for separation, and yield is
86%.
Qualitative characterization is carried out by GC-MS and NMR:
GC-MS (EI, 70eV) m/z.172,145,93,66.
1H NMR (600MHz, Acetone) δ 7.85 (d, J=2.4Hz, 1H), 7.36 (dd, J=8.8,2.5Hz, 1H),
6.40 (dd, J=8.8,0.5Hz, 1H), 5.52 (s, 2H)；
13C NMR (150MHz, Acetone) δ 158.72,148.30,139.33,109.90,106.06.
The embodiment of the present invention ten is the preparation of the chloro- 2- amino-pyridine of 6-: the difference of itself and embodiment one is only that: with 2-
The fluoro- chloro- pyridine of 6- substitutes the bromo- pyridine of the fluoro- 5- of 2-, and the yield of target product obtained is 79%；Qualitative characterization's data are as follows:
GC-MS (EI, 70eV) m/z.128,101,93,66.1H NMR (600MHz, Acetone) δ 7.38 (t, J=
7.8Hz, 1H), 6.54 (d, J=7.5Hz, 1H), 6.48 (d, J=8.1Hz, 1H), 5.83 (s, 2H)13C NMR (150MHz,
Acetone) 160.95,149.83,140.64,111.92,107.08 δ.
The embodiment of the present invention 11 is the preparation of the chloro- 2- amino-pyridine of 5-: the difference of itself and embodiment one is only that: with
The chloro- pyridine of the fluoro- 5- of 2- substitutes the bromo- pyridine of the fluoro- 5- of 2-, and the yield of target product obtained is 84%；Qualitative characterization's data are as follows:
GC-MS (EI, 70eV) m/z.128,101,93,66.1H NMR (600MHz, Acetone) δ 7.77 (d, J=3Hz,
1H), 7.25 (dd, J=8.8,2.7Hz, 1H), 6.43 (dd, J=8.8,0.6Hz, 1H), 5.49 (s, 2H)；13C NMR
(150MHz, Acetone) δ 158.53,146.00,136.75,118.73,109.20.
The embodiment of the present invention 12 is the preparation of the fluoro- 2- amino-pyridine of 3-: the difference of itself and embodiment one is only that: with
The fluoro- pyridine of the fluoro- 3- of 2- substitutes the bromo- pyridine of the fluoro- 5- of 2-, and the yield of target product obtained is 81%；Qualitative characterization's data are as follows:
GC-MS (EI, 70eV) m/z.112,85,57.
1H NMR (400MHz, CDCl3) δ 7.82 (d, J=5.0Hz, 1H), 7.17 (ddd, J=10.9,7.9,1.3Hz,
1H), 6.59 (ddd, J=8.3,5.0,3.5Hz, 1H), 4.78 (s, 2H)；
13C NMR (100MHz, CDCl3) δ 148.53 (d, JC-F=12.52Hz, 1C), 146.91 (d, JC-F=252.5Hz,
1C), 142.84 (d, JC-F=5.96Hz, 1C), 121.39 (d, JC-F=15.35Hz, 1C), 113.79 (d, JC-F=1.72Hz,
1C)。
The embodiment of the present invention 13 is the preparation of the bromo- 2- amino-pyridine of 3,5- bis-: the difference of itself and embodiment one only exists
In: the bromo- pyridine of the fluoro- 5- of 2- is substituted with the 2- bromo- pyridine of fluoro- 3,5- bis-, the yield of target product obtained is 83%；Qualitative characterization
Data are as follows:
GC-MS (EI, 70eV) m/z.254,252,249,170.
1H NMR (600MHz, Acetone) δ 8.03 (d, J=2.4Hz, 1H), 7.88 (d, J=1.8Hz, 1H), 5.96
(s, 2H)；
13C NMR (150MHz, Acetone) δ 156.33,148.40,142.31,106.14,104.48.
The embodiment of the present invention 14 is the preparation of 6- trifluoromethyl -2- amino-pyridine: the difference of itself and embodiment one only exists
In: the bromo- pyridine of the fluoro- 5- of 2- is substituted with the fluoro- 6- trifluoromethylpyridin of 2-, the yield of target product obtained is 82%；Qualitative table
It is as follows to levy data:
GC-MS (EI, 70eV) m/z.162,143,135,115,93,66.
1H NMR (600MHz, Acetone) δ 7.46 (t, J=7.8Hz, 1H), 6.80 (d, J=7.2Hz, 1H), 6.65
(d, J=8.4Hz, 1H), 5.84 (s, 2H)；
13C NMR (150MHz, Acetone) δ 160.049 (s, 1C), 145.82 (dd, JC-F=66.59,66.44Hz,
1C), 138.23 (s, 1C), 122.00 (d, JC-F=273.31Hz, 1C), 111.756 (s, 1C), 108.38 (dd, JC-F=
6.80,6.80Hz, 1C).
The embodiment of the present invention 15 is the preparation of 4- trifluoromethyl -2- amino-pyridine: the difference of itself and embodiment one only exists
In: the bromo- pyridine of the fluoro- 5- of 2- is substituted with the fluoro- 4- trifluoromethylpyridin of 2-, the yield of target product obtained is 61%；Qualitative table
It is as follows to levy data:
GC-MS (EI, 70eV) m/z.162,143,135,116.
1H NMR (600MHz, Acetone) δ 8.17 (d, J=4.8Hz, 1H), 6.81 (s, 1H), 6.77 (d, J=
4.8Hz, 1H), 5.94 (s, 2H)；
13C NMR (150MHz, Acetone) δ 161.31 (s, 1C), 150.68 (s, 1C), 139.56 (dd, JC-F=
65.53,65.69Hz, 1C), 124.36 (dd, JC-F=544.36,544.51Hz, 1C), 108.03 (t, JC-F=3.322Hz,
1C), 104.25 (t, JC-F=4.228Hz, 1C).
The embodiment of the present invention 16 is the preparation of the chloro- 5- trifluoromethyl -2- amino-pyridine of 3-: the area of itself and embodiment one
Be not only that: with the chloro- 5- trifluoromethylpyridin substitution bromo- pyridine of the fluoro- 5- of 2- of the fluoro- 3- of 2-, the yield of target product obtained is
94%；Qualitative characterization's data are as follows:
GC-MS (EI, 70eV) m/z.196,177,169,161,141.
1H NMR (151MHz, Acetone) δ 16.99 (d, J=1.8Hz, 1H), 13.80 (d, J=3.9Hz, 1H), 3.66
(s, 2H)；
13C NMR (150MHz, Acetone) δ 158.18 (s, 1C), 144.10 (dd, JC-F=8.91,8.76Hz, 1C),
133.41 (dd, JC-F=.80,6.80Hz, 1C), 124.07 (dd, JC-F=540.28,540.28Hz, 1C), 115.59 (dd
JC-F=66.44,66.59Hz, 1C), 113.48 (s, 1C).
The embodiment of the present invention 17 is the preparation of 5- nitro -2- amino-pyridine: the difference of itself and embodiment one is only that:
The bromo- pyridine of the fluoro- 5- of 2- is substituted with the fluoro- 5- nitro-pyridine of 2-, the yield of target product obtained is 98%；Qualitative characterization's data
It is as follows:
GC-MS (EI, 70eV) m/z.139,109,93,66.
1H NMR (600MHz, Acetone) δ 8.91 (d, J=2.8Hz, 1H), 8.20 (dd, J=9.2,2.8Hz, 1H),
6.89 (s, 2H), 6.73-6.63 (m, 1H).
13C NMR (150MHz, Acetone) δ 163.81,147.11,136.11,133.11,107.47.
The embodiment of the present invention 18 is 5- nitro -6- methyl-2-amino-pyridine preparation: the difference of itself and embodiment one
Be only that: with the fluoro- 5- nitro -6- methvl-pyridinium substitution bromo- pyridine of the fluoro- 5- of 2- of 2-, the yield of target product obtained is
97%；Qualitative characterization's data are as follows:
GC-MS (EI, 70eV) m/z 153,136,80.1H NMR (600MHz, CDCl3) δ 7.63 (d, J=9.1Hz, 1H),
6.90 (s, 2H), 5.92 (d, J=9.1Hz, 1H), 2.15 (s, 3H)；13C NMR (150MHz, CDCl3) δ 151.71,146.56,
125.22,124.74,96.21,15.49.
The embodiment of the present invention 19 is the preparation of 2- Aminopyrazine: the difference of itself and embodiment one is only that: with the fluoro- pyrrole of 2-
Piperazine substitutes the bromo- pyridine of the fluoro- 5- of 2-, and the yield of target product obtained is 52%；Qualitative characterization's data are as follows:
GC-MS (EI, 70eV) m/z.95,68,41.
1H NMR (600MHz, Acetone) δ 7.98 (d, J=1.2Hz, 1H), 7.89 (dd, J=2.4,2.4Hz, 1H),
7.73 (d, J=2.7Hz, 1H), 5.84 (s, 2H)；
13C NMR (150MHz, Acetone) δ 156.97,142.74,133.5,133.4.
Compared with prior art, the present invention program is by without transition metal-catalyzed mode, with 2- fluorine-substituted nitrogenous six
Membered heterocycles are raw material, using amidine hydrochloride as amine source, the alkaline matters such as sodium hydroxide are used to carry out as catalyst
Catalysis reaction, for product, low raw-material cost；The present invention program is both without using at high price and be difficult to recycle
The inflammable and explosive dangerous gas such as transition-metal catalyst, hydrogen, without using toxic bromine and lithium amide etc. to be difficult to
Production, safety and environmental protection can be realized in industrialized industrial chemicals, the present invention program under better simply industrial condition；Of the invention
Synthesizing 2-aminopyridine method has conversion ratio and high income, and process flow is short, and reaction scale is easily enlarged, and product separation is simpler
It is single, it is at low cost, it is suitable for industrialized production advantage.
In conclusion the preparation method for the nitrogenous hexa-member heterocycle class compound that a kind of 2- amino provided by the invention replaces,
This method synthesis condition is simple, reaction step is few, reaction condition is mild, used catalyst is cheap, waste discharge is few and function
Group's tolerance is good.
The above description is only an embodiment of the present invention, is not intended to limit the scope of the invention, all to utilize this hair
Equivalents made by bright specification and accompanying drawing content are applied directly or indirectly in relevant technical field, similarly include
In scope of patent protection of the invention.
Claims (10)
1. a kind of preparation method for the nitrogenous hexa-member heterocycle class compound that 2- amino replaces, it is characterised in that: the preparation method
The following steps are included: after the fluorine-substituted nitrogenous hexa-member heterocycle class compound of 2- is mixed with amidine hydrochloride salt compounds, in alkalinity
Reaction obtains the nitrogenous hexa-member heterocycle class compound of 2- amino substitution under the action of substance.
2. preparation method according to claim 1, it is characterised in that: the fluorine-substituted nitrogenous hexa-member heterocycle class chemical combination of 2-
Shown in the general structure of object such as formula (I):
In formula (I), in formula (I), A1And A2In one be N, another is CH or A1
And A2It is CH；R1For single or multiple substituent groups, the R1Selected from hydrogen, halogen, alkyl, alkoxy, nitro, aromatic radical, aldehyde
At least one of base, ester group, carboxyl.
3. preparation method according to claim 1, it is characterised in that: the general structure of the amidine hydrochloride salt compounds is such as
Shown in formula (II):
In formula (II), R2Selected from alkyl or aromatic radical.
4. preparation method according to claim 3, it is characterised in that: the R2Selected from methyl, ethyl, isopropyl, phenyl,
Butyl；Preferably, the R2Selected from methyl.
5. preparation method according to claim 1, it is characterised in that: the alkaline matter includes inorganic base and/or organic
Alkali；Preferably, the alkaline matter includes potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium tert-butoxide and/or sodium methoxide.
6. preparation method according to claim 1, it is characterised in that: the fluorine-substituted nitrogenous hexa-member heterocycle class chemical combination of 2-
The molar ratio of object and amidine hydrochloride salt is 1:(1~2), preferably 1:1.2.
7. preparation method according to claim 1, it is characterised in that: the dosage of the alkaline matter is 2- fluorine substitution
1~3 times of nitrogenous hexa-member heterocycle class compound amount；Preferably, the dosage of the alkaline matter is that the 2- is fluorine-substituted
2 times of nitrogenous hexa-member heterocycle class compound amount.
8. described in any item preparation methods according to claim 1~7, it is characterised in that: reaction temperature is 100~150 DEG C, instead
It is 24~36 hours between seasonable；Preferably 130 DEG C, reaction is for 24 hours.
9. described in any item preparation methods according to claim 1~7, it is characterised in that: the reaction carries out in the solution, molten
Agent includes organic solvent and inorganic solvent, and the organic solvent is selected from chlorobenzene, diethylene glycol dimethyl ether, N- pyrrolidones, diformazan
At least one in base sulfoxide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, toluene, dimethylbenzene and 1,4- dioxane
Kind；Organic solvent is preferably dimethyl sulfoxide.
10. described in any item preparation methods according to claim 1~7, it is characterised in that: the preparation method further includes reaction
After carry out purification processes operation, purification processes operation is added for ethyl acetate quenching reaction is added after reaction
Saturated common salt water washing, isolates organic phase；
Remaining water phase after isolating organic phase is extracted with ethyl acetate again, solution extracted is merged with the organic phase,
It is dry that anhydrous sodium sulfate is added, includes organic solvent and inorganic solvent through vacuum distillation removal solvent, after the organic solvent, then
Chromatograph to obtain the nitrogenous hexa-member heterocycle class compound of the substitution of 2- amino after purification through column.
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| CN115385852A (en) * | 2022-09-05 | 2022-11-25 | 湖南阿斯迪康药业有限公司 | Efficient synthesis method of 2-amino-4-trifluoromethylpyridine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102140096A (en) * | 2011-01-24 | 2011-08-03 | 中国科学院广州生物医药与健康研究院 | Synthesis method of nitrogen-containing heterocyclic compound |
| CN107573351A (en) * | 2017-11-02 | 2018-01-12 | 淮南师范学院 | A kind of method for synthesizing nitrogen-containing heterocycle compound |
-
2018
- 2018-10-09 CN CN201811172047.0A patent/CN109232402A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102140096A (en) * | 2011-01-24 | 2011-08-03 | 中国科学院广州生物医药与健康研究院 | Synthesis method of nitrogen-containing heterocyclic compound |
| CN107573351A (en) * | 2017-11-02 | 2018-01-12 | 淮南师范学院 | A kind of method for synthesizing nitrogen-containing heterocycle compound |
Non-Patent Citations (1)
| Title |
|---|
| LI YIBIAO ET AL.,: "Transition-metal-free access to 2-aminopyridine derivatives from 2-fluoropyridine and acetamidine hydrochloride", 《ORG. BIOMOL. CHEM.》 * |
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| CN115385852A (en) * | 2022-09-05 | 2022-11-25 | 湖南阿斯迪康药业有限公司 | Efficient synthesis method of 2-amino-4-trifluoromethylpyridine |
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