CN107628990B - Synthesis method of 5-bromopyridine-3-formaldehyde - Google Patents
Synthesis method of 5-bromopyridine-3-formaldehyde Download PDFInfo
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- NGUVGKAEOFPLDT-UHFFFAOYSA-N 5-bromopyridine-3-carbaldehyde Chemical compound BrC1=CN=CC(C=O)=C1 NGUVGKAEOFPLDT-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000001308 synthesis method Methods 0.000 title abstract description 11
- SOSPMXMEOFGPIM-UHFFFAOYSA-N 3,5-dibromopyridine Chemical compound BrC1=CN=CC(Br)=C1 SOSPMXMEOFGPIM-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 23
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 239000005457 ice water Substances 0.000 claims description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- 239000012043 crude product Substances 0.000 claims description 19
- 239000012074 organic phase Substances 0.000 claims description 16
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 150000004795 grignard reagents Chemical class 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- 239000007818 Grignard reagent Substances 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 7
- 239000012295 chemical reaction liquid Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- 238000004537 pulping Methods 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 3
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 239000003381 stabilizer Substances 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- CZFNISFYDPIDNM-UHFFFAOYSA-N n,n-dimethylformamide;oxolane Chemical compound CN(C)C=O.C1CCOC1 CZFNISFYDPIDNM-UHFFFAOYSA-N 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- QUXHCILOWRXCEO-UHFFFAOYSA-M magnesium;butane;chloride Chemical compound [Mg+2].[Cl-].CCC[CH2-] QUXHCILOWRXCEO-UHFFFAOYSA-M 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- LWLPYZUDBNFNAH-UHFFFAOYSA-M magnesium;butane;bromide Chemical compound [Mg+2].[Br-].CCC[CH2-] LWLPYZUDBNFNAH-UHFFFAOYSA-M 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- ADCLTLQMVAEBLB-UHFFFAOYSA-N 3-bromo-5-methylpyridine Chemical compound CC1=CN=CC(Br)=C1 ADCLTLQMVAEBLB-UHFFFAOYSA-N 0.000 description 1
- JXUWZXFVCBODAN-UHFFFAOYSA-N 5-methylpyridin-3-amine Chemical compound CC1=CN=CC(N)=C1 JXUWZXFVCBODAN-UHFFFAOYSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- CJLCJZSAZBWLLI-UHFFFAOYSA-N [Li]CCCC.Br Chemical compound [Li]CCCC.Br CJLCJZSAZBWLLI-UHFFFAOYSA-N 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- QYHFIVBSNOWOCQ-UHFFFAOYSA-N selenic acid Chemical class O[Se](O)(=O)=O QYHFIVBSNOWOCQ-UHFFFAOYSA-N 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of 5-bromopyridine-3-formaldehyde, which takes 3, 5-dibromopyridine as a raw material and tetramethylethylenediamine as a stabilizer to react with a format reagent to prepare a product, wherein the existence of the tetramethylethylenediamine reduces impurities in the product and improves the yield; the synthesis method has low requirement on temperature, can be completed under the condition of 5-25 ℃, saves energy consumption and is easy to operate; in the synthesis process, the post-treatment method is simple, the steps are few, the yield is high, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of 5-bromopyridine-3-formaldehyde.
Background
In the prior art, various methods for synthesizing 5-bromopyridine-3-formaldehyde exist; the literature reports the preparation of 5-bromopyridine-3-formaldehyde by using 3, 5-dibromopyridine as a raw material and exchanging with butyl lithium bromide under ultralow temperature (-78 ℃) (reference: Non-systematic, porous redox Non-innovative imine n NHC pyridine 'pigments' via a zinc ion temporal-associated synthesis, Simler, Thomas et al, Dalton interactions, 46(18), 5955-pyridine 5964; 2017), and the literature reports the synthesis of 5-bromopyridine-3-formaldehyde by using 3, 5-dibromopyridine as a raw material and matching butyl lithium with n-butyl magnesium chloride at-15 ℃ (Hagadorn, John Robert. U.S. 2008226); the two synthesis methods can be carried out only under the ultralow temperature condition, and the reaction conditions are harsh and difficult to industrialize; there are also reports in the literature of the oxidative synthesis of 5-bromopyridine-3-carbaldehyde from 5-bromo-3-methylpyridine by selenium dioxide (reference: Preparation of heterocyclic acetylhexyl Substistuted pyrimidine-2,4(1H,3H) -diodes for treating HIV infection. Jorgensen, William L.and Anderson, Karen S.U.S.Pat.Appl.Publ.,20150105351,16Apr 2015); however, in the reaction process, a large amount of selenic acid derivatives are attached to the inner wall of the reaction kettle, and the post-treatment is very difficult; another synthesis method is to use 5-methyl-3-aminopyridine as raw material, and obtain the product by bromination and hydrolysis twice in sequence (reference: Stilbene heterocycles: synthesis, antisense, antioxidant and antibiotic activities. Reddy, G.Chandrasekara et al. Pharma Innovation,3(12-A), 24-30; 2015), but the method has more steps and low yield.
Disclosure of Invention
The invention solves the technical problems in the prior art and provides a method for synthesizing 5-bromopyridine-3-formaldehyde.
In order to solve the problems, the technical scheme of the invention is as follows:
a method for synthesizing 5-bromopyridine-3-formaldehyde comprises the following steps:
the synthetic route is as follows:
s1, uniformly mixing 3, 5-dibromopyridine, Tetrahydrofuran (THF) and tetramethylethylenediamine, and cooling to 10-15 ℃ by using an ice water bath; the volume ratio of the 3, 5-dibromopyridine to the tetrahydrofuran is 1:3-6, and the mass ratio of the 3, 5-dibromopyridine to the tetramethylethylenediamine is 1: 0.5-1;
s2, dripping a Grignard reagent into the reaction liquid prepared in the step 1, and keeping the reaction temperature below 15 ℃;
s3, reacting the reaction solution obtained in the step 2 for 1-2 hours at the temperature of 20-25 ℃, and cooling the reaction solution to 5-10 ℃ by using an ice water bath;
s4, dissolving N, N-Dimethylformamide (DMF) in THF (tetrahydrofuran), wherein the THF is used for diluting the concentration of the DMF to prevent violent reaction during dropwise addition, slowly dropwise adding the DMF-THF mixed solution into the reaction solution obtained in the step 3, maintaining the temperature of 10-15 ℃ for reaction for 30min, and separating and purifying the reaction solution to obtain a crude product of 5-bromopyridine-3-formaldehyde;
the molar weight ratio of the 3, 5-dibromopyridine to the Grignard reagent to the DMF is 1:1.2-1.5: 1.5-2.
Preferably, the method for separating and purifying the reaction solution obtained in the step 4 comprises the following steps: pouring the reaction liquid into ice water, stirring for 10min, standing, separating liquid, washing an organic phase, drying, and distilling under reduced pressure to obtain a crude product of 5-bromopyridine-3-formaldehyde; in order to improve the yield, the water phase obtained by separating the liquid can be extracted once by ethyl acetate, and the organic phase is washed, dried and distilled under reduced pressure; more preferably, the volume of the ice water is 1.5 to 4 times the volume of tetrahydrofuran in the reaction solution.
Preferably, the purification method of the crude 5-bromopyridine-3-formaldehyde product comprises the following steps: adding Petroleum Ether (PE) and Ethyl Acetate (EA) mixed solvent of 6:1(W: W) into the crude product, pulping for 1h at 20-25 ℃, filtering, washing and drying; more preferably, the petroleum ether/ethyl acetate mixed solvent is added in an amount of: adding 1-2ml of petroleum ether/ethyl acetate mixed solvent into each gram of the 5-bromopyridine-3-formaldehyde crude product.
Preferably, the Grignard reagent is selected from any one of isopropyl magnesium bromide, methyl magnesium chloride or isopropyl magnesium chloride.
Compared with the prior art, the invention has the advantages that,
the method for synthesizing 5-bromopyridine-3-formaldehyde takes 3, 5-dibromopyridine as a raw material and tetramethylethylenediamine as a stabilizer, and the 3, 5-dibromopyridine and the tetramethylethylenediamine react with a format reagent to prepare a product, so that the existence of the tetramethylethylenediamine reduces impurities in the product and improves the yield;
the synthesis method has low requirement on temperature, can be completed under the condition of 5-25 ℃, saves energy consumption and is easy to operate;
in the synthesis process, the post-treatment method is simple, the steps are few, the yield is high, and the method is suitable for industrial production.
Detailed Description
Example 1:
250g of 3, 5-dibromopyridine, 1000ml of tetrahydrofuran and 150g of tetramethylethylenediamine are put into a 5L reaction bottle, and stirring is started. The system is cooled to 10-15 ℃ in ice water bath. 750ml of isopropyl magnesium chloride (2.6M, THF) was added dropwise to the reaction mixture, and the temperature was maintained at 15 ℃ or lower (slightly elevated). After dripping, removing the ice water bath, and reacting for 1-2h at 20-25 ℃. The reaction solution is cooled to 5-10 ℃ by using ice water bath. 130g of DMF was taken and dissolved in 100ml of THF. The DMF-THF mixture was slowly added dropwise to the reaction mixture while maintaining the internal temperature at 15 ℃ or lower (exothermic, it was added dropwise slowly). After dripping, the reaction is maintained at 10-15 ℃ for 30min. Pouring the reaction solution into 2L of ice water, stirring for 10min, standing, separating liquid, and respectively collecting a water phase and an organic phase. The aqueous phase was extracted once with 1L ethyl acetate and the organic phases were combined. The organic phase was washed successively with 1L of water and 1L of saturated brine, and dried over anhydrous sodium sulfate. Distilling at 50-55 deg.C under reduced pressure to obtain crude product. Adding 200ml of PE-EA 6:1(W: W) mixed solvent into the crude product, and pulping for 1h at 20-25 ℃. Filtration and the filter cake rinsed once with 50ml PE. Drying by an infrared lamp to obtain an off-white to off-white solid, 112g and the yield of 67.3 percent.
Example 2:
like example 1, only
The volume ratio of the 3, 5-dibromopyridine to the tetrahydrofuran is modified as follows: 1:3
The mass ratio of the 3, 5-dibromopyridine to the tetramethylethylenediamine is modified to be 1: 0.5;
the molar weight ratio of 3, 5-dibromopyridine, isopropyl magnesium chloride and DMF is modified to 1:1.2-: 1.5;
the volume of the ice water was 1.5 times the volume of tetrahydrofuran in the reaction mixture.
The yield of the desired product was 65.4%.
Example 3:
like example 1, only
The volume ratio of the 3, 5-dibromopyridine to the tetrahydrofuran is modified as follows: 1:6
The mass ratio of the 3, 5-dibromopyridine to the tetramethylethylenediamine is modified to 1: 1;
the molar weight ratio of 3, 5-dibromopyridine to isopropyl magnesium chloride to DMF is modified to 1:1.5: 2;
the volume of the ice water was 4 times the volume of tetrahydrofuran in the reaction solution.
The yield of the desired product was 66.3%.
Example 4:
in the same manner as in example 1, only isopropyl magnesium bromide, methyl magnesium bromide and methyl magnesium chloride were used instead of isopropyl magnesium chloride as Grignard reagents to participate in the reaction, and the yields of the target products were 62.9%, 64.1% and 63.8%, respectively.
Comparative example 1:
in the synthesis method, tetramethylethylenediamine is used as a stabilizer, so that the final yield of the reaction is influenced, and if tetramethylethylenediamine is not added, the prepared crude product has more impurities and low yield.
250g of 3, 5-dibromopyridine and 1000ml of tetrahydrofuran are put into a 5L reaction bottle, and stirring is started. The system is cooled to 10-15 ℃ in ice water bath. 750ml of isopropyl magnesium chloride (2.6M, THF) was added dropwise to the reaction mixture, and the temperature was maintained at 15 ℃ or lower (slightly elevated). After dripping, removing the ice water bath, and reacting for 1-2h at 20-25 ℃. The reaction solution is cooled to 5-10 ℃ by using ice water bath. DMF130g was taken and dissolved in 100ml THF. The DMF-THF mixture (diluted DMF concentration to prevent vigorous reaction during dropwise addition) was slowly added dropwise to the reaction mixture, and the internal temperature was maintained at 15 ℃ or lower (exothermic, and dropwise addition should be slow). After dripping, the reaction is maintained at 10-15 ℃ for 30min. Pouring the reaction solution into 2L of ice water, stirring for 10min, standing, separating liquid, and respectively collecting a water phase and an organic phase. The aqueous phase was extracted once with 1L ethyl acetate and the organic phases were combined. The organic phase was washed successively with 1L of water and 1L of saturated brine, and dried over anhydrous sodium sulfate. Distilling at 50-55 deg.C under reduced pressure to obtain crude product. Adding 200ml of PE-EA 6:1(W: W) mixed solvent into the crude product, and pulping for 1h at 20-25 ℃. Filtration and the filter cake rinsed once with 50ml PE. Drying by an infrared lamp to obtain an off-white to off-white solid, 34g and the yield is 17.4 percent.
Comparative example 2:
in the synthesis method, the selection of the format reagent influences the final yield of the reaction; the n-butyl magnesium bromide and the n-butyl magnesium chloride are respectively selected as Grignard reagents to participate in the reaction, and the yield is low.
The Grignard reagent is n-butyl magnesium bromide
250g of 3, 5-dibromopyridine, 1000ml of tetrahydrofuran and 150g of tetramethylethylenediamine are put into a 5L reaction bottle, and the system is cooled to 10-15 ℃ in ice water bath. 750ml of n-butylmagnesium bromide (2.6M, THF) was added dropwise to the reaction mixture, and the temperature was maintained at 15 ℃ or lower (slightly elevated). After dripping, removing the ice water bath, and reacting for 1-2h at 20-25 ℃. The reaction solution is cooled to 5-10 ℃ by using ice water bath. 130g of DMF was taken and dissolved in 100ml of THF. The DMF-THF mixture (diluted DMF concentration to prevent vigorous reaction during dropwise addition) was slowly added dropwise to the reaction mixture, and the internal temperature was maintained at 15 ℃ or lower (exothermic, and dropwise addition should be slow). After dripping, the reaction is maintained at 10-15 ℃ for 30min. Pouring the reaction solution into 2L of ice water, stirring for 10min, standing, separating liquid, and respectively collecting a water phase and an organic phase. The aqueous phase was extracted once with 1L ethyl acetate and the organic phases were combined. The organic phase was washed successively with 1L of water and 1L of saturated brine, and dried over anhydrous sodium sulfate. Distilling at 50-55 deg.C under reduced pressure to obtain crude product. Adding 200ml of PE-EA 6:1(W: W) mixed solvent into the crude product, and pulping for 1h at 20-25 ℃. Filtration and the filter cake rinsed once with 50ml PE. Drying by an infrared lamp to obtain an off-white to off-white solid, 42g and 21.5 percent of yield.
The Grignard reagent is n-butyl magnesium chloride
250g of 3, 5-dibromopyridine, 1000ml of tetrahydrofuran and 150g of tetramethylethylenediamine are put into a 5L reaction bottle, and the system is cooled to 10-15 ℃ in ice water bath. 750ml of n-butylmagnesium chloride (2.6M, THF) was added dropwise to the reaction mixture, and the temperature was maintained at 15 ℃ or lower (slightly elevated). After dripping, removing the ice water bath, and reacting for 1-2h at 20-25 ℃. The reaction solution is cooled to 5-10 ℃ by using ice water bath. 130g of DMF was taken and dissolved in 100ml of THF. The DMF-THF mixture (diluted DMF concentration to prevent vigorous reaction during dropwise addition) was slowly added dropwise to the reaction mixture, and the internal temperature was maintained at 15 ℃ or lower (exothermic, and dropwise addition should be slow). After dripping, the reaction is maintained at 10-15 ℃ for 30min. Pouring the reaction solution into 2L of ice water, stirring for 10min, standing, separating liquid, and respectively collecting a water phase and an organic phase. The aqueous phase was extracted once with 1L ethyl acetate and the organic phases were combined. The organic phase was washed successively with 1L of water and 1L of saturated brine, and dried over anhydrous sodium sulfate. Distilling at 50-55 deg.C under reduced pressure to obtain crude product. Adding 200ml of PE-EA 6:1(W: W) mixed solvent into the crude product, and pulping for 1h at 20-25 ℃. Filtration and the filter cake rinsed once with 50ml PE. Drying by an infrared lamp to obtain an off-white to off-white solid, 44g and the yield of 22.5 percent.
Comparative example 3:
in the synthesis method, the temperature when the Grignard reagent is dripped affects the final yield of the reaction; like example 1, the temperature was changed to 30 ℃ or 50 ℃ only when the grignard reagent was added:
at 30 ℃, the content of impurities in the crude product is high; the yield is 27.8%;
at 50 ℃, a lot of impurities exist, the product is few, and the yield is 10.2%; .
It should be noted that the above-mentioned embodiments are only preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, and all equivalent substitutions or substitutions made on the above-mentioned embodiments are included in the scope of the present invention.
Claims (8)
1. A method for synthesizing 5-bromopyridine-3-formaldehyde is characterized by comprising the following steps:
s1, uniformly mixing 3, 5-dibromopyridine, tetrahydrofuran and tetramethylethylenediamine, and cooling to 10-15 ℃ by using an ice water bath; the volume ratio of the 3, 5-dibromopyridine to the tetrahydrofuran is 1:3-6, and the mass ratio of the 3, 5-dibromopyridine to the tetramethylethylenediamine is 1: 0.5-1;
s2, dripping a Grignard reagent into the reaction liquid prepared in the step 1, and keeping the reaction temperature below 15 ℃;
s3, reacting the reaction solution obtained in the step 2 for 1-2 hours at the temperature of 20-25 ℃, and cooling the reaction solution to 5-10 ℃ by using an ice water bath;
s4, dropwise adding N, N-dimethylformamide into the reaction liquid obtained in the step 3, maintaining the temperature of 10-15 ℃ for reaction for 30min, and separating and purifying the reaction liquid to obtain a crude product of 5-bromopyridine-3-formaldehyde;
the molar weight ratio of the 3, 5-dibromopyridine to the Grignard reagent to the DMF is 1:1.2-1.5: 1.5-2.
2. The method of synthesizing 5-bromopyridine-3-carbaldehyde according to claim 1, wherein in the step 4, N-dimethylformamide is dissolved in tetrahydrofuran before being added to the reaction solution.
3. The method for synthesizing 5-bromopyridine-3-carbaldehyde according to claim 1, wherein the method for separating and purifying the reaction solution obtained in the step 4 comprises: pouring the reaction liquid into ice water, stirring for 10min, standing, separating liquid, washing an organic phase, drying, and distilling under reduced pressure to obtain a crude product of 5-bromopyridine-3-formaldehyde.
4. The method for synthesizing 5-bromopyridine-3-carbaldehyde according to claim 3, wherein the aqueous phase obtained by separation is extracted once with ethyl acetate, and the organic phase is washed, dried, and distilled under reduced pressure; to prepare a crude product of 5-bromopyridine-3-formaldehyde.
5. The method for synthesizing 5-bromopyridine-3-carbaldehyde according to claim 3, wherein the volume of the ice water is 1.5 to 4 times the volume of tetrahydrofuran in the reaction solution.
6. The method for synthesizing 5-bromopyridine-3-carbaldehyde as claimed in claim 3 or 4, wherein the method for purifying the crude 5-bromopyridine-3-carbaldehyde comprises: adding petroleum ether and ethyl acetate mixed solvent of 6:1(W: W) into the crude product, pulping for 1h at 20-25 ℃, filtering, washing and drying.
7. The method of synthesizing 5-bromopyridine-3-carbaldehyde according to claim 6, wherein the petroleum ether/ethyl acetate mixed solvent is added in an amount of: adding 1-2ml of petroleum ether/ethyl acetate mixed solvent into each gram of the 5-bromopyridine-3-formaldehyde crude product.
8. A process for the synthesis of 5-bromopyridine-3-carbaldehyde according to claim 1, wherein the Grignard reagent is selected from any one of isopropyl magnesium bromide, methyl magnesium chloride or isopropyl magnesium chloride.
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| JP7509573B2 (en) | 2019-08-27 | 2024-07-02 | 東ソー・ファインケム株式会社 | Method for producing oxystyrene compounds having polysubstituted ether substituents |
| CN112479991A (en) * | 2020-12-28 | 2021-03-12 | 重庆三圣实业股份有限公司 | Preparation method of 2-bromo-5-aldehyde pyridine |
| CN113135899B (en) * | 2021-06-21 | 2021-11-23 | 北京鑫开元医药科技有限公司 | Benzocycloheptapyridine compounds, process for their preparation and their use |
| CN115010656B (en) * | 2022-06-14 | 2024-04-26 | 苏州昊帆生物股份有限公司 | Preparation method of 5-acetyl-2-bromopyridine |
| CN116354875B (en) * | 2023-02-17 | 2025-05-16 | 无锡海伦生物科技有限公司 | A kind of preparation method of 2-pyridinecarboxaldehyde |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003059878A2 (en) * | 2002-01-14 | 2003-07-24 | Pharmacia & Upjohn Company | Thieno (3, 2-b) pyridones as antiviral compounds |
| US20030191121A1 (en) * | 2001-08-09 | 2003-10-09 | Miller Ross A. | Piperazine carboxamide intermediates of HIV protease inhibitors and processes for their preparation |
-
2017
- 2017-11-10 CN CN201711103036.2A patent/CN107628990B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030191121A1 (en) * | 2001-08-09 | 2003-10-09 | Miller Ross A. | Piperazine carboxamide intermediates of HIV protease inhibitors and processes for their preparation |
| WO2003059878A2 (en) * | 2002-01-14 | 2003-07-24 | Pharmacia & Upjohn Company | Thieno (3, 2-b) pyridones as antiviral compounds |
Non-Patent Citations (2)
| Title |
|---|
| Novel potent and selective αvβ3/αvβ5 integrin dual antagonists with reduced binding affinity for human serum albumin;Pierre Raboisson，等;《European Journal of Medicinal Chemistry》;20060511;第41卷;847–861 * |
| Tributylmagnesium ate complex-mediated novel bromine–magnesium exchange reaction for selective monosubstitution of dibromoarenes;Takehiko Iida,等;《Tetrahedron Letters》;20011231;第42卷;4841-4844 * |
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