CN114105975A - Synthetic method of [1,2,4] triazole [1,5-A ] pyridine-6-formaldehyde - Google Patents
Synthetic method of [1,2,4] triazole [1,5-A ] pyridine-6-formaldehyde Download PDFInfo
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- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 title claims abstract description 14
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000010189 synthetic method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 46
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 16
- 238000003756 stirring Methods 0.000 claims abstract description 15
- 239000008399 tap water Substances 0.000 claims abstract description 11
- 235000020679 tap water Nutrition 0.000 claims abstract description 11
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 8
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 230000000977 initiatory effect Effects 0.000 claims abstract description 8
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 8
- 239000011630 iodine Substances 0.000 claims abstract description 8
- 239000011777 magnesium Substances 0.000 claims abstract description 8
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 8
- 239000012074 organic phase Substances 0.000 claims abstract description 8
- 238000005406 washing Methods 0.000 claims abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 238000001816 cooling Methods 0.000 claims description 14
- 239000007818 Grignard reagent Substances 0.000 claims description 7
- 150000004795 grignard reagents Chemical class 0.000 claims description 7
- 238000010791 quenching Methods 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- 150000001923 cyclic compounds Chemical class 0.000 claims description 6
- 238000001308 synthesis method Methods 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003446 ligand Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 150000003222 pyridines Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
A synthetic method of [1,2,4] triazole [1,5-A ] pyridine-6-formaldehyde comprises the following steps: putting 55-65g of magnesium chips, 100ml of anhydrous tetrahydrofuran, a small amount of 2-chloropropane and a few of iodine into a 2L reaction bottle, vacuum replacing nitrogen, stirring, slightly heating to initiate reaction, dropwise adding 200-220g of 2-chloropropane/1.4L of tetrahydrofuran solution after initiation, releasing heat in the reaction, keeping the temperature T of tap water at 45-50 ℃, finishing the reaction at room temperature for 2h for later use, extracting a water layer by using 1.5L of multiplied by 2 ethyl acetate, combining organic phases, washing by using 2L of saturated saline, drying by using 1000g of anhydrous sodium sulfate, and concentrating under reduced pressure to dryness to obtain the product.
Description
Technical Field
The invention relates to the technical field of pyridine synthesis, in particular to a synthesis method of [1,2,4] triazole [1,5-A ] pyridine-6-formaldehyde.
Background
In recent years, coordination chemistry has been remarkably developed in the chemical field, and a large number of complexes having novel structures are designed and synthesized by coordinating organic polydentate ligands containing nitrogen, phosphorus, oxygen, and the like with different metals. Among them, pyridine derivatives, which are one of the most widely used ligands, have been a focus of coordination chemistry because of their strong coordination ability, diverse coordination modes, and the ability to form a complex compound with stable structure with various metal ions.
The pyridine derivative ligand can synthesize various complexes with novel structures and excellent properties through the actions of coordination bonds, hydrogen bonds, pi-pi stacking on aromatic rings and the like, and the metal organic complex has more reaction sites and higher catalytic activity, so the metal organic complex is widely used for a series of organic synthesis reactions such as coupling reaction, hydrogen transfer reaction, esterification reaction, olefin double decomposition reaction, olefin polymerization reaction, oxidation reaction, hydrogenation reaction and the like. In addition, the complex has good application prospects in the aspects of gas storage, ion exchange, molecular recognition, chiral resolution, hydrogen storage, drug slow release and the like. Therefore, the design and synthesis of the pyridine derivative ligand are of great significance to the research field and the catalytic industry field.
Disclosure of Invention
Technical problem to be solved
Aiming at the defects of the prior art, the invention provides a synthetic method of [1,2,4] triazole [1,5-A ] pyridine-6-formaldehyde.
(II) technical scheme
In order to achieve the purpose, the invention provides the following technical scheme: a synthetic method of [1,2,4] triazole [1,5-A ] pyridine-6-formaldehyde comprises the following steps:
step 1, putting 55-65g of magnesium chips, 100ml of anhydrous tetrahydrofuran, a small amount of 2-chloropropane and a plurality of iodine particles into a 2L reaction bottle, replacing nitrogen in vacuum, stirring, slightly heating to initiate reaction, dropwise adding 200-220g of 2-chloropropane/1.4L of tetrahydrofuran solution after initiation, releasing heat in the reaction, keeping the temperature T of tap water at 45-50 ℃, and reacting for 2 hours at room temperature for later use;
step 2, putting 400-450g of cyclic compound and 3L of tetrahydrofuran into a 10L reaction bottle, stirring, replacing nitrogen in vacuum, cooling to-2 to-8 ℃, dropwise adding the Grignard reagent, controlling the temperature T to be less than 0 ℃, finishing the addition, keeping the temperature at 0 ℃ for reaction for 1h, and detecting no raw material by TLC;
and step 3, dropping 240 plus 260gDMF, controlling the T <0 ℃, keeping the temperature for 0.5h after the addition is finished, and slowly increasing the temperature to react at room temperature overnight.
And step 4, cooling to 0 ℃ the next day, dropwise adding 3N hydrochloric acid to quench the reaction, adjusting the pH to 7-8, using 1.4L of 3N hydrochloric acid together, slowly increasing the pH value to room temperature, standing for layering, extracting a water layer by using 1.5L of multiplied by 2 ethyl acetate, combining organic phases, washing by using 2L of saturated saline solution, drying by using 1000g of anhydrous sodium sulfate, and concentrating under reduced pressure until the water layer is dry to obtain the product.
The improvement of the invention comprises the following steps:
step 1, putting 64g of magnesium chips, 100ml of anhydrous tetrahydrofuran, a small amount of 2-chloropropane and a few of iodine into a 2L reaction bottle, performing vacuum nitrogen replacement, stirring, slightly heating to initiate reaction, dropwise adding 207g of 2-chloropropane/1.4L of tetrahydrofuran solution after initiation, performing reaction heat release, keeping the temperature T of tap water at 45-50 ℃, and reacting for 2 hours after adding room temperature for later use;
step 2, putting 430g of cyclic compound and 3L of tetrahydrofuran into a 10L reaction bottle, stirring, replacing nitrogen in vacuum, cooling to-5C, dropwise adding the Grignard reagent, controlling the temperature T to be less than 0 ℃, finishing the addition, keeping the temperature at 0 ℃ for reaction for 1h, and detecting by TLC without raw materials;
and 3, dropwise adding 256g of DMF, controlling the T to be less than 0 ℃, keeping the temperature of 0 ℃ for 0.5h after the addition, and slowly increasing the temperature to react at room temperature overnight.
And step 4, cooling to 0 ℃ the next day, dropwise adding 3N hydrochloric acid to quench the reaction, adjusting the pH to 7-8, using 1.4L of 3N hydrochloric acid together, slowly increasing the pH value to room temperature, standing for layering, extracting a water layer by using 1.5L of multiplied by 2 ethyl acetate, combining organic phases, washing by using 2L of saturated saline solution, drying by using 1000g of anhydrous sodium sulfate, and concentrating under reduced pressure until the water layer is dry to obtain the product.
The improvement of the invention is that in the step 1, tap water is added for reaction for 2 hours after the temperature T is 48 ℃.
(III) advantageous effects
Compared with the prior art, the invention provides a synthesis method of [1,2,4] triazole [1,5-A ] pyridine-6-formaldehyde, which has the following beneficial effects:
the novel method is simple in reaction operation, the synthesis method of the [1,2,4] triazole [1,5-A ] pyridine-6-formaldehyde can be synthesized through simple steps, and the synthesis method has the advantages of high reaction efficiency, high speed, mild conditions, simple and easily-obtained substrate, wide applicability, short reaction time, high yield and the like, and is reasonable in route design, simple in experimental operation, easy to implement and high in yield of the obtained product.
Drawings
FIG. 1 is a scheme 1 of the present invention;
FIG. 2 shows reaction scheme 2 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A synthetic method of [1,2,4] triazole [1,5-A ] pyridine-6-formaldehyde comprises the following steps:
step 1, putting 55g of magnesium chips, 100ml of anhydrous tetrahydrofuran, a small amount of 2-chloropropane and a few of iodine into a 2L reaction bottle, performing vacuum nitrogen replacement, stirring, slightly heating to initiate reaction, dropwise adding 200g of 2-chloropropane/1.4L of tetrahydrofuran solution after initiation, performing reaction heat release, keeping the temperature T of tap water at 45-50 ℃, and reacting for 2 hours after adding at room temperature for later use;
step 2, putting 400g of cyclic compound and 3L of tetrahydrofuran into a 10L reaction bottle, stirring, replacing nitrogen in vacuum, cooling to-2 ℃, dropwise adding the Grignard reagent, controlling the temperature T to be less than 0 ℃, finishing the addition, keeping the temperature at 0 ℃ for reaction for 1h, and detecting by TLC without raw materials;
and 3, dropwise adding 240g of DMF, controlling the T to be less than 0 ℃, keeping the temperature of 0 ℃ for 0.5h after the addition, and slowly increasing the temperature to react at room temperature overnight.
And step 4, cooling to 0 ℃ the next day, dropwise adding 3N hydrochloric acid to quench the reaction, adjusting the pH to 7-8, using 1.4L of 3N hydrochloric acid together, slowly increasing the pH value to room temperature, standing for layering, extracting a water layer by using 1.5L of multiplied by 2 ethyl acetate, combining organic phases, washing by using 2L of saturated saline solution, drying by using 1000g of anhydrous sodium sulfate, and concentrating under reduced pressure until the water layer is dry to obtain the product.
Example 2
A synthetic method of [1,2,4] triazole [1,5-A ] pyridine-6-formaldehyde comprises the following steps:
step 1, putting 64g of magnesium chips, 100ml of anhydrous tetrahydrofuran, a small amount of 2-chloropropane and a few of iodine into a 2L reaction bottle, performing vacuum nitrogen replacement, stirring, slightly heating to initiate reaction, dropwise adding 207g of 2-chloropropane/1.4L of tetrahydrofuran solution after initiation, performing reaction heat release, keeping the temperature T of tap water at 45-50 ℃, and reacting for 2 hours after adding room temperature for later use;
step 2, putting 430g of cyclic compound and 3L of tetrahydrofuran into a 10L reaction bottle, stirring, replacing nitrogen in vacuum, cooling to-5C, dropwise adding the Grignard reagent, controlling the temperature T to be less than 0 ℃, finishing the addition, keeping the temperature at 0 ℃ for reaction for 1h, and detecting by TLC without raw materials;
and 3, dropwise adding 256g of DMF, controlling the T to be less than 0 ℃, keeping the temperature of 0 ℃ for 0.5h after the addition, and slowly increasing the temperature to react at room temperature overnight.
And step 4, cooling to 0 ℃ the next day, dropwise adding 3N hydrochloric acid to quench the reaction, adjusting the pH to 7-8, using 1.4L of 3N hydrochloric acid together, slowly increasing the pH value to room temperature, standing for layering, extracting a water layer by using 1.5L of multiplied by 2 ethyl acetate, combining organic phases, washing by using 2L of saturated saline solution, drying by using 1000g of anhydrous sodium sulfate, and concentrating under reduced pressure until the water layer is dry to obtain the product.
Example 3
A synthetic method of [1,2,4] triazole [1,5-A ] pyridine-6-formaldehyde comprises the following steps:
step 1, putting 65g of magnesium chips, 100ml of anhydrous tetrahydrofuran, a small amount of 2-chloropropane and a few of iodine into a 2L reaction bottle, performing vacuum nitrogen replacement, stirring, slightly heating to initiate reaction, dropwise adding 220g of 2-chloropropane/1.4L of tetrahydrofuran solution after initiation, performing reaction heat release, keeping the temperature T of tap water at 45-50 ℃, and reacting for 2 hours after adding at room temperature for later use;
step 2, putting 450g of cyclics and 3L of tetrahydrofuran into a 10L reaction bottle, stirring, replacing nitrogen in vacuum, cooling to-8 ℃, dropwise adding the Grignard reagent, controlling the temperature T to be less than 0 ℃, finishing the addition, keeping the temperature at 0 ℃ for reaction for 1h, and detecting by TLC without raw materials;
and 3, dropwise adding 260g of DMF, controlling the T to be less than 0 ℃, keeping the temperature of 0 ℃ for 0.5h after the addition, and slowly increasing the temperature to react at room temperature overnight.
And step 4, cooling to 0 ℃ the next day, dropwise adding 3N hydrochloric acid to quench the reaction, adjusting the pH to 7-8, using 1.4L of 3N hydrochloric acid together, slowly increasing the pH value to room temperature, standing for layering, extracting a water layer by using 1.5L of multiplied by 2 ethyl acetate, combining organic phases, washing by using 2L of saturated saline solution, drying by using 1000g of anhydrous sodium sulfate, and concentrating under reduced pressure until the water layer is dry to obtain the product.
In three examples, the reaction was carried out for 2h in step 1 by maintaining tap water at a temperature T ═ 48 ℃.
(HPLC conditions: MeOH: 0.1% TFA: 70:30,254nm), preparative HPLC of the product was > 95%.
The boiling point of the toluene is higher, the vacuum degree required by the reduced pressure concentration is higher, the water solubility of the ethyl acetate is larger, the ethyl acetate is not easy to separate from water, and the required amount is much larger than that of the toluene. The actual production can be selected according to the conditions.
The metering in specific example 2 can be referred to the following figure
Molar yield: 83.3 percent
Weight yield: 50.0 percent
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (3)
1. A synthetic method of [1,2,4] triazole [1,5-A ] pyridine-6-formaldehyde is characterized by comprising the following steps:
step 1, putting 55-65g of magnesium chips, 100ml of anhydrous tetrahydrofuran, a small amount of 2-chloropropane and a plurality of iodine particles into a 2L reaction bottle, replacing nitrogen in vacuum, stirring, slightly heating to initiate reaction, dropwise adding 200-220g of 2-chloropropane/1.4L of tetrahydrofuran solution after initiation, releasing heat in the reaction, keeping the temperature T of tap water at 45-50 ℃, and reacting for 2 hours at room temperature for later use;
step 2, putting 400-450g of cyclic compound and 3L of tetrahydrofuran into a 10L reaction bottle, stirring, replacing nitrogen in vacuum, cooling to-2 to-8 ℃, dropwise adding the Grignard reagent, controlling the temperature T to be less than 0 ℃, finishing the addition, keeping the temperature at 0 ℃ for reaction for 1h, and detecting no raw material by TLC;
and step 3, dropping 240 plus 260gDMF, controlling the T <0 ℃, keeping the temperature for 0.5h after the addition is finished, and slowly increasing the temperature to react at room temperature overnight.
And step 4, cooling to 0 ℃ the next day, dropwise adding 3N hydrochloric acid to quench the reaction, adjusting the pH to 7-8, using 1.4L of 3N hydrochloric acid together, slowly increasing the pH value to room temperature, standing for layering, extracting a water layer by using 1.5L of multiplied by 2 ethyl acetate, combining organic phases, washing by using 2L of saturated saline solution, drying by using 1000g of anhydrous sodium sulfate, and concentrating under reduced pressure until the water layer is dry to obtain the product.
2. The synthesis method of [1,2,4] triazole [1,5-A ] pyridine-6-formaldehyde according to claim 1, comprising the following steps:
step 1, putting 64g of magnesium chips, 100ml of anhydrous tetrahydrofuran, a small amount of 2-chloropropane and a few of iodine into a 2L reaction bottle, performing vacuum nitrogen replacement, stirring, slightly heating to initiate reaction, dropwise adding 207g of 2-chloropropane/1.4L of tetrahydrofuran solution after initiation, performing reaction heat release, keeping the temperature T of tap water at 45-50 ℃, and reacting for 2 hours after adding room temperature for later use;
step 2, putting 430g of cyclic compound and 3L of tetrahydrofuran into a 10L reaction bottle, stirring, replacing nitrogen in vacuum, cooling to-5C, dropwise adding the Grignard reagent, controlling the temperature T to be less than 0 ℃, finishing the addition, keeping the temperature at 0 ℃ for reaction for 1h, and detecting by TLC without raw materials;
and 3, dropwise adding 256g of DMF, controlling the T to be less than 0 ℃, keeping the temperature of 0 ℃ for 0.5h after the addition, and slowly increasing the temperature to react at room temperature overnight.
And step 4, cooling to 0 ℃ the next day, dropwise adding 3N hydrochloric acid to quench the reaction, adjusting the pH to 7-8, using 1.4L of 3N hydrochloric acid together, slowly increasing the pH value to room temperature, standing for layering, extracting a water layer by using 1.5L of multiplied by 2 ethyl acetate, combining organic phases, washing by using 2L of saturated saline solution, drying by using 1000g of anhydrous sodium sulfate, and concentrating under reduced pressure until the water layer is dry to obtain the product.
3. The synthesis method of [1,2,4] triazole [1,5-A ] pyridine-6-formaldehyde according to claim 2, wherein in the step 1, tap water is kept at a temperature T-48 ℃ and is added to react for 2 hours at room temperature.
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| CN1658866A (en) * | 2002-04-04 | 2005-08-24 | 比奥根艾迪克Ma公司 | Tri-substituted heteroaryls and methods of making and using the same |
| WO2006026305A1 (en) * | 2004-08-31 | 2006-03-09 | Biogen Idec Ma Inc | Pyrimidinylpyrazoles as tgf-beta inhibitors |
| CN105859536A (en) * | 2016-05-06 | 2016-08-17 | 蚌埠中实化学技术有限公司 | Method for preparing 3, 4-difluorobenzaldehyde |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1658866A (en) * | 2002-04-04 | 2005-08-24 | 比奥根艾迪克Ma公司 | Tri-substituted heteroaryls and methods of making and using the same |
| WO2006026305A1 (en) * | 2004-08-31 | 2006-03-09 | Biogen Idec Ma Inc | Pyrimidinylpyrazoles as tgf-beta inhibitors |
| US20080171755A1 (en) * | 2004-08-31 | 2008-07-17 | Wen-Cherng Lee | Pyrimidinylpyrazoles as Tgf-Beta Inhibitors |
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| Title |
|---|
| 王建新: "《精细有机合成》", 中国轻工业出版社, pages: 73 * |
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