CN117362278A - Preparation method of 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole - Google Patents
Preparation method of 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole Download PDFInfo
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- PXCDIRKSCUAMKA-UHFFFAOYSA-N 5-(furan-2-yl)-1h-1,2,4-triazol-3-amine Chemical compound NC1=NNC(C=2OC=CC=2)=N1 PXCDIRKSCUAMKA-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- -1 N, N' -di-Boc-2-furoyl guanidine Chemical compound 0.000 claims abstract description 42
- SKTSVWWOAIAIKI-UHFFFAOYSA-N furan-2-carbohydrazide Chemical compound NNC(=O)C1=CC=CO1 SKTSVWWOAIAIKI-UHFFFAOYSA-N 0.000 claims abstract description 35
- BPWBNUCDLIOPSJ-UHFFFAOYSA-N n-(diaminomethylidene)furan-2-carboxamide Chemical compound NC(N)=NC(=O)C1=CC=CO1 BPWBNUCDLIOPSJ-UHFFFAOYSA-N 0.000 claims abstract description 16
- SXRSKQKWYAYRGQ-UHFFFAOYSA-N N(C(=N)N)C=1OC=CC=1 Chemical compound N(C(=N)N)C=1OC=CC=1 SXRSKQKWYAYRGQ-UHFFFAOYSA-N 0.000 claims abstract description 10
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 9
- 230000018044 dehydration Effects 0.000 claims abstract description 6
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 84
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 39
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 claims description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 14
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical group OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 13
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 230000035484 reaction time Effects 0.000 claims description 11
- 238000005917 acylation reaction Methods 0.000 claims description 10
- 230000010933 acylation Effects 0.000 claims description 9
- 230000032050 esterification Effects 0.000 claims description 9
- 238000005886 esterification reaction Methods 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000007344 nucleophilic reaction Methods 0.000 claims description 4
- 238000005580 one pot reaction Methods 0.000 claims description 4
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 abstract description 9
- 238000007086 side reaction Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 23
- 239000000047 product Substances 0.000 description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- 239000006227 byproduct Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- UBDZFAGVPPMTIT-UHFFFAOYSA-N 2-aminoguanidine;hydron;chloride Chemical compound [Cl-].NC(N)=N[NH3+] UBDZFAGVPPMTIT-UHFFFAOYSA-N 0.000 description 2
- OFTKFKYVSBNYEC-UHFFFAOYSA-N 2-furoyl chloride Chemical compound ClC(=O)C1=CC=CO1 OFTKFKYVSBNYEC-UHFFFAOYSA-N 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 238000010009 beating Methods 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- NNBBQNFHCVVQHZ-UHFFFAOYSA-N methyl carbamimidothioate;sulfuric acid Chemical class CSC(N)=N.OS(O)(=O)=O NNBBQNFHCVVQHZ-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a preparation method of 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole, which comprises the following steps: step S1, providing 2-furoyl hydrazine; s2, enabling the 2-furoyl hydrazine and N, N '-di-Boc-1H-1-guanidyl pyrazole to undergo nucleophilic substitution reaction to generate N, N' -di-Boc-2-furoyl guanidine; step S3, removing Boc from the N, N' -di-Boc-2-furylguanidine to generate 2-furylguanidine; and S4, carrying out intramolecular dehydration on the 2-furoylguanidine to obtain 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole. According to the preparation method provided by the embodiment of the invention, compared with the reaction carried out by adopting cyanamide, the N, N' -di-Boc-1H-1-guanidyl pyrazole is adopted, the selectivity is better and safer, the unnecessary side reaction generated during nucleophilic substitution is avoided, and the operation is simple, convenient and easy.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and in particular relates to an alkyl substituted phosphoric acid cyclic anhydride derivative, and a synthesis method and application thereof.
Background
3- (2-furyl) -5-amino-1H-1, 2, 4-triazole is a heterocyclic compound of great importance in agriculture and medicine. 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole is used as a multifunctional ligand in metal organic chemistry and is considered as a major important material for constructing more complex structures, particularly fusion heterocycles having biological activity.
At present, the preparation method of the 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole mainly comprises the following steps:
1) 2-Furanoyl chloride and aminoguanidine hydrochloride were amidated under piperidine conditions. However, this route is slow to react, has a large amount of by-products, and uses piperidine as a solvent, and is also not easy to purify due to a large taste.
2) Nucleophilic substitution of S-methyl isothiourea sulfate and 2-furoyl hydrazine to obtain 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole. However, the reaction produced a pungent odor and the yield was low.
3) 2-furoyl hydrazine and cyanamide. The method completely needs a large excess of the cyanamide, the cyanamide is unstable, most of the cyanamide sold in the market is a 50% aqueous solution with the concentration, the post-treatment difficulty is increased, and the cyanamide is a highly toxic product, so that the use of the cyanamide is limited.
Disclosure of Invention
In view of the above, the invention aims to provide a preparation method of 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole, which has the advantages of good reaction selectivity, no generation of pungent smell, no by-product which is difficult to treat, simple and easy operation and high yield.
In order to solve the technical problems, the invention adopts the following technical scheme:
the preparation method of the 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole comprises the following steps:
step S1, providing 2-furoyl hydrazine;
s2, enabling the 2-furoyl hydrazine and N, N '-di-Boc-1H-1-guanidyl pyrazole to undergo nucleophilic substitution reaction to generate N, N' -di-Boc-2-furoyl guanidine;
step S3, removing Boc from the N, N' -di-Boc-2-furylguanidine to generate 2-furylguanidine;
and S4, carrying out intramolecular dehydration on the 2-furoylguanidine to obtain 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole.
Further, the step S1 includes:
step S11, acylating and esterifying the 2-furancarboxylic acid to generate 2-furancarboxylic acid ester;
step S12, reacting the 2-furancarboxylic acid ester with a hydrazinizing reagent to generate the 2-furanformylhydrazine.
Further, in the step S11, the combination of acylation and esterification is any one of thionyl chloride and methanol, oxalyl chloride and methanol, phosphorus oxychloride and methanol,
in the step S12, the hydrazinizing agent is hydrazine hydrate.
Further, the acylation and esterification are combined into thionyl chloride and methanol, and the 2-furancarboxylic acid: thionyl chloride: the molar ratio of hydrazine hydrate is 1.0 (1.0-1.2): (0.8-1.0).
Further, the step S1 includes:
dropwise adding the thionyl chloride into a methanol solution of 2-furancarboxylic acid to generate 2-furancarboxylic acid ester, wherein the temperature of dropwise adding the thionyl chloride is 35-40 ℃, and the reaction time is 3-5h;
and after the reaction is finished, adding the hydrazine hydrate, heating to 55-60 ℃, and reacting for 5-6 hours to obtain the 2-furoyl hydrazine by a one-pot method.
Further, the step S2 includes:
adding N, N '-di-Boc-1H-1-guanidinopyrazoles to a dichloromethane solution of 2-furoyl hydrazine to perform the nucleophilic reaction, to obtain the N, N' -di-Boc-2-furoyl guanidine.
Further, the molar ratio of the 2-furoyl hydrazine to the N, N '-di-Boc-1H-1-guanidylpyrazole is 1.0 (1.1-1.3), the temperature of the N, N' -di-Boc-1H-1-guanidylpyrazole is 20-30 ℃, and the reaction time after the addition is 5-6 hours.
Further, in the step S3, the N, N' -di-Boc-2-furoylguanidine is subjected to Boc removal by using a Boc removal reagent, wherein the Boc removal reagent is one or more selected from a methanol solution of hydrogen chloride, sulfuric acid, trifluoroacetic acid and hydrochloric acid.
Further, in the step S3, the methanol solution of hydrogen chloride is added dropwise to N, N '-di-Boc-2-furoylguanidine to generate 2-furoylguanidine, the Boc removing reagent is the methanol solution of hydrogen chloride, and the molar ratio of N, N' -di-Boc-2-furoylguanidine to hydrogen chloride is 1.0: (2-3), dropwise adding a hydrogen chloride methanol solution at a temperature of 20-30 ℃, and reacting at a reaction temperature of 30-40 ℃ for 2-3h.
Further, the step S4 includes:
adding the 2-furoylguanidine to water, and adding sodium hydroxide solid into the water in batches to form the 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole, wherein the molar ratio of the 2-furoylguanidine to the sodium hydroxide is 1.0: (0.8-1.2), the reaction temperature is 70-80 ℃ and the reaction time is 3-4h.
The technical scheme of the invention has at least one of the following beneficial effects:
according to the preparation method provided by the embodiment of the invention, compared with the reaction carried out by adopting cyanamide, the N, N' -di-Boc-1H-1-guanidylpyrazole is adopted, the selectivity is better and safer, unnecessary side reactions generated during nucleophilic substitution are avoided, the operation is simple and easy, and the purity of the obtained product is high;
further, the volume of the reaction system is greatly reduced, and the single kettle efficiency can be improved.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the present invention will be clearly and completely described below in connection with the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which are obtained by a person skilled in the art based on the described embodiments of the invention, fall within the scope of protection of the invention.
The preparation method of 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole according to the embodiment of the invention is specifically described below, and comprises the following steps:
step S1, providing 2-furoyl hydrazine;
s2, enabling the 2-furoyl hydrazine and N, N '-di-Boc-1H-1-guanidyl pyrazole to undergo nucleophilic substitution reaction to generate N, N' -di-Boc-2-furoyl guanidine;
step S3, removing Boc from the N, N' -di-Boc-2-furylguanidine to generate 2-furylguanidine;
and S4, carrying out intramolecular dehydration on the 2-furoylguanidine to obtain 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole.
According to the preparation method provided by the embodiment of the invention, compared with the reaction carried out by adopting cyanamide, the N, N' -di-Boc-1H-1-guanidyl pyrazole is adopted, the selectivity is better and safer, unnecessary side reactions generated during nucleophilic substitution are avoided, the operation is simple and easy, and the obtained product has a better crystal form. Further, the volume of the reaction system is greatly reduced, and the single kettle efficiency can be improved.
Next, the steps S1 to S4 are described in detail one by one.
Step S1, providing 2-furoyl hydrazine.
First, step S1, i.e., providing 2-furoyl hydrazine, is described.
The method aims at the problems that in the prior art, one of the raw materials of 2-furoyl chloride is used for carrying out an amidation reaction with aminoguanidine hydrochloride under the condition of piperidine, a large amount of byproducts exist, the piperidine is used as a solvent, the taste is large, the purification is difficult, and the like, and the problems of slow reaction, the taste is large and the like can be overcome by selecting the raw material of 2-furoyl hydrazine.
According to the preparation method of the present application, either commercially available chemically pure 2-furoyl hydrazine can be used as a raw material or the following method can be adopted.
In some embodiments of the invention, the step S1 includes:
step S11, acylating and esterifying the 2-furancarboxylic acid to generate 2-furancarboxylic acid ester.
That is, 2-furancarboxylic acid is used as a starting material, which is first subjected to acylation and esterification to obtain 2-furancarboxylic acid ester.
Wherein, as the combination of acylation and esterification, any one of thionyl chloride and methanol, oxalyl chloride and methanol, phosphorus oxychloride and methanol can be selected.
That is, the acylation reaction is carried out using thionyl chloride, oxalyl chloride, and phosphorus oxychloride as acylating agents, respectively, and the esterification is further carried out using methanol after the acylation to obtain 2-furancarboxylic acid ester.
Thionyl chloride (SOCl 2) is a commonly used acylating reagent to convert carboxylic acids, anhydrides, acid chlorides, etc. compounds to the corresponding acid chlorides. In addition, acid chloride as an intermediate can be further used for the synthesis of esters.
Step S12, reacting the 2-furancarboxylic acid ester with a hydrazinizing reagent to generate the 2-furanformylhydrazine.
In some embodiments of the invention, the hydrazinizing agent is hydrazine hydrate.
Further, the acylation and esterification are combined into thionyl chloride and methanol, and the 2-furancarboxylic acid: thionyl chloride: the molar ratio of hydrazine hydrate is 1.0 (1.0-1.2): (0.8-1.0), preferably at a molar ratio of 1.0:1.1:0.9. That is, it is preferable to use a slight excess of thionyl chloride, while the amount of hydrazine hydrate is slightly less than the stoichiometric amount. Thus, the hydrazine hydrate can be reacted completely to avoid danger in the post-treatment, and the remaining 2-furancarboxylic acid ester can be removed easily in the post-treatment.
Further, the step S1 includes:
dropwise adding the thionyl chloride into a methanol solution of 2-furancarboxylic acid to generate 2-furancarboxylic acid ester, wherein the temperature of dropwise adding the thionyl chloride is 35-40 ℃, and the reaction time is 3-5h;
and after the reaction is finished, adding the hydrazine hydrate, heating to 55-60 ℃, and reacting for 5-6 hours to obtain the 2-furoyl hydrazine by a one-pot method.
Specifically, the reaction formula is shown in the following formula (1):
that is, the application can prepare 2-furoyl hydrazine by using a one-pot method, in other words, acylation, esterification and hydrazide are sequentially carried out in the same reaction system, without extracting intermediate products, the operation is simple and easy, and three wastes are less.
In addition, the acylating reagent and the hydrazinizing reagent are respectively added in a dropwise adding mode, so that the reaction speed and the temperature are controllable, and the reaction is more sufficient.
In addition, step S1 may further include:
the sampling spot plate monitors the progress of the reaction. After the reaction, the reaction solution was concentrated, and PE: EA=3:1 was slurried to obtain 2-furoyl hydrazide.
That is, at the end of the reaction in step S1, red lotus root, the remaining 2-furancarboxylic acid ester may be removed by PE: ea=3:1 column chromatography treatment, and thus the resulting 2-furoyl hydrazine may be purified.
And (II) step S2, enabling the 2-furoyl hydrazine and N, N '-di-Boc-1H-1-guanidyl pyrazole to undergo nucleophilic substitution reaction to generate N, N' -di-Boc-2-furoyl guanidine.
In some embodiments of the present application, the step S2 includes:
adding N, N '-di-Boc-1H-1-guanidinopyrazoles to a dichloromethane solution of 2-furoyl hydrazine to perform the nucleophilic reaction, to obtain the N, N' -di-Boc-2-furoyl guanidine.
Specifically, the reaction formula is represented by the following formula (2):
that is, in the application, 2-furoyl hydrazine and N, N' -di-Boc-1H-1-guanidyl pyrazole are subjected to nucleophilic reaction, and then subsequent Boc removal and intramolecular dehydration are carried out to prepare a target product.
In the present application, the molar ratio of 2-furoyl hydrazine to N, N' -di-Boc-1H-1-guanidinopyrazoles is 1.0 (1.1-1.3), preferably 1.0:1.2. In addition, the temperature of the N, N' -di-Boc-1H-1-guanidinopyrazoles is 20-30 ℃, and the reaction time after the addition is 5-6H. The reaction condition is mild, the selectivity is high, and no unnecessary byproducts are generated.
In addition, step S2 may further include: after the reaction is finished, the reaction solution is washed by water to remove a byproduct pyrazole, separated liquid, concentrated in an organic phase, and pulped by EA=10:1 to remove excessive N, N '-di-Boc-1H-1-guanidyl pyrazole, so as to obtain N, N' -di-Boc-2-furylguanidine.
After the reaction in step S2 is completed, the intermediate is subjected to purification treatment, and by-products and excessive raw materials can be removed very easily.
(III) step S3, removing Boc from the N, N' -di-Boc-2-furylguanidine to form 2-furylguanidine.
That is, intermediate N, N' -di-Boc-2-furylguanidine is obtained by first removing Boc, and then obtaining intermediate 2-furylguanidine.
In some embodiments of the present application, in the step S3, the N, N' -di-Boc-2-furoylguanidine is debonded using a debonding agent selected from one or more of hydrogen chloride in methanol, sulfuric acid, trifluoroacetic acid, hydrochloric acid.
Further, in the step S3, the methanol solution of hydrogen chloride is dropwise added to N, N' -di-Boc-2-furylguanidine to generate 2-furylguanidine, that is, the Boc removing agent is hydrogen chloride methanol solution. Compared with the reaction by taking hydrochloric acid as a Boc removing reagent, the method has the advantages that the reaction is simpler and more convenient by taking the hydrogen chloride methanol solution for the post-treatment.
Specifically, the reaction formula is represented by the following formula (3):
further, the molar ratio of N, N' -di-Boc-2-furylguanidine to hydrogen chloride is 1.0: (2-3), dropwise adding a hydrogen chloride methanol solution at a temperature of 20-30 ℃, and reacting at a reaction temperature of 30-40 ℃ for 2-3h.
In addition, step S3 may further include: after the reaction is finished, the reaction solution is concentrated, the obtained solid is pulped by water, filtered and dried, and the 2-furoylguanidine is obtained.
That is, after the reaction in step S3 is completed, the crude product has better purity, and a small amount of residual acid can be removed cleanly by pulping with a small amount of water.
(IV) step S4, carrying out intramolecular dehydration on the 2-furoylguanidine to obtain 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole.
That is, after 2-furoylguanidine is obtained, it is dehydrated intramolecular to obtain the target product 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole.
In some embodiments of the present application, the step S4 includes:
the 2-furoylguanidine is added to water, and sodium hydroxide solid is added to the mixture in batches to produce the 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole.
Specifically, the reaction formula is shown in the following formula (4):
compared with the hydrogen chloride gas Wen Guan ring, the temperature is reduced after sodium hydroxide is used, inert gas is not needed to protect, the operation is more convenient, and only a conventional glass instrument is needed.
Wherein the molar ratio of the 2-furoylguanidine to the sodium hydroxide is 1.0: (0.8-1.2), preferably 1.0:1.0, at a reaction temperature of 70-80 ℃ for 3-4 hours.
Still further, step S4 may further include:
after the reaction is finished, hydrochloric acid is added into the reaction solution to adjust the pH to be=2, filtering is carried out, EA is used for pulping, filtering is carried out, and 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole is obtained after drying.
The pH value is regulated to enable the product to slowly precipitate crystalline solid, so that compared with the existing synthetic route, the obtained product has better crystal form.
In addition, the above description shows that after the reaction of each step is finished, the purification of the intermediate is simple and easy to operate, the method is safe and reliable, and the purity of the obtained product is high and can reach 99.4 percent.
The present invention will be further described in detail with reference to examples so that those skilled in the art can better understand the technical aspects of the present invention.
Experimental example 1: preparation of the Compound 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole
The first step: a250 ml three-necked flask was charged with methanol (100 ml, 4P) and 2-furoic acid (25 g,0.223mol,1.0 eq), and thionyl chloride (29.2 g,0.245mol,1.1 eq) was added dropwise thereto, and the reaction was carried out at room temperature of 35-40℃for 4 hours; then adding 80% hydrazine hydrate (12.6 g,0.201mol,0.9 eq) by mass fraction, heating to 55-60 ℃ and reacting for 5h.
The sampling spot plate monitors the progress of the reaction. After the reaction, the reaction solution was concentrated, and PE: EA=3:1 was slurried to obtain 24g of 2-furoyl hydrazide, with a yield of 85.3%.
And a second step of: a250 ml three-necked flask was charged with methylene chloride (72 ml, 3P) and 2-furoyl hydrazine (24 g,0.19mol,1.0 eq) and N, N' -di-Boc-1H-1-guanidinopyrazoles (70.8 g,0.228mol,1.2 eq) were added in portions, and the reaction was carried out at a temperature of 20-30℃and at room temperature for 5 hours.
After the reaction, the reaction mixture was washed with water, separated, the organic phase concentrated, and the excess N, N '-di-Boc-1H-1-guanidinopyrazoles were removed by beating with EA=10:1 to give 64.4g of N, N' -di-Boc-2-furoylguanidine in 92% yield.
And a third step of: a250 ml three-necked flask was charged with N, N' -di-Boc-2-furylguanidine (64.4 g,0.175mol,1.0 eq) and a 15% by mass solution of hydrogen chloride in methanol (105.9 g,0.438mol,2.5 eq) was added dropwise at a temperature of 20 to 30℃and a reaction temperature at 35℃was completed for 2 to 3 hours.
After the reaction, the reaction solution was concentrated, and the obtained solid was slurried with water, filtered and dried to obtain 25g of 2-furoylguanidine with a yield of 85%.
Fourth step: a250 ml three-necked flask was charged with 2-furylguanidine (25 g,0.148mol,1.0 eq) to water (100 ml, 4P) and sodium hydroxide solid (5.92 g,0.148mol,1.0 eq) was added in portions. The reaction temperature is 70-80 ℃ after the addition, and the reaction time is 3-4 hours.
After the reaction is finished, hydrochloric acid is added into the reaction solution to adjust the pH to be=2, filtering is carried out, filter cakes are pulped by EA, filtering is carried out, and 20g of 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole is obtained after drying, and the yield is 90%.
The nuclear magnetic resonance experiment is carried out on the reactant to confirm the structure of the product, and the data are as follows:
1 h NMR (model: AVANCE III HD 400M, d) 6 12.13 (s, 1H), 7.69 (s, 1H), 6.69 (dd, 1H), 6.54 (dd, 1H), 6.03 (s, 2H). The test results agree with the structure.
Experimental example 2: preparation of the Compound 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole
The first step: a500 ml three-necked flask was charged with methanol (200 ml, 4P) and 2-furoic acid (50 g, 0.4476 mol,1.0 eq) and thionyl chloride (58.4 g,0.49mol,1.1 eq) was added dropwise thereto, and the reaction was carried out at room temperature of 35-40℃for 4 hours; then 80% hydrazine hydrate (25.2 g,0.402mol,0.9 eq) by mass fraction is added, and the temperature is raised to 55-60 ℃ and the reaction time is 5h.
The sampling spot plate monitors the progress of the reaction. After the reaction, the reaction mixture was concentrated, and PE: EA=3:1 was slurried to give 46.7g of 2-furoyl hydrazide, yield 83%.
And a second step of: a500 ml three-necked flask was charged with methylene chloride (150 ml, 3P) and 2-furoyl hydrazine (46.7 g,0.37mol,1.0 eq) and N, N' -di-Boc-1H-1-guanidinopyrazoles (137.8 g,0.44 mol,1.2 eq) were added in portions, and the reaction was carried out at a temperature of 20℃to 30℃for 5 hours at room temperature.
After the reaction, the reaction mixture was washed with water, separated, the organic phase concentrated, and the excess N, N '-di-Boc-1H-1-guanidinopyrazoles were removed by beating with EA=10:1 to give 122.7g of N, N' -di-Boc-2-furoylguanidine in 90% yield.
And a third step of: a500 ml three-necked flask was charged with N, N' -di-Boc-2-furylguanidine (122.7 g,0.333mol,1.0 eq) and a 15% by mass solution of hydrogen chloride in methanol (202.7 g,0.833mol,2.5 eq) was added dropwise at a temperature of 20 to 30℃and a reaction temperature of 35℃after the addition was completed for 2 to 3 hours.
After the reaction, the reaction mixture was concentrated, and the obtained solid was slurried with water, filtered and dried to obtain 46.26g of 2-furoylguanidine, with a yield of 84.4%.
Fourth step: a500 ml three-necked flask was charged with 2-furylguanidine (46.26 g,0.275mol,1.0 eq) to water (190 ml, 4P) and sodium hydroxide solid (11 g,0.275mol,1.0 eq) was added in portions. The reaction temperature is 70-80 ℃ after the addition, and the reaction time is 3-4 hours.
After the reaction, hydrochloric acid was added to adjust the pH to=2, and the mixture was filtered, slurried with EA, filtered and dried to obtain 37.7g of 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole, with a yield of 91.3%.
The nuclear magnetic resonance experiment is carried out on the reactant to confirm the structure of the product, and the data are as follows:
1 h NMR (model: AVANCE III HD 400M, d) 6 12.09 (s, 1H), 7.69 (s, 1H), 6.68 (dd, 1H), 6.55 (dd, 1H), 6.03 (s, 2H). The test results agree with the structure.
While the foregoing is directed to the preferred embodiments of the present invention, it will be appreciated by those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the present invention.
Claims (10)
1. The preparation method of the 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole is characterized by comprising the following steps:
step S1, providing 2-furoyl hydrazine;
s2, enabling the 2-furoyl hydrazine and N, N '-di-Boc-1H-1-guanidyl pyrazole to undergo nucleophilic substitution reaction to generate N, N' -di-Boc-2-furoyl guanidine;
step S3, removing Boc from the N, N' -di-Boc-2-furylguanidine to generate 2-furylguanidine;
and S4, carrying out intramolecular dehydration on the 2-furoylguanidine to obtain 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole.
2. The method according to claim 1, wherein the step S1 comprises:
step S11, acylating and esterifying the 2-furancarboxylic acid to generate 2-furancarboxylic acid ester;
step S12, reacting the 2-furancarboxylic acid ester with a hydrazinizing reagent to generate the 2-furanformylhydrazine.
3. The method according to claim 2, wherein,
in the step S11, the combination of acylation and esterification is any one of thionyl chloride and methanol, oxalyl chloride and methanol, phosphorus oxychloride and methanol,
in the step S12, the hydrazinizing agent is hydrazine hydrate.
4. The method of claim 3, wherein the combination of acylation and esterification is thionyl chloride and methanol, and the 2-furancarboxylic acid: thionyl chloride: the molar ratio of hydrazine hydrate is 1.0 (1.0-1.2): (0.8-1.0).
5. The method according to claim 4, wherein the step S1 comprises:
dropwise adding the thionyl chloride into a methanol solution of 2-furancarboxylic acid to generate 2-furancarboxylic acid ester, wherein the temperature of dropwise adding the thionyl chloride is 35-40 ℃, and the reaction time is 3-5h;
and after the reaction is finished, adding the hydrazine hydrate, heating to 55-60 ℃, and reacting for 5-6 hours to obtain the 2-furoyl hydrazine by a one-pot method.
6. The method according to claim 1, wherein the step S2 comprises:
adding N, N '-di-Boc-1H-1-guanidinopyrazoles to a dichloromethane solution of 2-furoyl hydrazine to perform the nucleophilic reaction, to obtain the N, N' -di-Boc-2-furoyl guanidine.
7. The process according to claim 6, wherein the molar ratio of the 2-furoyl hydrazine to the N, N '-di-Boc-1H-1-guanidinopyrazoles is 1.0 (1.1-1.3), the temperature at which the N, N' -di-Boc-1H-1-guanidinopyrazoles is added is 20-30℃and the reaction time after the addition is 5-6 hours.
8. The method according to claim 1, wherein in the step S3, the N, N' -di-Boc-2-furoylguanidine is subjected to a Boc removal process using a Boc removal reagent selected from one or more of hydrogen chloride in methanol, sulfuric acid, trifluoroacetic acid, and hydrochloric acid.
9. The method according to claim 8, wherein in the step S3, the methanol solution of hydrogen chloride is added dropwise to N, N '-di-Boc-2-furylguanidine to form 2-furylguanidine, the Boc removing agent is a methanol solution of hydrogen chloride, and the molar ratio of N, N' -di-Boc-2-furylguanidine to hydrogen chloride is 1.0: (2-3), dropwise adding a hydrogen chloride methanol solution at a temperature of 20-30 ℃, and reacting at a reaction temperature of 30-40 ℃ for 2-3h.
10. The method according to claim 1, wherein the step S4 comprises:
adding the 2-furoylguanidine to water, and adding sodium hydroxide solid into the water in batches to form the 3- (2-furyl) -5-amino-1H-1, 2, 4-triazole, wherein the molar ratio of the 2-furoylguanidine to the sodium hydroxide is 1.0: (0.8-1.2), the reaction temperature is 70-80 ℃ and the reaction time is 3-4h.
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