CN113387805B - Process for preparing compounds based on alkyl diazonium salt substitution reaction - Google Patents
Process for preparing compounds based on alkyl diazonium salt substitution reaction Download PDFInfo
- Publication number
- CN113387805B CN113387805B CN202110823941.5A CN202110823941A CN113387805B CN 113387805 B CN113387805 B CN 113387805B CN 202110823941 A CN202110823941 A CN 202110823941A CN 113387805 B CN113387805 B CN 113387805B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- compound shown
- diazonium salt
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 98
- 239000012954 diazonium Substances 0.000 title claims abstract description 40
- 238000006467 substitution reaction Methods 0.000 title claims abstract description 31
- 238000004519 manufacturing process Methods 0.000 title description 3
- -1 diazonium salt compound Chemical class 0.000 claims abstract description 36
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 29
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 9
- 230000009471 action Effects 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical group [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 18
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 12
- 239000011707 mineral Substances 0.000 claims description 12
- 150000001989 diazonium salts Chemical class 0.000 claims description 11
- 150000001450 anions Chemical class 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 235000010288 sodium nitrite Nutrition 0.000 claims description 9
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 abstract description 12
- 229910052731 fluorine Inorganic materials 0.000 abstract description 11
- 238000002360 preparation method Methods 0.000 abstract description 10
- 239000000047 product Substances 0.000 description 21
- 238000001228 spectrum Methods 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- 238000004817 gas chromatography Methods 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- DWLJKCGOCUODFL-UHFFFAOYSA-N ethyl 2-amino-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)N DWLJKCGOCUODFL-UHFFFAOYSA-N 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 229940071870 hydroiodic acid Drugs 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JQULXIOYDDCNGR-UHFFFAOYSA-N 2-amino-2-methylpropanenitrile Chemical compound CC(C)(N)C#N JQULXIOYDDCNGR-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- NTJBWZHVSJNKAD-UHFFFAOYSA-N triethylazanium;fluoride Chemical compound [F-].CC[NH+](CC)CC NTJBWZHVSJNKAD-UHFFFAOYSA-N 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- CAOHBROWLMCZRP-UHFFFAOYSA-N 2-amino-2,3-dimethylbutanenitrile Chemical compound CC(C)C(C)(N)C#N CAOHBROWLMCZRP-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical group [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- IOLQWGVDEFWYNP-UHFFFAOYSA-N ethyl 2-bromo-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)Br IOLQWGVDEFWYNP-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000008423 fluorobenzenes Chemical class 0.000 description 1
- 229920001002 functional polymer Polymers 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/20—Diazonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
Abstract
The invention provides a preparation method of a compound based on an alkyl diazonium salt substitution reaction, which comprises the following steps: diazotizing a compound shown in a formula I under the action of inorganic acid and a diazotizing reagent to generate a diazonium salt compound shown in a formula II; allowing a diazonium salt compound represented by formula II to contain X 2 And (3) carrying out substitution reaction under the action of the compound of the group to generate the compound shown in the formula III.Wherein R is 1 、R 2 Selected from C1-C6 alkyl; x is X 1 Selected from CN, COOR, F, cl, br, I; x is X 2 Selected from F, cl, br, I, CN; x is X 3 n‑ The invention can synthesize the compound shown in the formula III with high efficiency and good yield of target products.
Description
Technical Field
The invention relates to synthesis and application of an alkyl diazonium compound, in particular to a preparation method of a compound based on an alkyl diazonium salt substitution reaction.
Background
In recent years, the application of diazonium compounds in chemical biology has also been growing, which are mainly applicable to cycloaddition reactions, research of biomolecules as probes, alkylation of proteins, modification of bioreversible proteins, production of carbenes for peptide and protein modifications, nuclear alkylation, preparation of active group polymers, etc. Then, in the prior art, researches on diazonium compounds are mainly focused on preparation and application of aryl diazonium compounds, and researches on alkyl diazonium compounds are carried out, specifically, diazonium groups of diazonium salts are easily substituted by a plurality of groups such as halogen, cyano groups, hydroxyl groups and the like, the reactions are collectively called as sandmeyer type reactions, catalysts in the diazonium salts are replaced on the basis of sandmeyer reactions, a gattmann reaction is derived, under the condition of the gattmann reaction, diazonium salts can react with sodium nitrite, sodium sulfite and sodium thiocyanate respectively to prepare aryl compounds, aromatic sulfonic acid compounds and aromatic thiocyanide compounds respectively, and the diazonium compounds can also react with fluoboric acid to prepare fluorobenzene compounds, and the reaction process is the most commonly used method for preparing fluoroaromatics from arylamines. The diazonium compound is widely applied to the fields of national defense, aerospace, biology, pharmacy, materials and the like, develops an application path of the alkyl diazonium compound, improves the yield of a target product, and has important significance for the practical application of the diazonium compound.
On the other hand, the compound shown in the formula III can be applied to the synthesis of active-group polymers, which are one of the current research hot spots, and are generally mainly used for preparing novel functional polymer materials, such as the report of U.S. patent document US 2006135711. How to improve the preparation efficiency of the compound shown in the formula III and the yield and purity of the target product is an important subject faced by the person skilled in the art.
R 1 、R 2 Selected from C1-C6 alkyl, X 2 Selected from F, cl, br, I, CN.
Disclosure of Invention
The invention provides a preparation method of a compound based on alkyl diazonium salt substitution reaction, which can efficiently synthesize a compound shown in a formula III and has good target product yield and purity.
In one aspect of the present invention, there is provided a method for preparing a compound based on an alkyl diazonium salt substitution reaction, comprising: diazotizing a compound shown in a formula I under the action of inorganic acid and a diazotizing reagent to generate a diazonium salt compound shown in a formula II; allowing a diazonium salt compound represented by formula II to contain X 2 Substitution reaction is carried out under the action of the compound of the group to generate a compound shown in a formula III;
wherein,
R 1 、R 2 selected from C1-C6 alkyl;
X 1 selected from CN, COOR, F, cl, br, I;
X 2 selected from F, cl, br, I, CN;
X 3 n- is an anion generated from the mineral acid.
According to an embodiment of the present invention, the inorganic acid includes at least one of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid.
According to an embodiment of the invention, the X 3 n- Selected from Cl - 、Br - 、HSO 4 - 、SO 4 2- 、CH 3 SO 3 - 、CF 3 SO 3 - 。
According to an embodiment of the invention, the diazotizing agent comprises sodium nitrite.
According to an embodiment of the present invention, the diazotisation reaction process includes: contacting a compound shown in a formula I with an inorganic acid to react to generate a salt compound; then adding diazotizing reagent into the mixture to react to form diazonium salt compound shown in formula II.
According to an embodiment of the present invention, the diazotisation reaction process includes: cooling inorganic acid to-10-0 ℃, adding a compound shown in a formula I into the inorganic acid, and maintaining the reaction at-10-0 ℃ for 4-16 hours; then the temperature of the system is controlled to be-10-0 ℃, diazotizing reagent is added into the system, and the diazonium salt compound shown in the formula II is obtained after the reaction for 14-16 hours at the temperature of-10-0 ℃.
According to an embodiment of the present invention, the substitution reaction process includes: allowing the diazonium salt compound of formula II to contain X 2 The compound of the group reacts for 44 to 50 hours at the temperature of 20 to 30 ℃ to obtain the compound shown in the formula III.
According to one embodiment of the present invention, the composition contains X 2 The compound of the group comprises at least one of hydrogen fluoride pyridine, hydrogen fluoride triethylamine, hydrochloric acid, bromine, hydrobromic acid, hydroiodic acid and trimethylcyano silane.
According to an embodiment of the present invention, the method further comprises subjecting the product system after completion of the substitution reaction to a purification treatment comprising: and adding an organic solvent into the product system for extraction, and drying, concentrating and distilling the obtained organic phase at reduced pressure to obtain the compound shown in the formula III.
An embodiment of the present invention provides a method for preparing a compound based on an alkyl diazonium salt substitution reaction, comprising: contacting a compound shown in a formula I with an inorganic acid to react to generate a salt compound; then adding a diazotizing reagent into the mixture to react to generate a diazonium salt compound shown in a formula II; then adding X-containing material 2 Carrying out substitution reaction on the compound of the group to generate a compound shown in a formula III;
wherein,
R 1 、R 2 selected from C1-C6 alkyl;
X 1 selected from CN, COOR, F, cl, br, I;
X 2 selected from F, cl, br, I, CN;
X 3 n- is an anion generated from the mineral acid.
The preparation method provided by the invention firstly adopts the compound shown in the formula I as a raw material to prepare the alkyl diazonium salt, then carries out substitution reaction on the alkyl diazonium salt and the compound containing the X2 group to obtain the compound based on the substitution reaction of the alkyl diazonium salt (namely the compound shown in the formula III), has high raw material conversion rate, can achieve good target product yield and purity (the target product yield is more than 85 percent, the purity is more than 98 percent), has the advantages of simple process flow, low cost and the like, and has important significance for practical industrialized application.
Drawings
FIG. 1 shows the hydrogen nuclear magnetic resonance spectrum of the compound of formula III in example 1 1 HNMR) map;
FIG. 2 shows nuclear magnetic resonance spectrum of the compound of formula III in example 1 13 CNMR) map;
FIG. 3 is a Gas Chromatograph (GC) diagram of the compound of formula III in example 1;
FIG. 4 shows the hydrogen nuclear magnetic resonance spectrum of the compound of formula III of example 2 1 HNMR) map;
FIG. 5 shows nuclear magnetic resonance spectrum of the compound of formula III of example 2 13 CNMR) map;
FIG. 6 is a Gas Chromatograph (GC) diagram of the compound of formula III in example 2.
Detailed Description
The present invention will be described in further detail below for the purpose of better understanding of the aspects of the present invention by those skilled in the art.
The preparation method of the compound based on the alkyl diazonium salt substitution reaction provided by the invention comprises the following steps: diazotizing a compound shown in a formula I under the action of inorganic acid and a diazotizing reagent to generate a diazonium salt compound shown in a formula II; allowing a diazonium salt compound represented by formula II to contain X 2 Substitution reaction is carried out under the action of the compound of the group to generate a compound shown in a formula III;
wherein,
R 1 、R 2 selected from C1-C6 alkyl;
X 1 selected from CN, COOR, F, cl, br, I;
X 2 selected from F, cl, br, I, CN;
X 3 n- is an anion generated from a mineral acid.
Specifically, X 1 Can be COOR, R can be C1-C6 alkyl, can be straight-chain alkyl without branched chains, such as methyl, ethyl, n-propyl, n-butyl and the like, and can also be branched chain isomeric alkyl, such as isopropyl, isobutyl and the like.
The compound of formula I is an alkyl primary amine, for example, the compound of formula I may include ethyl 2-aminoisobutyrate2-amino-2-isopropyl propionitrile->2-amino-2-methylpropanenitrile->At least one of them.
The inorganic acid is used for converting the compound shown in the formula I into corresponding salt, and can specifically comprise hydrochloric acid (HCl), hydrobromic acid (HBr), sulfuric acid (H 2 SO 4 ) At least one of methanesulfonic acid and trifluoromethanesulfonic acid. X is X 2 n- From mineral acids, which may be anions of mineral acids or anions converted from mineral acids, may be chosen in particular from Cl - 、Br - 、HSO 4 - 、SO 4 2- 、CH 3 SO 3 、CF 3 SO 3 - . Specifically, when the inorganic acid is hydrochloric acid, X 2 n- Is Cl - The method comprises the steps of carrying out a first treatment on the surface of the When the mineral acid is hydrobromic acid, X 2 n- Is Br - The method comprises the steps of carrying out a first treatment on the surface of the When the mineral acid is methanesulfonic acid, X 2 n- Is CH 3 SO 3 - The method comprises the steps of carrying out a first treatment on the surface of the When the inorganic acid is trifluoromethanesulfonic acid, X 2 n- Is CF (CF) 3 SO 3 - The method comprises the steps of carrying out a first treatment on the surface of the When the inorganic acid is sulfuric acid, the amount of sulfuric acid to be used is large (generally H 2 SO 4 The molar ratio of the compound shown in the formula I to the compound shown in the formula I is more than 1), X 2 n- Typically HSO 4 - The dosage of sulfuric acid is small, X 2 n- Is SO 4 2- 。
Diazotisation reagents are used to diazotize compounds of formula I, and in some embodiments, the diazotisation reagent may include sodium nitrite, but is not limited thereto.
In some embodiments, the process of diazotisation may include: contacting a compound shown in a formula I with an inorganic acid to react to generate a salt compound; then adding diazotizing reagent into the mixture to react to form diazonium salt compound shown in formula II.
Through further research, inorganic acid can be cooled to-10-0 ℃, and the compound of the formula I is added into the inorganic acid, and the reaction is maintained for 4-16 hours at-10-0 ℃; and then controlling the temperature of the system to be-10-0 ℃, adding a diazotizing reagent into the system, and reacting for 14-16 hours at the temperature of-10-0 ℃ to obtain the diazonium salt compound shown in the formula II, thereby being beneficial to improving the preparation efficiency, saving the energy consumption and simplifying the process. Wherein, the compound shown in the formula I can be dripped into inorganic acid, and the reaction is maintained for 4 to 16 hours at the temperature of-10 to 0 ℃ after the dripping is finished.
The inorganic acid generally contains water, and the mass concentration of the inorganic acid used can be 20% -40%, but is not limited thereto. For example, in some embodiments, the mineral acid comprises hydrobromic acid (formed from HBr and water), wherein the mass fraction of HBr is 20% to 40%, such as 30%. The molar ratio of inorganic acid to compound of formula I is generally not less than 1 (i.e., the inorganic acid is in excess of the compound of formula I) based on the available anions that the inorganic acid is capable of providing, which is advantageous for increasing the conversion of the compound of formula I.
In the specific implementation, the diazotizing agent is generally dissolved in a solvent (such as water, etc.) to prepare a diazotizing agent solution, the diazotizing agent solution is added into the system in a dropwise manner, and after the dropwise addition is finished, the diazotizing agent solution is reacted at the temperature of-10 to 0 ℃ for 14 to 16 hours to generate the diazonium salt compound shown in the formula II. Wherein, in the diazotizing agent solution, the molar concentration of the diazotizing agent can be 5-7 mol/L. The diazotising agent may generally be used in an excess relative to the compound of formula I to increase the conversion of the compound of formula I.
In the compound shown in the formula III, X 2 From a group containing X 2 The diazo group in the alkyl diazonium salt compound shown in formula II is X after substitution reaction 2 The group substitution, and then the compound shown in the formula III is obtained. Containing X 2 The compound of the group may be in particular a halogenating agent and/or a cyanating agent, for example comprising at least one of hydrogen fluoride pyridine, hydrogen fluoride triethylamine, hydrochloric acid, bromine, hydrobromic acid, hydroiodic acid, trimethylcyano silane, in particular when X 2 When F is F, X is contained 2 The compounds of the radicals may beTo include hydrogen-pyridine fluoride and/or hydrogen-triethylamine fluoride, when X 2 When Cl, X is contained 2 The compound of the group may include hydrochloric acid, when X 2 When Br is used, X is contained 2 The compounds of the radicals may include bromine and/or hydrobromic acid, when X 2 When I, X is contained 2 The compound of the group may include hydroiodic acid when X 2 In the case of CN, X is contained 2 The compound of groups may include trimethylcyanosilane.
In some embodiments, X is contained 2 The compound of the group is bromine, and X in the generated compound shown in the formula III is generated after substitution reaction 2 For example, the compound of formula III has the structural formula Br
In other embodiments, X is contained 2 The compound of the group is trimethyl cyano silane, and X in the generated compound shown in the formula III is generated after substitution reaction 2 For example, the structural formula of the compound represented by formula III is
In some embodiments, the process of the substitution reaction comprises: by reacting diazonium salt compounds of formula II with X 2 The compound of the group reacts for 44 to 50 hours at the temperature of 20 to 30 ℃ to obtain the compound shown in the formula III.
After the diazotization reaction is finished, the reaction product can be directly added into the system without purifying the reaction product, and the system contains X 2 The compound of the group undergoes substitution reaction. In practice, the temperature of the system containing the diazonium salt compound of formula II may be controlled to not exceed 5℃and then X is added dropwise thereto 2 Compounds of groups (when containing X 2 When the compound of the group is solid, the solvent can be added dropwise after being added in the solvent, and after the addition, the system temperature is adjusted to 20-30 ℃ to react for 44-50 hours to generate the compound shown in the formula III.
In particular, the product system after the substitution reaction may be further purified to further increase the purity of the target product, and in some embodiments, the purification process includes: adding an organic solvent into the product system for extraction, and drying, concentrating and distilling the obtained organic phase at reduced pressure (vacuum rectification) to obtain the compound shown in the formula III. The organic solvent may include dichloromethane, anhydrous sodium sulfate and other desiccant may be used to dry the organic phase, and rectification column may be used to perform vacuum rectification.
In some embodiments of the invention, a method for preparing a compound based on an alkyl diazonium salt substitution reaction comprises: contacting a compound shown in a formula I with an inorganic acid to react to generate a salt compound; then adding a diazotizing reagent into the mixture to react to generate a diazonium salt compound shown in a formula II; then adding X-containing material 2 Carrying out substitution reaction on the compound of the group to generate a compound shown in a formula III;
wherein,
R 1 、R 2 selected from C1-C6 alkyl;
X 1 selected from CN, COOR, F, cl, br, I;
X 2 selected from F, cl, br, I, CN;
X 3 n- is an anion generated from a mineral acid.
The present invention will be further illustrated by the following specific examples and comparative examples. Unless otherwise indicated, reagents and apparatus used hereinafter are conventional reagents and conventional apparatus, and the reagents involved are commercially available and may be synthesized by conventional synthetic methods. In the following examples, nuclear magnetic resonance hydrogen spectrum [ ] 1 H-NMR), carbon spectrum, gas Chromatography (GC) analysis, mass spectrometry analysis procedures are all routine in the art, unless otherwise specified, GC analysis parameters are as follows:
(1) The data processing method comprises the following steps: an area normalization method;
(2) Instrument conditions:
A. sample inlet: S/SL (split/no split sample inlet);
carrier gas at a temperature of 280.0 ℃): n (N) 2
Split flow rate: split ratio of 0.0 mL/min: 20.0:1
B. Chromatographic column:
capillary, 30m×0.32mm×1.00 μm column flow (constant flow): 1.0mL/min
Column temperature: programmed heating (heating rate 20 ℃/min, final temperature 280 ℃)
C. A detector: FID (hydrogen flame)
Hydrogen flow rate at 300.0 ℃): 40.0mL/min
Air flow rate: tail blowing at 400.0 mL/min: n (N) 2 ，25.0mL/min
Example 1
100g hydrobromic acid (HBr mass fraction is 30%) is added into a 250mL four-mouth bottle, the temperature is reduced to-5 ℃, 13.1g of ethyl 2-aminoisobutyrate is dripped into a reaction bottle, and after the dripping is finished, the reaction is carried out for 4 hours at-5 ℃;
then, 21mL of sodium nitrite solution (the concentration of sodium nitrite is 6 mol/L) is dropwise added into the reaction kettle under the condition that the temperature of the reaction kettle is kept to be not more than 0 ℃, and the reaction kettle is kept at 0 ℃ for 14 hours after the dropwise addition is finished;
then 17.6g bromine is added dropwise into the system under the condition that the temperature of the system is kept not to exceed 5 ℃, after the dropwise addition is finished, the temperature of the system is increased to 25 ℃, and the reaction is carried out for 48 hours under the condition that the temperature is kept;
adding 100mL of dichloromethane into a product system obtained after the reaction is finished, standing for layering, separating liquid, drying an obtained organic phase by using 5g of anhydrous sodium sulfate, then performing rotary evaporation and concentration to obtain a concentrated solution (20.4 g), performing vacuum distillation on the concentrated solution by using a distillation column with the length of 50cm, and collecting a fraction at 75-77 ℃ to obtain a product A (namely a compound shown in a formula III, ethyl 2-bromoisobutyrate) with the yield of 85.1% and the GC (chromatographic purity) purity of 99.5%.
Wherein the yield w=x1/x 2, x1 is the actual number of moles of the product a prepared by the above preparation process, and x2 is the theoretical number of moles of the compound represented by formula III calculated based on the amount (number of moles) of ethyl 2-aminoisobutyrate; GC purity represents the molar content of the compound of formula III in product a.
The reaction equation for the above synthesis is schematically as follows:
through nuclear magnetic resonance hydrogen spectrum 1 H-NMR), carbon spectrum, gas Chromatography (GC) analysis, mass spectrometry analysis, etc., to give the product A asWhich is a kind of 1 The HNMR spectrum is shown in figure 1, 13 CNMR spectra are shown in FIG. 2, GC analysis results are shown in Table 1, and GC spectra are shown in FIG. 3.
TABLE 1 analysis of product A
Example 2
100g hydrobromic acid (HBr mass fraction is 30%) is added into a 250mL four-mouth bottle, the temperature is reduced to-5 ℃, 8.4g 2-amino-2-methylpropanenitrile is dripped into a reaction bottle, and after the dripping is finished, the reaction is carried out for 4 hours at the temperature of-5 ℃;
then 21mL of sodium nitrite solution (the concentration of sodium nitrite is 6 mol/L) is dropwise added into the reaction kettle while the temperature of the reaction kettle is kept at not more than 0 ℃, and the reaction kettle is maintained at 0 ℃ for 14 hours after the dropwise addition is completed;
then, 23g of trimethylcyano silane is added dropwise into the system under the condition that the temperature of the system is kept not to exceed 5 ℃, after the addition, the temperature of the system is increased to 25 ℃, and the system is kept at the temperature for reaction for 48 hours;
100mL of methylene dichloride is added into a product system obtained after the reaction is finished, standing and layering are carried out, the obtained organic phase is dried by 5g of anhydrous sodium sulfate, then rotary evaporation and concentration are carried out to obtain concentrated solution (16.5 g), the concentrated solution is subjected to reduced pressure rectification by a rectification column with the length of 50cm, and fractions with the temperature of 74-76 ℃ are collected to obtain about 8.4g of a product B (namely a compound shown as a formula III), the yield of the product B is 89.4%, and the GC purity is 96.9%.
The reaction equation for the above synthesis is schematically as follows:
through nuclear magnetic resonance hydrogen spectrum 1 H-NMR), carbon spectrum, mass spectrometry, determination of product B asWhich is a kind of 1 The HNMR spectrum is shown in figure 4, 13 CNMR spectra are shown in FIG. 5, GC analysis results are shown in Table 2, and GC spectra are shown in FIG. 6.
TABLE 2 GC analysis results for product B
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. A method for preparing a compound based on an alkyl diazonium salt substitution reaction, comprising:
diazotizing a compound shown in a formula I under the action of inorganic acid and a diazotizing reagent to generate a diazonium salt compound shown in a formula II;
allowing a diazonium salt compound represented by formula II to contain X 2 Substitution reaction is carried out under the action of the compound of the group to generate a compound shown in a formula III;
wherein,
R 1 、R 2 selected from C1-C6 alkyl;
X 1 selected from CN;
X 2 selected from CN;
X 3 n- is an anion generated from the mineral acid;
the inorganic acid is at least one of hydrochloric acid, hydrobromic acid and sulfuric acid;
the diazotizing agent is selected from sodium nitrite;
the composition contains X 2 The compound of the group is selected from trimethylcyanosilane.
2. The method of claim 1, wherein the diazotisation reaction comprises: contacting a compound shown in a formula I with an inorganic acid to react to generate a salt compound; then adding diazotizing reagent into the mixture to react to form diazonium salt compound shown in formula II.
3. The method of claim 1, wherein the diazotisation reaction comprises: cooling inorganic acid to-10-0 ℃, adding a compound shown in a formula I into the inorganic acid, and maintaining the reaction at-10-0 ℃ for 4-16 hours; then the temperature of the system is controlled to be-10-0 ℃, diazotizing reagent is added into the system, and the diazonium salt compound shown in the formula II is obtained after the reaction for 14-16 hours at the temperature of-10-0 ℃.
4. The method of claim 1, wherein the substitution reaction comprises: allowing the diazonium salt compound of formula II to contain X 2 The compound of the group reacts for 44 to 50 hours at the temperature of 20 to 30 ℃ to obtain the compound shown in the formula III.
5. The method according to claim 1 or 4, further comprising subjecting the product system after completion of the substitution reaction to a purification treatment comprising: and adding an organic solvent into the product system for extraction, and drying, concentrating and distilling the obtained organic phase at reduced pressure to obtain the compound shown in the formula III.
6. A method for preparing a compound based on an alkyl diazonium salt substitution reaction, comprising: contacting a compound shown in a formula I with an inorganic acid to react to generate a salt compound; then adding a diazotizing reagent into the mixture to react to generate a diazonium salt compound shown in a formula II; then adding X-containing material 2 Carrying out substitution reaction on the compound of the group to generate a compound shown in a formula III;
wherein,
R 1 、R 2 selected from C1-C6 alkyl;
X 1 selected from CN;
X 2 selected from CN;
X 3 n- is an anion generated from the mineral acid;
the inorganic acid is at least one of hydrochloric acid, hydrobromic acid and sulfuric acid;
the diazotizing agent is selected from sodium nitrite;
the composition contains X 2 The compound of the group is selected from trimethylcyanosilane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110823941.5A CN113387805B (en) | 2021-07-21 | 2021-07-21 | Process for preparing compounds based on alkyl diazonium salt substitution reaction |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110823941.5A CN113387805B (en) | 2021-07-21 | 2021-07-21 | Process for preparing compounds based on alkyl diazonium salt substitution reaction |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113387805A CN113387805A (en) | 2021-09-14 |
| CN113387805B true CN113387805B (en) | 2024-01-12 |
Family
ID=77626562
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110823941.5A Active CN113387805B (en) | 2021-07-21 | 2021-07-21 | Process for preparing compounds based on alkyl diazonium salt substitution reaction |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113387805B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5399578A (en) * | 1990-02-19 | 1995-03-21 | Ciba-Geigy Corp | Acyl compounds |
| US6248755B1 (en) * | 1999-04-06 | 2001-06-19 | Merck & Co., Inc. | Pyrrolidine modulators of chemokine receptor activity |
| US6680403B1 (en) * | 1999-11-30 | 2004-01-20 | E. I. Du Pont De Nemours And Company | Process for hydrogenating dinitriles in aminonitriles |
-
2021
- 2021-07-21 CN CN202110823941.5A patent/CN113387805B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5399578A (en) * | 1990-02-19 | 1995-03-21 | Ciba-Geigy Corp | Acyl compounds |
| US6248755B1 (en) * | 1999-04-06 | 2001-06-19 | Merck & Co., Inc. | Pyrrolidine modulators of chemokine receptor activity |
| US6680403B1 (en) * | 1999-11-30 | 2004-01-20 | E. I. Du Pont De Nemours And Company | Process for hydrogenating dinitriles in aminonitriles |
Non-Patent Citations (1)
| Title |
|---|
| "Exploring the reaction of iodine with a-diazo esters";Giancarlo Verardo et al.,;《J.Phys.Org.Chem.》;第22卷;第24–30页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113387805A (en) | 2021-09-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2020147861A1 (en) | Electrochemical preparation method for β-trifluoromethylamide compound | |
| CN103408445B (en) | Arylamine derivatives and preparation method thereof | |
| CN111018740B (en) | Synthesis method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester | |
| WO2011035532A1 (en) | Preparation method of aromatic borate ester compound | |
| WO2022073343A1 (en) | Synthesis method for 9,9-bis[4-(2-hydroxyethoxy)phenyl]fluorene | |
| CN113387805B (en) | Process for preparing compounds based on alkyl diazonium salt substitution reaction | |
| CN114369011A (en) | Green novel method for preparing 2-diarylmethyl substituted-1-naphthol compound | |
| CN102942463A (en) | Preparation method for benzophenone compound | |
| KR101942059B1 (en) | Production method of 1,2,3,5,6-pentatriene plate | |
| CN116478022A (en) | Preparation method of alkynylamide-mediated ketone compound | |
| CN111362795B (en) | Preparation method of substituted butyrate derivatives | |
| KR100282819B1 (en) | New halogenated royal resins useful for combinatorial chemical synthesis | |
| Garlyauskayte et al. | Synthesis of new organic super acids—N-(trifluoromethylsulfonyl) imino derivatives of trifluoromethanesulfonic acid and bis (trifluoromethylsulfonyl) imide | |
| CN111072539A (en) | Simple and convenient preparation method of methyl thiomethanesulfonate | |
| Hamper et al. | Synthesis of highly substituted 5‐(trifluoromethyl) ketoimidazoles using a mixed‐solid/solution phase motif | |
| CN115626861B (en) | Method for synthesizing trifluoromethyl aromatic compound | |
| CN114507867B (en) | Preparation method of fluoroamide derivative | |
| CN1023634C (en) | Homogeneous phase-transfering catalyst for liquid and its production and use | |
| CN115232019B (en) | Synthesis method of 3-acetamido benzotrifluoride compound | |
| CN109721565A (en) | A kind of important fluorine intermediate synthesis technology | |
| CN110343047B (en) | Preparation method of aminopyrene compound | |
| CN116969871A (en) | Synthesis method of difluoromethyl seleno ether compound | |
| CN109665937B (en) | Synthetic method of 2, 7-dibromo-benzo [9,10] phenanthrene | |
| CN109020842B (en) | Preparation method of taurine ammonia | |
| CN108822060B (en) | 3-aryl substituted oxetane and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |