CN113387805A - Preparation method of compound based on alkyl diazonium salt substitution reaction - Google Patents
Preparation method of compound based on alkyl diazonium salt substitution reaction Download PDFInfo
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- CN113387805A CN113387805A CN202110823941.5A CN202110823941A CN113387805A CN 113387805 A CN113387805 A CN 113387805A CN 202110823941 A CN202110823941 A CN 202110823941A CN 113387805 A CN113387805 A CN 113387805A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 103
- 239000012954 diazonium Substances 0.000 title claims abstract description 39
- 238000006467 substitution reaction Methods 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 40
- -1 diazonium salt compound Chemical class 0.000 claims abstract description 31
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 25
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 21
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 18
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 16
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 15
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 15
- 150000001989 diazonium salts Chemical class 0.000 claims abstract description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 9
- 150000001450 anions Chemical class 0.000 claims abstract description 9
- 230000009471 action Effects 0.000 claims abstract description 8
- 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 abstract description 7
- 238000000034 method Methods 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 235000010288 sodium nitrite Nutrition 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 claims description 4
- NTJBWZHVSJNKAD-UHFFFAOYSA-N triethylazanium;fluoride Chemical compound [F-].CC[NH+](CC)CC NTJBWZHVSJNKAD-UHFFFAOYSA-N 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 3
- DANBQHLZCHUINA-UHFFFAOYSA-N [SiH4].N#CC#N Chemical compound [SiH4].N#CC#N DANBQHLZCHUINA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000047 product Substances 0.000 description 22
- 238000004817 gas chromatography Methods 0.000 description 17
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 150000008049 diazo compounds Chemical class 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 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
- 239000002904 solvent Substances 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
- 239000002253 acid Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000009145 protein modification Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000000926 separation method 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
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-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
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- 238000006350 Schiemann fluorination reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000005804 alkylation 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
- 239000012159 carrier gas Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product 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
- 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
- 238000010438 heat treatment Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 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
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 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
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 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
- 150000003839 salts Chemical class 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
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- 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
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- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Toxicology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of a compound based on alkyl diazonium salt substitution reaction, which comprises the following steps: carrying out diazotization reaction on a compound shown in a formula I under the action of inorganic acid and a diazotization reagent to generate a diazonium salt compound shown in a formula II; reacting a diazonium salt compound of formula II with X2And carrying out substitution reaction under the action of the compound of the group to generate the compound shown in the formula III.
Wherein R is1、R2Selected from C1-C6 alkyl; x1Selected from CN, COOR, F, Cl, Br, I; x2Selected from F, Cl, Br, I, CN; x3 n‑Is an anion generated by the inorganic acid, the invention can efficiently synthesize the compound shown in the formula III and has good yield of the target product.
Description
Technical Field
The invention relates to synthesis and application of alkyl diazo compounds, in particular to a preparation method of a compound based on alkyl diazonium salt substitution reaction.
Background
In recent years, diazo compounds have been increasingly used in chemical biology, and are mainly used for cycloaddition reactions, research of biomolecules as probes, protein alkylation, bioreversible protein modification, production of carbene pair peptide and protein modification, nucleic acid alkylation, preparation of active group polymers, and the like. Then, in the prior art, research on diazo compounds mainly focuses on preparation and application of aryl diazo compounds, and there is only research on alkyl diazo compounds, specifically, diazo groups of diazonium salts are easily substituted by various groups such as halogen, cyano, hydroxyl and the like, which are collectively referred to as sandmeyer type reactions, on the basis of the sandmeyer reactions, catalysts in the diazonium salts are replaced, gatmeman reactions are derived, under the gatmeman reaction conditions, the diazonium salts can respectively react with sodium nitrite, sodium sulfite and sodium thiocyanate to respectively prepare aryl compounds, aromatic sulfonic acid compounds and aromatic thiocyanide compounds, and the diazonium compounds can also react with fluoroboric acid to prepare fluorobenzene compounds through the schiemann reaction, which is the most common method for preparing fluoroarene from arylamine. The diazo compound is widely applied to aspects of national defense, aerospace, biology, pharmacy, materials and the like, develops an application path of the alkyl diazo compound, improves the yield of a target product, and has important significance for the practical application of the diazo compound.
On the other hand, the compound shown in formula III can be applied to synthesis of an active group polymer, which is one of the current research hotspots and is generally mainly used for preparing a novel functional polymer material, for example, the report of US 2006135711. How to improve the preparation efficiency of the compound shown in formula III and improve the yield and purity of the target product is an important subject faced by those skilled in the art.
Disclosure of Invention
The invention provides a preparation method of a compound based on an alkyl diazonium salt substitution reaction, which can be used for efficiently synthesizing 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: carrying out diazotization reaction on a compound shown in a formula I under the action of inorganic acid and a diazotization reagent to generate a diazonium salt compound shown in a formula II; reacting a diazonium salt compound of formula II with X2Carrying out substitution reaction under the action of the compound of the group to generate a compound shown in a formula III;
wherein,
R1、R2selected from C1-C6 alkyl;
X1selected from CN, COOR, F, Cl, Br, I;
X2selected from F, Cl, Br, I, CN;
X3 n-is an anion generated from the inorganic acid.
According to an embodiment of the invention, the inorganic acid comprises at least one of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid.
According to an embodiment of the present invention, X is3 n-Selected from Cl-、Br-、HSO4 -、SO4 2-、CH3SO3 -、CF3SO3 -。
According to an embodiment of the invention, the diazotizing agent comprises sodium nitrite.
According to an embodiment of the present invention, the diazotization reaction process comprises: contacting and reacting a compound shown as a formula I with an inorganic acid to generate a salt compound; then, a diazotizing agent is added into the mixture to react to generate the diazonium salt compound shown in the formula II.
According to an embodiment of the present invention, the diazotization reaction process comprises: cooling inorganic acid to-10-0 ℃, adding the compound shown in the formula I into the inorganic acid, and maintaining the reaction at-10-0 ℃ for 4-16 hours; and then controlling the temperature of the system to be-10-0 ℃, adding a diazotization reagent into the system, and reacting for 14-16 hours at-10-0 ℃ to obtain the diazonium salt compound shown in the formula II.
According to an embodiment of the present invention, the process of the substitution reaction comprises: reacting a diazonium salt compound of formula II with a compound containing X2Reacting the compound of the group at 20-30 ℃ for 44-50 hours to obtain the compound shown in the formula III.
According to an embodiment of the present invention, the compound contains X2The compound of the group comprises at least one of hydrogen fluoride pyridine, hydrogen fluoride triethylamine, hydrochloric acid, bromine, hydrobromic acid, hydroiodic acid and trimethyl cyanogen silane.
According to an embodiment of the present invention, the method further comprises performing a purification treatment on the product system after the substitution reaction is completed, wherein the purification treatment comprises: and adding an organic solvent into the product system for extraction, and drying, concentrating and distilling the obtained organic phase under reduced pressure in turn to obtain the compound shown in the formula III.
One embodiment of the present invention provides a method for preparing a compound based on an alkyl diazonium salt substitution reaction, comprising: contacting and reacting a compound shown as a formula I with an inorganic acid to generate a salt compound; then adding a diazotization reagent into the mixture to react to generate a diazonium salt compound shown in a formula II; adding X to the mixture2Carrying out substitution reaction on the compound of the group to generate a compound shown in a formula III;
wherein,
R1、R2selected from C1-C6 alkyl;
X1selected from CN, COOR, F, Cl, Br, I;
X2selected from F, Cl, Br, I, CN;
X3 n-is made byAnions derived from said mineral acids.
According to the preparation method provided by the invention, the compound of the formula I is adopted as a raw material to prepare the alkyl diazonium salt, and then the alkyl diazonium salt and the compound containing the X2 group are subjected to substitution reaction to obtain the compound based on the alkyl diazonium salt substitution reaction (namely the compound shown in the formula III), so that the raw material conversion rate is high, the good target product yield and purity can be achieved (the target product yield is more than 85 percent, and the purity is more than 98 percent), and the preparation method has the advantages of simple process flow, low cost and the like, and has important significance for practical industrial application.
Drawings
FIG. 1 shows the NMR spectra of the compound of formula III in example 1: (1HNMR) map;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the compound of the formula III in example 1: (13CNMR) map;
FIG. 3 is a Gas Chromatography (GC) chart of the compound of formula III in example 1;
FIG. 4 is a NMR spectrum of a compound represented by the formula III in example 2: (1HNMR) map;
FIG. 5 is the NMR spectrum of a compound of the formula III in example 2 (C:)13CNMR) map;
FIG. 6 is a Gas Chromatography (GC) chart of the compound of formula III in example 2.
Detailed Description
The present invention is described in further detail below in order to enable those skilled in the art to better understand the aspects of the present invention.
The invention provides a preparation method of a compound based on alkyl diazonium salt substitution reaction, which comprises the following steps: carrying out diazotization reaction on a compound shown in a formula I under the action of inorganic acid and a diazotization reagent to generate a diazonium salt compound shown in a formula II; reacting a diazonium salt compound of formula II with X2Carrying out substitution reaction under the action of the compound of the group to generate a compound shown in a formula III;
wherein,
R1、R2selected from C1-C6 alkyl;
X1selected from CN, COOR, F, Cl, Br, I;
X2selected from F, Cl, Br, I, CN;
X3 n-is an anion generated from an inorganic acid.
Specifically, X1It may be COOR, R may be C1-C6 alkyl, straight-chain alkyl without a branch, such as methyl, ethyl, n-propyl, n-butyl, etc., or isomeric alkyl with a branch, such as isopropyl, isobutyl, etc.
The compound of formula I is an alkyl primary amine, for example, the compound of formula I may comprise ethyl 2-aminoisobutyrate
2-amino-2-isopropylpropionitrile
2-amino-2-methylpropanenitrile
At least one of (1).
The inorganic acid is used for converting the compound of formula I into the corresponding salt, and specifically, the inorganic acid may include hydrochloric acid (HCl), hydrobromic acid (HBr), sulfuric acid (H)2SO4) At least one of methanesulfonic acid and trifluoromethanesulfonic acid. X2 n-Is derived from an inorganic acid, which may be an anion of the inorganic acid or an anion converted from the inorganic acid, and may be selected from Cl-、Br-、HSO4 -、SO4 2-、CH3SO3、CF3SO3 -. Specifically, when the inorganic acid is hydrochloric acid, X2 n-Is Cl-(ii) a When the inorganic acid is hydrobromic acid, X2 n-Is Br-(ii) a When the mineral acid is methanesulfonic acid, X2 n-Is CH3SO3 -(ii) a When the inorganic acid is trifluoromethanesulfonic acid, X2 n-Is CF3SO3 -(ii) a When the inorganic acid is sulfuric acid, the amount of sulfuric acid used is large (generally H)2SO4The molar ratio of the compound of the formula I to the compound of the formula I is more than 1), X2 n-Typically HSO4 -When the amount of sulfuric acid used is small, X2 n-Is SO4 2-。
The diazotizing agent is used to diazotize the compound of formula I, and in some embodiments, the diazotizing agent may include, but is not limited to, sodium nitrite.
In some embodiments, the course of the diazotization reaction may include: contacting and reacting a compound shown as a formula I with an inorganic acid to generate a salt compound; then, a diazotizing agent is added into the mixture to react to generate the diazonium salt compound shown in the formula II.
Through further research, the inorganic acid can be cooled to-10-0 ℃, 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 diazotization reagent into the system, and reacting for 14-16 hours at-10-0 ℃ to obtain the diazonium salt compound shown in the formula II, which is 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 after the dripping is finished, the reaction is maintained at-10-0 ℃ for 4-16 hours.
The inorganic acid generally contains water, and the mass concentration of the inorganic acid used may be, but is not limited to, 20% to 40%. For example, in some embodiments, the inorganic acid comprises hydrobromic acid (formed from HBr and water), wherein the HBr has a mass fraction of between 20% and 40%, e.g., 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 relative to the compound of formula I) based on the available anion that the inorganic acid can provide, which facilitates improved conversion of the compound of formula I.
In specific implementation, a diazotization reagent is generally dissolved in a solvent (such as water and the like) to prepare a diazotization reagent solution, the diazotization reagent solution is dropwise added into a system, and after the dropwise addition is finished, the reaction is carried out for 14-16 hours at the temperature of-10-0 ℃ to generate a diazonium salt compound shown in the formula II. Wherein, in the diazotization reagent solution, the molar concentration of the diazotization reagent can be 5-7 mol/L. The amount of diazotizing agent may generally be in excess relative to the compound of formula I to increase the conversion of the compound of formula I.
In the compound of formula III, X2From a compound containing X2Compounds of the radicals, i.e. the diazo group in the alkyldiazonium compounds of the formula II after a substitution reaction by X2And (4) carrying out group substitution to obtain the compound shown in the formula III. Containing X2The compound of the group may be specifically a halogenating agent and/or a cyanating agent, and includes, for example, at least one of pyridinium hydrogen fluoride, triethylamine hydrogen fluoride, hydrochloric acid, bromine, hydrobromic acid, hydroiodic acid, and trimethylsilyl cyanide, specifically when X is2When F is, X is contained2The compound of the group may include hydrogen fluoride pyridine and/or hydrogen fluoride triethylamine when X2When Cl, contains X2Compounds of the group may include hydrochloric acid, when X2When is Br, contains X2The compounds of the radicals may include bromine and/or hydrobromic acid when X2When is I, containing X2Compounds of the radicals may include hydriodic acid when X2When is CN, contains X2The compound of the group may include trimethylsilyl cyanide.
In some embodiments, X is2The compound of the group is bromine, and X in the compound shown in the formula III is generated after substitution reaction2Is Br, for example, the compounds of the formula III are of the formula
In other embodiments, X is2The compound of the group is trimethylsilyl cyanide, and X in the compound shown in the formula III is generated after substitution reaction2Is Cyano (CN), for example, the compounds of formula III have the formula
In some embodiments, the process of the substitution reaction comprises: reacting a diazonium salt compound of formula II with a compound containing X2Reacting the compound of the group at 20-30 ℃ for 44-50 hours 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 purifying2The compound of the group undergoes a substitution reaction. In specific implementation, the temperature of the system containing the diazonium salt compound of the formula II can be controlled not to exceed 5 ℃, and then the compound containing X is dropwise added into the system2Compound of group (when containing X)2When the compound of the group is solid, the solvent of the compound can be added into the solvent and then dropwise added), and after the dropwise addition is finished, the temperature of the system is adjusted to 20-30 ℃ to react for 44-50 hours to generate the compound shown in the formula III.
In specific implementation, the product system after the substitution reaction is completed may be further subjected to a purification treatment to further improve the purity of the target product, and in some embodiments, the purification treatment includes: adding an organic solvent into the product system for extraction, and drying, concentrating and distilling the obtained organic phase under reduced pressure (reduced pressure rectification) in turn to obtain the compound shown in the formula III. Wherein the organic solvent may comprise dichloromethane, and the organic phase may be dried with drying agent such as anhydrous sodium sulfate, and may be rectified under reduced pressure with rectifying column.
In some embodiments of the invention, a method for preparing a compound based on an alkyl diazonium salt substitution reaction comprises: contacting and reacting a compound shown as a formula I with an inorganic acid to generate a salt compound; then adding a diazotization reagent into the mixture to react to generate a diazonium salt compound shown in a formula II; adding X to the mixture2Carrying out substitution reaction on the compound of the group to generate a compound shown in a formula III;
wherein,
R1、R2selected from C1-C6 alkyl;
X1selected from CN, COOR, F, Cl, Br, I;
X2selected from F, Cl, Br, I, CN;
X3 n-is an anion generated from an inorganic acid.
The present invention will be further illustrated by the following specific examples and comparative examples. Unless otherwise specified, the reagents and instruments used in the following description are all conventional reagents and conventional instruments, and are commercially available, and the reagents may be synthesized by a conventional synthesis method. In the following examples, NMR spectra1H-NMR), carbon spectrum, Gas Chromatography (GC) analysis and mass spectrum analysis are all conventional analysis processes in the field, and the GC analysis parameters are as follows if not specifically indicated:
(1) the data processing method comprises the following steps: area normalization;
(2) the instrument conditions were as follows:
A. a sample inlet: S/SL (split/no split injection port);
temperature 280.0 ℃ carrier gas: n is a radical of2
Flow splitting: 0.0mL/min split ratio: 20.0:1
B. A chromatographic column:
capillary, 30m × 0.32mm × 1.00 μm column flow (constant flow): 1.0mL/min
Column temperature: temperature programming (heating rate 20 ℃/min, final temperature 280 ℃ C.)
C. A detector: FID (Hydrogen flame)
Temperature 300.0 ℃ hydrogen flow: 40.0mL/min
Air flow rate: 400.0mL/min tail-blow: n is a radical of2，25.0mL/min
Example 1
Adding 100g of hydrobromic acid (HBr mass fraction is 30%) into a 250mL four-mouth bottle, cooling to-5 ℃, dropwise adding 13.1g of ethyl 2-aminoisobutyrate into the reaction bottle, and after dropwise adding, maintaining the temperature at-5 ℃ for reaction for 4 hours;
then, under the condition that the temperature of the system is kept to be not more than 0 ℃, 21mL of sodium nitrite solution (the concentration of sodium nitrite is 6mol/L) is dripped into the system, and after the dripping is finished, the reaction is maintained at 0 ℃ for 14 hours;
then under the condition that the temperature of the system is kept not to exceed 5 ℃, 17.6g of bromine is dripped into the system, after the dripping is finished, the temperature of the system is raised to 25 ℃, and the temperature is kept to react for 48 hours;
100mL of dichloromethane was added to the product system obtained after the reaction was completed, the mixture was allowed to stand for layer separation, the obtained organic phase was dried over 5g of anhydrous sodium sulfate, and then concentrated by rotary evaporation to obtain a concentrated solution (20.4g), the concentrated solution was subjected to rectification under reduced pressure using a rectification column having a length of 50cm, and the fraction at 75 to 77 ℃ was collected to obtain about 16.6g of a product A (i.e., the compound represented by formula III, ethyl 2-bromoisobutyrate), the yield of the product A was 85.1%, and the GC (chromatographic purity) purity was 99.5%.
Wherein the yield w is x1/x2, x1 is the actual moles of the product a obtained by the above preparation process, and x2 is the theoretical moles of the compound represented by formula III converted from the amount (moles) of ethyl 2-aminoisobutyrate used; the GC purity represents the molar content of the compound of formula III in product A.
The reaction equation of the above synthesis process is shown as follows:
by nuclear magnetic resonance hydrogen spectroscopy (1H-NMR), carbon spectrum, Gas Chromatography (GC) analysis, mass spectrometry analysis, etc., to obtain product A
It is composed of1The HNMR spectrum is shown in FIG. 1,13the CNMR spectra are shown in FIG. 2, the GC analysis results are shown in Table 1, and the GC spectra are shown in FIG. 3.
TABLE 1 analysis results of product A
Example 2
Adding 100g of hydrobromic acid (HBr mass fraction is 30%) into a 250mL four-mouth bottle, cooling to-5 ℃, dropwise adding 8.4g of 2-amino-2-methylpropionitrile into the reaction bottle, and after dropwise adding, maintaining the temperature at-5 ℃ for reaction for 4 hours;
then, while keeping the temperature of the system not more than 0 ℃, dropwise adding 21mL of sodium nitrite solution (the concentration of sodium nitrite is 6mol/L), and after the dropwise adding is finished, maintaining the temperature of 0 ℃ for reaction for 14 hours;
then under the condition that the temperature of the system is kept not to exceed 5 ℃, 23g of trimethyl cyano silane is dripped into the system, after the dripping is finished, the temperature of the system is raised to 25 ℃, and the temperature is kept to react for 48 hours;
100mL of dichloromethane is added into a product system obtained after the reaction is finished, standing and layering are carried out, liquid separation is carried out, 5g of anhydrous sodium sulfate is used for drying an obtained organic phase, then rotary evaporation and concentration are carried out to obtain a concentrated solution (16.5g), a rectifying column with the length of 50cm is used for carrying out reduced pressure rectification on the concentrated solution, and fractions with the temperature of 74-76 ℃ are collected, so that about 8.4g of a product B (namely the compound shown in the formula III) is obtained, the yield of the product B is 89.4%, and the GC purity is 96.9%.
The reaction equation of the above synthesis process is shown as follows:
by nuclear magnetic resonance hydrogen spectroscopy (1H-NMR), carbon spectrum and mass spectrum analysis, and the product B is
It is composed of1The HNMR spectrum is shown in FIG. 4,13the CNMR spectra are shown in FIG. 5, the GC analysis results are shown in Table 2, and the GC spectra are shown in FIG. 6.
TABLE 2 GC analysis of 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, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for preparing a compound based on an alkyl diazonium salt substitution reaction, comprising:
carrying out diazotization reaction on a compound shown in a formula I under the action of inorganic acid and a diazotization reagent to generate a diazonium salt compound shown in a formula II;
reacting a diazonium salt compound of formula II with X2Carrying out substitution reaction under the action of the compound of the group to generate a compound shown in a formula III;
wherein,
R1、R2selected from C1-C6 alkyl;
X1selected from CN, COOR, F, Cl, Br, I;
X2selected from F, Cl, Br, I, CN;
X3 n-is an anion generated from the inorganic acid.
2. The method according to claim 1, wherein the inorganic acid comprises at least one of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, and trifluoromethanesulfonic acid.
3. The method according to claim 1 or 2, wherein X is3 n-Selected from Cl-、Br-、HSO4 -、SO4 2-、CH3SO3 -、CF3SO3 -。
4. The method of claim 1, wherein the diazotizing agent comprises sodium nitrite.
5. The method according to claim 1, wherein the diazotization reaction comprises: contacting and reacting a compound shown as a formula I with an inorganic acid to generate a salt compound; then, a diazotizing agent is added into the mixture to react to generate the diazonium salt compound shown in the formula II.
6. The method according to claim 1, wherein the diazotization reaction comprises: cooling inorganic acid to-10-0 ℃, adding the compound shown in the formula I into the inorganic acid, and maintaining the reaction at-10-0 ℃ for 4-16 hours; and then controlling the temperature of the system to be-10-0 ℃, adding a diazotization reagent into the system, and reacting for 14-16 hours at-10-0 ℃ to obtain the diazonium salt compound shown in the formula II.
7. The method of claim 1, wherein the substitution reaction comprises: reacting a diazonium salt compound of formula II with a compound containing X2Reacting the compound of the group at 20-30 ℃ for 44-50 hours to obtain the compound shown in the formula III.
8. The method according to claim 1 or 7, wherein the X-containing compound is2The compound of the group comprises at least one of hydrogen fluoride pyridine, hydrogen fluoride triethylamine, hydrochloric acid, bromine, hydrobromic acid, hydroiodic acid and trimethyl cyanogen silane.
9. The method according to claim 1 or 7, further comprising a purification treatment of the product system after completion of the substitution reaction, the purification treatment comprising: and adding an organic solvent into the product system for extraction, and drying, concentrating and distilling the obtained organic phase under reduced pressure in turn to obtain the compound shown in the formula III.
10. A method for preparing a compound based on an alkyl diazonium salt substitution reaction, comprising: contacting a compound shown as a formula I with inorganic acid for reactionTo form a salt compound; then adding a diazotization reagent into the mixture to react to generate a diazonium salt compound shown in a formula II; adding X to the mixture2Carrying out substitution reaction on the compound of the group to generate a compound shown in a formula III;
wherein,
R1、R2selected from C1-C6 alkyl;
X1selected from CN, COOR, F, Cl, Br, I;
X2selected from F, Cl, Br, I, CN;
X3 n-is an anion generated from the inorganic acid.
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| 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 |
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| 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 |
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