CN111099942A - Preparation method of alkyl nitrile compound - Google Patents

Preparation method of alkyl nitrile compound Download PDF

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CN111099942A
CN111099942A CN201811256811.2A CN201811256811A CN111099942A CN 111099942 A CN111099942 A CN 111099942A CN 201811256811 A CN201811256811 A CN 201811256811A CN 111099942 A CN111099942 A CN 111099942A
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刘元红
夏爱游
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The invention discloses a preparation method of alkyl nitrile compounds. The invention provides a preparation method of alkyl nitrile compounds shown in a formula I, which comprises the following steps: in a solvent, in the presence of an additive, performing a substitution reaction on a cyanolation reagent and an alkyl halide shown as a formula II to obtain an alkyl nitrile compound shown as a formula I; the cyanation reagent is Zn (CN)2And/or Cu (CN)2(ii) a The additive is one or more of inorganic base, organic base and quaternary ammonium salt.

Description

Preparation method of alkyl nitrile compound
Technical Field
The invention relates to a preparation method of alkyl nitrile compounds.
Background
Alkyl nitriles are important intermediates in organic synthesis, can be converted into a plurality of corresponding alkyl amides, alkyl amines, nitrogen-containing heterocycles, alkyl carboxylic acids and derivatives thereof, and the like, are also important structural units of medicines, pesticides and some organic materials (Fleming, f.f.; Yao, l.; Ravikumar, p.c.; Funk, l.; wood, b.c.j.med.chem.2010,53,7902.). for example, in 4 months of 2018, baricitinib brought by cereulide and Incyte companies is a once-a-day oral JAK inhibitor mainly used for the treatment of inflammation and autoimmune diseases, currently, the american counseling committee of arthritis has proposed the approval of 2mg baricitinib as a once-a-day oral drug therapy for moderate to severe rheumatoid arthritis (adult) patients who do not respond well or tolerate methotrexate (methohexeate), soremetum as a first generation of a first-day oral drug therapy, is considered as a first generation of β, is considered as a weak mechanism for the bacterial cell wall modification, is also considered to be used as a primary inhibitor for the anti-zootic drug, is a broad spectrum of the cell wall modification of the bacterial resistance, and is concerned with the influence of various bacterial resistance and is considered as a pilot for the research of various kinds of the anti-nociceptin.
Figure BDA0001842914410000011
In pesticides, cyano is also an indispensable active group, which is beneficial to promote the hydrophilic-lipophilic balance, electron transfer and active presentation of the compound. According to the statistics of 576 pesticides for crop protection in the world, 45 of them are cyano-containing pesticide varieties. Among them, 26 insecticides (57.78%) were present; 14 bactericides (31.11 percent); the number of herbicides is 5 (11.11%).
In addition, the alkyl nitrile compound also has certain application value in the aspect of organic functional materials. By utilizing the weak coordination between cyano-group in alkyl nitrile compound and lithium ion, when the cyano-group-containing ion plastic crystal is used as electrolyte, the room-temperature solubility of lithium salt in the cyano-group-containing ion plastic crystal is greatly increased, the room-temperature conductivity of ionic liquid is also greatly improved, and the ionic liquid can be better applied to the field of secondary lithium ion batteries. In addition, due to the coordination of the lithium ion and the lithium salt, the lithium ion can form a lithium ion channel in the ion plastic crystal, so that the transference number of the lithium ion is increased, and the compatibility of an electrolyte and an electrode interface is improved. It is also found that when alkyl cyanide fragments are introduced into the disperse dye, the color brightness of the disperse dye is greatly improved, and various fastnesses of the dye are also obviously improved, so that the disperse dye can be better applied to dyeing and printing of synthetic fibers such as terylene and the like.
In view of the application value of alkyl nitrile compounds, the research on the synthesis method thereof is also receiving attention from chemists. The most classical and commonly used method is the nucleophilic substitution of alkyl halides with metal cyanide salts (KCN or NaCN).
For the cyanation of primary alkyl halides, nucleophilic substitution is a very efficient process. This process generally requires the use of polar solvents such as ethanol/water, N-dimethylformamide, dimethylsulfoxide, etc., which gives the cyanated product in good to excellent yields. However, this reaction often requires the use of highly toxic KCN, NaCN, TBACN (tetrabutylammonium cyanide) and acetone cyanohydrin, which may generate hydrogen cyanide during use, as a source of cyanide. However, the nucleophilic substitution reaction involving zinc cyanide as a cyanation reagent, which is low in cost and toxicity, has not been reported.
In addition, the cyanidation reaction of the organic halide realized by using a transition metal catalytic means undoubtedly provides a simple, convenient and efficient method for synthesizing the organic cyanide. Most of the work reported to date has been limited to metal catalyzed cyanation of benzyl halides. In 2011, the Wangjiaoji group of Henan science and technology university finds that K is the best of K4[Fe(CN)6]As a source of cyanogen in the catalytic system Pd (OAc)2/PPh3Adding a proper amount of Na2CO3A first-order cyanation reaction of benzyl chloride is achieved at 140 ℃ (Ren, Y.; Yan, M.; ZHao, S.; Sun, Y.; Wang, J.; Yin, W.; Liu, Z. tetrahedron letters.2011,52,5107.). It is to be noted that when a sterically hindered methyl group is introduced at the ortho position of the benzene ring in benzyl chloride, the yield of the cyanated product is significantly reduced. When the catalyst is replaced by CuI, Na does not need to be added into the system2CO3First-order cyanation of benzyl chloride can be achieved at 180 ℃ (Ren, y.; Dong, c.; Zhao, s.; Sun, y.; Wang, j.; Ma, j.; Hou, c.tetrahedron letters2012,53,2825.). Compared with the prior art, the catalytic system is simpler, the yield of the cyanation product with steric hindrance at the ortho-position of the benzene ring can be improved to 66%, and the influence of the steric hindrance on the cyanation reaction is overcome to a certain extent. The disadvantage is that the temperature of the system is too high. The metal-catalyzed cyanation of benzyl halides is mainly focused on the first-order benzyl chloride, and the cyanation of the second-order benzyl chloride is only one example, that is, in 2014, Obora et al, which uses TMSCN as a cyanogen source and uses a catalytic system Ni (cod)2/PPh3The cyanation reaction of the first-level benzyl chloride and the second-level benzyl chloride is realized under mild conditions. (Satoh, Y.; Obora, Y. RSC adv.2014,4,15736.). However, this reaction uses unstable zero-valent nickel in air, and the cyanogen source used is also expensive and highly toxic; and the reaction is only applicable to primary and secondary benzyl chlorides, but not to unactivated alkyl halides. Very few non-activated primary alkyl halide cyanation reactions have been reported.
Therefore, it is very urgent and desirable to explore and develop a more efficient, simple and mild method for cyanating alkyl halides with cheap catalysts such as nickel and cheap ligands, and provide better application prospects for industrial synthesis of alkyl nitriles.
Disclosure of Invention
The invention aims to solve the technical problems that a cyanation reagent used in the existing preparation method of the primary alkyl nitrile compound has high toxicity, a catalyst is unstable in air and expensive, a special reaction device is required, long-time irradiation of ultraviolet light harmful to human bodies is required, functional group compatibility is poor, substrate universality is poor and the like, and provides a preparation method of the alkyl nitrile compound. The preparation method can simply and efficiently realize the cyanation of the primary alkyl halide by using a low-toxicity cyanation reagent, and has good functional group compatibility and substrate universality.
The present invention solves the above-mentioned problems by the following technical means.
The invention provides a preparation method of alkyl nitrile compounds shown in a formula I, which comprises the following steps: in a solvent, in the presence of an additive, performing a substitution reaction on a cyanolation reagent and an alkyl halide shown as a formula II to obtain an alkyl nitrile compound shown as a formula I; the cyanation reagent is Zn (CN)2And/or Cu (CN)2(ii) a The additive is one or more of inorganic base, organic base and quaternary ammonium salt;
Figure BDA0001842914410000031
wherein X is halogen;
R1is unsubstituted or R1-1Substituted aliphatic radical, unsubstituted or R1-2Substituted alicyclic hydrocarbon radical, unsubstituted or R1-3Substituted heterocycloalkyl, unsubstituted or R1-4Substituted heterocycloalkenyl, unsubstituted or R1-5Substituted aryl or, unsubstituted or R1-6Substituted heteroaryl;
said R1-1、R1-2、R1-3、R1-4、R1-5And R1-6Independently F, -CN, -NO2、-SO2H、-SO3H、-OH、-CO2H. -CHO, ═ O (i.e., two gem-hydrogens on a carbon atom are replaced with a group O), ═ S (i.e., two gem-hydrogens on a carbon atom are replaced with a group S), - (CH)2)n-NHR1-1-1、-(CH2)n-OR1-1-2、-(CH2)n-SR1-1-3Or Rx(ii) a Said RxIndependently is unsubstituted or R1-1-7Substituted with the following groups: c1～C10Alkyl radical, C2～C10Alkenyl radical, C2-C10Alkynyl, C3～C12Cycloalkyl- (CH)2)n-, "has C2-C10Carbon atom and hetero atom selected from N, O and S, and heterocyclic radical- (CH) with 1-4 hetero atoms2)n-, "has C3-C10Carbon atom, heteroatom selected from N, O and S, and heterocyclenyl- (CH) with 1-4 heteroatoms2)n-、C6-C14Aryl- (CH)2)n-, "has C1-C10A carbon atom, a heteroatom selected from N, O and S, a heteroaryl- (CH) with 1-4 heteroatoms2)n-、C1～C10Alkoxy, or C6-C14Aryl- (CH)2)n-O-；
Or, said R1-3And R1-4And is also independently a nitrogen protecting group (when attached to a nitrogen atom);
R1-1-1is a nitrogen protecting group, R1-1-2Is an oxygen protecting group; r1-1-3Is a sulfur protecting group; n is independently 0,1, 2,3 or 4;
said R1-1-7Each independently of the other is F, -CF3、-CN、-NO2、-SO2H、-SO3H、-OH、-CO2H、-CHO、＝O、＝S、C1～C4Alkyl radical, C1～C4Alkoxy orA phenyl group.
In the present invention, the solvent may be a solvent which is conventional in such reactions in the art, and in the present invention, preferred are one or more of a sulfoxide-based solvent (e.g., dimethyl sulfoxide), an amide-based solvent (e.g., one or more of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), hexamethylphosphoramide (HMPA or HMPT), and N-methylpyrrolidone (NMP), and further, for example, one or more of N-methylpyrrolidone), and a nitrile-based solvent (e.g., acetonitrile).
The amount of the solvent may be used without limitation so as not to affect the reaction; the molar volume ratio of the alkyl halide shown in the formula II to the solvent can be 0.1-2 mol/L, and preferably 0.25-1 mol/L.
In the present invention, the organic base is preferably a pyridine-based organic base (e.g., one or more of pyridine, 4-methylpyridine, 4-aminopyridine and 4-Dimethylaminopyridine (DMAP); e.g., 4-aminopyridine and/or 4-dimethylaminopyridine) and/or C1-C4Alkyl-substituted amines (e.g., triethylamine and/or tributylamine).
In the present invention, the inorganic base is preferably K2CO3、Na2CO3、Cs2CO3And CsF; more preferably Cs2CO3。
In the invention, the quaternary ammonium salt is preferably one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide and tetrabutylammonium acetate; more preferably tetrabutylammonium chloride and/or tetrabutylammonium bromide.
In one embodiment of the present invention, the additive is the quaternary ammonium salt, or the quaternary ammonium salt and the organic base.
In the present invention, the molar ratio of the alkyl halide represented by the formula II to the cyanation reagent may be a molar ratio conventionally used in the reaction in this kind of field, and is preferably 1:0.5 to 1:5 (e.g., 1: 0.8).
In the present invention, the molar ratio of the alkyl halide represented by the formula II to the additive may be 1:0.5 to 1:5, preferably 1:1 to 1:2.5 (e.g. 1:1, 1:2, 1: 2.5).
In the present invention, the temperature of the substitution reaction may be a temperature conventional in such reactions in the art, for example, 50 ℃ to 200 ℃, preferably 80 ℃ to 140 ℃ (for example, 80 ℃, 100 ℃, 120 ℃, 140 ℃).
In the present invention, the substitution reaction can be carried out under an inert atmosphere, preferably nitrogen and/or argon, which is conventional in such reactions in the art.
In the reaction, the progress of the reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), and is generally terminated when the alkyl halide represented by formula II disappears or no longer reacts.
The preparation method preferably comprises the following steps: and (2) only in the presence of the solvent and the additive, carrying out the substitution reaction on the cyanoation reagent and the alkyl halide shown in the formula II to obtain the alkyl nitrile compound shown in the formula I.
In the invention, X is preferably chlorine, bromine or iodine; more preferably chlorine or bromine.
In the invention, the number of the "substitution" can be one or more; when the number of the "substitution" is plural, the number is 2,3,4 or 5; when a plurality of "substitutions" are present, the "substitutions" may be the same or different.
In the present invention, n is preferably each independently 0 or 1.
In the present invention, when R is1Is unsubstituted or R1-1When substituted, the aliphatic groups may independently be alkyl, alkenyl or alkynyl groups as is conventional in the art. The alkyl is independently C1～C10Alkyl (e.g. C)1～C6Alkyl radicals, such as the methyl, ethyl, propyl, butyl, pentyl radical [ e.g. n-pentyl radical ]]Or hexyl). Said alkenyl is independently C2-C10Alkenyl (e.g. C)2-C6Alkenyl). Said alkynyl is independently C2-C10Alkynyl (e.g. C)2-C6Alkynyl).
In the present invention, when R is1Is unsubstituted or R1-2When substituted, the alicyclic hydrocarbon group may independently be C3-C20An alicyclic hydrocarbon group.
In the present invention, when R is1Is unsubstituted or R1-3When substituted, the heterocycloalkyl group may independently be C2-C10Carbon atom and hetero atom selected from N, O and S, and hetero atom number is 1-4 heterocycloalkyl.
In the present invention, when R is1Is unsubstituted or R1-4When substituted, the heterocycloalkenyl can independently be C3-C10The carbon atom and the heteroatom are selected from N, O and S, and the heteroatom number is 1-4.
In the present invention, when R is1Is unsubstituted or R1-5When substituted, the aryl group may be independently C6-C14Aryl (e.g., phenyl).
In the present invention, when R is1Is unsubstituted or R1-6When substituted, the heteroaryl group can independently be a group having C1-C10The carbon atom and the heteroatom are selected from N, O and S, and the heteroatom number is 1-4.
In the present invention, when said R isxIs unsubstituted or R1-1-7Substituted C1～C10When alkyl, said C1～C10Alkyl may independently be C1-C6An alkyl group.
In the present invention, when said R isxIs unsubstituted or R1-1-7Substituted C2-C10When alkenyl, said C2-C10Alkenyl may independently be C2-C6An alkenyl group.
In the present invention, when said R isxIs unsubstituted or R1-1-7Substituted C2-C10When it is alkynyl, said C2-C10Alkynyl may independently be C2-C6Alkynyl.
In the present invention, when said R isxIs unsubstituted or R1-1-7Substituted C3～C12Cycloalkyl- (CH)2)nWhen said C is3～C12Cycloalkyl may independently be C3-C6A cycloalkyl group.
In the present invention, when said R isxIs unsubstituted or R1-1-7Substituted "with C2-C10Carbon atom, heteroatom selected from N, O and S, and heterocycloalkyl- (CH) with 1-4 heteroatoms2)nWhen said heterocyclyl may be independently "having C2-C5A carbon atom, a heteroatom selected from N, O and S, a heterocycloalkyl group having 1-3 heteroatoms (e.g., pyrrolidinyl [ also e.g., pyrrolidinyl ]
Figure BDA0001842914410000051
])。
In the present invention, when said R isxIs unsubstituted or R1-1-7Substituted "with C3-C10Carbon atom, heteroatom selected from N, O and S, and heterocyclenyl- (CH) with 1-4 heteroatoms2)nWhen-is-said heterocycloalkenyl group may independently be "having C3-C5A carbon atom, a heteroatom selected from N, O and S, a heterocycloalkenyl group having 1-2 heteroatoms (e.g., 2, 3-dihydro-1H-pyrrolyl [ and e.g.
Figure BDA0001842914410000052
])。
In the present invention, when said R isxIs unsubstituted or R1-1-7Substituted C6-C14Aryl, or, unsubstituted or R1-1-7Substituted C6-C14Aryl- (CH)2)nwhen-O-, said C6-C14Aryl may independently be C6-C12Aryl (e.g., phenyl).
In the present invention, when said R isxIs unsubstituted or R1-1-7Substituted "with C1-C10A carbon atom, a heteroatom selected from N, O and S, a heteroaryl- (CH) with 1-4 heteroatoms2)nWhen said heteroAryl may independently be "having C2-C9A heteroaryl group having 1 to 3 carbon atoms, a heteroatom selected from N, O and S (e.g. pyrrolyl)
Figure BDA0001842914410000053
Or indolyl
Figure BDA0001842914410000054
)。
In the present invention, when said R isxIs unsubstituted or R1-1-7Substituted "with C2-C10Carbon atom, heteroatom selected from N, O and S, and heterocycloalkyl- (CH) with 1-4 heteroatoms2)nWhen said R is1-1-7Substituted "with C2-C10Carbon atom and hetero atom selected from N, O and S, and heterocyclic group with 1-4 hetero atoms is 1, 3-diketone-2-isoindolyl
Figure BDA0001842914410000061
In the present invention, when said R isxIs unsubstituted or R1-1-7Substituted C6-C14Aryl, or, unsubstituted or R1-1-7Substituted C6-C14Aryl- (CH)2)nWhen it is-O-, said R1-1-7Substituted C6-C14Aryl- (CH)2)n-O-is
Figure BDA0001842914410000062
In the present invention, when said R isxIs unsubstituted or R1-1-7Substituted C1～C10At alkoxy, said C1～C10Alkoxy may be C1-C4Alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy or isobutoxy, also e.g., methoxy).
In the present invention, when said R is1-3Or R1-4Is a nitrogen protecting group, or when said R is1-1-1When a nitrogen protecting group is used, the nitrogen protecting group is preferably t-Butylcarbamate (BOC) or p-toluenesulfonyl (Tosyl, Ts or Tos).
In the present invention, when said R is1-1-2When an oxygen protecting group is used, the oxygen protecting group is preferably tert-butyldimethylsilyl (TBDMS/TBS).
In the present invention, when said R is1-1-7Is C1～C4When alkyl, said C1-C4Alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl.
In the present invention, when said R is1-1-7Is C1～C4At alkoxy, said C1-C4Alkoxy is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl.
In the present invention, when said R is1Independently is unsubstituted or R1-5When substituted aryl, said R1-5Can be C1～C4An alkoxy group.
In the present invention, when said R is1Independently is unsubstituted or R1-5When substituted aryl, said R1Can be phenyl or
Figure BDA0001842914410000063
In the present invention, when said R isxIndependently is unsubstituted or R1-1-7Substituted C6-C14Aryl- (CH)2)n-, or, unsubstituted or R1-1-7Substituted C6-C14Aryl- (CH)2)nwhen-O-, said C6-C14Aryl- (CH)2)nIt may be phenyl or benzyl.
In one embodiment of the present invention, certain groups of the alkyl halide of formula II are defined as follows, and undefined groups are as described in any of the preceding embodiments: r1Independently is unsubstituted or R1-1Substituted aliphatic radical, or, unsubstituted or R1-5A substituted aryl group;
preferably, R is1-1Or R1-5Independently is ═ O, - (CH)2)n-OR1-1-2Or Rx(ii) a Said RxIndependently is unsubstituted or R1-1-7Substituted with the following groups: "has C2-C10Carbon atom, heteroatom selected from N, O and S, and heterocycloalkyl- (CH) with 1-4 heteroatoms2)n-, "has C3-C10Carbon atom, heteroatom selected from N, O and S, and heterocyclenyl- (CH) with 1-4 heteroatoms2)n-、C6-C14Aryl- (CH)2)n-, "has C1-C10A carbon atom, a heteroatom selected from N, O and S, a heteroaryl- (CH) with 1-4 heteroatoms2)n-or C6-C14Aryl- (CH)2)n-O-。
The alkyl halide shown in the formula II can be selected from any one of the following structures:
Figure BDA0001842914410000071
the alkyl nitrile compound shown in the formula I can be selected from any one of the following structures:
Figure BDA0001842914410000072
the invention also provides an application of the additive as a catalyst in the preparation of the alkyl nitrile compound shown in the formula I, wherein the additive is one or more of inorganic base, organic base and quaternary ammonium salt;
Figure BDA0001842914410000073
wherein, the additive and R1Is as defined above.
The application comprises the following steps: in a solvent in the presence of an additivePerforming substitution reaction on a cyanoation reagent and alkyl halide shown as a formula II to obtain an alkyl nitrile compound shown as a formula I; the cyanation reagent is Zn (CN)2And/or Cu (CN)2；
Figure BDA0001842914410000081
Wherein the operation and conditions of the substitution reaction are as described above.
Definition of
The compounds described herein may contain one or more asymmetric centers and thus may exist in a variety of isomeric forms, for example, enantiomers and/or diastereomers. For example, the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures as well as mixtures of complex one or more stereoisomers. Isomers may be separated from mixtures by methods known to those skilled in the art, including chiral High Pressure Liquid Chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.
The term "substituted" means that at least one hydrogen on a group (e.g., a carbon or nitrogen atom) is replaced with an allowed substituent. Unless otherwise specified, "substituted group" means that there is a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents at each position are either the same or different. The term "substituted" is intended to include substitution by all permissible substituents of organic compounds, any of which described herein can result in the formation of stable compounds. The present invention contemplates any and all of such combinations in order to achieve a stable compound.
The term "substituted" means that the groups are connected by single bonds, double bonds or by fusion.
Exemplary carbon atom substituents include, but are not limited to, -CN, -NO2、-SO2H、-SO3H、-OH、-CO2H、-CHO、C1-10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, C3-C20Cycloalkyl, 3-10 membered heterocyclyl, C6-C14Aryl and 5-6 membered heteroaryl; or two gem hydrogens on a carbon atom are replaced by a group (e.g. O, S or N) (e.g. forming ═ O, ═ S or imine).
In the present invention, the heteroatom (e.g., nitrogen) may have a hydrogen substituent and/or any suitable substituent that satisfies the valence of the heteroatom and results in the formation of a stable moiety as described herein.
In the present invention, the nitrogen atoms may be substituted or unsubstituted, as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -CN, C1-10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, C3-C20Cycloalkyl, 3-10 membered heterocyclic group, and C6-C14And (4) an aryl group. In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen Protecting Groups are well known in the art and include those described in detail in Organic Synthesis (Protecting Groups in Organic Synthesis), T.W.Greene and P.G.M.Wuts, third edition, John Wiley International publication (John Wiley)&Sons), 1999, incorporated herein by reference. For example, nitrogen protecting groups (e.g., amide groups) include, but are not limited to, formamide, acetamide, and benzamide; nitrogen protecting groups (e.g., carbamate groups) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenemethylcarbamate (Fmoc), 2, 7-di-tert-butyl- [9- (10, 10-dioxo-10, 10,10, 10-tetrahydrothioxanthyl)]Methyl carbamate (DBD-Tmoc), 4-methoxybenzoyl carbamate (Phenoc), 2,2, 2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenethyl carbamate (hZ), 1- (1-adamantyl) -1-methylethyl carbamate (Adpoc), 1-dimethyl-2, 2-dibromoethylcarbamate (ADPoc)Esters (DB-t-BOC), 1-dimethyl-2, 2, 2-Trichloroethylcarbamate (TCBOC), 1-methyl-1- (4-diphenyl) ethylcarbamate (Bpoc), 1- (3, 5-di-tert-butylphenyl) -1-methylethylcarbamate (t-Bumeoc), 2- (2 '-and 4' -pyridyl) ethylcarbamate (Pyoc), tert-Butylcarbamate (BOC), 1-adamantylcarbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), Benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), 4-methylsulfinylbenzyl carbamate (Msz), [2- (1, 3-cyclopentyldisulfide)]Methyl carbamate (Dmoc), 4-methylphenylsulfanyl carbamate (Mtpc), 2, 4-dimethylphenylsulfanyl carbamate (Bmpc), 2-ethylphosphonothioyl carbamate (Peoc), 2-triphenylisopropylphosphoranyl carbamate (Ppoc), 5-benzisoxazolylmethylcarbamate, and 2- (trifluoromethyl) -6-chromonylmethylcarbamate (Tcroc), nitrogen protecting groups (such as sulfonamide groups) including, but not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6, -trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4, 6-trimethoxybenzenesulfonamide (Mtb), 2, 6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5, 6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4, 6-tritylsulfonamide (Mts), 2, 6-dimethoxy-4-methylbenzenesulfonamide (iMmcs), 2,5, 7-pentamethylsilyl-4- (N-methylsilyl), 2, 6-trimethylsilyl) sulfonamide (Mbps), 2, 6-pentamethylsilyl-4-ethyl-4-methanesulfonamide (Mbs), N-6-trimethylsilyl) amide (Mbps), N-4, N-ethyl-4-methylsulfamide (Mbps), N-trimethylsilyl) and other protecting groups including, N-4-trimethylsilyl) including, N-ethyl-4-Methylsulfamide (MBS) and N-methyl-4-ethyl-4-ethyl-]Methylamine (SEM), N-triphenylmethylamine (Tr), N- [ (4-methoxyphenyl) diphenylmethyl]Amines (MMTr), N-9-phenylfluorenamines (PhF), N-ferrocenylmethylamino (Fcm), N-cyclohexylidene amines, N-borane derivatives, N-copper chelates, N-zinc chelates, N-nitramines, N-nitrosamines, amine N-oxides, diphenylphosphinamines (Dpp), dimethylthiophosphamines (Mpt), diphenylphosphinamines (Ppt), o-nitrobenzenesulfinamides(Nps), and 3-nitropyridine sulfinamide (Npys).
In the present invention, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Organic Synthesis (protecting groups in Organic Synthesis), t.w.greene and p.g.m.wuts, third edition, John Wiley & Sons, 1999, incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), (phenyldimethylsilyl) methoxymethyl (SMOM), Benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy) methyl (p-AOM), Guaiacolmethyl (GUM), t-butoxymethyl, 4-Pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2- (trimethylsilyl) ethoxymethyl (SEMOR), Tetrahydropyranyl (THP), 4-Methoxytetrahydropyranyl (MTHP), 1- [ (2-chloro-4-methyl) phenyl ] -4-methoxypiperidin-4-yl (CTMP), 1-ethoxyethyl (ETHE), 1- (2-chloroethoxy) ethyl group, 2-trimethylsilylethyl group, 2- (phenylhydrogenselenyl) ethyl group, t-butyl group, allyl group, p-chlorophenyl group, p-methoxyphenyl group, 2, 4-dinitrophenyl group, benzyl group (Bn), p-methoxybenzyl group, 3, 4-dimethoxybenzyl group, o-nitrobenzyl group, p-halobenzyl group, trimethylsilyl group (TMS), triethylsilyl group (TES), triisopropylsilyl group (TIPS), dimethylisopropylsilyl group (IPDMS), diethylisopropylsilyl group (DEIPS), dimethylhexylsilyl group, t-butyldimethylsilyl group (TBDMS), t-butyldiphenylsilyl group (TBDPS), tribenzylsilyl group, tri-p-xylylsilyl group, triphenylsilyl group, diphenylmethylsilyl group (DPMS), T-butylmethoxyphenylsilyl (TBMPS), formic acid ester, 9-fluorenylmethyl carbonate (Fmoc), 2- (trimethylsilyl) ethyl carbonate (TMSEC), 2- (phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonium) ethyl carbonate (Peoc), sulfuric acid ester, methanesulfonic acid ester (mesylate), benzyl sulfonic acid ester, and toluenesulfonic acid ester (Ts).
In the present invention, the substituent present on the sulfur atom is a sulfur-protecting group (also referred to as a mercapto-protecting group). Sulfur protecting groups are well known in the art and include those described in detail in organic synthesis, exemplary sulfur protecting groups can be the exemplary oxygen protecting groups described above.
The term "halogen" refers to fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I).
The term "aliphatic radical" refers to an alkyl, alkenyl or alkynyl radical.
The term "alkyl" refers to a group having 1 to 20 carbon atoms ("C)1-C20Alkyl ") straight or branched saturated hydrocarbon groups. In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C)1-C10Alkyl "). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C)1-C6Alkyl "), preferably C1～C4An alkyl group. The term "C1～C6Alkyl is preferably independently methyl, ethyl, propyl, butyl, pentyl or hexyl; wherein, methyl (C)1) Ethyl (C)2) N-propyl (C)3) Isopropyl (C)3) N-butyl (C)4) Tert-butyl (C)4) Sec-butyl (C)4) Isobutyl (C)4) N-pentyl group (C)5) 1-ethyl-propyl (3-pentyl, C)5) 1-methyl-butyl (2-pentyl, C)5) 2-methyl-1-butyl (C)5) 3-methyl-1-butyl (C)5) Neopentyl (C)5) Isopentyl or 3-methyl-2-butyl (C)5) Tert-amyl (C)5) N-hexyl (C)6) And isohexyl (C)6). The term "C1～C4Alkyl "is meant to include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, or isobutyl.
The term "alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no carbon-carbon triple bonds ("C)2-C20Alkenyl) ". The one or more carbon-carbon double bonds may be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group).In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C)2-C10Alkenyl "). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C)2-C6Alkenyl radicals "), for example vinyl (C)2) 1-propenyl (C)3) 2-propenyl (C)3) 1-butenyl (C)4) 2-butenyl (C)4) Butadiene (C)4) Pentenyl (C)5) Pentadienyl (C)5) Hexenyl (C)6) And so on. Further examples of alkenyl groups include heptenyl (C)7) Octenyl (C)8) Octrienyl (C)8) And so on.
"alkynyl" refers to a straight or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more carbon-carbon double bonds ("C)2-C20Alkynyl "). The one or more carbon-carbon triple bonds may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C)2-C10Alkynyl "). In some embodiments, alkynyl groups have 2 to 6 carbon atoms ("C)2-C6Alkynyl "), for example, ethynyl (C)2) 1-propynyl (C)3) 2-propynyl (C)3) 1-butynyl (C)4) 2-butynyl (C)4) Pentynyl group (C)5) Hexynyl (C)6) And so on. Additional instances of alkynyl include heptynyl (C)7) (C) octynyl group8) And so on.
The term "alicyclic hydrocarbon group" refers to a monocyclic ("monocyclic alicyclic hydrocarbon group") or a monocyclic ring system containing a fused, bridged or spiro polycyclic ring system (e.g., a bicyclic ring system ("bicyclic alicyclic hydrocarbon group")) and may be a saturated or may be a partially unsaturated carbocyclic substituent. In some embodiments, a ring having 3 to 20 carbon atoms in the alicyclic group may be represented by C3-C20An alicyclic hydrocarbon group. In some embodiments, a ring having 3 to 10 carbon atoms of the alicyclic group may be represented by C3-C10Alicyclic hydrocarbon radicals including, but not limited to, cyclopropyl (C)3) Cyclopropenyl group (C)3) Cyclobutyl (C)4) Cyclobutenyl radical (C)4) Cyclopentyl (C)5) Cyclopentenyl group (C)5) Cyclohexyl (C)6) Cyclohexenyl (C)6) Cyclohexadienyl (C)6) Cycloheptyl (C)7) Cycloheptenyl (C)7) Cycloheptadienyl (C)7) Cycloheptatrienyl (C)7) Cyclooctyl (C)8) Cyclooctenyl (C)8) Bicyclo [2.2.1]Heptyl (C)7) Bicyclo [2.2.2]Octyl radical (C)8) Cyclononyl (C)9) Cyclononenyl (C)9) Cyclodecyl (C)10) Cyclodecenyl (C)10) 2, 3-indanyl (C)9) octahydro-1H-indenyl (C)9) 1,2,3, 4-tetrahydro-naphthyl (C)10) 5,6,7, 8-tetrahydro-naphthyl (C)10) Decahydronaphthyl (C)10) Spiro [4.5 ]]Decyl (C)10). In some embodiments, an "alicyclic group" is a monocyclic, saturated carbocyclyl group having 3 to 10 ring atoms ("C)3-C10Cycloalkyl "). Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-C10A carbocyclic group. In certain embodiments, the carbocyclyl group is substituted C3-C10A carbocyclic group.
The term "cycloalkyl" refers to a monocyclic saturated ring, or a carbocyclic substituent comprising a fused, bridged or spiro polycyclic ring system. In some embodiments, a ring having 3-20 carbon atoms may be represented as C3-C20A cycloalkyl group. In some embodiments, "C3-C12Cycloalkyl "is a monocyclic, saturated carbocyclic group having 3 to 12 carbon atoms, preferably C3-C6Cycloalkyl radicals, e.g. cyclopropyl (C)3) Cyclobutyl (C)4) Cyclopentyl (C)5) Cyclohexyl (C)6). Additional embodiments of cycloalkyl groups include cycloheptyl (C)7) Cyclooctyl (C)8) Adamantyl (C)10) And cyclododecyl (C)12)。
"Heterocyclyl" includes "heterocycloalkyl" and "heterocycloalkenyl". "Heterocyclyl" means having C2-C10Carbon atoms and a non-aromatic ring system of 1 to 4 heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. The heterocyclyl group may be either monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system (e.g., a bicyclic system ("bicyclic heterocyclyl")) and may be saturated or may be partially unsaturated. The heterocyclic bicyclic ring system may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes heterocyclic systems as defined above, fused to one or more carbocyclic groups (where the point of attachment is on the carbocyclic group or on the heterocyclic ring), or heterocyclic systems as defined above, fused to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocyclic ring). In some embodiments, the heterocyclyl group is of C2-C10A carbon atom and 1-4 heteroatoms (wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur).
"Heterocycloalkyl" refers to a "heterocyclyl" group of a saturated non-aromatic ring system as described above. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thietanyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, glycidylalkyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiafuranyl (oxathiafuranyl), dithiofuranyl (disulphuranyl), and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiaDiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and sulfocyclopentanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinyl (triazinanyl). Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepinyl, and thiacycloheptyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azacyclooctyl (azocanyl), oxocyclooctyl (oxocanyl), and thiocyclooctanetyl (thiocanyl). Condensed to C6Exemplary 5-membered heterocyclyl groups for aryl rings (also referred to herein as 5, 6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6, 6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
"heterocycloalkenyl" refers to a "heterocyclyl" group containing an ethylenically unsaturated, non-aromatic ring system, as described above. In some embodiments, heterocycloalkenyl refers to heterocycloalkenyl having 1-2, 5-6 members heteroatoms of one or more of N, O and S. Exemplary 1,2,5, 6-tetrahydropyridinyl, 4, 5-dihydrooxazolyl.
"aryl" refers to a group having 6-14 atoms and zero heteroatoms, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n +2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) ("C)6-C14Aryl "). In some embodiments, the aryl group has 6 ring atoms ("C)6Aryl "; for example, phenyl). In some embodiments, the aryl group has 10 ring atoms ("C)10Aryl "; for example, biphenyl or naphthyl<Such as 1-naphthyl and 2-naphthyl>). In some embodiments, the aryl group has 14 ring atoms ("C)14Aryl "; for example, phenanthryl or anthracyl). Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is optionally substituted C6-C14And (4) an aryl group. In certain embodiments, the aryl group is optionally substituted C6-C12And (4) an aryl group. In the present invention, the aryl group includes unsubstituted or substituted aryl groups, wherein substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of: c1～C4Alkyl radical, C1～C4Alkoxy radical, C3～C10Cycloalkyl, -CN, hydroxy, aldehyde, acyl, -NR2-3R2-4Wherein R is2-3And R2-4Is H or C1-C4An alkyl group. Representative aryl groups include aryl groups bearing electron donating and/or electron withdrawing substituents, such as p-tolyl, p-methoxyphenyl, p-fluorophenyl, and the like. )
"heteroaryl" refers to a group ("5-10 membered heteroaryl") having carbon atoms and a 5-10 membered monocyclic or bicyclic 4n +2 aromatic ring system (e.g., having 6 or 10 shared p electrons in the cyclic array) of 1-4 heteroatoms (wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. The point of attachment in a bicyclic heteroaryl group (e.g., indolyl, quinolinyl, carbazolyl, etc.) wherein one ring does not include a heteroatom can be on one of the rings, i.e., either the ring carries a heteroatom (e.g., 2-indolyl) or the ring does not include a heteroatom (e.g., 5-indolyl). In certain embodiments, a heteroaryl group is a 5-6 membered aromatic ring system ("5-6 membered heteroaryl") having carbon atoms and 1-4 heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur; heteroaryl within the scope of this definition, exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl alone. Exemplary 5, 6-bicyclic heteroaryl groups include, but are not limited to, indolyl, indazolyl, benzotriazolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6, 6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, acridinyl, carbazolyl. "heteroaryl" is also to be understood as including any N-oxide derivative of a nitrogen-containing heteroaryl group. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is an optionally substituted 5-10 membered heteroaryl.
The term "alkoxy" denotes a cyclic or acyclic alkyl group having the indicated number of carbon atoms attached through an oxygen bridge. Thus, "alkoxy" encompasses the above definitions of alkyl and cycloalkyl.
The term "alkylthio" denotes a cyclic or acyclic alkyl group having the indicated number of carbon atoms attached through a sulfur bridge. Thus, "alkylthio" encompasses the above definitions of alkyl and cycloalkyl.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the preparation method can simply and efficiently realize the cyanation of the primary alkyl halide by using a low-toxicity metal cyanation reagent, and has good functional group compatibility and substrate universality.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Preparation example 1(4c)
Figure BDA0001842914410000131
Indole (2.34g,20.0mmol), dimethyl sulfoxide (40mL), potassium hydroxide (1.46g,26.0mmol) were added in this order to a reaction flask equipped with a stirrer under argon, and after stirring at room temperature for 15min, 1-bromo-3-chloropropane (5.93mL,60.0mmol) was slowly added to the mixture, which was allowed to react at room temperature for 16 h. TLC detection reaction is complete, water quenching reaction is carried out, ethyl acetate is used for extracting an organic phase, anhydrous sodium sulfate is used for drying, concentration is carried out, silica gel column chromatography is carried out, and eluent is petroleum ether: ethyl acetate 500:1, product 2.87g as a pale yellow liquid, 74% yield,1h NMR purity was greater than 98%.1H NMR(400MHz,CDCl3)δ7.62(d,J＝8.0Hz,1H),7.33(d,J＝8.4Hz,1H),7.20(t,J＝7.2Hz,1H),7.12-7.08(m,2H),6.48(d,J＝3.2Hz,1H),4.27(t,J＝6.4Hz,2H),3.38(t,J＝6.0Hz,2H),2.19(quint,J＝6.4Hz,2H)；13C NMR(100MHz,CDCl3)δ135.74,128.62,127.96,121.56,121.00,119.42,109.18,101.41,42.73,41.80,32.50.
Preparation example 2(6f)
Figure BDA0001842914410000141
6-bromo-n-hexanol (1.81g,10mmol), dichloromethane (20mL), and imidazole (1.36g,20mmol) were added sequentially to a reaction flask equipped with a stirrer under air, after fully dissolving, tert-butyldimethylsilyl chloride (2.26g,15mmol) was slowly added to the system at room temperature, and a large amount of white solid was precipitated and reacted at room temperature for 7h. TLC detection reaction is complete, saturated ammonium chloride solution quenches reaction, dichloromethane extracts organic phase, anhydrous sodium sulfate is dried, concentration is carried out, silica gel column chromatography is carried out, and eluent is petroleum ether: ethyl acetate 100:1, product 2.33g as yellow liquid, 79% yield,1h NMR purity was greater than 98%.1H NMR(400MHz,CDCl3)δ3.60(t,J＝6.4Hz,2H),3.40(t,J＝6.8Hz,2H),1.86(quint,J＝6.8Hz,2H),1.55-1.31(m,6H),0.89(s,9H),0.04(s,6H)；13C NMR(100MHz,CDCl3)δ62.99,33.88,32.78,32.58,27.95,25.94,24.99,18.33,-5.31.
Preparation example 3(6g)
Figure BDA0001842914410000142
Phthalimide (1.47g,10mmol), potassium carbonate (4.15g,30mmol), tetrabutylammonium bromide (322.4mg,1mmol) were added to a reaction flask equipped with a stirrer in this order under argon, and then, 1, 3-dibromopropane (3.0mL,30mmol) was added thereto under argon purging three times, followed by reaction at room temperature for 4 hours. TLC detecting reaction, water quenching reaction, dichloromethane extracting organic phase, drying with anhydrous sodium sulfate, concentrating, silica gel column chromatography, eluting with petroleum ether to 5:1 of petroleum ether and ethyl acetate, obtaining white solid 1.21g with yield of 45%,1h NMR purity was greater than 98%.1H NMR(400MHz,CDCl3)δ7.87-7.84(m,2H),7.76-7.73(m,2H),3.86-3.83(m,2H),3.44-3.41(m,2H),2.30-2.23(m,2H)；13C NMR(100MHz,CDCl3)δ168.18,134.01,131.90,123.25,36.64,31.56,29.79.
Example 1(5a)
Figure BDA0001842914410000151
In a glove box filled with nitrogen, a 4mL sample bottle was charged with Zn (CN)2(47.0mg,0.4mmol)，n-Bu4NCl (277.9mg,1.0mmol), stoppered, removed from the glove box, and N-methylpyrrolidone (0.5mL), 4a (77.3mg,0.5mmol) added sequentially under air, stoppered, and allowed to react at 140 ℃ for 6h. TLC detection reaction is complete, water quenching reaction is carried out, an organic phase is extracted by ether, drying is carried out by anhydrous sodium sulfate, concentration and silica gel column chromatography are carried out, and an eluent is petroleum ether: dichloromethane 3:1, 57.3mg of product as colorless liquid, yield 79%,1h NMR purity was greater than 98%.1H NMR(400MHz,CDCl3)δ7.32-7.17(m,5H),2.76(t,J＝7.6Hz,2H),2.29(t,J＝7.2Hz,2H),1.99-1.92(m,2H)；13C NMR(100MHz,CDCl3)δ139.61,128.53,128.33,126.36,119.42,34.22,26.77,16.22.
Example 2(5b)
Figure BDA0001842914410000152
The scheme of example 1 is adopted, the solvent is replaced by acetonitrile, and the reaction is carried out for 4h at 80 ℃. Silica gel column chromatography, eluent petroleum ether: ethyl acetate 10:1 to 8:1, 73.8mg of product as white solid, 93% yield,1h NMR purity was greater than 98%.1H NMR(400MHz,CDCl3)δ7.95(d,J＝7.2Hz,2H),7.61(t,J＝7.2Hz,1H),7.49(t,J＝8.0Hz,2),3.38(t,J＝7.2Hz,2H),2.76(t,J＝7.2Hz,2H)；13C NMR(100MHz,CDCl3)δ195.30,135.45,133.78,128.74,127.89,119.20,34.10,11.66.
Example 3(5c)
Figure BDA0001842914410000153
The scheme of example 1 is adopted, reaction is carried out for 4h at 140 ℃, silica gel column chromatography is carried out, and eluent is petroleum ether: ethyl acetate 8:1 to 6:1, 66.4mg of product as yellow liquid, yield 72%,1h NMR purity was greater than 98%.1H NMR(400MHz,CDCl3)δ7.62(d,J＝8.0Hz,1H),7.30(d,J＝8.0Hz,1H),7.21(t,J＝7.6Hz,1H),7.11(t,J＝7.2Hz,1H),7.05(d,J＝3.2Hz,1H),6.50(d,J＝3.2Hz,1H),4.21(t,J＝6.4Hz,2H),2.15-2.05(m,4H)；13C NMR(100MHz,CDCl3)δ135.58,128.61,127.56,121.78,121.09,119.59,118.71,108.96,101.86,44.15,25.78,14.39.
Example 4(5d)
Figure BDA0001842914410000154
The scheme of example 1 is adopted, reaction is carried out for 2.5h at 120 ℃, silica gel column chromatography is carried out, and eluent is petroleum ether: ethyl acetate 30:1, product 40.6mg as colorless liquid, 69% yield,1h NMR purity was greater than 98%.1H NMR(400MHz,CDCl3)δ7.40-7.31(m,5H),3.73(s,2H)；13C NMR(100MHz,CDCl3)δ129.81,129.03,127.94,127.82,117.84,23.48.
Example 5(5a)
Figure BDA0001842914410000161
The scheme of example 1 is adopted, reaction is carried out for 6h at 140 ℃, silica gel column chromatography is carried out, and eluent is petroleum ether: dichloromethane 3:1, 44.4mg of product as colorless liquid, yield 61%,1h NMR purity was greater than 98%.
Example 6(5e)
Figure BDA0001842914410000162
The scheme of example 1 is adopted, reaction is carried out for 7h at 140 ℃, silica gel column chromatography is carried out, and eluent is petroleum ether: ethyl acetate 8:1 to 6:1, 49.2mg of product as yellow liquid, 56% yield,1h NMR purity was greater than 98%.1H NMR(400MHz,CDCl3)δ7.37-7.24(m,5H),4.51(s,2H),3.57(t,J＝5.6Hz,2H),2.47(t,J＝7.2Hz,2H),1.92(quint,J＝6.4Hz,2H)；13C NMR(100MHz,CDCl3)δ137.79,128.35,127.68,127.56,119.43,73.05,67.47,25.70,14.06.
Example 7(5f)
Figure BDA0001842914410000163
The scheme of example 1 is adopted, reaction is carried out for 3h at 140 ℃, silica gel column chromatography is carried out, and eluent is petroleum ether: ethyl acetate 30:1, 63.4mg of product as yellow liquid, 53% yield,1h NMR purity was greater than 98%.1H NMR(400MHz,CDCl3)δ3.59(t,J＝6.4Hz,2H),2.32(t,J＝7.2Hz,2H),1.65(quint,J＝7.2Hz,2H),1.54-1.33(m,6H),0.87(s,9H),0.03(s,6H)；13C NMR(100MHz,CDCl3)δ119.70,62.79,32.34,28.36,25.86,25.28,24.96,18.25,16.98,-5.39.IR(neat):2929,2857,2244,1471,1461,1389,1360,1254,1098,834,774,661.HRMS(ESI)calcd for C13H28NOSi[M+H]+:242.1935,found242.1927.
Example 8(5g)
Figure BDA0001842914410000164
The scheme of example 1 is adopted, reaction is carried out for 4h at 140 ℃, silica gel column chromatography is carried out, and eluent is petroleum ether: ethyl acetate 8:1 to 6:1, product 65.1mg as white solid, yield 61%,1h NMR purity was greater than 98%.1H NMR(400MHz,CDCl3)δ7.88-7.84(m,2H),7.77-7.72(m,2H),3.82(t,J＝6.8Hz,2H),2.45(t,J＝7.2Hz,2H),2.12-2.05(m,2H)；13C NMR(100MHz,CDCl3)δ168.07,134.08,131.67,123.27,118.70,36.47,24.58,14.93.
Example 9
Figure BDA0001842914410000171
The scheme of example 1 is adopted, the solvent is replaced by acetonitrile, and the reaction is carried out for 6h at 120 ℃. Silica gel column chromatography, eluent petroleum ether: ethyl acetate 20:1 to 15:1, product 46.8mg as a pale yellow liquid, 64% yield,1h NMR purity was greater than 98%.1H NMR(400MHz,CDCl3)δ7.23(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),3.80(s,3H),3.67(s,2H)；13C NMR(100MHz,CDCl3)δ159.25,129.00,121.72,118.17,114.42,55.25,22.69.
Example 10
Figure BDA0001842914410000172
The reaction is carried out for 4h at 140 ℃ by adopting the scheme of example 1. Silica gel column chromatography, eluent petroleum ether: ethyl acetate 8:1 to 6:1, 55.4mg of product as colorless liquid, 59% yield,1h NMR purity was greater than 98%.1H NMR(400MHz,CDCl3)δ8.05(d,J＝7.6Hz,2H),7.58(t,J＝7.6Hz,1H),7.45(t,J＝7.6Hz,2H),4.43(t,J＝6.0Hz,2H),2.54(t,J＝7.2Hz,2H),2.14(quint,J＝6.4Hz,2H)；13C NMR(100MHz,CDCl3)δ166.13,133.13,129.52,129.48,128.35,118.84,62.59,24.85,14.29.
Example 11
Figure BDA0001842914410000173
The reaction was carried out using the protocol of example 1, using different amounts and temperatures. The results are shown below:
screening of primary alkyl halide cyanation conditions
Figure BDA0001842914410000174
aIsolation yield
Example 12
Figure BDA0001842914410000181
The reaction was carried out using the protocol of example 1, using different amounts and temperatures. The results are shown below:
screening of primary alkyl halide cyanation conditions
Figure BDA0001842914410000182
COMPARATIVE EXAMPLE 1(5a)
Figure BDA0001842914410000183
In a glove box filled with nitrogen, a 4mL sample bottle was charged with a stirrer, Zn (CN)2(47.0mg,0.4mmol), 4a (77.3mg,0.5mmol), the glove box was removed with the cap closed, N-methylpyrrolidone (0.5mL) was added under air, and the mixture was placed in a preheated oil bath at 140 ℃ for reaction for 6 hours. No cyanation product was formed by TLC.
COMPARATIVE EXAMPLE 2(5a)
Figure BDA0001842914410000184
In a glove box filled with nitrogen, NiCl was sequentially added to a 4mL sample bottle2·6H2O(5.9mg,0.025mmol)，DMAP(122.2mg,1.0mmol)，Zn(CN)2(47.0mg,0.4mmol)，Zn(13.1mg,0.2mmol)，n-Bu4NCl (69.5mg,0.25mmol), XantPhos (14.5mg,0.025mmol), 4a (136.9mg,0.5mmol) and CH3CN (1.0 mL). And (3) after a cover is covered, moving out of the glove box, reacting for 8h at 100 ℃, and carrying out silica gel column chromatography, wherein the eluent is petroleum ether: dichloromethane 3:1, 23.5mg of product as colorless liquid, yield 32%,1h NMR purity was greater than 98%.
Comparative example 3
Figure BDA0001842914410000185
In a glove box filled with nitrogen, a 4mL sample bottle was charged with a stirrer, 3-chloropropiophenone (84.3mg,0.5mmol), DMAP (122.2mg,1.0mmol), acetonitrile (0.5mL), TMSCN (79.4mg,0.8mmol) in this order, the glove box was removed with the lid closed, and the mixture was placed in a preheated 100 ℃ oil bath for reaction for 6 hours. TLC detection reaction is complete, concentration and silica gel column chromatography are carried out, and the eluent is petroleum ether: ethyl acetate 5:1 gave 19.1mg of a white solid in 24% yield.

Claims (10)

1. A preparation method of alkyl nitrile compounds shown in formula I is characterized by comprising the following steps: in a solvent, in the presence of an additive, performing a substitution reaction on a cyanolation reagent and an alkyl halide shown as a formula II to obtain an alkyl nitrile compound shown as a formula I; the cyanation reagent is Zn (CN)2And/or Cu (CN)2(ii) a The additive is one or more of inorganic base, organic base and quaternary ammonium salt;
Figure FDA0001842914400000011
wherein X is halogen;
R1is unsubstituted or R1-1Substituted aliphatic radical, unsubstituted or R1-2Substituted alicyclic hydrocarbon radical, unsubstituted or R1-3Substituted heterocycloalkyl, unsubstituted or R1-4Substituted heterocycloalkenyl, unsubstituted or R1-5Substituted aryl or, unsubstituted or R1-6Substituted heteroaryl;
said R1-1、R1-2、R1-3、R1-4、R1-5And R1-6Independently F, -CN, -NO2、-SO2H、-SO3H、-OH、-CO2H、-CHO、＝O、＝S、-(CH2)n-NHR1-1-1、-(CH2)n-OR1-1-2、-(CH2)n-SR1-1-3Or Rx(ii) a Said RxIndependently is unsubstituted or R1-1-7Substituted with the following groups: c1～C10Alkyl radical, C2～C10Alkenyl radical, C2-C10Alkynyl, C3～C12Cycloalkyl- (CH)2)n-, "has C2-C10Carbon atom, heteroatom selected from N, O and S, and heterocycloalkyl- (CH) with 1-4 heteroatoms2)n-, "has C3-C10Carbon atom, heteroatom selected from N, O and S, and heterocyclenyl- (CH) with 1-4 heteroatoms2)n-、C6-C14Aryl- (CH)2)n-, "has C1-C10A carbon atom, a heteroatom selected from N, O and S, a heteroaryl- (CH) with 1-4 heteroatoms2)n-、C1～C10Alkoxy, or C6-C14Aryl- (CH)2)n-O-；
Or, said R1-3And R1-4And is also independently a nitrogen protecting group;
R1-1-1is a nitrogen protecting group, R1-1-2Is an oxygen protecting group; r1-1-3Is a sulfur protecting group; n is independently 0,1, 2,3 or 4;
said R1-1-7Each independently of the other is F, -CF3、-CN、-NO2、-SO2H、-SO3H、-OH、-CO2H、-CHO、＝O、＝S、C1～C4Alkyl radical, C1～C4Alkoxy or phenyl.
2. The method according to claim 1, wherein the solvent is one or more of a sulfoxide-based solvent, an amide-based solvent and a nitrile-based solvent;
and/or the organic base is pyridine organic base and/or C1-C4Alkyl-substituted amines;
and/or, the inorganic base is K2CO3、Na2CO3、Cs2CO3And CsF;
and/or the quaternary ammonium salt is one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide and tetrabutylammonium acetate;
and/or, the additive is the quaternary ammonium salt, or the quaternary ammonium salt and the organic base;
and/or the molar volume ratio of the alkyl halide shown as the formula II to the solvent is 0.1-2 mol/L;
and/or the molar ratio of the alkyl halide shown as the formula II to the cyanation reagent is 1: 0.5-1: 5;
and/or the molar ratio of the alkyl halide shown as the formula II to the additive is 1: 0.5-1: 5;
and/or the temperature of the substitution reaction is 50-200 ℃;
and/or, the substitution reaction is carried out under an inert atmosphere.
3. The method according to claim 2, wherein when the solvent is an amide-based solvent, the amide-based solvent is one or more of N, N-dimethylformamide, N-dimethylacetamide, hexamethylphosphoramide, and N-methylpyrrolidone;
and/or, when the solvent is a sulfoxide solvent, the sulfoxide solvent is dimethyl sulfoxide;
and/or, when the solvent is a nitrile solvent, the nitrile solvent is acetonitrile;
and/or, when the organic base is pyridine organic base, the pyridine organic base is one or more of pyridine, 4-methylpyridine, 4-aminopyridine and 4-dimethylaminopyridine;
and/or, when the organic base is C1-C4When an alkyl-substituted amine is used, said C1-C4The alkyl-substituted amine is triethylamine and/or tributylamine;
and/or the inorganic base is Cs2CO3；
And/or the quaternary ammonium salt is tetrabutylammonium chloride and/or tetrabutylammonium bromide;
and/or the molar volume ratio of the alkyl halide shown as the formula II to the solvent is 0.25-1 mol/L;
and/or the molar ratio of the alkyl halide shown as the formula II to the cyanation reagent is 1: 0.8;
and/or the molar ratio of the alkyl halide shown as the formula II to the additive is 1: 1-1: 2.5;
and/or the temperature of the substitution reaction is 80-140 ℃;
and/or, when the substitution reaction is carried out under an inert atmosphere, the inert atmosphere is nitrogen and/or argon.
4. The process according to claim 3, wherein the cyanoating agent and the alkyl halide represented by the formula II are subjected to the substitution reaction only in the presence of the solvent and the additive to obtain the alkyl nitrile compound represented by the formula I.
5. The process according to any one of claims 1 to 4, wherein X is chlorine, bromine or iodine;
and/or, n is independently 0 or 1;
and/or, the number of said "substitution" can be one or more;
and/or when R1Is unsubstituted or R1-1When the aliphatic radical is substituted, the aliphatic radical is alkyl, alkenyl or alkynyl;
and/or when R1Is unsubstituted or R1-2When the alicyclic hydrocarbon group is substituted, the alicyclic hydrocarbon group is C3-C20An alicyclic hydrocarbon group;
and/or when R1Is unsubstituted or R1-3When the heterocycloalkyl group is substituted, the heterocycloalkyl group is a group having C2-C10Carbon atom and heteroatom selected from N, O and S, and heterocycloalkyl with 1-4 heteroatoms;
and/or when R1Is unsubstituted or R1-4When substituted, the heterocycloalkenyl is C2-C10Carbon atom and heteroatom selected from N, O and S, and heterocyclic alkenyl with 1-4 heteroatoms;
and/or when R1Is unsubstituted or R1-5When substituted aryl, said aryl is C6-C14An aryl group;
and/or when R1Is unsubstituted or R1-6When substituted, the heteroaryl is C1-C10Carbon atoms and hetero atoms are selected from N, O and S, and the hetero atoms are 1-4 heteroaryl;
and/or, when said R isxIs unsubstituted or R1-1-7Substituted C1～C10When alkyl, said C1～C10Alkyl is independently C1-C6An alkyl group;
and/or, when said R isxIs unsubstituted or R1-1-7Substituted C2-C10When alkenyl, said C2-C10Alkenyl is independently C2-C6An alkenyl group;
and/or, when said R isxIs unsubstituted or R1-1-7Substituted C2-C10When it is alkynyl, said C2-C10Alkynyl is independently C2-C6An alkynyl group;
and/or, when said R isxIs unsubstituted or R1-1-7Substituted C3～C12Cycloalkyl- (CH)2)nWhen said C is3～C12Cycloalkyl is independently C3-C6A cycloalkyl group;
and/or, when said R isxIs unsubstituted or R1-1-7Substituted "with C2-C10Carbon atom, heteroatom selected from N, O and S, and heterocycloalkyl- (CH) with 1-4 heteroatoms2)nWhen said heterocycloalkyl is independently "having C2-C5Carbon atoms and heteroatoms selected from N, O and S, and heterocycloalkyl with 1-3 heteroatoms;
and/or, when said R isxIs unsubstituted or R1-1-7Substituted "with C3-C10Carbon atom, heteroatom selected from N, O and S, and heterocyclenyl- (CH) with 1-4 heteroatoms2)nWhen said heterocycloalkenyl is independently "having C3-C5A carbon atom, a heteroatom selected from N, O and S, a heterocycloalkenyl group with 1-2 heteroatoms;
and/or, when said R isxIs unsubstituted or R1-1-7Substituted C6-C14Aryl radicalsOr, unsubstituted or R1-1-7Substituted C6-C14Aryl- (CH)2)nwhen-O-, said C6-C14Aryl is independently C6-C12An aryl group;
and/or, when said R isxIs unsubstituted or R1-1-7Substituted "with C1-C10A carbon atom, a heteroatom selected from N, O and S, a heteroaryl- (CH) with 1-4 heteroatoms2)nWhen said heteroaryl is independently "having C2-C9A heteroaryl group having 1 to 3 carbon atoms and heteroatoms selected from N, O and S;
and/or, when said R isxIs unsubstituted or R1-1-7Substituted C1～C10At alkoxy, said C1～C10Alkoxy is C1-C4An alkoxy group;
and/or, when said R is1-3Or R1-4Is a nitrogen protecting group, or when said R is1-1-1When the nitrogen protecting group is a tert-butyl carbamate or a p-toluenesulfonyl group;
and/or, when said R is1-1-2When the group is an oxygen protecting group, the oxygen protecting group is tert-butyldimethylsilyl;
and/or, when said R is1-1-7Is C1～C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl;
and/or, when said R is1-1-7Is C1～C4At alkoxy, said C1-C4Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy or isobutoxy.
6. The process according to claim 5, wherein X is chlorine or bromine;
and/or, when the number of said "substitutions" is plural, the number of said "substitutions" is 2,3,4 or 5;
and/or, when there are a plurality of "substitutions", the "substitutions" are the same or different;
and/or when R1Is unsubstituted or R1-1Substituted aliphatic radical, when the aliphatic radical is alkyl, the alkyl is C1～C10An alkyl group;
and/or when R1Is unsubstituted or R1-1Substituted aliphatic radical, when the aliphatic radical is alkenyl radical, the alkenyl radical is C2-C10An alkenyl group;
and/or when R1Is unsubstituted or R1-1Substituted aliphatic radical, when said aliphatic radical is alkynyl, said alkynyl is C2-C10An alkynyl group;
and/or, when said R is1Independently is unsubstituted or R1-5When substituted aryl, said R1-5Is C1～C4An alkoxy group;
and/or, when said R isxIndependently is unsubstituted or R1-1-7Substituted "with C2-C10Carbon atom, heteroatom selected from N, O and S, and heterocycloalkyl- (CH) with 1-4 heteroatoms2)n-when said heterocyclylalkyl group is independently pyrrolidinyl;
and/or, when said R isxIndependently is unsubstituted or R1-1-7Substituted "with C3-C10Carbon atom, heteroatom selected from N, O and S, and heterocyclenyl- (CH) with 1-4 heteroatoms2)n-when said heterocycloalkenyl is independently 2, 3-dihydro-1H-pyrrolyl;
and/or, when said R isxIndependently is unsubstituted or R1-1-7Substituted C6-C14Aryl- (CH)2)n-, or, unsubstituted or R1 -1-7Substituted C6-C14Aryl- (CH)2)nwhen-O-, said C6-C14Aryl is independently phenyl;
and/or, when said R isxIs unsubstituted or R1-1-7Substituted "with C1-C10A carbon atom, a heteroatom selected from N, O and S, a heteroaryl- (CH) with 1-4 heteroatoms2)n-when said heteroaryl is independently pyrrolyl or indolyl;
and/or, when said R is1-1Is unsubstituted or R1-1-7Substituted C1～C10Alkoxy group of1～C10Alkoxy is C1-C4At alkoxy, said C1-C4Alkoxy is methoxy.
7. The method of claim 6, wherein when R is1Is unsubstituted or R1-1Substituted aliphatic radical, said aliphatic radical being C1～C10When alkyl, said C1～C10Alkyl is C1～C6An alkyl group;
and/or when R1Is unsubstituted or R1-1Substituted aliphatic radical, said aliphatic radical being C2-C10When alkenyl, said C2-C10Alkenyl is C2-C6An alkenyl group;
and/or when R1Is unsubstituted or R1-1Substituted aliphatic radical, said aliphatic radical being C2-C10When it is alkynyl, said C2-C10Alkynyl is C2-C6An alkynyl group;
and/or, when said R is1Independently is unsubstituted or R1-5When substituted aryl, said R1Is phenyl or
Figure FDA0001842914400000041
And/or, when said R isxIndependently is unsubstituted or R1-1-7Substituted "with C2-C10Carbon atom, heteroatom selected from N, O and S, and heterocycloalkyl- (CH) with 1-4 heteroatoms2)nWhen said heterocycloalkyl is independently
Figure FDA0001842914400000042
And/or, when said R isxIndependently is unsubstituted or R1-1-7Substituted "with C3-C10Carbon atom, heteroatom selected from N, O and S, and heterocyclenyl- (CH) with 1-4 heteroatoms2)nWhen said heterocycloalkenyl is independently
Figure FDA0001842914400000051
And/or, when said R isxIs unsubstituted or R1-1-7Substituted "with C1-C10A carbon atom, a heteroatom selected from N, O and S, a heteroaryl- (CH) with 1-4 heteroatoms2)nWhen said heteroaryl is independently
Figure FDA0001842914400000052
Figure FDA0001842914400000053
And/or, when said R isxIndependently is unsubstituted or R1-1-7Substituted "with C2-C10Carbon atom, heteroatom selected from N, O and S, and heterocycloalkyl- (CH) with 1-4 heteroatoms2)nWhen said R is1-1-7Substituted "with C2-C10The carbon atom and the heteroatom are selected from N, O and S, and the heterocyclic radical with 1-4 heteroatoms is 1, 3-diketone-2-isoindolyl;
and/or, when said R isxIs unsubstituted or R1-1-7Substituted C6-C14Aryl, or, unsubstituted or R1-1-7Substituted C6-C14Aryl- (CH)2)nWhen it is-O-, said R1-1-7Substituted C6-C14Aryl- (CH)2)n-O-is
Figure FDA0001842914400000054
8. The method of claim 1, wherein R is1Independently is unsubstituted or R1-1Substituted aliphatic radical, or, unsubstituted or R1-5A substituted aryl group;
said R1-1Or R1-5Independently is ═ O, - (CH)2)n-OR1-1-2Or Rx(ii) a Said RxIndependently is unsubstituted or R1-1-7Substituted with the following groups: "has C2-C10Carbon atom, heteroatom selected from N, O and S, and heterocycloalkyl- (CH) with 1-4 heteroatoms2)n-, "has C3-C10Carbon atom, heteroatom selected from N, O and S, and heterocyclenyl- (CH) with 1-4 heteroatoms2)n-、C6-C14Aryl- (CH)2)n-, "has C1-C10A carbon atom, a heteroatom selected from N, O and S, a heteroaryl- (CH) with 1-4 heteroatoms2)n-or C6-C14Aryl- (CH)2)n-O-。
9. The method of claim 1, wherein the alkyl halide represented by formula II is selected from any one of the following structures:
Figure FDA0001842914400000055
the alkyl nitrile compound shown in the formula I is selected from any one of the following structures:
Figure FDA0001842914400000061
10. the application of an additive as a catalyst in the preparation of alkyl nitrile compounds shown in the formula I;
Figure FDA0001842914400000062
wherein R is1As defined in any one of claims 1 and 5 to 9; the additive is as defined in any one of claims 1 to 3.
CN201811256811.2A 2018-10-26 2018-10-26 Preparation method of alkyl nitrile compound Pending CN111099942A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112300117A (en) * 2020-10-30 2021-02-02 山东海科新源材料科技股份有限公司 Novel additive and application thereof in lithium ion battery electrolyte
CN117384037A (en) * 2023-12-13 2024-01-12 山东国邦药业有限公司 Preparation method of ethyl difluoroacetate

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112300117A (en) * 2020-10-30 2021-02-02 山东海科新源材料科技股份有限公司 Novel additive and application thereof in lithium ion battery electrolyte
CN117384037A (en) * 2023-12-13 2024-01-12 山东国邦药业有限公司 Preparation method of ethyl difluoroacetate
CN117384037B (en) * 2023-12-13 2024-03-08 山东国邦药业有限公司 Preparation method of ethyl difluoroacetate

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