CN114805108A - Preparation method of chiral beta-alkyl amide compound - Google Patents

Preparation method of chiral beta-alkyl amide compound Download PDF

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CN114805108A
CN114805108A CN202210403991.2A CN202210403991A CN114805108A CN 114805108 A CN114805108 A CN 114805108A CN 202210403991 A CN202210403991 A CN 202210403991A CN 114805108 A CN114805108 A CN 114805108A
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舒伟
赵文涛
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Southwest University of Science and Technology
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Abstract

The invention discloses a preparation method of a chiral beta-alkylamide compound, which comprises the following steps: under the protection of inert gas, performing coupling reaction on an iodide and a brominated alkylamide compound in an organic solvent in the presence of a catalyst, a ligand, a reducing agent and an additive to obtain a chiral beta-alkylamide compound; the preparation method has the characteristics of high enantioselectivity, small environmental pollution and high yield.

Description

Preparation method of chiral beta-alkyl amide compound
Technical Field
The invention relates to the technical field of synthesis of drug intermediates and organic chiral building block molecules, and particularly discloses a preparation method of a chiral beta-alkylamide compound.
Background
Chiral C (sp3) -C (sp3) The bond is widely present in natural products and drugs with biological activity, chiral C (sp3) -C (sp3) The construction of bonds has been a focus of research in organic synthesis. Transition metal catalyzed enantioselective cross coupling reaction is efficient synthesis of chiral C (sp3) -C (sp3) One of the methods for bonding compounds, the process for this purpose, is limited by the preparation and use of organometallic reagents. Another construction of chiral C (sp3) -C (sp3) The bond method is an asymmetric hydroalkylation reaction of olefins, which takes olefins as raw materials to obtain hydroalkylation products through a metal hydrogen species reaction, wherein the regioselectivity of the reaction is a big difficulty. The metal-catalyzed reduction coupling reaction is an important method for constructing carbon-carbon bonds, and the reaction is directly coupled by using an electrophilic reagent, so that the preparation and the use of a metal reagent are avoided, and the method is widely developed in recent years. Wherein asymmetric reductive coupling reactions using secondary electrophiles can efficiently synthesize a series of chiral compounds, but asymmetric reductive coupling reactions are mainly focused on the construction of chiral C (sp2) -C (sp3) Bond, construction of chiral C by Metal-catalyzed reductive coupling reaction to date (sp3) -C (sp3) No bond has been reported.
The main challenge of metal catalyzed two-molecule alkyl electrophile asymmetric reduction coupling reactions is the control of reaction selectivity and chirality. Due to the similarity of the raw materials and the high reactivity of the alkyl electrophile, a large number of self-coupling side reactions occur during the reaction, which leads to a decrease in the selectivity of cross-coupling, and the chiral control of the alkyl metal species is also a great difficulty. The present invention provides an efficient way to accomplish this conversion process.
Chiral beta-alkyl amide compounds are an important organic synthon, and the chiral skeleton is contained in a plurality of natural products and biological inhibitors. In the prior art, few reports of chiral beta-alkyl amide compounds exist, and therefore, the development of an effective synthetic route of chiral beta-alkyl amide compounds with high stereoselectivity is urgently needed.
The invention content is as follows:
on one hand, the invention discloses a preparation method of chiral beta-alkyl amide compounds,
Figure BDA0003601503990000011
wherein: the preparation method comprises the following steps: under the protection of inert gas, carrying out coupling reaction on a compound shown in a formula (II) and a compound shown in a formula (III) in an organic solvent in the presence of a catalyst, a ligand, a reducing agent and an additive to obtain a compound shown in a formula (I);
each R 1 And R 2 Independently is C 1-12 Alkyl radical, C 1-12 Hydroxyalkyl radical, C 6-10 aryl-C 1-8 Alkylene or heteroaryl of 5 to 12 atoms-C 1-8 Alkylene, wherein said C 1-12 Alkyl radical, C 1-12 Hydroxyalkyl radical, C 6-10 aryl-C 1-8 Alkylene and heteroaryl of 5 to 12 atoms-C 1-8 Alkylene is independently unsubstituted or substituted by 1,2,3,4 or 5 groups selected from D, F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、-OC(O)CH 3 、-OC(O)C 6 H 5 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy, tert-butyldimethylsilyl, C 3-8 Cycloalkyl, heterocyclic ring of 3-8 atomsBase, C 6-10 Aryl radical, C 6-10 aryl-C 1-6 Alkylene and 5-12 atoms;
R 3 independently is C 1-6 Alkyl radical, C 3-8 Cycloalkyl or C 6-10 Aryl, wherein said C 1-6 Alkyl radical, C 3-8 Cycloalkyl and C 6-10 Aryl is independently unsubstituted or substituted by 1,2,3,4 or 5 groups selected from D, F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 3-8 Cycloalkyl and C 6-10 Aryl group.
In some embodiments, wherein each R is 1 And R 2 Independently is C 1-10 Alkyl radical, C 1-10 Hydroxyalkyl radical, C 6-10 aryl-C 1-6 Alkylene or heteroaryl of 5 to 12 atoms-C 1-6 Alkylene, wherein said C 1-10 Alkyl radical, C 1-10 Hydroxyalkyl radical, C 6-10 aryl-C 1-6 heteroaryl-C consisting of alkyl and 5-12 atoms 1-6 Alkyl is independently unsubstituted or substituted by 1,2,3,4 or 5 groups selected from D, F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、-OC(O)CH 3 、-OC(O)C 6 H 5 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy, tert-butyldimethylsilane, C 3-6 Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C 6-10 Aryl radical, C 6-10 aryl-C 1-4 Alkylene and 5-10 atoms;
R 3 independently is C 1-4 Alkyl radical, C 3-6 Cycloalkyl or C 6-10 Aryl, wherein said C 1-4 Alkyl radical, C 3-6 Cycloalkyl and C 6-10 Aryl is independently unsubstituted or substituted by 1,2,3,4 or 5 groups selected from D, F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl and C 6-10 Aryl group.
In some embodiments, wherein each R is 1 And R 2 Independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octane, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, C 6-10 aryl-C 1-4 Alkylene or heteroaryl of 5 to 12 atoms-C 1-4 Alkylene, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octane, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, C 6-10 aryl-C 1-4 Alkylene and heteroaryl of 5 to 12 atoms-C 1-4 Alkylene is independently unsubstituted or substituted by 1,2,3,4 or 5 groups selected from D, F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、-OC(O)CH 3 、-OC(O)C 6 H 5 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 Methoxy, ethylenepropoxy, n-oxy, isopropoxy, tert-butyldimethylsilyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, dioxacyclopentyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, phenylmethylene, phenylethylene, benzofuranyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl;
R 3 independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butylTert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or naphthyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or naphthyl is independently unsubstituted or substituted by 1,2,3,4 or 5 groups selected from D, F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 Methoxy, ethylenepropyleneoxy, n-oxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and naphthyl.
In some embodiments, wherein the compound of formula (I) comprises at least one of the following compounds:
Figure BDA0003601503990000021
Figure BDA0003601503990000022
Figure BDA0003601503990000031
Figure BDA0003601503990000041
in some embodiments, the catalyst for preparing the compound represented by the formula (I) is zero-valent nickel or divalent nickel; preferably, the catalyst for the coupling reaction is Ni (cod) 2 Nickel chloride, nickel bromide, nickel iodide, ethylene glycol dimethyl ether nickel chloride, ethylene glycol dimethyl ether nickel bromide, nickel acetylacetonate or nickel acetate.
In some embodiments, the ligand for preparing the compound of formula (I) is selected from the group consisting of:
Figure BDA0003601503990000042
in some embodiments, the reducing agent for preparing the compound represented by formula (I) is manganese metal, and is in the form of powder, and the particle size is 100-500 meshes.
In some embodiments, wherein the additive for preparing the compound of formula (I) is zinc iodide.
In some embodiments, the organic solvent for preparing the compound represented by the formula (I) is an alcohol solvent; preferably, the organic solvent having a coupling reaction is ethanol, n-propanol, n-butanol, isobutanol, n-pentanol, isopentanol, sec-pentanol, or n-hexanol.
In some embodiments, the reaction temperature for preparing the compound shown in the formula (I) is 10-40 ℃; preferably, the reaction temperature is 15-35 ℃.
In some embodiments, the reaction time for preparing the compound shown in the formula (I) is 18-30 h; preferably, the reaction time is 20-26 h.
In some embodiments, the preparation method of the chiral beta-alkylamide compound and the derivative thereof provided by the invention adopts a coupling reaction catalyzed by metal, and has the advantages of high yield, excellent enantioselectivity of the product, high atom economy and the like.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including but not limited to defined terminology, terminology application, described techniques, and so on), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs and all patent publications cited throughout the disclosure of the present invention are hereby incorporated by reference in their entirety.
The following definitions shall apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are described in the periodic table of elements, CAS version and handbook of chemicals, 75, th ed, 1994. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltio: 1999, and "March's Advanced Organic Chemistry", by Michael B&Sons, New York, 2007, and therefore all the contents of the present invention are incorporated by reference.
Many different aspects and embodiments of the present disclosure will be described below, and each aspect and each embodiment is not limiting as to the scope of the present disclosure. The terms "aspect" and "embodiment" are intended to be non-limiting, regardless of whether the terms "aspect" or "embodiment" appear anywhere in the specification. As used herein, the transitional term "comprising" which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements.
In the context of the present invention, all numbers disclosed herein are approximate values. The numerical value of each number may vary by 1%, 2%, 5%, 7%, 8%, or 10%. Whenever a number is disclosed with a value of N, any number within the values of N +/-1%, N +/-2%, N +/-3%, N +/-5%, N +/-7%, N +/-8% or N +/-10% is explicitly disclosed, wherein "+/-" means plus or minus. Whenever a lower limit, DL, and an upper limit, DU, are disclosed in a range of values, any value falling within the disclosed range is expressly disclosed.
All reaction steps described in the present invention are carried out to a certain extent such as a raw material consumption of about more than 70%, more than 80%, more than 90%, more than 95%, or a post-treatment such as cooling, collection, extraction, filtration, separation, purification or a combination thereof after the detection that the raw material for the reaction has been consumed. The degree of reaction can be detected by a conventional method such as Thin Layer Chromatography (TLC), High Performance Liquid Chromatography (HPLC), Gas Chromatography (GC) and the like. The reaction solution may be subjected to a post-treatment by a conventional method, for example, by evaporating under reduced pressure or conventionally distilling the reaction solvent, collecting the crude product, and directly subjecting to the next reaction; or directly filtering to obtain a crude product, and directly putting the crude product into the next reaction; or after standing, pouring out supernatant to obtain a crude product, and directly putting the crude product into the next reaction; or selecting proper organic solvent or their combination to make purification steps of extraction, distillation, crystallization, column chromatography, rinsing and pulping.
The addition processes and the reactions of the steps are all carried out under certain temperature conditions, and any temperature suitable for the addition processes or the reactions is included in the invention. Further, many similar modifications, equivalents, or equivalents of the temperatures and temperature ranges recited in this disclosure are deemed to be within the scope of the present disclosure. The invention provides the preferred temperature or temperature range of each dropping process and the preferred reaction temperature of each reaction.
The solvent used in each reaction step described in the present invention is not particularly limited, and any solvent that can dissolve the starting materials to some extent and does not inhibit the reaction is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention. The invention provides a preferable solvent used in each reaction step.
"room temperature" in the present invention means a temperature of from about 10 ℃ to about 40 ℃. In some embodiments, "room temperature" refers to a temperature of from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to 20 ℃, 22.5 ℃,25 ℃, 27.5 ℃, and the like.
The term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". The terms "optionally," "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. In general, the term "optionally" whether or not preceded by the term "substituted" indicates that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituent can be, but is not limited to, F, Cl, Br, I, CN, N 3 、OH、OR a 、NR b R c 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical C 3-6 Cycloalkyl radical, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclic group consisting of 3 to 6 atoms, (heterocyclic group consisting of 3 to 6 atoms) -C 1-4 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5 to 10 atoms or (heteroaryl of 5 to 10 atoms) -C 1-4 Alkylene, wherein R a 、R b And R c Have the definitions as described in the present invention.
The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms. Unless otherwise specified, alkyl groups contain 1 to 20 carbon atoms, some embodiments being alkyl groups containing 1 to 12 carbon atoms, other embodiments being alkyl groups containing 1 to 10 carbon atoms, other embodiments being alkyl groups containing 1 to 8 carbon atoms, other embodiments being alkyl groups containing 1 to 6 carbon atoms, other embodiments being alkyl groups containing 1 to 4 carbon atoms, and other embodiments being alkyl groups containing 1 to 3 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH) 3 ) Ethyl (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH)) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like, wherein the alkyl groups can be independently unsubstituted or substituted with one or more substituents described herein.
The term "alkyl" and its prefix "alk", as used herein, are intended to encompass both straight and branched saturated carbon chains.
The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a straight or branched chain saturated hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 10 carbon atoms, in other embodiments 1 to 6 carbon atoms, in other embodiments 1 to 4 carbon atoms, and in other embodiments 1 to 2 carbon atoms. Examples of this include methylene (-CH) 2 -, ethylene (-CH) 2 CH 2 -, isopropylidene (-CH (CH) 3 )CH 2 -) and the like, wherein the alkylene groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 20 carbon atoms, some examples of which are alkoxy groups containing 1 to 10 carbon atoms, other examples of which are alkoxy groups containing 1 to 8 carbon atoms, other examples of which are alkoxy groups containing 1 to 6 carbon atoms, other examples of which are alkoxy groups containing 1 to 4 carbon atoms, and other examples of which are alkoxy groups containing 1 to 3 carbon atoms.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propyl)Oxy, -OCH 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentyloxy (n-pentyloxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyloxy (-OCH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyloxy (-OCH (CH)) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH)) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And the like, wherein the alkoxy group may independently be unsubstituted or substituted with one or more substituents described herein.
The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" denote alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy and the like.
The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl group having one or more hydroxyl substituents, wherein the alkyl group has the meaning as described herein. Examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl (-CH) 2 CH 2 OH), 1-hydroxyethyl (-CH) 2 OHCH 3 ) 1, 2-dihydroxyethyl, 2, 3-dihydroxypropyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, hydroxybutyl, and the like. The hydroxyalkyl group may be optionally substituted with one or more substituents described herein.
The term "cycloalkyl" refers to a saturated, monocyclic, bicyclic, or tricyclic ring system containing 3-12 carbon atoms having one or more points of attachment to the rest of the molecule. The bicyclic ring system includes spirobicyclic rings and fused bicyclic rings. In some of these embodiments, cycloalkyl is a ring system containing 3 to 10 carbon atoms; in other embodiments, the cycloalkyl group is a ring system containing 3 to 8 carbon atoms; in other embodiments, the cycloalkyl group is a ring system containing 3 to 6 carbon atoms; in other embodiments, the cycloalkyl group is a ring system containing 5 to 6 carbon atoms; examples of cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. And the cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents as described herein.
The term "cycloalkylalkylene" means that the alkyl group may be substituted by one or more cycloalkyl groups, wherein alkyl and cycloalkyl groups have the meaning as described herein. In some of these embodiments, cycloalkylalkylene groups refer to "lower cycloalkylalkylene" groups, i.e., the cycloalkyl group is attached to C 1-6 On the alkyl group of (a). In other embodiments, the cycloalkyl group is attached to C 1-4 On the alkyl group of (a). In other embodiments, the cycloalkyl group is attached to C 1-3 On the alkyl group of (a). In other embodiments, the cycloalkyl group is attached to C 1-2 On the alkyl group of (a). Examples include, but are not limited to, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. The cycloalkylalkylene groups may be independently unsubstituted or substituted with one or more substituents described herein.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic, or tricyclic ring system containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen, and wherein the ring system has one or more attachment points to the remainder of the molecule. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH 2 -the group may optionally be replaced by-C (═ O) -.The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, thiazepanyl, homopiperazinyl, oxazepanyl, and the like
Figure BDA0003601503990000071
Radical, diaza
Figure BDA0003601503990000072
Radical, S-N-aza
Figure BDA0003601503990000073
Radicals, indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. In heterocyclic radicals of-CH 2 Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane and 1, 1-dioxothiomorpholinyl. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.
In some embodiments, heterocyclyl is a 3-6 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 3 to 6 atoms may be carbon-based or nitrogen-based, and-CH 2 -the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may beOptionally oxidized to S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 3 to 6 atoms include, but are not limited to: oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl. In heterocyclic radicals of-CH 2 Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl and 3, 5-dioxopiperidinyl. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane and 1, 1-dioxothiomorpholinyl. Said heterocyclyl group of 3 to 6 atoms may be optionally substituted by one or more substituents as described herein.
In some embodiments, heterocyclyl is a 5-6 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 5-6 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 5 to 6 atoms may be carbon-based or nitrogen-based, and-CH 2 -the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 5 to 6 atoms include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl. In heterocyclic radicals of-CH 2 Examples of substitution of the-group by-C (═ O) -Including, but not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl and 3, 5-dioxopiperidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, 1, 1-dioxothiomorpholinyl. Said heterocyclyl group of 5 to 6 atoms may be optionally substituted by one or more substituents as described herein.
In other embodiments, heterocyclyl is a 5-atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 5 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a 5-atom heterocyclic group may be carbon-based or nitrogen-based, and-CH 2 -the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of 5-atom heterocyclic groups include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl. In heterocyclic radicals of-CH 2 Examples of-groups substituted with-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl and oxo-1, 3-thiazolidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group. The 5-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In other embodiments, heterocyclyl is a 6-atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 6 atoms may be carbon-based or nitrogen-based, and-CH 2 -the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 6 atoms include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl. In heterocyclic radicals of-CH 2 Examples of-groups substituted with-C (═ O) -include, but are not limited to, 2-piperidinonyl and 3, 5-dioxopiperidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, 1, 1-dioxothiomorpholinyl. The 6-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
The term "heterocyclylalkylene" means that an alkyl group may be substituted with one or more heterocyclyl groups, where alkyl and heterocyclyl groups have the meanings as described herein. In some of these embodiments, heterocyclylalkylene groups refer to "lower heterocyclylalkylene" groups, i.e., the heterocyclyl group is attached to C 1-6 On the alkyl group of (a). In other embodiments, the heterocyclyl group is attached to C 1-4 On the alkyl group of (a). In other embodiments, the heterocyclyl group is attached to C 1-2 On the alkyl group of (a). Examples include, but are not limited to, 2-pyrrolidinoethyl, 3-azetidinemethyl, and the like. The heterocyclylalkylene group may independently be unsubstituted or substituted with one or more substituents described herein.
The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state form of N, S and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
The term "halogen" refers to F, Cl, Br or I.
The term "aryl" used alone or as a majority of "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms forming a ring and one or more attachment points are attached to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g., aromatic rings may include phenyl, naphthyl and anthracenyl. The aryl group can be independently unsubstituted or substituted with one or more substituents described herein.
The term "arylalkylene" means that an alkyl group can be substituted with one or more aryl groups, wherein alkyl and aryl groups have the meaning described herein, and wherein in some embodiments, an arylalkylene group refers to a "lower arylalkylene" group, i.e., an aryl group attached to C 1-6 On the alkyl group of (a). In other embodiments, the arylalkylene group refers to a C-containing group 1-4 The "phenylalkylene" of an alkyl group of (a). In other embodiments, an arylalkylene group refers to an aryl group attached to C 1-2 On the alkyl group of (a). Specific examples thereof include benzyl, diphenylmethyl, phenethyl and the like. The arylalkylene group can independently be unsubstituted or substituted with one or more substituents described herein.
The term "heteroaryl" may be used alone or as a majority of "heteroarylalkyl" or "heteroarylalkoxy" and refers to monocyclic, bicyclic, and tricyclic ring systems containing 5 to 14 ring atoms, or 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is 5-12 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-10 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-6 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 6 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N.
In other embodiments, heteroaryl includes, but is not limited to, the following monocyclic groups: 2-furyl group, 3-furyl group, N-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, N-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, pyridazinyl group (e.g., 3-pyridazinyl group), 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, tetrazolyl group (e.g., 5H-tetrazolyl group, 2H-tetrazolyl group), triazolyl group (e.g., 2-triazolyl group, 5-triazolyl group, 4H-1,2, 4-triazolyl, 1H-1,2, 4-triazolyl, 1,2, 3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic groups are also included, but are in no way limited to these bicyclic groups: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl). The heteroaryl group is optionally substituted with one or more substituents described herein.
The term "heteroarylalkylene" means that the alkyl group may be substituted with one or more heteroaryl groups, wherein the alkyl and heteroaryl groups have the meaning as described herein, and wherein in some embodiments, a heteroarylalkylene group refers to a "lower heteroarylalkylene" group, i.e., the heteroaryl group is attached to C 1-6 On the alkyl group of (a). In other embodiments, the heteroaryl group is attached to C 1-4 On the alkyl group of (a). In other embodiments, the heteroaryl group is attached to C 1-2 On the alkyl group of (a). Wherein the concrete isExamples include 2-picolyl, 3-furanethyl, and the like. The heteroarylalkylene group can be independently unsubstituted or substituted with one or more substituents described herein.
The terms "cycloalkylalkylene", "heterocyclylalkylene", "arylalkylene", "heteroarylalkylene" denote cycloalkyl, heterocyclyl, aryl and heteroaryl groups connected to the rest of the molecule through an alkylene group, wherein the alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups all have the meaning as indicated in the present invention. The alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups of the "alkylenecycloalkyl", "alkyleneheterocyclyl", "alkylenearyl", "alkyleneheteroaryl" groups are optionally substituted with one or more substituents as described herein.
The term "unsaturated" as used in the present invention means that the group contains one or more unsaturations.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.
"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
The term "enantiomeric excess (enantiomeric excess)" or "ee%" is used to describe. It represents the excess of one enantiomer over the other, usually expressed as a percentage.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). The optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. Racemic products can also be separated by chiral chromatographyE.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2) nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:APractical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The compounds of the present disclosure may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention contemplates that all stereoisomeric forms of the compounds of formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, and mixtures thereof, such as racemic mixtures, are integral to the invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.
General synthetic procedure
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (II), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents other than those described herein, or by some routine modification of the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.
NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer, CDC1 3 、DMSO-d 6 、CD 3 OD or acetone-d 6 To dissolveThe agents (in ppm) were referenced to TMS (0ppm) or chloroform (7.26 ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).
The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18,2.1X30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase: 5% -95% (CH with 0.1% formic acid) 3 CN) in (H containing 0.1% formic acid) 2 O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.
The purity of the compound was determined by High Performance Liquid Chromatography (HPLC), using Agilent 1260HPLC (column model: Agilent zorbax Eclipse Plus C18) and detected by DAD detector, and finally calculated by area normalization to obtain the purity of the compound.
The following acronyms are used throughout the invention:
MeOH methanol CDCl 3 Deuterated chloroform
DCM Methylene dichloride Mn Manganese powder
PE Petroleum ether ZnI 2 Zinc iodide
EtOAc Ethyl acetate NiBr 2 dme Ethylene glycol dimethyl ether nickel bromide
The following synthetic scheme sets forth the experimental procedures for preparing the compounds of formula (I). Wherein R and n have the meanings given in the description.
Reaction scheme 1
Figure BDA0003601503990000111
The compound represented by formula (5) can be prepared by reaction scheme 1. Formula (A), (B) and1) The compound reacts under the action of sodium borohydride to obtain a compound shown in a formula (I)2) The compounds shown. Formula (A), (B) and2) Reacting the compound shown in the formula (I) with elemental bromine to obtain a compound shown in the formula (I)3) The compounds shown. Formula (A), (B) and3) A compound of the formula4) The compound is subjected to coupling reaction under the action of a catalyst to obtain a compound shown in the formula (I)5) The compounds shown.
Reaction scheme 2
Figure BDA0003601503990000112
Formula (A), (B) and5) The compounds shown can be prepared by reaction scheme 2. Formula (A), (B) and6) A compound of the formula7) The compound is subjected to condensation reaction to obtain a compound of the formula (A)4) The compounds shown. Formula (A), (B) and3) A compound of the formula4) The compound is subjected to coupling reaction under the action of a catalyst to obtain a compound shown in the formula (I)5) The compounds shown.
Reaction scheme 3
Figure BDA0003601503990000121
The compound represented by formula (5) can be prepared by reaction scheme 3. Formula (A), (B) and8) A compound of the formula9) The compound shown in the formula (I) is reacted to obtain2) The compounds shown. Formula (A), (B) and2) Reacting the compound shown in the formula (I) with elemental bromine to obtain a compound shown in the formula (I)3) The compounds shown. Formula (A), (B) and3) A compound of the formula4) The compound is subjected to coupling reaction under the action of a catalyst to obtain a compound shown in the formula (I)5) The compounds shown.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Examples
Synthesis of ligand L1
Figure BDA0003601503990000122
Under the protection of nitrogen, a chiral oxazoline precursor (1.0g,3.0mmol) was dissolved in dry tetrahydrofuran (20mL), the temperature was reduced to-40 ℃, LiHMDS (9.0mL,9.0mmol,1M in THF) was added dropwise to the system, the mixture was stirred for 30 minutes, bromomethyl-1, 1' -biphenyl (2.2g,9.0mmol) was added to the system, and the mixture was stirred at room temperature for 12 hours. Quenched by addition of saturated ammonium chloride, extracted with ethyl acetate (3 × 50mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 4:1) to give chiral oxazoline ligand L1. White solid, 1.0g, yield 50%.
1 H NMR(400MHz,CDCl 3 )δ7.60(dd,J＝15.1,7.8Hz,8H),7.49–7.40(m,8H),7.40–7.27(m,7H),7.24(t,J＝7.3Hz,2H),7.17(d,J＝7.1Hz,4H),4.39(dq,J＝9.2,5.5Hz,2H),4.21(t,J＝8.9Hz,2H),3.97(t,J＝8.0Hz,2H),3.47(d,J＝2.6Hz,4H),3.08(dd,J＝13.7,5.2Hz,2H),2.47(dd,J＝13.7,9.2Hz,2H).
13 C NMR(101MHz,CDCl 3 )δ166.73,140.90,139.74,137.99,135.88,130.96,129.14,128.74,128.51,127.16,127.02,126.77,126.43,72.03,67.40,48.33,41.55,39.18.
Synthesis of ligand L2
Figure BDA0003601503990000123
1-Bromomethylnaphthalene (12.2g,55mmol) and potassium carbonate (8.6g,62.5mmol) were added to a solution of malononitrile (1.7g,25mmol) in acetonitrile (50mL) at room temperature and stirred at room temperature for 24 hours. Concentrated under reduced pressure, dichloromethane (100mL) was added and washed with water three times (3X 50 mL). Vacuum concentrating to solid, washing with petroleum ether to obtain the intermediate product in equivalent yield, and further purifying.
1 H NMR(400MHz,CDCl 3 )δ7.99(d,J＝8.3Hz,2H),7.91(d,J＝7.9Hz,4H),7.69(d,J＝6.8Hz,2H),7.60–7.47(m,6H),3.86(s,4H). 13 C NMR(101MHz,CDCl 3 )δ134.02,132.09,129.71,129.42,129.13,128.17,126.66,126.16,125.34,123.18,115.46,40.44,39.07.
Figure BDA0003601503990000131
Zinc chloride (4.1g,30mmol) was added to a solution of substituted malononitrile (3.5g,10mmol) in chlorobenzene (30mL) at room temperature, followed by (S) -2-amino-3-phenylpropyl-1-ol (4.5g,30mmol), warmed to 130 deg.C and stirred for 24 hours. The reaction mixture was cooled to room temperature, and water (10mL) and ethylenediamine (5mL) were added thereto, followed by stirring at room temperature for 1 hour. The system was extracted with water (100mL) and dichloromethane (50mL) and extracted three times with dichloromethane (3X 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 4:1) to give chiral oxazoline ligand L2. White solid, 4.7g, yield 77%.
1 H NMR(400MHz,CDCl 3 )δ8.35–8.20(m,2H),7.89(dd,J＝5.7,3.8Hz,2H),7.79(d,J＝8.1Hz,2H),7.70(d,J＝7.0Hz,2H),7.52(dd,J＝6.2,3.4Hz,4H),7.48–7.39(m,2H),7.29–7.17(m,6H),7.02(d,J＝7.0Hz,4H),4.24–3.94(m,6H),3.69(t,J＝8.9Hz,2H),3.51(t,J＝7.9Hz,2H),2.83(dd,J＝13.6,5.0Hz,2H),1.92(dd,J＝13.6,9.6Hz,2H).
13 C NMR(101MHz,CDCl 3 )δ166.79,138.01,133.80,133.42,133.04,129.02,128.72,128.36,127.99,127.39,126.26,125.52,125.24,125.15,124.17,71.63,67.16,48.24,40.93,36.05.
Example 1(R) -3-methyl-N, 5-diphenylpentanamide 3a
Figure BDA0003601503990000132
Under nitrogen protection, ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL) were added to a 10mL reaction tube, stirred at room temperature for 30 minutes, and zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylbutylamide 1a (48.0mg,0.2mmol) and (2-iodoethyl) benzene 2a (139.2mg,0.6mmol,3.0eq.) were added to the reaction system, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10:1) to give the title compound as a white solid 3a, 40mg (yield 76%), 92% ee.
1 H NMR(600MHz,CDCl 3 ))δ7.42(d,J＝7.7Hz,2H),7.24(t,J＝7.7Hz,2H),7.21–7.18(m,2H),7.07(dd,J＝47.6,7.1Hz,5H),2.71–2.48(m,2H),2.32(dd,J＝13.3,5.2Hz,1H),2.07(ddt,J＝20.2,13.6,7.6Hz,2H),1.73–1.63(m,1H),1.49(d,J＝6.3Hz,1H),1.00(d,J＝6.1Hz,3H).
13 C NMR(151MHz,CDCl 3 )δ170.62,142.31,137.85,128.98,128.39,128.34,125.79,124.24,119.83,119.77,45.43,38.58,33.37,30.63,19.64.
Example 2(R) -N- (4-methoxyphenyl) -3-methyl-5-phenylpentanamide 3b
Figure BDA0003601503990000133
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N- (4-methoxyphenyl) butanamide 1b (54.0mg,0.2mmol), and (2-iodoethyl) benzene 2a (139.2mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 4:1) to give the title compound as a white solid 3b, 44mg (yield 74%), 92% ee.
1 H NMR(400MHz,CDCl 3 )δ7.35–7.27(m,2H),7.19(dd,J＝12.5,4.6Hz,3H),7.13–7.05(m,3H),6.80–6.71(m,2H),3.69(s,3H),2.57(dddd,J＝39.3,13.7,10.2,5.8Hz,2H),2.28(q,J＝9.5Hz,1H),2.10–1.97(m,2H),1.64(dt,J＝14.4,5.3Hz,1H),1.45(dddd,J＝13.2,10.5,7.4,5.7Hz,1H),0.97(d,J＝5.9Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.58,156.33,142.33,130.96,128.33,128.29,125.72,121.85,114.04,55.42,45.12,38.58,33.33,30.63,19.59.
Example 3 methyl (R) -4- (3-methyl-5-phenylpentanamide) benzoate 3c
Figure BDA0003601503990000141
Under nitrogen protection, ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL) were added to a 10mL reaction tube, stirred at room temperature for 30 minutes, and zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), methyl 4- (3-bromobutyramide) benzoate 1c (62.0mg,0.2mmol) and (2-iodoethyl) benzene 2a (139.2mg,0.6mmol,3.0eq.), stirred at room temperature for 24 hours were added to the reaction system. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 4:1) to give the title compound as a white solid 3c, 52mg (yield 76%), 92% ee.
1 H NMR(400MHz,CDCl 3 )δ7.89(d,J＝8.4Hz,2H),7.80(s,1H),7.52(d,J＝8.4Hz,2H),7.17(t,J＝7.4Hz,2H),7.11–7.00(m,3H),4.26(q,J＝7.1Hz,2H),2.54(dddd,J＝41.5,13.7,10.2,5.9Hz,2H),2.32(dd,J＝13.9,5.8Hz,1H),2.07(ddd,J＝30.0,13.7,7.4Hz,2H),1.62(ddt,J＝15.8,10.9,5.6Hz,1H),1.51–1.39(m,1H),1.29(t,J＝7.1Hz,3H),0.96(d,J＝6.4Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ171.18,166.23,142.14,142.11,130.65,128.32,128.23,125.74,125.65,118.80,60.85,45.26,38.43,33.24,30.45,19.54,14.26.
Example 4(R) -3-methyl-5-phenyl-N- (2-methylphenyl) pentanamide 3d
Figure BDA0003601503990000142
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N- (2-methylphenyl) butanamide 1d (51.0mg,0.2mmol) and (2-iodoethyl) benzene 2a (139.2mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 20:1) to give the title compound as a white solid 3d, 47mg (yield 83%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ8.25(d,J＝8.2Hz,1H),8.18(s,1H),7.39(d,J＝7.5Hz,1H),7.20(q,J＝7.0Hz,3H),7.13–7.05(m,3H),6.98(t,J＝7.6Hz,1H),2.60(dddd,J＝30.0,13.6,10.3,5.8Hz,2H),2.41(dd,J＝14.0,5.8Hz,1H),2.26(s,3H),2.12(ddd,J＝36.1,13.4,7.2Hz,2H),1.68(td,J＝10.9,9.1,5.0Hz,1H),1.59–1.45(m,1H),1.02(d,J＝6.5Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.67,142.24,138.23,132.80,128.84,128.32,128.29,125.72,125.08,124.28,120.63,45.67,38.60,33.36,30.70,19.66,18.86.
Example 5(R) -N- (2-methoxyphenyl) -3-methyl-5-phenylpentanamide 3e
Figure BDA0003601503990000151
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N- (2-methoxyphenyl) butanamide 1e (54.0mg,0.2mmol), and (2-iodoethyl) benzene 2a (139.2mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 2:1) to give the title compound as a white solid 3e, 38mg (yield 64%) and 90% ee.
1 H NMR(400MHz,CDCl 3 )δ8.31(d,J＝7.4Hz,1H),7.65(s,1H),7.22–7.16(m,2H),7.11(d,J＝7.8Hz,3H),6.96(t,J＝7.7Hz,1H),6.88(t,J＝7.7Hz,1H),6.79(d,J＝8.0Hz,1H),3.79(s,3H),2.60(dtd,J＝24.1,13.7,5.8Hz,2H),2.37(dd,J＝13.7,5.6Hz,1H),2.11(ddd,J＝26.5,13.3,7.2Hz,2H),1.68(ddt,J＝16.2,10.9,5.6Hz,1H),1.55–1.42(m,1H),1.00(d,J＝6.4Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.46,147.65,142.38,128.31,127.64,125.69,123.51,121.07,119.78,109.81,55.61,45.69,38.65,33.41,30.67,19.64.
Example 6(R) -3-methyl-5-phenyl-N- (3,4, 5-trimethoxyphenyl) pentanamide 3f
Figure BDA0003601503990000152
Under nitrogen protection, ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL) were added to a 10mL reaction tube, stirred at room temperature for 30 minutes, and zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N- (3,4, 5-trimethoxyphenyl) butyramide 1f (66.0mg,0.2mmol) and (2-iodoethyl) benzene 2a (139.2mg,0.6mmol,3.0eq.), stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 2:1) to give the title compound as a colorless oil 3f, 50mg (yield 70%), 92% ee.
1 H NMR(600MHz,CDCl 3 )δ7.27(s,1H),7.22–7.17(m,2H),7.12–7.06(m,3H),6.76(s,2H),3.73(s,9H),2.62(ddd,J＝13.7,10.5,5.6Hz,1H),2.53(ddd,J＝13.7,10.4,6.1Hz,1H),2.35–2.24(m,1H),2.05(tt,J＝13.8,7.9Hz,2H),1.68–1.61(m,1H),1.46(tt,J＝13.2,6.6Hz,1H),0.98(d,J＝6.2Hz,3H).
13 C NMR(151MHz,CDCl 3 )δ170.73,153.20,142.22,134.40,134.14,128.33,128.30,128.26,125.74,97.35,60.89,55.98,45.32,38.51,33.31,30.53,19.58.
Example 7(R) -3-methyl-5-phenyl-N- (4- (trifluoromethyl) phenyl) pentanamide 3g
Figure BDA0003601503990000161
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N- (4- (trifluoromethyl) phenyl) butanamide 1g (62.0mg,0.2mmol) and (2-iodoethyl) benzene 2a (139.2mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 15:1) to give the title compound as a white solid 3g, 49mg (yield 73%), 90% ee.
1 H NMR(400MHz,CDCl 3 )δ7.54(d,J＝8.5Hz,2H),7.47(d,J＝8.6Hz,2H),7.32(s,1H),7.20(dd,J＝8.3,6.4Hz,2H),7.14–7.05(m,3H),2.58(dddd,J＝41.0,13.7,10.1,6.0Hz,2H),2.33(dd,J＝13.9,5.8Hz,1H),2.17–1.98(m,2H),1.66(dddd,J＝13.4,10.2,6.3,5.2Hz,1H),1.48(dddd,J＝13.4,10.0,7.8,5.7Hz,1H),0.99(d,J＝6.5Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.97,142.12,140.86,128.40,128.30,126.21(q,J＝4.0Hz),125.85,124.03(q,J＝270.0Hz),119.32,45.35,38.45,33.28,30.50,19.58.
19 F NMR(376MHz,CDCl 3 )δ-62.10.
Example 8(R) -3-methyl-N- (naphthalen-1-yl) -5-phenylpentanamide 3h
Figure BDA0003601503990000162
Under nitrogen protection, ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL) were added to a 10mL reaction tube, stirred at room temperature for 30 minutes, and zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N- (naphthyl-L-yl) butanamide (58.0mg,0.2mmol) and (2-iodoethyl) benzene 2a (139.2mg,0.6mmol,3.0eq.) were added to the reaction system, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10:1) to give the title compound as a white solid for 3h, 40mg (yield 63%), 85% ee.
1 H NMR(400MHz,CDCl 3 )δ7.78(d,J＝5.8Hz,2H),7.73–7.65(m,1H),7.60(d,J＝8.0Hz,1H),7.49(s,1H),7.45–7.33(m,3H),7.19(dd,J＝12.3,5.0Hz,2H),7.15–7.05(m,3H),2.74–2.50(m,2H),2.44(dd,J＝13.8,5.8Hz,1H),2.21(dd,J＝13.7,8.2Hz,1H),2.10(dd,J＝12.5,6.3Hz,1H),1.79–1.65(m,1H),1.55–1.46(m,1H),1.04(d,J＝6.3Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ171.22,142.31,134.06,132.21,128.69,128.36,128.31,127.28,126.20,125.91,125.82,125.76,125.66,121.25,120.67,45.13,38.63,33.35,30.79,19.70.
Example 9(R) -N-cyclohexyl-3-methyl-5-phenylpentanamide 3i
Figure BDA0003601503990000171
To a 10mL reaction tube were added, under nitrogen protection, ethyleneglycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-cyclohexylbutanamide 1i (49.0mg,0.2mmol) and (2-iodoethyl) benzene 2a (139.2mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 2:1) to give the title compound as a white solid 3i, 31mg (yield 58%), 84% ee.
1 H NMR(400MHz,CDCl 3 )δ7.24–7.16(m,2H),7.14–7.05(m,3H),5.28(s,1H),3.80–3.61(m,1H),2.56(ddp,J＝30.0,13.7,5.8Hz,2H),2.13(dd,J＝12.7,5.2Hz,1H),1.97–1.80(m,4H),1.69–1.51(m,4H),1.48–1.37(m,1H),1.34–1.22(m,2H),1.16–0.98(m,3H),0.93(d,J＝6.3Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ171.35,142.46,128.31,128.30,125.68,48.06,44.65,38.65,33.34,33.25,33.18,30.64,25.50,24.84,19.51.
Example 10(R) -N-benzyl-3-methyl-5-phenylpentanamide 3j
Figure BDA0003601503990000172
Under nitrogen protection, ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL) were added to a 10mL reaction tube, stirred at room temperature for 30 minutes, and zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), N-benzyl-3-bromobutanamide 1j (51.0mg,0.2mmol) and (2-iodoethyl) benzene 2a (139.2mg,0.6mmol,3.0eq.) were added to the reaction system, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 2:1) to give the title compound as a white solid 3j, 41mg (yield 73%), 87% ee.
1 H NMR(400MHz,CDCl 3 )δ7.27–7.15(m,7H),7.12–7.03(m,3H),5.73(s,1H),4.34(d,J＝5.7Hz,2H),2.65–2.44(m,2H),2.16(dt,J＝9.6,4.8Hz,1H),2.04–1.89(m,2H),1.61(ddt,J＝15.9,10.9,5.6Hz,1H),1.49–1.35(m,1H),0.93(d,J＝6.3Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ172.14,142.37,138.35,128.64,128.30,128.27,127.78,127.43,125.68,44.37,43.52,38.59,33.31,30.57,19.59.
Example 11(R) -3-phenyl-N-phenylhexanamide 3k
Figure BDA0003601503990000173
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (1148mg,3.6mmol,18.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylhexanamide 1k (54.0mg,0.2mmol) and (2-iodoethyl) benzene 2a (139.2mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 15:1) to give the title compound as a white solid 3k, 33mg (yield 56%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ7.41(d,J＝7.9Hz,2H),7.26–7.15(m,5H),7.13–7.06(m,3H),7.01(t,J＝7.2Hz,1H),2.65–2.48(m,2H),2.23(d,J＝6.9Hz,2H),1.97(q,J＝6.0Hz,1H),1.66–1.51(m,2H),1.37–1.22(m,4H),0.82(t,J＝6.8Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.96,142.44,137.87,128.92,128.34,128.30,125.73,124.17,119.87,42.73,36.01,35.61,35.00,32.97,19.65,14.32.
Example 12(R) -3-phenyl-N-phenylcapramide 3l
Figure BDA0003601503990000181
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (3.1mg,0.01mmol,10 mol%), ligand L1(8.0mg,0.012mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3, 1.0mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (479.0mg,1.5mmol,9.0eq.), manganese powder (16.5mg,0.3mmol,3.0eq.), 3-bromo-N-phenyldecanoamide 1L (33.0mg,0.1mmol), and (2-iodoethyl) benzene 2a (70.0mg,0.3mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 15:1) to give the title compound as a white solid, 3l, 21mg (yield 61%), 92% ee.
1 H NMR(400MHz,CDCl 3 )δ7.41(d,J＝7.7Hz,2H),7.27–7.16(m,4H),7.11(d,J＝6.6Hz,3H),7.07–6.98(m,2H),2.58(t,J＝7.9Hz,2H),2.24(d,J＝6.9Hz,2H),1.97(dt,J＝12.6,6.0Hz,1H),1.69–1.58(m,2H),1.41–1.29(m,2H),1.19(s,10H),0.80(t,J＝6.6Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.84,142.46,137.85,128.96,128.37,128.33,125.76,124.20,119.81,42.81,35.61,35.24,33.71,33.02,31.82,29.84,29.27,26.50,22.64,14.08.
Example 13(R) -3-phenyl-N, 6-diphenylhexanamide 3m
Figure BDA0003601503990000182
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (3.1mg,0.01mmol,10 mol%), ligand L1(8.0mg,0.012mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3, 1.0mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (479.0mg,1.5mmol,9.0eq.), manganese powder (16.5mg,0.3mmol,3.0eq.), 3-bromo-N, 5-diphenylpentanamide 1m (33.0mg,0.1mmol), and 3-iodopropylbenzene 2b (74.0mg,0.3mmol,3.0eq.), and stirred at room temperature for 24 hours. To the reaction system, water and ethyl acetate were added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10:1) to give the title compound as a pale yellow oil 3m, 20mg (yield 53%), 92% ee.
1 H NMR(400MHz,CDCl 3 )δ7.39(d,J＝7.9Hz,2H),7.27–7.15(m,6H),7.14–6.96(m,8H),2.53(q,J＝7.3Hz,4H),2.31–2.12(m,2H),1.98(dq,J＝12.4,6.2Hz,1H),1.58(d,J＝9.3Hz,4H),1.40(dt,J＝12.1,6.4Hz,2H).
13 C NMR(101MHz,CDCl 3 )δ170.74,142.35,142.31,137.79,128.94,128.36,128.31,128.27,125.78,125.71,124.24,119.88,42.65,36.01,35.50,35.02,33.22,32.96,28.34.
Example 14(S) -6- (5-Methylfuran-2-yl) -3-phenyl-N-phenylhexanamide 3N
Figure BDA0003601503990000191
Under nitrogen protection, to a 10mL reaction tube were added ethyleneglycol dimethyl ether nickel bromide (3.1mg,0.01mmol,10 mol%), ligand L1(8.0mg,0.012mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3, 1.0mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (479mg,1.5mmol,15.0eq.), manganese powder (16.5mg,0.3mmol,3.0eq.), 3-bromo-5- (5-methylfuran-2-yl) -N-phenylpentanamide 1N (34.0mg,0.1mmol), and (2-iodoethyl) benzene 2a (70.0mg,0.3mmol,3.0eq.), stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 11:1) to give the title compound as a white solid, 3n, 24mg (yield 67%), 90% ee.
1 H NMR(400MHz,CDCl 3 )δ7.38(d,J＝7.9Hz,2H),7.29(s,1H),7.18(dt,J＝11.5,7.3Hz,4H),7.07(t,J＝8.6Hz,3H),6.99(t,J＝7.2Hz,1H),5.75(s,2H),2.54(q,J＝7.7,6.5Hz,4H),2.24(d,J＝6.9Hz,2H),2.13(s,3H),1.99(dt,J＝12.7,6.3Hz,1H),1.67(ddd,J＝25.4,14.7,6.4Hz,4H).
13 C NMR(101MHz,CDCl 3 )δ170.69,153.87,150.27,142.17,137.80,128.87,128.33,128.29,125.75,124.20,119.96,105.83,105.51,42.25,35.43,34.69,32.86,31.88,25.14,13.44.
Example 15(R) -3-methyl-N-phenylpentanamide 3o
Figure BDA0003601503990000192
Under nitrogen protection, ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL) were added to a 10mL reaction tube, stirred at room temperature for 30 minutes, and zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylbutylamide 1a (48.0mg,0.2mmol) and iodoethane 2c (94.0mg,0.6mmol,3.0eq.), stirred at room temperature for 24 hours were added to the reaction system. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10:1) to give the title compound as a white solid 3o, 35mg (yield 93%), 89% ee.
1 H NMR(600MHz,CDCl 3 )δ7.52(d,J＝7.9Hz,2H),7.49(s,1H),7.30(t,J＝7.9Hz,2H),7.09(t,J＝7.4Hz,1H),2.36(dd,J＝14.0,6.1Hz,1H),2.11(dd,J＝14.0,8.2Hz,1H),1.99(dq,J＝14.0,7.0Hz,1H),1.43(tt,J＝13.2,7.4Hz,1H),1.26(dq,J＝13.9,7.4,6.2Hz,1H),0.98(d,J＝6.6Hz,3H),0.91(t,J＝7.4Hz,3H).
13 C NMR(151MHz,CDCl 3 )δ171.18,137.94,128.89,124.14,119.89,45.12,32.41,29.38,19.17,11.31.
Example 16(R) -3-methyl-N, 6-diphenylhexanamide 3p
Figure BDA0003601503990000201
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylbutylamide 1a (48.0mg,0.2mmol) and 3-iodopropylbenzene 2d (148.0mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10:1) to give the title compound as a white solid, 3p, 34mg (yield 61%), 90% ee.
1 H NMR(400MHz,CDCl 3 )δ7.42(d,J＝7.9Hz,2H),7.26–7.17(m,4H),7.15–7.05(m,4H),7.02(t,J＝7.4Hz,1H),2.53(h,J＝6.9Hz,2H),2.26(q,J＝9.3Hz,1H),2.03(q,J＝7.8Hz,2H),1.64–1.53(m,2H),1.37(td,J＝11.9,10.3,5.4Hz,1H),1.21(dd,J＝10.5,6.8Hz,1H),0.92(d,J＝6.1Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.80,142.48,137.84,128.96,128.35,128.26,125.67,124.22,119.84,45.50,36.37,35.98,30.75,28.86,19.64.
Example 17(R) -3-methyl-N, 7-diphenylpentanamide 3q
Figure BDA0003601503990000202
Under nitrogen protection, ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL) were added to a 10mL reaction tube, stirred at room temperature for 30 minutes, and zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylbutylamide 1a (48.0mg,0.2mmol) and (4-iodobutyl) benzene 2e (156.0mg,0.6mmol,3.0eq.) were added to the reaction system, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10:1) to give the title compound as a white solid 3q, 38mg (yield 56%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ7.43(d,J＝7.9Hz,2H),7.28(s,1H),7.20(dt,J＝14.7,7.3Hz,4H),7.09(t,J＝6.7Hz,3H),7.01(t,J＝7.4Hz,1H),2.52(t,J＝7.7Hz,2H),2.30–2.19(m,1H),2.07–1.93(m,2H),1.53(p,J＝7.2,6.5Hz,2H),1.32(dt,J＝12.8,6.0Hz,2H),1.21–1.13(m,2H),0.89(d,J＝6.3Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.99,142.59,137.88,128.92,128.35,128.20,125.58,124.18,119.87,45.46,36.59,35.84,31.51,30.79,26.57,19.66.
Example 18(R) -3-methyl-N-phenylcapramide 3R
Figure BDA0003601503990000203
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (957.0mg,3.0mmol,15.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylbutanamide 1a (48.0mg,0.2mmol), and 1-iodoheptane 2f (144.0mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 15:1) to give the title compound as a white solid 3r, 33mg (yield 59%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ7.52(d,J＝7.9Hz,2H),7.31(q,J＝8.1,6.9Hz,3H),7.09(t,J＝7.4Hz,1H),2.35(dd,J＝13.3,5.3Hz,1H),2.08(ddd,J＝19.1,12.5,6.3Hz,2H),1.44–1.19(m,14H),0.98(d,J＝6.3Hz,3H),0.88(t,J＝6.8Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ171.05,137.93,128.93,124.15,119.85,45.59,36.84,31.86,30.89,29.77,29.58,29.27,26.97,22.64,19.67,14.08.
Example 19(R) -3-methyl-5-phenoxy-N-phenylpentanamide 3s
Figure BDA0003601503990000211
To a 10mL reaction tube were added, under nitrogen protection, ethyleneglycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylbutylamide 1a (48.0mg,0.2mmol) and 2g (149.0mg,0.6mmol,3.0eq.) of (2-iodoethoxy) benzene, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 4:1) to give the title compound as a white solid 3s, 38mg (yield 67%), 92% ee.
1 H NMR(400MHz,CDCl 3 )δ7.52(s,1H),7.44(d,J＝7.9Hz,2H),7.25–7.15(m,4H),7.02(t,J＝7.3Hz,1H),6.93–6.76(m,3H),3.97(ddt,J＝15.8,9.4,5.2Hz,2H),2.46–2.10(m,3H),1.77(ddq,J＝57.8,13.0,6.1Hz,3H),1.01(d,J＝6.5Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.54,158.68,137.87,129.49,128.94,124.20,120.81,119.85,114.42,65.90,44.97,35.39,28.54,19.84.
Example 20(R) -3-methyl-5- (naphthalen-2-yl) -N-phenylpentanamide 3t
Figure BDA0003601503990000212
Under nitrogen protection, ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL) were added to a 10mL reaction tube, stirred at room temperature for 30 minutes, and zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylbutanamide 1a (48.0mg,0.2mmol) and 2- (2-iodoethyl) naphthalene were added to the reaction system for 2 hours (169.0mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 15:1) to give the title compound as a white solid 3t, 38mg (yield 59%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ7.93(d,J＝8.6Hz,1H),7.80–7.72(m,1H),7.62(d,J＝8.1Hz,1H),7.48–7.33(m,4H),7.34–7.27(m,1H),7.27–7.16(m,3H),7.13(s,1H),7.01(t,J＝7.3Hz,1H),3.03(dddd,J＝47.6,13.9,10.8,5.5Hz,2H),2.35(dd,J＝13.2,5.1Hz,1H),2.25–2.05(m,2H),1.77(ddt,J＝16.1,10.8,5.4Hz,1H),1.59(dddd,J＝13.2,10.8,7.6,5.5Hz,1H),1.07(d,J＝6.3Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.62,138.44,137.78,133.88,131.71,128.94,128.79,126.60,125.84,125.79,125.57,125.43,124.25,123.65,119.88,45.37,37.95,31.12,30.59,19.70.
Example 21(R) -5- (2, 3-dihydrobenzofuran-6-yl) -3-methyl-N-phenylpentanamide 3u
Figure BDA0003601503990000221
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylbutylamide 1a (48.0mg,0.2mmol) and 6- (2-iodoethyl) -2, 3-dihydrobenzofuran 2i (164.0mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10:1) to give the title compound as a white solid 3u, 42mg (yield 68%), 87% ee.
1 H NMR(400MHz,CDCl 3 )δ7.50(d,J＝7.9Hz,2H),7.31(t,J＝7.8Hz,2H),7.23(s,1H),7.10(t,J＝7.3Hz,1H),7.01(s,1H),6.90(d,J＝7.9Hz,1H),6.69(d,J＝8.1Hz,1H),4.53(t,J＝8.7Hz,2H),3.14(t,J＝8.6Hz,2H),2.72–2.48(m,2H),2.38(dd,J＝13.4,5.5Hz,1H),2.13(ddt,J＝20.2,13.6,7.6Hz,2H),1.70(ddt,J＝15.5,10.7,5.7Hz,1H),1.52(dq,J＝11.5,6.7,5.8Hz,1H),1.06(d,J＝6.3Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.69,158.16,137.85,134.27,128.94,127.62,127.01,124.80,124.19,119.81,108.90,71.10,45.42,39.06,32.70,30.51,29.75,19.63.
Example 22(R) -3-methyl-N-phenyl-6- (thien-2-yl) hexanamide 3v
Figure BDA0003601503990000222
Under nitrogen protection, ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL) were added to a 10mL reaction tube, stirred at room temperature for 30 minutes, and zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylbutanamide 1a (48.0mg,0.2mmol) and 2- (3-iodopropyl) -thiophene 2j (151.0mg,0.6mmol,3.0eq.), stirred at room temperature for 24 hours were added to the reaction system. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10:1) to give the title compound as a white solid 3v, 45mg (yield 78%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ7.51(d,J＝7.8Hz,2H),7.31(t,J＝7.9Hz,2H),7.23(s,1H),7.15–7.06(m,2H),6.90(dd,J＝5.1,3.4Hz,1H),6.80–6.69(m,1H),2.92–2.73(m,2H),2.35(q,J＝9.3Hz,1H),2.20–2.04(m,2H),1.82–1.67(m,2H),1.48(ddt,J＝15.7,10.5,5.2Hz,1H),1.32(dt,J＝10.3,6.3Hz,1H),1.00(d,J＝6.1Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.75,145.34,137.83,128.96,126.66,124.24,124.07,122.83,119.86,45.40,36.11,30.63,29.95,29.17,19.62.
Example 23(R) -5- (3-chlorophenyl) -3-methyl-N-phenylpentanamide 3w
Figure BDA0003601503990000231
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylbutylamide 1a (48.0mg,0.2mmol), and 1-chloro-3- (2-iodoethyl) phenyl 2k (160.0mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10:1) to give the title compound as a white solid 3w, 41mg (yield 68%) and 90% ee.
1 H NMR(400MHz,CDCl 3 )δ7.50(d,J＝7.8Hz,2H),7.31(t,J＝7.9Hz,3H),7.22–7.13(m,3H),7.10(t,J＝7.4Hz,1H),7.05(d,J＝7.1Hz,1H),2.74–2.51(m,2H),2.38(dd,J＝13.5,5.5Hz,1H),2.14(ddt,J＝19.0,12.6,7.1Hz,2H),1.72(dq,J＝15.9,5.4Hz,1H),1.58–1.47(m,1H),1.06(d,J＝6.3Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.51,144.32,137.77,134.06,129.60,128.97,128.40,126.52,125.96,124.29,119.87,45.31,38.29,33.07,30.53,19.57.
Example 24(R) -4- (3-methyl-5-oxo-5- (anilino) pentyl) phenylacetate 3X
Figure BDA0003601503990000232
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylbutylamide 1a (48.0mg,0.2mmol), and 2L of 4- (2-iodoethyl) phenylacetate (174.0mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10:1) to give the title compound as a white solid, 3 ×, 33mg (yield 51%), 90% ee.
1 H NMR(400MHz,CDCl 3 )δ7.50(d,J＝8.0Hz,2H),7.31(t,J＝7.8Hz,2H),7.24(s,1H),7.17(d,J＝8.3Hz,2H),7.10(t,J＝7.4Hz,1H),6.98(d,J＝8.4Hz,2H),2.65(dtt,J＝24.0,13.8,5.8Hz,2H),2.36(td,J＝9.3,4.2Hz,1H),2.29(s,3H),2.13(tt,J＝13.4,7.5Hz,2H),1.73(ddt,J＝15.5,10.6,5.5Hz,1H),1.59–1.48(m,1H),1.06(d,J＝6.2Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.57,169.73,148.67,139.89,137.84,129.21,128.95,124.21,121.35,119.82,45.35,38.49,32.73,30.55,21.11,19.58.
Example 25(R) -4-methyl-6-oxo-6- (phenylamine) hexylbenzyl ester 3y
Figure BDA0003601503990000233
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L2(15.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylbutylamide 1a (48.0mg,0.2mmol) and 3-iodopropylbenzyl ester 2m (174.0mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 4:1) to give the title compound as a white solid 3y, 33mg (yield 50%), 90% ee.
1 H NMR(400MHz,CDCl 3 )δ8.09–7.99(m,2H),7.56–7.50(m,3H),7.43(t,J＝7.7Hz,2H),7.30(t,J＝7.9Hz,2H),7.09(t,J＝7.4Hz,1H),4.50(dt,J＝11.4,6.5Hz,1H),4.35(dt,J＝11.2,6.6Hz,1H),2.50(dd,J＝13.5,5.3Hz,1H),2.24(ddd,J＝32.7,13.6,7.5Hz,2H),1.88(dq,J＝12.9,6.4Hz,1H),1.73(dq,J＝13.8,6.7Hz,1H),1.09(d,J＝6.5Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.40,166.91,137.90,133.00,130.13,130.07,129.56,128.94,128.38,124.20,119.78,62.86,44.79,35.38,28.23,19.76.
Example 26(R) -5- (1, 3-Dioxolan-2-yl) -3-methyl-N-phenylpentanamide 3z
Figure BDA0003601503990000241
Under nitrogen protection, to a 10mL reaction tube were added ethyleneglycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylbutylamide 1a (48.0mg,0.2mmol) and 2- (2-iodoethyl) -1, 3-dioxolane 2N (137.0mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 4:1) to give the title compound as a colorless oil 3z, 33mg (yield 62%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ7.51(d,J＝7.9Hz,2H),7.40(s,1H),7.30(t,J＝7.9Hz,2H),7.09(t,J＝7.4Hz,1H),4.85(t,J＝4.7Hz,1H),4.02–3.90(m,2H),3.90–3.79(m,2H),2.38(q,J＝9.2Hz,1H),2.18–2.04(m,2H),1.71(ddt,J＝19.0,13.6,7.1Hz,2H),1.52(ddt,J＝15.8,10.6,5.4Hz,1H),1.37(dq,J＝17.9,6.5Hz,1H),1.01(d,J＝6.1Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.71,137.93,128.93,124.14,119.81,104.58,64.83,64.81,45.10,31.13,30.72,30.66,19.63.
Example 27(R) -5- (benzyloxy) -3-methyl-N-phenylpentanamide 3aa
Figure BDA0003601503990000242
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylbutylamide 1a (48.0mg,0.2mmol) and ((2-iodoethoxy) methyl) benzene 2o (157.0mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 10:1) to give the title compound as a white solid 3aa, 45mg (yield 75%), 93% ee.
1 H NMR(400MHz,CDCl 3 )δ7.92(s,1H),7.32–7.19(m,7H),7.19–7.10(m,2H),6.95(t,J＝7.3Hz,1H),4.43(s,2H),3.53(dddd,J＝37.3,9.5,6.7,5.1Hz,2H),2.37–2.07(m,3H),1.60(hept,J＝8.2Hz,2H),0.95(d,J＝6.6Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.77,138.09,137.89,128.72,128.49,128.00,127.85,123.78,119.57,73.38,68.66,44.63,35.24,29.18,20.05.
Example 28(R) -5- ((tert-butyldimethylsilyl) oxy) -3-methyl-N-phenylpentanamide 3ab
Figure BDA0003601503990000251
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (3.1mg,0.01mmol,10 mol%), ligand L1(8.0mg,0.012mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3, 1.0mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2mg,1.8mmol,9.0eq.), manganese powder (16.5mg,0.3mmol,3.0eq.), 3-bromo-N-phenylbutanamide 1a (24.0mg,0.1mmol), and tert-butyl- (2-iodoethoxy) dimethylsilane 2p (103.0mg,0.3mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 15:1) to give the title compound as a colorless oil 3ab, 21mg (yield 56%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ7.52(d,J＝7.9Hz,2H),7.35–7.24(m,3H),7.09(t,J＝7.4Hz,1H),3.59(t,J＝6.6Hz,2H),2.42–2.29(m,1H),2.16–1.98(m,2H),1.56–1.44(m,2H),1.42–1.18(m,8H),0.98(d,J＝6.3Hz,3H),0.89(s,9H),0.04(s,6H).
13 C NMR(101MHz,CDCl 3 )δ170.96,137.92,128.94,124.16,119.81,63.27,45.58,36.78,32.81,30.87,29.56,26.96,25.97,25.77,19.66,18.36,5.27.
Example 29(R) -4-cyclohexyl-3-methyl-N-phenylpentanamide 3ac
Figure BDA0003601503990000252
Under nitrogen protection, to a 10mL reaction tube were added ethylene glycol dimethyl ether nickel bromide (6.2mg,0.02mmol,10 mol%), ligand L1(16.0mg,0.024mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3,1.5mL), stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (1148.0mg,3.6mmol,18.0eq.), manganese powder (33.0mg,0.6mmol,3.0eq.), 3-bromo-N-phenylbutylamide 1a (48.0mg,0.2mmol) and (iodomethyl) cyclohexane 2q (134.0mg,0.6mmol,3.0eq.), and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 15:1) to give the title compound as a colorless oil 3ac, 25mg (yield 49%), 87% ee.
1 H NMR(400MHz,CDCl 3 )δ7.52(d,J＝7.9Hz,2H),7.31(t,J＝7.8Hz,3H),7.09(t,J＝7.4Hz,1H),2.33(dd,J＝13.6,5.5Hz,1H),2.18(dq,J＝13.7,6.9,6.2Hz,1H),2.08(dd,J＝13.6,8.2Hz,1H),1.67(q,J＝14.9,11.5Hz,5H),1.33–1.04(m,6H),0.97(d,J＝6.5Hz,3H),0.84(dt,J＝20.5,11.3Hz,2H).
13 C NMR(101MHz,CDCl 3 )δ170.98,137.92,128.94,124.15,119.85,45.94,44.83,34.83,34.04,32.90,27.78,26.62,26.38,26.27,19.88.
Example 30(3R) -3,6, 10-trimethyl-N-phenylundecanamide 3ad
Figure BDA0003601503990000261
Under nitrogen protection, ethylene glycol dimethyl ether nickel bromide (3.1mg,0.01mmol,10 mol%), ligand L1(8.0mg,0.012mmol,12 mol%), a mixed solvent of isobutanol and sec-amyl alcohol (1:3, 1.0mL) were added to a 10mL reaction tube, stirred at room temperature for 30 minutes, and zinc iodide (479.0mg,1.5mmol,15.0eq.), manganese powder (16.5mg,0.3mmol,3.0eq.), 3-bromo-N-phenylbutanamide 1a (24.0mg,0.1mmol) and 1-iodo-3, 7-dimethyloctane 2r (80.0mg,0.3mmol,3.0eq.) were added to the reaction system, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) ═ 15:1) to give the title compound as a white solid, 3ad, 21mg (yield 70%), 87%/88% ee.
1 H NMR(400MHz,CDCl 3 )δ7.52(d,J＝8.0Hz,3H),7.30(t,J＝7.8Hz,2H),7.09(t,J＝7.4Hz,1H),2.37(ddd,J＝14.2,8.7,5.7Hz,1H),2.07(ddt,J＝33.0,18.5,7.3Hz,2H),1.51(dp,J＝13.2,6.6Hz,1H),1.40–1.07(m,11H),0.98(dd,J＝6.4,2.7Hz,3H),0.93–0.79(m,9H).
13 C NMR(101MHz,CDCl 3 )δ171.15,137.94,128.89,124.14,119.92,45.63,45.41,39.30,39.28,37.37,37.07,34.30,34.27,34.22,34.18,32.98,32.85,31.25,31.13,27.92,24.75,24.69,22.68,22.58,19.81,19.72,19.62,19.56.
While the methods of the present invention have been described in terms of several embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other variations and combinations of the techniques described herein, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention. Those skilled in the art can modify the reaction parameters appropriately to achieve the desired results in view of the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.

Claims (10)

1. A preparation method of chiral beta-alkyl amide compounds,
Figure FDA0003601503980000011
wherein: the preparation method comprises the following steps: under the protection of inert gas, carrying out coupling reaction on a compound shown in a formula (II) and a compound shown in a formula (III) in an organic solvent in the presence of a catalyst, a ligand, a reducing agent and an additive to obtain a compound shown in a formula (I);
each R 1 And R 2 Independently is C 1-12 Alkyl radical, C 1-12 Hydroxyalkyl radical, C 6-10 aryl-C 1-8 Alkylene or heteroaryl of 5 to 12 atoms-C 1-8 Alkylene, wherein said C 1-12 Alkyl radical, C 1-12 Hydroxyalkyl radical, C 6-10 aryl-C 1-8 Alkylene and heteroaryl of 5 to 12 atoms-C 1-8 Alkylene is independently unsubstituted or substituted by 1,2,3,4 or 5 groups selected from D, F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、-OC(O)CH 3 、-OC(O)C 6 H 5 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy, tert-butyldimethylsilyl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3 to 8 atoms, C 6-10 Aryl radical, C 6-10 aryl-C 1-6 Alkylene and 5-12 atoms;
R 3 independently is C 1-6 Alkyl radical, C 3-8 Cycloalkyl or C 6-10 Aryl, wherein said C 1-6 Alkyl radical, C 3-8 Cycloalkyl and C 6-10 Aryl is independently unsubstituted or substituted by 1,2,3,4 or 5 groups selected from D, F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 3-8 Cycloalkyl and C 6-10 Aryl group.
2. The method of claim 1, wherein each R is 1 And R 2 Independently is C 1-10 Alkyl radical, C 1-10 Hydroxyalkyl radical, C 6-10 aryl-C 1-6 Alkylene or heteroaryl of 5 to 12 atoms-C 1-6 Alkylene, wherein said C 1-10 Alkyl radical, C 1-10 Hydroxyalkyl radical, C 6-10 aryl-C 1-6 Alkylene and heteroaryl of 5 to 12 atoms-C 1-6 Alkylene is independently unsubstituted or substituted by 1,2,3,4 or 5 groups selected from D, F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、-OC(O)CH 3 、-OC(O)C 6 H 5 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy, tert-butyldimethylsilyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C 6-10 Aryl radical, C 6-10 aryl-C 1-4 Alkylene and 5-10 atoms;
R 3 independently is C 1-4 Alkyl radical, C 3-6 Cycloalkyl or C 6-10 Aryl, wherein said C 1-4 Alkyl radical, C 3-6 Cycloalkyl and C 6-10 Aryl is independently unsubstituted or substituted by 1,2,3,4 or 5 groups selected from D, F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl and C 6-10 Aryl group.
3. The method of claim 1, wherein each R is 1 And R 2 Independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octane, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, C 6-10 aryl-C 1-4 Alkylene or heteroaryl of 5 to 12 atoms-C 1-4 Alkylene, wherein the methyl groupEthyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octane, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, C 6-10 aryl-C 1-4 Alkylene and heteroaryl of 5 to 12 atoms-C 1-4 Alkylene is independently unsubstituted or substituted by 1,2,3,4 or 5 groups selected from D, F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、-OC(O)CH 3 、-OC(O)C 6 H 5 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 Methoxy, ethylenepropoxy, n-oxy, isopropoxy, tert-butyldimethylsilyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, dioxacyclopentyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, phenylmethylene, phenylethylene, benzofuranyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl;
R 3 independently is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or naphthyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or naphthyl is independently unsubstituted or substituted by 1,2,3,4 or 5 groups selected from D, F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 Methoxy, ethylenepropyleneoxy, n-oxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and naphthyl.
4. The production method according to claim 1, wherein the compound represented by the formula (I) comprises at least one of the following compounds:
Figure FDA0003601503980000021
Figure FDA0003601503980000031
5. the method according to claim 1, wherein the catalyst is zero-valent nickel or divalent nickel; preferably, the catalyst for the coupling reaction is Ni (cod) 2 Nickel chloride, nickel bromide, nickel iodide, ethylene glycol dimethyl ether nickel chloride, ethylene glycol dimethyl ether nickel bromide, nickel acetylacetonate or nickel acetate.
6. The method of claim 1, wherein the ligand is selected from the group consisting of:
Figure FDA0003601503980000032
7. the method according to claim 1, wherein the reducing agent is manganese metal, and the reducing agent is in the form of powder and has a particle size of 200-500 meshes.
8. The method of claim 1 wherein the additive is zinc iodide.
9. The process according to claim 1, wherein the organic solvent is an alcohol solvent; preferably, the organic solvent is ethanol, n-propanol, n-butanol, isobutanol, n-pentanol, isopentanol, sec-pentanol, or n-hexanol.
10. The method according to claim 1, wherein the reaction temperature is 10 ℃ to 50 ℃; preferably, the reaction temperature is 15-35 ℃; the reaction time is 18-30 h; preferably, the reaction time is 20-26 h.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101896461A (en) * 2007-12-13 2010-11-24 安姆根有限公司 Gamma secretase modulators
CN106317055A (en) * 2015-07-02 2017-01-11 中国科学院上海药物研究所 Compound with kinase inhibition activity and its preparation method and use
CN113105444A (en) * 2021-04-19 2021-07-13 南方科技大学 Chiral pyridine bisoxazoline ligand and preparation method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101896461A (en) * 2007-12-13 2010-11-24 安姆根有限公司 Gamma secretase modulators
CN106317055A (en) * 2015-07-02 2017-01-11 中国科学院上海药物研究所 Compound with kinase inhibition activity and its preparation method and use
CN113105444A (en) * 2021-04-19 2021-07-13 南方科技大学 Chiral pyridine bisoxazoline ligand and preparation method and application thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
FERDINAND H. LUTTER ET AL.: "Cobalt-Catalyzed Csp3−Csp3 Cross-Coupling of Functionalized Alkylzinc Reagents with Alkyl Iodides", vol. 22, pages 3028 - 3032 *
HUO, HAOHUA ET AL.: "Catalyst-controlled doubly enantioconvergent coupling of racemic alkyl nucleophiles and electrophiles", vol. 2004, no. 6477, pages 559 - 564 *
JIAN-XIN ZHANG ET AL.: "Ni-Catalyzed Reductive 1,2-Cross-Dialkylation of Unactivated Alkenes with Two Alkyl Bromides", vol. 24, pages 3844 - 3849 *
WEN-TAO ZHAO ET AL.: "Ligand-Controlled Nickel-Catalyzed Regiodivergent Cross- Electrophile Alkyl-Alkyl Couplings of Alkyl Halides", vol. 62, pages 1 - 7 *

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