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CN109689651B - Novel chiral phase transfer catalyst and method for preparing alpha-amino acid by using same - Google Patents

Novel chiral phase transfer catalyst and method for preparing alpha-amino acid by using same Download PDF

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CN109689651B
CN109689651B CN201780039350.0A CN201780039350A CN109689651B CN 109689651 B CN109689651 B CN 109689651B CN 201780039350 A CN201780039350 A CN 201780039350A CN 109689651 B CN109689651 B CN 109689651B
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methyl
dibromide
cinchonidine
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CN109689651A (en
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南基平
李延智
任培根
禹承我
吴智仁
孙源京
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Movas Co ltd
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Abstract

The present invention relates to a novel chiral phase transfer catalyst and a method for preparing an alpha-amino acid using the same. According to the present invention, alpha-amino acids having high optical purity can be synthesized in high yield under reaction conditions that are easy to be industrially applied by using a novel cinchona alkaloid compound as a chiral phase transfer catalyst, and thus, the present invention can be used as a key technology in the field of synthesis and preparation of asymmetric alpha-amino acids.

Description

Novel chiral phase transfer catalyst and method for preparing alpha-amino acid by using same
Technical Field
The present invention relates to a novel chiral phase transfer catalyst and a method for preparing an alpha-amino acid using the same.
Background
Optically active alpha-amino acids and derivatives thereof are widely used in the body. Recently, a method of synthesizing amino acids by phase transfer reaction using quaternary ammonium salts as phase transfer catalysts has attracted considerable attention as a synthesis method for producing these amino acids on a large scale. In particular, asymmetric synthesis of optically active α -amino acids is made possible by using ammonium salts derived from chiral alkaloids as catalysts. M.j.o 'Donnell first reported the asymmetric synthesis of alpha-amino acids using a compound of formula a as a chiral phase transfer catalyst, a tetraalkylammonium halide derived from cinchona alkaloid, a chiral alkaloid (O' Donnell, m.j.; Bennett, w.d.; Wu, s.j.am.chem.soc.1989,111, 2353). However, in the reaction using the compound of the following formula a as a catalyst, the optical purity of the α -amino acid product is only about 80% ee, which has a limitation in mass production.
Figure BDA0001918549330000011
Thereafter, the Lygo group [ Lygo, b.; wainwright, p.g. tetrahedron lett.1997,38,8595 ] and Corey group [ Corey, e.j.; xu, f.; noe, M.C.J.am.chem.Soc.1997,119,12414 ] developed compounds of formula B as shown below as novel catalysts based on cinchona alkaloids, and asymmetric alpha-amino acids synthesized by alkylation using the compounds as phase transfer catalysts. However, the temperature condition for the synthesis of α -amino acids is-78 ℃, and thus practical industrial application is limited.
Figure BDA0001918549330000021
Furthermore, the Park group [ Park, h. -g.; jeong, B. -S.; yoo, m. -s.; lee, j. -h; park, m. -k.; lee, y. -j.; kim, m. -j.; jew, s. — s.angelw.chem.int.ed.2002, 41,3036.] developed a catalyst of formula C shown below, which was used as a phase transfer catalyst for the asymmetric synthesis of α -amino acids, but the reaction required 5 mol% catalyst, 5 equivalents of reactants, and the reaction temperature had to be kept at 0 ℃, which still made industrial application difficult.
Figure BDA0001918549330000022
Under these circumstances, research has been actively conducted on a novel chiral phase transfer catalyst capable of asymmetrically synthesizing an α -amino acid having high optical purity under industrially applicable reaction conditions, but the research is still insufficient.
Disclosure of Invention
[ problem ] to provide a method for producing a semiconductor device
The present invention is provided to solve the above problems, and the present inventors have conducted intensive studies to find a new material useful as a chiral phase transfer catalyst. As a result, the present inventors have discovered a novel chiral phase transfer catalyst derived from cinchona-alkaloid which can react with a small amount of catalyst and equivalent reagent at room temperature.
Accordingly, it is an object of the present invention to provide a novel cinchona alkaloid compound.
Another purpose of the invention is to provide a new application of the cinchona alkaloid compound as a chiral phase transfer catalyst for asymmetric synthesis of alpha-amino acid.
However, the technical object to be solved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood from the following description by those of ordinary skill in the art.
[ technical solution ] A
In order to achieve the above object, the present invention provides a cinchona compound represented by the following formula 1.
[ formula 1]
Figure BDA0001918549330000031
In the formula 1, the first and second groups,
x represents-CH2-, -C (oh) H-, -C (═ O), -O-, -S (═ O) -, or-S (O)2) -; and R represents
Figure BDA0001918549330000032
Or
Figure BDA0001918549330000033
Wherein R is1Represents hydrogen, C1To C10Alkyl or C1To C5An alkoxy group;
R2represents a vinyl group or an ethyl group;
R3represents hydrogen, C1To C10Alkyl, allyl, C5To C10Aryl, naphthalen-1-yl-methyl or anthracen-9-yl-methyl; and is
Y-Represents a halogen anion selected from fluorine, chlorine, bromine and iodine, IO4 -、ClO4 -、R4SO3 -Triflate (OTf)-) Or HSO4 -Wherein R is4Is represented by C1-C4Alkyl or C5-C10And (4) an aryl group.
The present invention also provides a method for synthesizing an alpha-amino acid using the cinchona alkaloid compound of formula 1 as a chiral phase transfer catalyst, a composition for synthesizing an alpha-amino acid, which comprises the cinchona alkaloid compound as an active ingredient, and the use of the cinchona alkaloid compound for synthesizing an alpha-amino acid.
In an exemplary embodiment of the present invention, the amino acid synthesis reaction using the catalyst of the present invention may be performed at 10 ℃ to 20 ℃, preferably at room temperature (20 ℃) or near room temperature with high optical purity.
In another exemplary embodiment of the present invention, a chiral phase transfer catalyst may be used in the range of 0.0005-0.012 equivalents or less per equivalent of reactant, preferably, 0.01 equivalents (1.0% equivalents) or less may be used to obtain high optical purity with respect to one equivalent of reactant.
[ PROBLEMS ] the present invention
The novel cinchona alkaloid compounds according to the present invention can be synthesized by a relatively simple process, and when the compounds are used as chiral phase transfer catalysts, α -amino acids can be asymmetrically synthesized with high optical purity under reaction conditions convenient for industrial use. Therefore, the novel cinchona alkaloid compound can be used as a key technology in the field of synthesizing and preparing alpha-amino acid.
Detailed Description
The present invention will be described in detail below.
The present invention provides cinchona alkaloid compounds represented by the following formula 1.
[ formula 1]
Figure BDA0001918549330000041
In the formula 1, the first and second groups,
x represents-CH2-, -C (oh) H-, -C (═ O) -, -O-, -S (═ O) -, or-S (O)2) -; and R represents
Figure BDA0001918549330000042
Or
Figure BDA0001918549330000043
Wherein R is1Represents hydrogen, C1To C10Alkyl or C1To C5An alkoxy group;
R2represents a vinyl group or an ethyl group;
R3represents hydrogen, C1To C10Alkyl, allyl, C5To C10Aryl, naphthalen-1-yl-methyl or anthracen-9-yl-methyl; and is
Y-Represents a halogen anion selected from fluorine, chlorine, bromine and iodine, IO4 -、ClO4 -、R4SO3 -Triflate (OTf)-) Or HSO4 -Wherein R is4Is represented by C1-C4Alkyl or C5-C10And (4) an aryl group.
As used herein, "alkyl" refers to straight and branched chain saturated hydrocarbon groups, which generally have the indicated number of carbon atoms (e.g., 1 to 10 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and n-heptyl. Alkyl groups may be attached to any ring atom of the parent group or substrate if the attachment satisfies the valence requirements.
"alkoxy" refers to alkyl-O-wherein the alkyl is as defined above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, and the like. An alkoxy group may be attached to any ring atom of the parent group or substrate if the attachment satisfies the valence requirements. Likewise, an alkoxy group may include one or more non-hydrogen substituents if the linkage satisfies the valence requirement.
"aryl" refers to monovalent and divalent aromatic groups comprising 5-and 6-membered monocyclic aromatic groups, respectively; "heteroaryl" refers to monovalent and divalent aromatic groups including 5-and 6-membered monocyclic aromatic groups containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, respectively. Examples of monocyclic aryl and heteroaryl groups include, but are not limited to, phenyl, pyridyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and the like. Aryl and heteroaryl also include bicyclic and tricyclic groups, including 5-and 6-membered fused rings as defined above. Examples of polycyclic aryl and heteroaryl groups include, but are not limited to, isoquinolyl, naphthyl, diphenyl, anthracyl, pyrenyl, carbazolyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzimidazolyl, benzothienyl, quinolyl, indolyl, benzofuranyl, purinyl, indolizinyl, and the like. Aryl and heteroaryl groups may be attached to any ring atom of the parent group or substrate if the attachment satisfies the valence requirements. Likewise, aryl and heteroaryl groups may include one or more non-hydrogen substituents if the linkage satisfies the valence requirements. The non-hydrogen substituents of the aryl and heteroaryl groups may also be substituted with additional non-hydrogen substituents.
In formula 1, when X is-CH2when-C (OH) H-or-C (═ O) -, R is preferred1Represents hydrogen or C1-C5An alkoxy group; r2Represents a vinyl group or an ethyl group; r3Represents hydrogen, C1-C10Alkyl, allyl or C5-C10An aryl group; and Y is-Represents a halogen anion selected from fluorine, chlorine, bromine and iodine,
more preferably, R1Represents hydrogen or methoxy; r2Represents a vinyl group or an ethyl group; r3Represents hydrogen or allyl; and Y is-Represents a halogen anion selected from fluorine, chlorine, bromine and iodine, and
most preferably, the compound of formula 1 represents 4, 4' -bis (cinchonidine-N-methyl) benzophenone dibromide; 4, 4' -bis (O (9) -allylcinchonidine-N-methyl) benzophenone dibromide; 4, 4' -bis (hydrogenated cinchonidine-N-methyl) benzophenone dibromide; 4, 4' -bis (O (9) -allylhydridocinnidine-N-methyl) benzophenone dibromide; 3, 4' -bis (cinchonidine-N-methyl) benzophenone dibromide; 3, 4' -bis (O (9) -allylcinchonidine-N-methyl) benzophenone dibromide; 3, 3' -bis (cinchonidine-N-methyl) benzophenone dibromide; 3, 3' -bis (O (9) -allylcinchonidine-N-methyl) benzophenone dibromide; 4, 4' -bis (cinchonidine-N-methyl) diphenylmethane dibromide; 4, 4' -bis (O (9) -allylcinchonidine-N-methyl) diphenylmethane dibromide; 4, 4' -bis (hydrogenated cinchonidine-N-methyl) diphenylmethane dibromide; 4, 4' -bis (O (9) -allylhydridocinnidine-N-methyl) diphenylmethane dibromide; 4, 4' -bis (quinine-N-methyl) diphenylmethane dibromide; 4, 4' -bis (O (9) -allylquinine-N-methyl) diphenylmethane dibromide; 4, 4' -bis (cinchonidine-N-methyl) benzhydrol dibromide; 4, 4' -bis (O (9) -allylcinchonidine-N-methyl) benzhydrol dibromide; 4, 4' -bis (hydrogenated cinchonidine-N-methyl) benzhydrol dibromide; 4, 4' -bis (O (9) -allylhydridocinnidine-N-methyl) benzhydrol dibromide; 4, 4' -bis (cinchoni-N-methyl) benzophenone dibromide; 4, 4' -bis (O (9) -allylcinchoni-N-methyl) benzophenone dibromide; 4, 4' -bis (cinchoni-N-methyl) diphenylmethane dibromide; 4, 4' -bis (O (9) -allylcinchoni-N-methyl) diphenylmethane dibromide; 4, 4' -bis (quinidine-N-methyl) diphenylmethane dibromide; 4, 4' -bis (O (9) -allylquinidine-N-methyl) diphenylmethane dibromide; 4, 4' -bis (cinchoni-N-methyl) benzhydrol dibromide; or 4, 4' -bis (O (9) -allylcinchoni-N-methyl) benzhydrol dibromide, but the present invention is not limited thereto.
In formula 1, when X is-O-, -S-, or-S (═ O) -, R is preferably selected1Represents hydrogen or C1-C5An alkoxy group; r2Represents a vinyl group or an ethyl group; r3Represents hydrogen, C1-C10Alkyl, allyl or C5-C10An aryl group; and Y is-Represents a halogen anion selected from fluorine, chlorine, bromine and iodine,
more preferably, R1Represents hydrogen or methoxy; r2Represents a vinyl group or an ethyl group; r3Represents hydrogen, allyl or benzyl; and Y is-Represents a halogen anion selected from fluorine, chlorine, bromine and iodine, and
most preferably, the compound of formula 1 represents 4, 4' -bis (cinchonidine-N-methyl) diphenyl ether dibromide; 4, 4' -bis (O (9) -allylcinchonidine-N-methyl) diphenyl ether dibromide; 4, 4' -bis (O (9) -benzyl-cinchonidine-N-methyl) diphenyl ether dibromide; 4, 4' -bis (hydrogenated cinchonidine-N-methyl) diphenyl ether dibromide; 4, 4' -bis (O (9) -allylhydridoconconidine-N-methyl) diphenyl ether dibromide; 4, 4' -bis (quinine-N-methyl) diphenyl ether dibromide; 4, 4' -bis (O (9) -allylquinine-N-methyl) diphenylether dibromide; 3, 3' -bis (cinchonidine-N-methyl) diphenyl ether dibromide; 3, 3' -bis (O (9) -allylcinchonidine-N-methyl) diphenyl ether dibromide; 4, 4' -bis (cinchonidine-N-methyl) diphenyl sulfide dibromide; 4, 4' -bis (O (9) -allylcinchonidine-N-methyl) diphenyl sulfide dibromide; 4, 4' -bis (hydrogenated cinchonidine-N-methyl) diphenyl sulfide dibromide; 4, 4' -bis (O (9) -allylhydridocinnidine-N-methyl) diphenyl sulfide dibromide; 4, 4' -bis (quinine-N-methyl) diphenyl sulfide dibromide; 4, 4' -bis (O (9) -allylquinine-N-methyl) diphenyl sulfide dibromide; 3, 3' -bis (cinchonidine-N-methyl) diphenyl sulfide dibromide; 3, 3' -bis (O (9) -allylcinchonidine-N-methyl) diphenyl sulfide dibromide; 4, 4' -bis (cinchonidine-N-methyl) diphenylsulfoxide dibromide; 4, 4' -bis (O (9) -allylcinchonidine-N-methyl) diphenylsulfoxide dibromide; 4, 4' -bis (hydrogenated cinchonidine-N-methyl) diphenylsulfoxide dibromide; 4, 4' -bis (O (9) -allylhydridocinnidine-N-methyl) diphenylsulfoxide dibromide; 4, 4' -bis (cinchoni-N-methyl) diphenyl ether dibromide; 4, 4' -bis (O (9) -allylcinchoni-N-methyl) diphenyl ether dibromide; 4, 4' -bis (quinidine-N-methyl) diphenyl ether dibromide; 4, 4' -bis (O (9) -allylquinidine-N-methyl) diphenylether dibromide; 4, 4' -bis (cinchoni-N-methyl) diphenyl sulfide dibromide; 4, 4' -bis (O (9) -allylcinchoni-N-methyl) diphenyl sulfide dibromide; 4, 4' -bis (quinidine-N-methyl) diphenyl sulfide dibromide; 4, 4' -bis (cinchoni-N-methyl) diphenylsulfoxide dibromide; or 4, 4' -bis (O (9) -allylcinchoni-N-methyl) diphenylsulfoxide dibromide, but the present invention is not limited thereto.
In formula 1, when X is-S (O)2) When, preferably R1Represents hydrogen or C1-C5An alkoxy group; r2Represents a vinyl group or an ethyl group; r3Represents hydrogen, C1-C10Alkyl, allyl or C5-C10An aryl group; and Y is-Represents a halogen anion selected from fluorine, chlorine, bromine and iodine,
more preferably, R1Represents hydrogen; r2Represents a vinyl group or an ethyl group; r3Represents hydrogen or allyl; and Y is-Represents a halogen anion selected from fluorine, chlorine, bromine and iodine, and
most preferably, the compound of formula 1 represents 4, 4' -bis (cinchonidine-N-methyl) diphenylsulfone dibromide; 4, 4' -bis (O (9) -allylcinchonidine-N-methyl) diphenylsulfone dibromide; 4, 4' -bis (hydrogenated cinchonidine-N-methyl) diphenylsulfone dibromide; 4, 4' -bis (O (9) -allylhydridocinnidine-N-methyl) diphenylsulfone dibromide; 4, 4' -bis (cinchoni-N-methyl) diphenylsulfone dibromide; or 4, 4' -bis (O (9) -allylcinchoni-N-methyl) diphenylsulfone dibromide, but the present invention is not limited thereto.
Meanwhile, the cinchona alkaloid compound of formula 1 according to the present invention may be prepared by several methods.
In an exemplary embodiment, as shown in reaction scheme 2, cinchona alkaloid compounds represented by formula 3, 5, 7, 9,11, 13, or 15 can be synthesized by reacting a compound of formula 2a (e.g., (-) -cinchonidine, (-) -hydrogenated cinchonidine, (-) -quinine, or (-) -hydrogenated quinine), respectively, with: bis (4- (bromomethyl) phenyl) methanone, bis (3,4 '- (bromomethyl) phenyl) methanone, bis (3- (bromomethyl) phenyl) methanone, bis (4- (bromomethyl) phenyl) methane, bis (4- (bromomethyl) phenyl) methanol, 4' -oxybis- (bromomethyl) benzene, bis (4- (bromomethyl) phenyl) sulfane, 4 '-sulfinylbis (bromomethyl) benzene, or 4, 4' -sulfonylbis- (bromomethyl) benzene. Further, the cinchona alkaloid compounds represented by formula 4, 6, 8, 10, 12, 14 or 16 can be prepared by reacting each of the products obtained with a halogenated compound (e.g., various allyl halides, various benzyl halides or C)1-C10Any of the alkyl halides) under basic conditions.
[ reaction scheme 2]
Figure BDA0001918549330000081
And, as shown in reaction scheme 3, the cinchona alkaloid compound represented by formula 17, 19, 21, 23, 25, 27 or 29 can be synthesized by reacting a compound represented by formula 2b (e.g., (+) -cinchoni, (+) -hydrogenated cinchoni, (+) -quinidine or (+) -hydrogenated quinidine) with: bis (4- (bromomethyl) phenyl) methanone, bis (4- (bromomethyl) phenyl) methane, bis (bromomethyl) methyl ether4- (bromomethyl) phenyl) methanol, 4 ' -oxybis- (bromomethyl) benzene, bis (4- (bromomethyl) phenyl) sulfane, 4 ' -sulfinylbis (bromomethyl) benzene or 4,4 ' -sulfonylbis- (bromomethyl) benzene. Cinchona alkaloid compounds represented by formula 18, 20, 22, 24, 26, 28 or 30 can be prepared by reacting each of the resulting products with a halogenated compound (e.g., various allyl halides, various benzyl halides, and C)1-C10Any of the alkyl halides) under basic conditions.
[ reaction scheme 3]
Figure BDA0001918549330000091
In one experimental example of the present invention, asymmetric α -amino acids were synthesized using cinchona alkaloid compounds represented by formulae 3 to 30, prepared according to the synthesis strategies of reaction schemes 2 and 3, as chiral phase transfer catalysts, with the result that the reaction was performed under improved reaction conditions as compared to the conventional method, and the optical purity was also significantly improved as compared to the conventional mono-benzyl ammonium catalyst. Therefore, it was confirmed that the novel cinchona alkaloid compounds of the present invention can be used as a core technology in the field of synthesis and preparation of α -amino acids.
Accordingly, the present invention also provides a method for synthesizing an α -amino acid using the cinchona alkaloid compound of formula 1 as a chiral phase transfer catalyst, a composition for synthesizing an α -amino acid, which comprises the cinchona alkaloid compound as an active ingredient, and the use of the cinchona alkaloid compound for synthesizing an α -amino acid.
Most biological reactions are asymmetric reactions that produce specific chiral species, whereas synthetic reactions typically produce racemic mixtures, and thus specific chiral compounds can only be obtained with resolution. However, due to the nature of the racemate, these conventional methods produce a maximum yield of only 50% of the particular chiral compound and are therefore inefficient. As a means for solving such low efficiency, studies have been actively made on chiral phase transfer catalysts capable of synthesizing substances having a specific chirality without synthesizing racemates. Thus, the Merck group of research successfully performed asymmetric synthesis for the first time in the methylation of phenyl indanones using N-benzyl-cinchonidine phase transfer catalysts and developed various chiral phase transfer catalysts. However, in the case of the conventional chiral phase transfer catalyst, low temperature conditions (-78 ℃ to-10 ℃) are required for the entire reaction, and ion pairing may be weakened or a solvent may participate in the reaction at room temperature, thereby rapidly reducing optical purity. Therefore, the conventional catalyst is difficult to use in industrial applications.
Meanwhile, the method for synthesizing an α -amino acid using the cinchona alkaloid compound of the present invention as a catalyst can exhibit high optical purity, a low amount of catalyst and almost equivalent amount of reagents even at room temperature, and thus is simple in industrial application. In addition, unlike the benzene ring or naphthalene ring used as the linking group in the conventional dimerization catalyst, the dimerization ammonium catalyst of the present invention linked by the linking group-X-may have elasticity and rotatability such as a bent shape, may be adjusted to a structure more suitable for the corresponding catalytic reaction, thereby exhibiting better catalytic efficiency, and similar elasticity and rotatability may also be expected by the combination of-XX-or-X'. Thus, more improved catalytic function can be expected.
In one exemplary embodiment, as shown in reaction scheme 1, the method of synthesizing an α -amino acid comprises preparing a compound of formula III by reacting a compound of formula I with a compound of formula II in the presence of a cinchona alkaloid compound, which is a chiral phase transfer catalyst, and preparing a compound of formula IV by hydrolyzing the compound of formula III prepared in the above step under acidic conditions. However, this method is only one example of a method for preparing an α -amino acid, and the method for preparing an α -amino acid may include any method for synthesizing an amino acid having a specific chirality without limitation.
[ reaction scheme 1]
Figure BDA0001918549330000111
Meanwhile, in reaction scheme 1, R' may beIs C2-C6Alkyl, R' may be C2-C6Alkyl or C5-C10Aryl, and preferably, R' is t-butyl, alkyl and R "is benzyl, but the invention is not so limited.
Furthermore, the step of reacting the compound of formula I with the compound of formula II is preferably carried out at 10 ℃ to 20 ℃, more preferably at 13 ℃ to 17 ℃, most preferably at 15 ℃. Preferably, 0.8 to 1.6 equivalents of compound of formula II are used per equivalent of compound of formula I, more preferably 1.0 to 1.4 equivalents, and most preferably 1.2 equivalents. The amount of the chiral phase transfer catalyst used is preferably in the range of 0.0005 to 0.012 equivalents (0.05% equivalents to 1.2% equivalents), more preferably 0.009 equivalents-0.011 equivalents (0.9% equivalents to 1.1% equivalents), and most preferably 0.010 equivalents (1.0% equivalents), but the present invention is not limited thereto.
To assist in understanding the invention, exemplary embodiments will be set forth below. However, the following examples are provided only for easier understanding of the present invention and are not intended to limit the present invention.
Example 1.4, 4' -bis (cinchonidine-N-methyl) benzophenone dibromide (3)
(-) -cinchonidine (145mg, 0.49mmol) and bis (4- (bromomethyl) phenyl) methanone (100mg, 0.27mmol) were added to a 25mL round bottom flask and stirred at reflux for 4 hours in toluene solvent (5mL) at 110 deg.C. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (50mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (205mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ9.00(d,J＝4.5Hz,2H),8.35(d,J＝8.4Hz,2H),8.12(dd,J＝8.3,1.6Hz,2H),7.99(m,8H),7.94-7.71(m,6H),6.82(m,2H),6.60(m,2H),5.80-5.62(m,2H),5.35(m,2H),5.20(d,J＝17.3Hz,4H),4.98(d,J＝10.6Hz,2H),4.38(m,2H),4.15-3.94(m,2H),3.87(m,2H),3.41(m,2H),3.17(m,2H),2.72(m,2H),2.13(m,4H),2.03(m,2H),1.85(m,2H),1.40-1.21(m,2H)。
Example 2.4, 4' -bis (O (9) -allylcinchonidine-N-methyl) benzophenone dibromideThing (4)
After compound 3(304mg, 0.31mmol) obtained by the method of example 1 was suspended in dichloromethane (10mL), 50% potassium hydroxide solution (0.35mL, 3.1mmol) and allyl bromide (0.16mL, 1.9mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting filtrate was dropwise added to diethyl ether (50mL), thereby obtaining a solid. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a light orange solid (270mg) as the desired product.
1H NMR (300Mhz, trichloromethane-d) δ 8.98(m,2H),8.81(d, J ═ 8.5Hz,2H),8.20-8.10(m,6H),7.86(m,4H),7.83-7.69(m,6H),6.73(d, J ═ 11.5Hz,2H),6.24(m,2H),6.27-6.04(m,2H),5.64-5.52(m,2H),5.42(m,6H),5.02(m,4H),4.77(d, J ═ 10.7Hz,2H),4.64(m,2H),4.29(m,4H),4.13(m,2H),3.58(m,2H),3.44(m,2H),2.71(m,2H),2.12(m, 2H), 1.41H (m, 1H).
Example 3.4, 4' -bis (hydrogenated cinchonidine-N-methyl) benzophenone dibromide (3-1)
To a 25mL round bottom flask was added (-) -hydrogenated cinchonidine (292mg, 0.98mmol) and bis (4- (bromomethyl) phenyl) methanone (200mg, 0.55mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: a mixed solvent (3mL) of chloroform (5: 6: 2) was neutralized and refluxed at 110 ℃ for 3 hours with stirring. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (50mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (300mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ9.01(d,J＝4.4Hz,2H),8.36(d,J＝8.6Hz,2H),8.12(d,J＝8.3Hz,2H),8.05(m,6H),7.82(m,4H),7.71(m,4H),6.79(m,2H),6.60(m,2H),5.39(d,J＝12.2Hz,2H),5.14(d,J＝12.3Hz,2H),4.43-4.36(m,2H),4.06-3.95(m,2H),3.58(m,2H),3.42-3.20(m,4H),2.10(m,4H),2.00(m,2H),1.77(m,4H),1.35(m,2H),1.20(m,4H),0.73(m,6H)。
Example 4.4, 4' -bis (O: (I))9) Allyl hydrogenated cinchonidine N-methyl benzophenone dibromide (4-1)
After suspending compound 3-1(200mg, 0.21mmol) obtained by the method of example 3 in dichloromethane (3mL), 50% potassium hydroxide solution (0.25mL, 2.2mmol) and allyl bromide (0.127mL, 1.46mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting solution was distilled under reduced pressure to obtain a solid. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a light orange solid (144mg) as the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.99(d, J ═ 4.5Hz,2H),8.83(d, J ═ 8.6Hz,2H),8.14(m,4H),8.12(m,2H),7.82(m,2H),7.79(m,4H),7.75(m,4H),6.51(d, J ═ 11.9Hz,2H),6.31(m,2H),6.14(m,2H),5.50(m,2H),5.36(m,2H),4.81(d, J ═ 11.9Hz,2H),4.70(m,4H),4.41(m,2H),4.33(m,2H),4.08(m,2H),3.46(m,2H),3.32(m,2H), 4.19 (m,2H), 1.47(m, 2H).
Example 5, 4' -bis (cinchonidine-N-methyl) benzophenone dibromide (3-2)
In a 25mL round bottom flask, (3- (bromomethyl) phenyl) (4- (bromomethyl) phenyl) methanone (300mg, 0.815mmol) was added to (-) -cinchonidine (432mg, 1.46mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: a mixed solvent (4mL) of chloroform (5: 6: 2) was neutralized at 110 ℃ and refluxed with stirring for 5 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (200mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a white solid (238mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.98(m,2H),8.41-8.28(m,3H),8.06(m,4H),7.94(s,4H),7.89-7.69(m,7H),6.85-6.72(m,2H),6.57(m,2H),5.72-5.55(m,2H),5.39-5.01(m,6H),4.9-4.74(m,2H),4.34(m,2H),3.98(m,2H),3.83(m,2H),3.62(m,2H),3.40-3.21(m,2H),2.73(m,2H),2.18-1.81(m,8H),1.23(m,2H)。
Example 6, 4' -bis (O (9) -allylcinchonidine-N-methyl) benzophenone dibromide (4-2)
After suspending compound 3-2(200mg, 0.209mmol) obtained by the method of example 5 in dichloromethane (4mL), 50% potassium hydroxide solution (0.25mL, 2.2mmol) and allyl bromide (178mL, 1.46mmol) were added, and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (162mg) as the desired product.
1H NMR (300MHz, trichloromethane-d) δ 9.06-8.87(m,1H),8.86-8.70(m,1H),8.14(d, J ═ 8.8Hz,2H),7.94-7.55(m,2H),6.59(t, J ═ 12.4Hz,2H),6.35-5.97(m,4H),5.70-5.49(m,2H),5.48-5.34(m,6H),5.01-4.78(m,4H),4.33-4.20(m,4H),4.08-3.96(m,2H),3.72(m,1H),3.43(m,1H),3.08(m,1H),2.91(m,1H),2.71-2.43(m,2H), 2.27-1H (m,1H), 1.89(m, 1H), 1H (m, 1H).
Example 7.3, 3' -bis (cinchonidine-N-methyl) benzophenone dibromide (3-3)
In a 25mL round bottom flask, bis (3- (bromomethyl) phenyl) methanone (300mg, 0.815mmol) was added to (-) -cinchonidine (456mg, 1.55mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: chloroform (5: 6: 2) in a mixed solvent (4.5mL) at 110 ℃ under stirring and refluxing for 6.5 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (20mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (225mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝4.5Hz,2H),8.34(d,J＝8.7Hz,2H),8.27(s,2H),8.08(d,J＝8.3Hz,4H),7.97(d,J＝7.7Hz,2H),7.86-7.69(m,8H),6.74(d,J＝5.0Hz,2H),6.56(m,2H),5.70-5.59(m,2H),5.41(d,J＝14.5Hz,2H),5.27(m,4H),4.94(d,J＝10.5Hz,2H),4.34(m,2H),3.97-3.89(m,4H),3.49(m,2H),3.30(m,2H),2.74(m,2H),2.09(m,4H),1.99(m,2H),1.87(m,2H),1.28(m,2H)。
Example 8.3, 3' -bis (O (9) -allylcinchonidine-N-methyl) benzophenone dibromide (4-3)
After suspending compound 3-3(100mg, 0.105mmol) obtained by the method of example 7 in dichloromethane (1.7mL), 50% potassium hydroxide solution (0.15mL, 4.06mmol) and allyl bromide (88.50mL, 0.732mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (83mg) which was the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.96(d, J ═ 4.5Hz,2H),8.81(d, J ═ 8.5Hz,2H),8.50(m,2H),8.12(m,4H),7.84(m,4H),7.74(m,2H),7.69-7.52(m,4H),6.47(d, J ═ 12.1Hz,2H),6.32(m,2H),6.22-6.05(m,2H),5.62(m,2H),5.46-5.39(m,2H),5.39-5.32(m,3H),5.29(m,1H),4.98-4.90(m,2H),4.86(m,2H),4.64(d, J ═ 11.9, 2H),4.81 (m,2H),4.42 (m,3H), 4.65 (m,2H), 3H), 4.43 (m,2H), 3H), 3.65 (m,3H), 2.22-2.03(m,8H),1.50-1.36(m, 2H).
Example 9.4, 4' -bis (cinchonidine-N-methyl) diphenylmethane dibromide (5)
In a 25mL round bottom flask, bis (4- (bromomethyl) phenyl) methane (300mg, 0.847mmol) was added to (-) -cinchonidine (449mg, 1.52mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: chloroform (5: 6: 2) in a mixed solvent (4mL) at 110 ℃ under stirring and refluxing for 3.5 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (50mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (352mg) which was the desired product.
1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝4.4Hz,2H),8.31(d,J＝8.5Hz,2H),8.10(dd,J＝8.4,1.3Hz,2H),7.88-7.65(m,10H),7.49(d,J＝8.1Hz,4H),6.73(d,J＝4.9Hz,2H),6.55(d,J＝4.9Hz,2H),5.73-5.58(m,2H),5.27-5.10(m,4H),5.06(d,J＝12.2Hz,2H),4.95(d,J＝10.5Hz,2H),4.40-4.21(m,2H),4.14(s,2H),4.09-3.86(m,4H),3.85-3.72(m,2H),3.40-3.30(m,2H),2.69(d,J＝7.9Hz,2H),2.16-1.94(m,6H),1.91-1.74(m,2H),1.37-1.20(m,2H)。
Example 10.4, 4' -bis (O (9) -allylcinchonidine-N-methyl) diphenylmethane dibromide (6)
After compound 5(280mg, 0.297mmol) obtained by the method of example 9 was suspended in dichloromethane (7mL), 50% potassium hydroxide solution (0.35mL, 3.1mmol) and allyl bromide (254mL, 2.08mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was distilled under reduced pressure to obtain a solid. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (141.6mg) which was the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.98(d, J ═ 4.5Hz,2H),8.82(d, J ═ 8.5Hz,2H),8.14(d, J ═ 8.4Hz,2H),8.02-7.41(m,10H),7.34-7.23(m,4H),6.47(d, J ═ 11.8Hz,2H),6.22(m,2H),6.11(m,2H),5.68(m,2H),5.38(m,6H),4.98(m,2H),4.82(d, J ═ 14.1Hz,2H),4.65(d, J ═ 12.1Hz,4H),4.29(m,4H),4.08(s,2H),4.03(m,2H),3.44(m, 6H), 3.26(m,2H), 2H, 6.6.6.6.6.6.6.6.6.6.6.6, 6.6H, 6H, 2H, 6H, 2H, 6H, 2H, 6H, 2H, etc.
Example 11.4, 4' -bis (hydrogenated cinchonidine-N-methyl) diphenylmethane dibromide (5-1)
In a 25mL round bottom flask, bis (4- (bromomethyl) phenyl) methane (300mg, 0.847mmol) was added to (-) -hydrogenated cinchonidine (452mg, 1.52mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: a mixed solvent (5mL) of chloroform (5: 6: 2) was neutralized at 110 ℃ and refluxed with stirring for 3.5 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (50mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (495.7mg) which was the desired product.
1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝4.5Hz,2H),8.29(d,J＝8.5Hz,2H),8.10(d,J＝8.3Hz,2H),7.89-7.76(m,4H),7.75-7.57(m,6H),7.48(d,J＝8.1Hz,4H),6.71(m,2H),6.55(m,2H),5.22(d,J＝12.4Hz,2H),4.94(d,J＝12.3Hz,2H),4.31(m,2H),4.13(s,2H),3.95(m,2H),3.52-3.41(m,2H),3.20-3.13(m,2H),3.04(t,J＝7.3Hz,2H),2.14-2.00(m,4H),1.97-1.88(m,2H),1.84-1.67(m,4H),1.42-1.28(m,2H),1.17(m,4H),0.69(m,6H)。
Example 12.4, 4' -bis (O (9) -allylhydridocinnidine-N-methyl) diphenylmethane dibromide (6- 1)
After suspending compound 5-1(300mg, 0.317mmol) obtained by the method of example 11 in dichloromethane (7mL), 50% potassium hydroxide solution (0.35mL, 3.1mmol) and allyl bromide (271mL, 2.22mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (228mg) as the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.97(d, J ═ 4.5Hz,2H),8.80(d, J ═ 8.5Hz,2H),8.13(d, J ═ 8.4Hz,2H),7.94-7.66(m,10H),7.31(d, J ═ 5.2Hz,4H),6.33-6.19(m,4H),6.10(m,2H),5.40(d, J ═ 6.5Hz,2H),4.70(d, J ═ 11.9Hz,4H),4.61-4.50(m,2H),4.33-4.18(m,4H),4.11(d, J ═ 6.7Hz,2H),4.06(s,2H),3.37(m,2H), 3.31.19 (m, 3.19H), 19(m,4H), 1.6H, 1.7H, 1(m,2H), 1.6 (m,2H), 1H), 1.6H, 2H, 1, 2H, 1H, and 1H.
Example 13, 4' -bis (quinine-N-methyl) diphenylmethane dibromide (5-2)
In a 25mL round bottom flask, bis (4- (bromomethyl) phenyl) methane (200mg, 0.565mmol) was added to (-) -quinine (330mg, 1.02mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: a mixed solvent (3mL) of chloroform (5: 6: 2) was neutralized at 110 ℃ and refluxed with stirring for 4 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (200mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (301mg) which was the desired product.
1H NMR(300MHz,DMSO-d6)δ8.81(d,J＝4.5Hz,2H),8.02(dd,J＝9.2,2.8Hz,2H),7.75(d,J＝4.5Hz,2H),7.68(d,J＝8.2Hz,4H),7.48(dd,J＝7.1,2.4Hz,6H),7.42(d,J＝2.7Hz,2H),6.70-6.55(m,4H),5.75(dddd,J＝17.2,9.5,6.8,2.7Hz,2H),5.47(d,J＝12.3Hz,2H),5.13(m,2H),5.01(m,2H),4.74(d,J＝12.2Hz,2H),4.39-4.24(m,2H),4.12(s,2H),4.02(s,6H),3.90(t,J＝8.8Hz,2H),3.79-3.62(m,2H),3.44-3.31(m,2H),3.24(m,2H),2.79-2.64(m,2H),2.32-2.10(m,4H),2.06-1.97(m,2H),1.93-1.78(m,2H),1.56-1.41(m,2H)。
Example 14.4, 4' -bis (O (9) -allylquinine-N-methyl) diphenylmethane dibromide (6-2)
After suspending the compound 5-2(150mg, 0.150mmol) obtained by the method of example 13 in dichloromethane (3mL), 50% potassium hydroxide solution (0.35mL, 3.1mmol) and allyl bromide (0.128mg, 1.05mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting solid was purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (107mg) which was the desired product.
1H NMR(300MHz,DMSO-d6)δ8.83(d,J＝4.5Hz,2H),8.04(d,J＝9.1Hz,2H),7.73-7.61(m,6H),7.55-7.40(m,8H),6.57(m,2H),6.24-6.05(m,2H),5.81-5.67(m,2H),5.59(d,J＝12.4Hz,2H),5.46(m,2H),5.28(dd,J＝10.5,1.6Hz,2H),5.15-4.97(m,4H),4.75(d,J＝12.2Hz,2H),4.50(dd,J＝12.6,5.3Hz,2H),4.13(s,2H),4.00(m,8H),3.98-3.89(m,4H),3.38-3.29(m,4H),2.78-2.63(m,2H),2.44-2.32(m,2H),2.24-2.12(m,2H),2.07-2.00(m,2H),1.96-1.83(m,2H),1.61-1.49(m,2H),1.23(m,2H)。
Example 15.4, 4' -bis (cinchonidine-N-methyl) benzhydrol dibromide (7)
In a 25mL round bottom flask, bis (4- (bromomethyl) phenyl) methanol (100mg, 0.27mmol) was added to (-) -cinchonidine (151mg, 0.513mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: a mixed solvent (1.5mL) of chloroform (5: 6: 2) was neutralized at 110 ℃ and refluxed with stirring for 1 hour. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (20mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (70mg) which was the desired product.
1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝4.5Hz,2H),8.29(d,J＝8.2Hz,2H),8.10(m,2H),7.89-7.78(m,5H),7.74(m,5H),7.64(d,J＝8.4Hz,4H),6.79(d,J＝4.7Hz,2H),6.55(d,J＝4.7Hz,2H),6.23(d,J＝4.4Hz,1H),5.90(d,J＝4.5Hz,1H),5.67(m,2H),5.28-5.12(m,4H),5.03(d,J＝12.2Hz,2H),4.95(d,J＝10.5Hz,2H),4.30(m,2H),4.03-3.86(m,2H),3.79(d,J＝9.9Hz,2H),3.35-3.12(m,4H),2.70(m,2H),2.16-1.91(m,6H),1.82(m,2H),1.33-1.21(m,2H)。
Example 16.4, 4' -bis (O (9) -allylcinchonidine-N-methyl) benzhydrol dibromide (8)
After compound 7(70mg, 0.073mmol) obtained by the method of example 15 was suspended in dichloromethane (1.4mL), 50% potassium hydroxide solution (0.11mL, 3.0mmol) and allyl bromide (88mg, 0.73mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting solid was purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (25mg) which was the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.98(d, J ═ 4.5Hz,2H),8.83(d, J ═ 8.6Hz,2H),8.14(d, J ═ 7.4Hz,4H),7.78-7.66(m,4H),7.62(d, J ═ 7.5Hz,2H),7.57-7.39(m,4H),6.51(m,2H),6.25(d, J ═ 6.5Hz,2H),6.04(d, J ═ 11.9Hz,1H),5.44-5.35(m,4H),5.06-4.93(m,2H),4.83(d, J ═ 10.9Hz,2H),4.76(s,4H),4.24(m,4H), 4.92 (m, 3.92, 13.43, 3.43H), 3.9 (m,3H), 3.9H, 3H, 3.8 (m,3H), 3.9H, 3H, 1H, 3H, 1H, 3H, 2H, 3H, 2H, 3H, 2H, and so as shown in the like.
Example 17.4, 4' -bis (hydrogenated cinchonidine-N-methyl) benzhydrol dibromide (7-1)
In a 25mL round bottom flask, bis (4- (bromomethyl) phenyl) methanol (100mg, 0.2702mmol) was added to (-) -hydrogenated cinchonidine (152.2mg, 0.5134mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: chloroform (5: 6: 2) in a mixed solvent (1.5mL) at 110 ℃ under stirring and refluxing for 1.5 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (20mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a light orange solid (130mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.98(m,2H),8.26(m,2H),8.11(d,J＝8.4Hz,2H),7.90-7.79(m,4H),7.77-7.56(m,10H),6.73(m,2H),6.53(m,2H),6.26-6.16(m,1H),5.91-5.84(m,1H),5.24-5.03(m,2H),4.89(m,2H),4.63-4.37(m,2H),4.27(d,J＝10.9Hz,2H),4.08-3.76(m,4H),3.22(d,J＝10.7Hz,4H),2.18-1.87(m,8H),1.76(m,6H),1.32(m,2H),1.16(m,4H)。
Example 18.4, 4' -bis (O (9) -allylhydridocinnidine-N-methyl) benzhydrol dibromide (8- 1)
After compound 7-1(90mg, 0.0935mmol) obtained by the method of example 17 was suspended in dichloromethane (1.6mL), 50% potassium hydroxide solution (0.14mL, 3.79mmol) and allyl bromide (118.7mL, 0.9813mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (87mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.98(m,2H),8.82(d,J＝8.5Hz,2H),8.19-8.11(m,2H),7.98-7.75(m,8H),7.62-7.53(m,2H),7.49(m,4H),6.28(m,4H),6.08-5.89(m,3H),5.55(m,1H),5.43-5.34(m,4H),5.21-5.09(m,2H),4.61(m,4H),4.27(m,4H),4.08-3.92(m,6H),3.38(d,J＝14.7Hz,2H),3.22(m,2H),2.14(m,4H),2.04(m,6H),1.39(m,4H),1.23(m,2H),0.77(m,6H)。
Example 19.4, 4' -bis (cinchonidine-N-methyl) diphenylether dibromide (9)
In a 25mL round-bottom flask, (4, 4-oxybis (bromomethyl) benzene (200mg, 0.56mmol) was added to (-) -cinchonidine (314mg, 1.07mmol) and stirred under reflux in a mixed solvent of ethanol, N-dimethylformamide, chloroform (5: 6: 2) (3mL) and 110 ℃ for 4 hours the reaction mixture was cooled to room temperature and added dropwise to diethyl ether (50mL) to precipitate a solid, which was then filtered under reduced pressure.
1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝4.5Hz,2H),8.39-8.28(d,2H),8.11(d,J＝8.3,1.4Hz,2H),7.92-7.70(m,10H),7.28(d,J＝8.2Hz,4H),6.74(d,J＝4.8Hz,2H),6.66-6.51(m,2H),5.79-5.59(m,2H),5.27(d,J＝12.4Hz,2H),5.19(d,J＝17.2,1.3Hz,2H),5.11(d,J＝12.2Hz,2H),4.96(d,J＝10.5,1.4Hz,2H),4.32(m,2H),3.97(t,J＝9.2Hz,2H),3.81(m,2H),3.41(t,J＝11.6Hz,2H),3.25(m,2H),2.11(m,6H),1.86(m,2H),1.32(m,2H)。
Example 19-1.3, 3' -bis (cinchonidine-N-methyl) diphenylether dibromide (9-1)
In a 25mL round-bottom flask, (3, 3-oxybis (bromomethyl) benzene (150mg, 0.421mmol) was added to (-) -cinchonidine (223.2mg, 0.758mmol) and refluxed with stirring in a mixed solvent of ethanol, N-dimethylformamide, trichloromethane (5: 6: 2) (3mL) for 5 hours the reaction mixture was cooled to room temperature and added dropwise to ether (100mL) to precipitate a solid, which was then filtered under reduced pressure.
1H NMR(300MHz,DMSO-d6)δ9.00(d,J＝4.5Hz,2H),8.31(d,J＝7.6Hz,2H),8.08(d,J＝8.3Hz,2H),7.87-7.77(m,4H),7.73-7.57(m,2H),7.69(d,J＝8.1Hz,2H),7.58(m,4H),7.32(m,2H),6.72(d,J＝5.0Hz,2H),6.51(d,J＝12.3Hz,2H),5.66(m,2H),5.35(s,2H),5.08(m,6H),4.99-4.88(m,2H),4.30-3.13(m,2H),3.94(t,J＝8.6Hz,2H),3.85-2.00(m,2H),3.58-3.45(m,2H),3.34-1.67(m,2H),2.79-1.28(m,2H),2.17(m,8H),1.24(m,2H)。
EXAMPLE 20, 4' -bis (O (9) -allylcinchonidine-N-methyl) diphenylether dibromideArticle (10)
After compound 9(180mg, 0.190mmol) obtained by the method of example 19 was suspended in dichloromethane (3mL), 50% potassium hydroxide solution (0.25mL, 2.2mmol) and allyl bromide (0.11mL, 1.33mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (3mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting filtrate was dropwise added to diethyl ether (50mL), thereby obtaining a solid. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a light orange solid (200mg) as the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.99(d, J ═ 4.4Hz,2H),8.86(d, J ═ 8.5Hz,2H),8.15(d, J ═ 8.3Hz,2H),8.02(d, J ═ 8.3Hz,4H),7.88(m,2H),7.77(m,2H),7.63(s,2H),7.19-7.03(m,4H),6.56(d, J ═ 11.7, 2H),6.23(m,2H),6.19-6.07(m,2H),5.67(m,2H),5.49-5.32(m,6H),4.98(d, J ═ 10.4Hz,2H),4.89(m,2H),4.64(m,4H), 4.42 (m,3H), 3.42H, 3H, 3.3H), 3.3.3H, 3H, 3.3H, 3H, 6H, etc.
Example 20-1: 3, 3' -bis (O (9) -allylcinchonidine-N-methyl) diphenyl ether dibromide (10-1)
After compound 9-1(70mg, 0.074mmol) obtained by the method of example 19-1 was suspended in dichloromethane (2mL), 50% potassium hydroxide solution (0.25mL, 6.77mmol) and allyl bromide (0.043mL, 0.518mmol) were added, and the mixture was stirred in ice water for 4 hours. The reaction mixture was diluted with water (2mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting filtrate was dropwise added to diethyl ether (50mL), thereby obtaining a solid. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (60.0mg) which was the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.95(d, J ═ 4.5Hz,2H),8.77(d, J ═ 8.8Hz,2H),8.12(m,2H),8.04(m,2H),7.87(m,2H),7.75(m,2H),7.65(m,2H),7.48(m,2H),7.35(m,2H),7.18(m,2H),6.35(d, J ═ 11.7Hz,2H),6.25-6.15(m,2H),6.15-6.01(m,2H),5.62(m,2H),5.43-5.38(m,2H),5.36(m,2H),5.31-5.26(m,2H),4.89(m,2H),4.70(d,J＝12.3Hz,2H),4.62(m,2H),4.56-4.47(m,2H),4.24(m,4H),4.03(m,2H),3.81-3.65(m,2H),3.53(t,J＝11.6Hz,2H),2.79(m,2H),2.23-2.08(m,8H),1.41(m,2H)。
Example 21.4, 4' -bis (O (9) -benzylcinchonidine-N-methyl) diphenylether dibromide (10-1-1)
After compound 9(50mg, 0.053mmol) obtained by the method of example 19 was suspended in dichloromethane (3mL), 50% potassium hydroxide solution (0.25mL, 2.2mmol) and allyl bromide (0.044mL, 0.37mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (3mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting filtrate was dropwise added to diethyl ether (50mL), thereby obtaining a solid. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a light orange solid (83mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ9.87(d,J＝6.2Hz,2H),8.82(d,J＝8.2Hz,2H),8.60(d,J＝9.0Hz,2H),8.46-7.76(m,2H),8.30-7.57(m,2H),8.17(d,J＝7.7Hz,2H),7.83(m,2H),7.61(m,2H),7.43(d,J＝12.4Hz,2H),6.50(d,J＝12.3Hz,4H),5.71(m,2H),5.24(s,2H),5.16(m,2H),5.01-4.40(m,2H),4.22-4.15(m,2H),4.03(t,J＝7.3Hz,4H),3.38-2.00(m,4H),2.72-2.30(m,2H),2.02-1.85(m,2H),1.60-1.28(m,2H),1.25(m,2H),0.86(m,2H)。
Example 22.4, 4' -bis (hydrogenated cinchonidine-N-methyl) diphenylether dibromide (9-2)
To a 25mL round bottom flask was added (-) -hydrogenated cinchonidine (600mg, 2.02mmol) and 4, 4' -oxybis (bromomethyl) benzene (400mg, 1.12mmol) in ethanol: n, N-dimethylformamide: a mixed solvent (6mL) of chloroform (5: 6: 2) was neutralized and refluxed at 110 ℃ for 2 hours with stirring. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (50mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was recrystallized from methanol-ether to give a pale yellow solid (2.346g) which was the desired product.
1H NMR(300MHz,DMSO-d6)δ8.99(d,J＝4.6Hz,2H),8.31(d,J＝8.4Hz,2H),8.11(d,J＝8.3Hz,2H),7.89-7.70(m,10H),7.27(d,J＝8.2Hz,4H),6.74(m,2H),6.55(m,2H),5.21(d,J＝12.7Hz,2H),4.95(d,J＝12.2Hz,2H),4.27(m,2H),3.92(m,2H),3.44(m,2H),3.31-3.20(m,4H),2.08(m,4H),1.96(m,2H),1.77(m,4H),1.34(m,2H),1.16(m,4H),0.71(m,J＝7.1Hz,6H)。
Example 23.4, 4' -bis (O (9) -allylhydridoconconidine-N-methyl) diphenylether dibromide (10-2)
After compound 9-2(150mg, 0.16mmol) obtained by the method of example 22 was suspended in dichloromethane (3mL), 50% potassium hydroxide solution (0.25mL, 2.2mmol) and allyl bromide (0.09mL, 1.10mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water (3mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting filtrate was dropwise added to diethyl ether (50mL), thereby obtaining a solid. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a light orange solid (135mg) as the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.98(d, J ═ 4.1Hz,2H),8.85(d, J ═ 8.5Hz,2H),8.16(d, J ═ 8.4,1.4Hz,2H),8.00(d, J ═ 8.8Hz,4H),7.93(m,2H),7.85-7.78(m,4H),7.13(d, J ═ 8.2Hz,4H),6.45(d, J ═ 11.8Hz,2H),6.32-6.21(m,2H),6.18-6.04(m,2H),5.48-5.33(m,4H),4.71(m, J ═ 12.2, 2H),4.61(d, J ═ 11.5, 2H), 4.31, 3.31, 3.3.19 (m, 3.3H), 1.3.79 (m, 3.3, 3, 2H) 0.83-0.65(m, 6H).
Example 24.4, 4' -bis (quinine-N-methyl) diphenylether dibromide (9-3)
In a 25mL round bottom flask, 4-oxybis (bromomethyl) benzene (200mg, 0.56mmol) was added to (-) -quinine (328mg, 1.01mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: a mixed solvent (3mL) of chloroform (5: 6: 2) was neutralized and refluxed at 110 ℃ for 3 hours with stirring. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (50mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (541mg) which was the desired product.
1H NMR(300MHz,DMSO-d6)δ8.82(d,J＝4.4Hz,2H),8.03(d,J＝9.1Hz,2H),7.76(m,6H),7.50(d,J＝9.2,2.5Hz,2H),7.39(d,J＝2.6Hz,2H),7.27(d,J＝8.2Hz,4H),6.70(d,J＝4.2Hz,2H),6.60(m,2H),5.75-5.67(m,2H),5.45(d,J＝12.3Hz,2H),5.12(d,J＝17.3Hz,2H),5.01(d,J＝10.4Hz,2H),4.73(d,J＝12.3Hz,2H),4.23(m,2H),4.02(s,J＝6.1Hz,6H),3.86(m,2H),3.68(m,2H),3.41(m,2H),3.25(m,2H),2.72(m,2H),2.18(m,4H),2.02(m,2H),1.86(m,2H),1.46(m,J＝11.7Hz,2H)。
Example 25.4, 4' -bis (O (9) -allylquinine-N-methyl) diphenylether dibromide (10-3)
After suspending compound 9-3(100mg, 0.10mmol) obtained by the method of example 24 in chloroform (3mL), 50% potassium hydroxide solution (0.25mL, 2.2mmol) and allyl bromide (0.06mL, 0.70mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (3mL) and the organic layer was extracted with dichloromethane (2x, 3 mL). The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered, then evaporated in vacuo. The resulting product was isolated and purified by column chromatography (dichloromethane/methanol) to give a light brown solid (30mg) as the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.92-8.76(m,2H),8.15-8.01(m,2H),7.86(d, J ═ 8.2Hz,2H),7.41(d, J ═ 11.5Hz,2H),7.21(d, J ═ 9.0Hz,2H),7.11(m,2H),7.05-6.83(m,2H),6.25-6.01(m,4H),5.97-5.75(m,2H),5.40(m,4H),5.33-5.22(m,4H),4.25(d, J ═ 23.5Hz,4H),4.03(m,4H),3.93(m,2H),3.88-3.80(m,4H),3.62(m,2H),3.41(m,2H), 1.7 (m, 1.7H), 1.44(m,2H), 1.07 (m,2H), 4H) 0.84(m, 4H).
Example 26.4, 4' -bis (cinchonidine-N-methyl) diphenyl sulfide dibromide (11)
In a 25mL round bottom flask, bis (4- (bromomethyl) phenyl) sulfane (492mg, 1.32mmol) was added to (-) -cinchonidine (700mg, 2.4mmol) and the reaction mixture was stirred in ethanol: n, N-dimethylformamide: chloroform (5: 6: 2) in a mixed solvent (5mL) at 110 ℃ under stirring and refluxing for 4.5 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (50mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a bright red solid (781mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.97(d,J＝4.5Hz,2H),8.30(d,J＝7.9Hz,2H),8.10(d,J＝8.5Hz,2H),7.91-7.69(m,10H),7.56(m,4H),6.76(m,2H),6.54(m,2H),245.75(m,2H),5.66(m,2H),5.29-5.01(m,6H),4.94(m,2H),4.26(m,2H),3.91(m,2H),3.78(m,2H),3.36(m,2H),3.26(m,2H),2.68(m,2H),2.03(m,6H),1.82(m,2H),1.27(m,2H)。
Example 26-1.3, 3' -bis (cinchonidine-N-methyl) diphenyl sulfide dibromide (11-1)
In a 10mL round bottom flask, bis (3-bromomethylphenyl) sulfide (165g, 443mmol) was added to (-) -cinchonidine (235mg, 798mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: chloroform (5: 6: 2) in a mixed solvent (2.5mL) was refluxed with stirring for 4.5 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (200mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (184mg) which was the desired product.
1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝4.5Hz,2H),8.29(d,J＝8.3Hz,2H),8.15-8.01(m,5H),7.84-7.73(m,9H),7.54(t,J＝7.9Hz,2H),6.72(d,J＝4.6Hz,2H),6.52(d,J＝5.1Hz,2H),5.73-5.58(m,2H),5.23-5.13(m,4H),5.08-5.01(m,2H),4.98-4.92(m,2H),4.30(m,2H),3.91(t,J＝9.4Hz,2H),3.82-3.71(m,2H),3.39(m,2H),2.69(m,2H),2.17-1.97(m,8H),1.82(d,J＝4.1Hz,2H),1.34-1.24(m,2H)。
Example 27.4, 4' -bis (O (9) -allylcinchonidine-N-methyl) diphenyl sulfide dibromide (12)
After compound 11(150mg, 0.156mmol) obtained by the method of example 26 was suspended in dichloromethane (3.5mL), 50% potassium hydroxide solution (0.25mL, 2.2mmol) and allyl bromide (133mg, 1.10mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a light orange solid (88mg) as the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.97(d, J ═ 7.6,4.4Hz,2H),8.85(d, J ═ 8.9Hz,2H),8.13(d, J ═ 8.3,4.8Hz,2H),7.97(m,4H),7.90(m,2H),7.69(m,2H),7.61(m,2H),7.44(d, J ═ 8.3Hz,4H),6.60(d, J ═ 11.9Hz,2H),6.23(m,2H),6.20-6.02(m,2H),5.66(m,2H),5.48-5.34(m,6H),4.98(d, J ═ 10.6Hz,2H),4.91(m,2H),4.62(m, 4.31H), 4.31, 2H),3.31, 2H, 3.31 (m,2H),3.31, 2H, 3H, 3.52(m, 3, 2H), 3H), 3.31 (m, 2H).
Example 27-1.3, 3' -bis (O (9) -allylcinchonidine-N-methyl) diphenyl sulfide dibromide (12-1)
After compound 11-1(72mg, 74.9mmol) obtained by the method of example 26-1 was suspended in dichloromethane (1.5mL), 50% potassium hydroxide solution (0.2mL, 1.78mmol) and allyl bromide (64mg, 525mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with sodium bromide and water (5mL) and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and filtered. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (42mg) as the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.97(d, J ═ 4.5Hz,2H),8.83(d, J ═ 8.7Hz,2H),8.14(dd, J ═ 8.4,2.9Hz,4H),7.95-7.84(m,4H),7.77(t, J ═ 7.3Hz,2H),7.64(m,4H),7.39(t, J ═ 7.9Hz,2H),6.61(d, J ═ 12.0Hz,2H),6.24(m,2H),6.19-6.01(m, ddh), 5.70(d, J ═ 17.0,10.5,6.2Hz,2H),5.46-5.33(m,6H),5.06-4.89(m,4H), 4.59(m, 4.9H), 4.3.3, 3.19-4H), 3.3.3, 3.19-4H, 3.9 (m,3H), 3.07 (m,2H), 1.87(m,2H),1.45(m, 2H).
Example 28.4, 4' -bis (hydrogenated cinchonidine-N-methyl) diphenyl sulfide dibromide (11-2)
In a 25mL round bottom flask, bis (4- (bromomethyl) phenyl) sulfane (600mg, 1.61mmol) was added to (-) -hydrogenated cinchonidine (860mg, 2.90mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: chloroform (5: 6: 2) in a mixed solvent (8mL) at 110 ℃ under stirring and refluxing for 2.5 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (50mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a yellow solid (950mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ9.00(d,J＝4.7Hz,2H),8.28(d,J＝8.2Hz,2H),8.12(d,J＝8.3Hz,2H),7.91-7.79(m,4H),7.74(m,6H),7.56(m,4H),6.72(m,2H),6.54(m,2H),5.15(m,2H),4.91(m,2H),4.25(m,2H),3.89(m,2H),3.40(m,2H),3.15(m,4H),2.08(m,4H),1.96(m,2H),1.75(m,4H),1.35(m,2H),1.27-1.08(m,4H),0.71(m,6H)。
Example 29.4, 4' -bis (O (9) -allylhydrocinnamonidine-N-methyl) diphenyl sulfide dibromide (12- 2)
After compound 11-2(152mg, 0.157mmol) obtained by the method of example 28 was suspended in dichloromethane (2mL), 50% potassium hydroxide solution (0.25mL, 2.2mmol) and allyl bromide (135mg, 1.10mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting solid was purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (96mg) which was the desired product.
1H NMR (300MHz, trichloromethane-d) δ 9.00(d, J ═ 4.3Hz,2H),8.89(d, J ═ 8.7Hz,2H),8.16(d, J ═ 8.2Hz,2H),7.94(m,6H),7.82(m,2H),7.46(d, J ═ 8.5Hz,4H),6.58(d, J ═ 11.2Hz,2H),6.19(m,4H),6.15-6.01(m,2H),5.49-5.33(m,4H),4.81(m,4H),4.49(d, J ═ 11.3Hz,2H),4.42-4.20(m,4H),3.97(m,2H),3.37(m,2H), 3.27.3.11-3.3 Hz,2H), 1.80(m, 1H), 1.1H), 1H, 1.9 (m,1H), 1.9H, 1H, 3H, 1H, and 1H. Total H68
Example 30.4, 4' -bis (quinine-N-methyl) diphenyl sulfide dibromide (11-3)
In a 25mL round bottom flask, bis (4- (bromomethyl) phenyl) sulfane (127mg, 0.343mmol) was added to (-) -quinine (200mg, 0.616mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: chloroform (5: 6: 2) in 3mL of a mixed solvent and stirred at 110 ℃ under reflux for 2.5 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (25mL) to precipitate a solid, followed by filtration under reduced pressure. Then, an orange solid (320mg) was obtained as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.82(d,J＝4.5Hz,2H),8.03(d,J＝9.0Hz 2H),7.80-7.69(m,6H),7.52(d,J＝8.1Hz,4H),7.50(m,2H),7.38(d,J＝3.2Hz,2H),6.70(d,J＝4.1Hz,2H),6.59(m,2H),5.85-5.66(m,2H),5.45(d,J＝12.4Hz,2H),5.12(d,J＝17.3Hz,2H),5.01(d,J＝10.3Hz,2H),4.73(d,J＝12.5Hz,2H),4.29-4.07(m,2H),4.01(s,6H),4.00-3.97(m,2H),3.83(m,2H),3.67(m,2H),3.23(m,2H),2.68(m,2H),2.17(m,4H),2.01(m,2H),1.84(m,2H),1.46(m,2H)。
Example 31.4, 4' -bis (O (9) -allylquinine-N-methyl) diphenyl sulfide dibromide (12-3)
After compound 11-3(100mg, 0.10mmol) obtained by the method of example 30 was suspended in dichloromethane (1mL), 50% potassium hydroxide solution (0.25mL, 2.23mmol) and allyl bromide (82mg, 0.67mmol) were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with sodium bromide and water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (39.4mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.84(d,J＝4.5Hz,2H),8.04(d,J＝9.1Hz,2H),7.78(d,J＝8.4Hz,4H),7.65(d,J＝4.5Hz,2H),7.58(d,J＝8.3Hz,4H),7.51(dd,J＝9.2,2.6Hz,2H),7.43(m,2H),6.58(m,2H),6.14(m,2H),5.88-5.56(m,8H),5.54-5.40(m,2H),5.28(m,2H),5.15-4.96(m,4H),4.81(d,J＝11.8Hz,2H),4.51(m,2H),4.02-3.89(m,10H),2.72(m,2H),2.38(d,J＝12.8Hz,2H),2.25-2.13(m,2H),2.07-2.00(m,2H),1.91(m,2H),1.64-1.48(m,2H),1.22(m,2H)。
Example 32.44' -bis (cinchonidine-N-methyl) diphenylsulfoxide dibromide (13)
In a 25mL round bottom flask, 4' -sulfinylbis (bromomethyl) benzene (200mg, 0.815mmol) was added to (-) -cinchonidine (272mg, 1.38mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: a mixed solvent (3mL) of chloroform (5: 6: 2) was neutralized and refluxed at 110 ℃ for 3 hours with stirring. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (20mL) to precipitate a solid, which was then filtered under reduced pressure. From the resulting solid, a pale orange solid (320mg) was obtained as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝4.4Hz,2H),8.33(m,2H),8.10(d,J＝8.4Hz,2H),7.90-7.65(m,10H),7.57(d,J＝8.3Hz,4H),6.78(d,J＝4.7Hz,2H),6.56(m,2H),5.65(m,2H),5.32-5.09(m,6H),4.99-4.89(m,2H),4.31(m,2H),3.95(m,2H),3.84(m,2H),3.41-3.26(m,4H),2.70(m,2H),2.18-1.96(m,6H),1.88-1.80(m,2H),1.26(m,2H)。
Example 33, 4' -bis (O (9) -allylcinchonidine-N-methyl) diphenylsulfoxide dibromide (14)
After compound 13(85mg, 0.0804mmol) obtained by the method of example 32 was suspended in chloroform (2mL), 50% potassium hydroxide solution (0.08mL, 0.704mmol) and allyl bromide (68mg, 0.563mmol) were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with NaBr (5mL) and water (5mL) and the organic layer was separated. The chloroform solution was dried over anhydrous magnesium sulfate and filtered. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (30mg) which was the desired product.
1H NMR(300MHz,DMSO-d6)δ9.01(d,J＝4.5,4.0Hz,2H),8.29(d,J＝8.4Hz,2H),8.14(d,J＝8.3Hz,2H),7.94-7.73(m,8H),7.69(d,J＝7.9Hz,2H),7.62-7.54(m,4H),6.45(s,2H),6.16(m,2H),5.80-5.61(m,2H),5.69(m,2H),5.34-5.24(m,2H),5.29(m,2H),5.22-5.09(m,4H),5.00(m,4H),4.38(m,2H),4.03(m,6H),3.77(m,2H),3.55-3.25(m,4H),2.71(m,2H),2.28(m,2H),2.11(m,2H),2.03(m,2H),1.88(m,2H),1.43(m,2H)。
Example 34.4, 4' -bis (hydrogenated cinchonidine-N-methyl) diphenylsulfoxide dibromide (13-1)
In a 25mL round bottom flask, 4-sulfinylbis (bromomethyl) benzene (300mg, 0.815mmol) was added to (-) -hydrogenated cinchonidine (411mg, 1.39mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: a mixed solvent (3mL) of chloroform (5: 6: 2) was neutralized at 110 ℃ and refluxed with stirring for 5.5 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (20mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a light orange solid (150mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝4.5Hz,2H),8.31(m,2H),8.10(m,2H),7.90-7.62(m,10H),7.61-7.36(m,4H),6.76(m,2H),6.55(m,2H),5.25(m,2H),5.01(m,2H),4.31(m,2H),3.94(m,2H),3.50(m,2H),3.38-3.29(m,4H),2.07(m,4H),1.94(m,2H),1.76(m,4H),1.33(m,2H),1.16(m,4H),0.75-0.62(m,6H)。
Example 35, 4' -bis (O (9) -allylhydrocinnamonidine-N-methyl) diphenylsulfoxide dibromide (14- 1)
After compound 13-1(148mg, 0.140mmol) obtained by the method of example 34 was suspended in dichloromethane (1.5mL), 50% potassium hydroxide solution (0.25mL, 2.2mmol) and allyl bromide (119mg, 0.980mmol) were added, and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was diluted with NaBr (5mL) and water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting solid was purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (105mg) which was the desired product.
1H NMR(300MHz,DMSO-d6)δ9.02(d,J＝4.4Hz,2H),8.27(d,J＝8.4Hz,2H),8.14(d,J＝8.4Hz,2H),7.88(m,2H),7.83-7.49(m,14H),6.43(m,2H),6.15(m,2H),5.52-5.37(m,2H),5.29(m,2H),5.15(m,2H),4.92(m,2H),4.37(m,2H),3.99(m,4H),3.29-3.14(m,4H),2.26(m,2H),2.08(m,2H),1.98(m,2H),1.79(m,4H),1.47(m,4H),1.18(m,4H),0.70(t,6H)。
Examples 36.4, 4' -bis (cinchonidine-N-methyl) diphenylsulfone dibromide (15)
In a 25mL round bottom flask, 4-sulfonylbis (bromomethyl) benzene (268mg, 0.663mmol) was added to (-) -cinchonidine (332mg, 1.27mmol) and the mixture was cooled in ethanol: n, N-dimethylformamide: a mixed solvent (6mL) of chloroform (5: 6: 2) was neutralized and refluxed at 110 ℃ for 4 hours with stirring. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (100mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a bright red solid (576mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.96(d,J＝4.6Hz,2H),8.25(m,6H),8.07(m,6H),7.92-7.76(m,4H),7.71-7.36(m,4H),6.76(m,2H),6.52(m,2H),6.60(m,4H),5.65(m,2H),5.28(m,2H),5.15(m,2H),4.93(m,2H),4.29-3.29(m,2H),3.92(m,2H),3.77(m,2H),3.25(m,2H),2.64(m,2H),2.19(m,8H),1.78-1.23(m,2H)。
Example 37.4, 4' -bis (O (9) -allylcinchonidine-N-methyl) diphenylsulfone dibromide (16)
After compound 15(50mg, 0.05mmol) obtained by the method of example 36 was suspended in dichloromethane (1mL), 50% potassium hydroxide solution (0.20mL, 1.78mmol) and allyl bromide (43mg, 0.35mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with sodium bromide and water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (27mg) which was the desired product.
11H NMR (300MHz, trichloromethane-d) δ 8.96(d, J ═ 4.4Hz,2H),8.69(d, J ═ 8.6Hz,2H),8.29-7.97(m,10H),7.72(m,6H),6.30(d, J ═ 7.4Hz,4H),6.11(m,10.6,5.8Hz,2H),5.59(m,2H),5.45-5.24(m,6H),4.93(m,4H),4.51(d, J ═ 13.1Hz,2H),4.40(d, J ═ 13.4Hz,4H),4.29(d, J ═ 8.6Hz,2H),4.22(d, J ═ 6.0, 4H),3.67-3.33, 4.7 (m, 3.77H), 2.1 (m,6H), 1.48H), 1.6H, 6H, 1H, 6H, 1H, 3.7 (m, 3H).
Example 38.4, 4' -bis (hydrogenated cinchonidine-N-methyl) diphenylsulfone dibromide (15-1)
In a 25mL round bottom flask, 4-sulfonylbis (bromomethyl) benzene (500mg, 1.24mmol) was added to (-) -hydroxycinnidine hydride (660mg, 2.23mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: chloroform (5: 6: 2) in a mixed solvent (5mL) at 110 ℃ under stirring and refluxing for 4.5 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (40mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (253mg) as the desired product.
1H-NMR(300MHz,DMSO-d6)δ8.98(d,J＝4.5Hz,2H),8.26(m,6H),8.07(m,6H),7.83(m,4H),7.72(m,2H),6.72(m,2H),6.53(m,2H),5.31(d,J＝12.2Hz,2H),5.07(d,J＝12.2Hz,2H),4.32(m,2H),3.95(m,2H),3.50(m,2H),3.26(m,4H),2.24-1.99(m,4H),1.94(m,2H),1.74(m,4H),1.34(m,2H),1.16(m,4H),0.70(m,6H)。
Example 39, 4' -bis (O (9) -allylhydridocinnidine-N-methyl) diphenylsulfone dibromide (16-1)
After compound 15-1(300mg, 0.31mmol) obtained by the method of example 38 was suspended in dichloromethane (10mL), 50% potassium hydroxide solution (0.35mL, 3.1mmol) and allyl bromide (0.16mL, 1.9mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting filtrate was dropwise added to diethyl ether (50mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a light orange solid (270mg) as the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.96(d, J ═ 4.5Hz,2H),8.70(d, J ═ 8.4Hz,2H),8.22-8.19(m,4H),8.14-8.11(m,2H),8.00(d, J ═ 8.2Hz,4H),7.89-7.55(m,6H),6.28(m,4H),6.21-5.98(m,2H),5.48-5.31(m,4H),4.89(d, J ═ 11.7Hz,2H),4.52(m,2H),4.38(m,4H),4.21(m,4H),3.56-3.35(m,2H),3.27(m,2H),2.17(m,4H), 2.91(m, 2H), 1.1H, 1, 1.1H), 1.1.1H, 1H, 1.31 (m, 1H).
Example 40.4, 4' -bis (cinchoni-N-methyl) benzophenone dibromide (17)
In a 25mL round bottom flask, bis (4- (bromomethyl) phenyl) methanone (101mg, 0.27mmol) was added to (+) -cinchonil (144mg, 0.49mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: a mixed solvent (5mL) of chloroform (5: 6: 2) was neutralized at 110 ℃ and refluxed with stirring for 4 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (50mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (223mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ9.01(d,J＝4.6Hz,2H),8.38(d,J＝8.7Hz,2H),8.17-8.08(m,2H),7.99(m,6H),7.92-7.71(m,8H),6.89(m,2H),6.55(m,2H),6.06-5.94(m,2H),5.31-5.18(m,6H),5.05(d,J＝12.5Hz,2H),4.28(m,2H),3.98-3.78(m,4H),3.52(m,2H),3.06(m,2H),2.66(m,2H),2.30(m,2H),1.84-1.72(m,6H),1.09(m,2H)。
Example 41.4, 4' -bis (O (9) -allylcinchoni-N-methyl) benzophenone dibromide (18)
After compound 17(50mg, 0.052mmol) obtained by the method of example 40 was suspended in dichloromethane (3mL), 50% potassium hydroxide solution (0.25mL, 2.2mmol) and allyl bromide (38mg, 0.31mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (5mL) and the organic layer was extracted with dichloromethane (2x, 20 mL). The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered, then evaporated in vacuo. The resulting product was isolated and purified by column chromatography (dichloromethane/methanol) to give a light orange solid (42mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ9.00(d,J＝4.5Hz,2H),8.98-8.81(m,2H),8.16(m,6H),8.01-7.74(m,10H),6.72(d,J＝10.8Hz,2H),6.23(m,2H),6.20-6.06(m,2H),5.99-5.84(m,2H),5.44-5.20(m,12H),4.55(d,J＝11.7Hz,2H),4.40-4.18(m,6H),4.04(dd,J＝11.9,6.2Hz,2H),3.58(m,2H),2.91(m,2H),2.60(m,2H),2.37(m,2H),2.01-1.88(m,4H)1.13(m,2H)。
Examples42.4, 4' -bis (cinchoni-N-methyl) diphenylmethane dibromide (19)
In a 25mL round bottom flask, bis (4- (bromomethyl) phenyl) methane (300mg, 0.847mmol) was added to (+) -cinchoni (449mg, 1.52mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: a mixed solvent (4mL) of chloroform (5: 6: 2) was neutralized at 110 ℃ and refluxed with stirring for 5 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (50mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pink solid (468mg) which was the desired product.
1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝4.5Hz,2H),8.37(d,J＝7.4Hz,2H),8.10(dd,J＝8.4,1.5Hz,2H),7.87-7.79(m,4H),7.79-7.69(m,6H),7.50(d,J＝8.3Hz,4H),6.82(d,J＝4.4Hz,2H),6.56-6.47(m,2H),6.11-5.92(m,2H),5.25(m,2H),5.21(m,2H),5.15(m,2H),5.04(d,J＝12.4Hz,2H),4.25(t,J＝9.5Hz,2H),4.15(s,2H),4.04-3.87(m,4H),3.49(t,J＝11.3Hz,2H),3.06-2.91(m,2H),2.75-2.59(m,2H),2.35-2.22(m,2H),1.88(m,2H),1.83-1.69(m,4H),1.11-0.95(m,2H)。
Example 43.4, 4' -bis (O (9) -allylcinchoni-N-methyl) diphenylmethane dibromide (20)
After compound 19(200mg, 0.212mmol) obtained by the method of example 42 was suspended in dichloromethane (7mL), 50% potassium hydroxide solution (0.35mL, 3.1mmol) and allyl bromide (181mg, 1.48mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. After vacuum distillation, the resulting solid was purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (114mg) which was the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.98(d, J ═ 4.5Hz,2H),8.94(d, J ═ 7.6Hz,2H),8.15(dd, J ═ 8.5,1.3Hz,2H),8.03-7.58(m,10H),7.29(d, J ═ 8.5Hz,4H),6.49(d, J ═ 11.2Hz,2H),6.22-6.16(m,2H),6.10(m,2H),5.92(m,2H),5.46-5.47-5.22(m,12H),4.70(m,2H),4.43(d, J ═ 11.9Hz,2H),4.33-4.15(m,4H),4.08(s,2H), 3.9H), 4.9-6.16 (m,2H), and the like7(m,2H),3.60(t,J＝11.9Hz,2H),2.96-2.79(m,2H),2.62(q,J＝8.3Hz,2H),2.36(t,J＝12.1Hz,2H),1.99-1.88(m,4H),1.10(m,2H)。
Example 44.4, 4' -bis (quinine)T-shirt-N-methyl) diphenylmethane dibromide (19-1)
In a 25mL round bottom flask, bis (4- (bromomethyl) phenyl) methane (200mg, 0.565mmol) was added to (+) -quinidine (330mg, 1.02mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: chloroform (5: 6: 2) in a mixed solvent (4mL) at 110 ℃ under stirring and refluxing for 4 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (200mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (202mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.80(d,J＝4.5Hz,2H),8.01(d,J＝9.1Hz,2H),7.77(dd,J＝8.4,4.5Hz,2H),7.69-7.79(m,4H),7.53-7.39(m,8H),6.81(d,J＝4.2Hz,2H),6.54(d,J＝4.9Hz,2H),6.13-5.95(m,2H),5.30-5.18(m,4H),5.15(m,2H),5.21(m,2H),5.15(m,2H),4.77(d,J＝12.8Hz,2H),4.32(t,J＝9.5Hz,2H),4.14(s,2H),4.06-3.87(m,8H),3.89(t,J＝9.1Hz,2H),3.50-2.91(m,2H),3.03-2.86(m,2H),2.69-2.22(m,2H),2.47(m,2H),1.94-1.87(m,2H),1.84-1.68(m,4H)。
Example 45.4, 4' -bis (O (9) -allylquinineT-shirt-N-methyl) diphenylmethane dibromide (20-1)
After compound 19-1(100mg, 0.100mmol) obtained by the method of example 44 was suspended in dichloromethane (3mL), 50% potassium hydroxide solution (0.35mL, 3.1mmol) and allyl bromide (101mg, 0.828mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting product was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (63mg) which was the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.82(d, J ═ 4.5Hz,2H),8.04(d, J ═ 9.2Hz,2H),7.81(d, J ═ 7.9Hz,6H),7.40(dd, J ═ 9.3,2.7Hz,2H),7.30(d, J ═ 7.5Hz,4H),6.18-6.01(m,4H),5.92(m,2H),5.50-5.25(m,8H),4.26-4.10(m,6H),4.08(s,2H),4.02(dd, J ═ 12.7,6.2Hz,4H),3.60(t, J ═ 11.6Hz,2H),2.85(q, J ═ 9.70H), 1.80(m,8H), 1.7 (m,6H), 1.8H, 8H, 6H, 1.8H, 8H, 1.5H, 6H, and 1.8H).
Example 46.4, 4' -bis (cinchoni-N-methyl) benzhydrol dibromide (21)
In a 25mL round bottom flask, bis (4- (bromomethyl) phenyl) methanol (50mg, 0.135mmol) was added to (+) -cinchonil (75.5mg, 0.256mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: chloroform (5: 6: 2) in a mixed solvent (4mL) at 110 ℃ under stirring and refluxing for 4 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (20mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (53mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝4.5Hz,2H),8.35(d,J＝8.5Hz,2H),8.10(m,2H),7.84(m,4H),7.75(d,J＝7.8Hz,6H),7.64(d,J＝7.9Hz,4H),6.85(d,J＝4.1Hz,2H),6.50(m,2H),6.23(d,J＝4.4Hz,1H),6.00(m,2H),5.31-5.16(m,4H),5.12(d,J＝12.2Hz,2H),4.95(d,J＝12.5Hz,2H),4.23(m,2H),4.05(s,1H),3.94(m,4H),3.48(d,J＝11.4Hz,2H),2.99-2.81(m,2H),2.65(d,J＝9.2Hz,2H),2.27(m,2H),1.86(m,2H),1.75(m,4H),1.03(m,2H)。
Example 47.4, 4' -bis (O (9) -allylcinchoni-N-methyl) benzhydrol dibromide (22)
After compound 21(30mg, 0.0313mmol) obtained by the method of example 46 was suspended in dichloromethane (0.5mL), 50% potassium hydroxide solution (0.05mL, 1.35mmol) and allyl bromide (39.7mg, 0.329mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (5mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The resulting product was purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (20mg) which was the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.98(d, J ═ 4.3Hz,2H),8.96-8.88(m,2H),8.15(d, J ═ 8.7Hz,2H),7.99-7.92(m,4H),7.85-7.76(m,4H),7.56(d, J ═ 8.1Hz,2H),7.51-7.46(m,4H),6.59-6.44(m,2H),6.18(d, J ═ 6.8Hz,2H),6.10-6.00(m,2H),6.00-5.95(m,1H),5.95-5.87(m,2H),5.55(s,1H),5.42-5.36(m,4H),5.17-5.10(m,2H), 4.59(m,4H), 4H, 3.49(m, 4H), 3.31, 4H), 3.49(m, 4H), 3.6.6.6.6.6.6.6H, 2H) 1.95(d, J ═ 20.1Hz,8H),1.79(d, J ═ 9.9Hz,2H),1.41(d, J ═ 19.8Hz,2H),1.26(m, 2H).
Example 48.4, 4' -bis (cinchoni-N-methyl) diphenylether dibromide (23)
In a 25mL round bottom flask, 4-oxybis (bromomethyl) benzene (200mg, 0.56mmol) was added to (+) -cinchoni (314mg, 1.077mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: a mixed solvent (3mL) of chloroform (5: 6: 2) was neutralized and refluxed at 110 ℃ for 3 hours with stirring. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (50mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale pink solid (768mg) which was the desired product.
1H NMR(300MHz,DMSO-d6)δ9.00(d,J＝4.4Hz,2H),8.36(d,J＝8.5Hz,2H),8.12(d,J＝8.4Hz,2H),7.93-7.67(m,10H),7.28(d,J＝8.3Hz,4H),6.82(d,J＝3.7Hz,2H),6.53(m,2H),6.13-5.93(m,2H),5.27(s,2H),5.22(d,J＝6.9Hz,2H),5.13(d,J＝12.3Hz,2H),4.93(d,J＝12.6Hz,2H),4.21(t,J＝10.1Hz,2H),3.93(m,4H),3.49(m,2H),3.00(m,2H),2.67(m,2H),2.30(t,J＝11.5Hz,2H),1.84(m,6H),1.10-1.05(m,2H)。
Example 49.4, 4' -bis (O (9) -allylcinchoni-N-methyl) diphenyl ether dibromide (24)
After compound 23(200mg, 0.21mmol) obtained by the method of example 48 was suspended in dichloromethane (3mL), 50% potassium hydroxide solution (0.25mL, 2.2mmol) and allyl bromide (0.12mL, 1.47mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water (3mL) and the organic layer was separated. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered, then evaporated in vacuo. The resulting product was isolated and purified by column chromatography (dichloromethane/methanol) to give the desired product (270mg) as an orange solid.
1H NMR (300MHz, trichloromethane-d) δ 8.99(d, J ═ 4.4Hz,2H),8.95(d, J ═ 8.4Hz,2H),8.15(d, J ═ 8.4,1.3Hz,2H),8.02-7.98(m,8H),7.81(m,2H),7.17-7.10(m,4H),6.57(d, J ═ 11.8Hz,2H),6.21(m,2H),6.13-6.06(m,2H),5.97-5.87(m,2H),5.47-5.24(m,12H),4.47(d, J ═ 11.9Hz,2H),4.35-4.11(m,6H),4.05-3.97(m,2H),3.62(m,2H), 2H (m, 90H), 2H),1.1, 2H, 1H, 2H), 2H, 1H, 2H, and m,1H)
Example 50.4, 4' -bis (quinidine-N-methyl) diphenylether dibromide (23-1)
In a 25mL round bottom flask, 4-oxybis (bromomethyl) benzene (200mg, 0.56mmol) was added to (+) -quinidine (328.0mg, 1.01mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: a mixed solvent (3mL) of chloroform (5: 6: 2) was neutralized at 110 ℃ and refluxed with stirring for 4 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (50mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale grey solid (636mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.81(d,J＝4.5Hz,2H),8.01(d,J＝9.2Hz,2H),7.95(m,2H),7.82-7.72(m,4H),7.61-7.37(m,8H),6.86(d,J＝3.7Hz,2H),6.52(m,2H),6.04-5.98(m,2H),5.30-5.18(m,4H),5.09(d,J＝12.6Hz,2H),4.76(d,J＝12.6Hz,2H),4.22(m,2H),4.07(s,6H),3.98(m,2H),3.83(m,2H),3.48(m,2H),3.04-2.91(m,2H),2.72(m,2H),2.38(m,2H),1.90(m,2H),1.77(m,4H),1.11(m,2H)。
Example 51.4, 4' -bis (O (9) -allylquinidine-N-methyl) diphenylether dibromide (24-1)
After compound 23-1(100mg, 0.10mmol) obtained by the method of example 50 was suspended in chloroform (3mL), 50% potassium hydroxide solution (0.25mL, 2.2mmol) and allyl bromide (0.06mL, 0.70mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (3mL) and the organic layer was extracted with dichloromethane (2X 3 mL). The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered, then evaporated in vacuo. The resulting product was isolated and purified by column chromatography (dichloromethane/methanol) to give a light brown solid (33mg) as the desired product.
1H NMR (300MHz, trichloromethane-d) δ 8.92-8.76(m,2H),8.15-8.01(m,2H),7.86(d, J ═ 8.2Hz,2H),7.41(d, J ═ 11.5Hz,2H),7.21(d, J ═ 9.0Hz,2H),7.11(m,2H),7.05-6.83(m,2H),6.25-6.01(m,4H),5.97-5.75(m,2H),5.40(m,4H),5.33-5.22(m,4H),4.25(d, J ═ 23.5Hz,4H),4.03(m,4H),3.93(m,2H),3.88-3.80(m,4H),3.62(m,2H),3.41(m,2H), 1.7 (m, 1.7H), 1.44(m,2H), 1.07 (m,2H), 4H) 0.84(m, 4H).
Example 52.4, 4' -bis (cinchoni-N-methyl) diphenyl sulfide dibromide (25)
In a 25mL round bottom flask, bis (4- (bromomethyl) phenyl) sulfane (140mg, 0.38mmol) was added to (+) -cinchoni (200mg, 0.68mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: chloroform (5: 6: 2) in 3mL of a mixed solvent and stirred at 110 ℃ under reflux for 2.5 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (25mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a beige solid (74mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ9.00(d,J＝4.5Hz,2H),8.35(d,J＝9.0Hz,2H),8.12(d,J＝8.5Hz,2H),7.92-7.70(m,10H),7.58(d,J＝8.2Hz,4H),6.82(m,2H),6.52(m,2H),6.01(m,2H),5.32-5.18(m,4H),5.14(m,2H),4.94(d,J＝12.4Hz,2H),4.22(m,2H),3.92(m,4H),3.49(t,J＝11.1Hz,2H),3.00(m,2H),2.67(m,2H),2.29(m,2H),1.83(m,6H),1.07(m,2H)。
Example 53, 4' -bis (O (9) -allylcinchoni-N-methyl) diphenyl sulfide dibromide (26)
After compound 25(150mg, 0.156mmol) obtained by the method of example 52 was suspended in dichloromethane (2mL), 50% potassium hydroxide solution (0.25mL, 2.2mmol) and allyl bromide (133mg, 1.09mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water (5mL) and the organic layer was extracted with dichloromethane (2X 2 mL). The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered, then evaporated in vacuo. The resulting solid was purified by column chromatography (dichloromethane/methanol) to give a yellow solid (61mg) as the desired product.
1H NMR (300MHz, trichloromethane-d) δ 9.00(m,4H),8.16(d, J ═ 9.1Hz,2H),7.97(m,6H),7.83(m,4H),7.47(d, J ═ 8.6Hz,4H),6.63(m,2H),6.26 to 6.01(m,4H),5.93(m,2H),5.52 to 5.32(m,12H),4.36 to 4.14(m,8H),3.96(m,2H),3.59(m,2H),2.90(m,2H),2.65(m,2H),2.36(m,2H),1.99(m,4H),1.12(m, 2H).
Example 54, 4' -bis (quinidine-N-methyl) diphenyl sulfide dibromide (25-1)
In a 25mL round bottom flask, bis (4- (bromomethyl) phenyl) sulfane (127mg, 0.343mmol) was added to (+) -quinidine (200mg, 0.617mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: chloroform (5: 6: 2) in 3mL of a mixed solvent and stirred at 110 ℃ under reflux for 2.5 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (25mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a dark red solid (320mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.81(d,J＝4.5Hz,2H),8.01(d,J＝9.2,2.7Hz,2H),7.83-7.72(m,6H),7.56-7.43(m,8H),6.86(m,2H),6.52(m,2H),6.04(m,2H),5.32-5.16(m,4H),5.09(m,2H),4.76(m,2H),4.24(m,2H),4.09(s,6H),3.83(m,2H),3.57-3.43(m,2H),3.16(m,2H),3.02-2.92(m,2H),2.70-2.60(m,2H),2.40(m,4H),1.90(m,2H),1.77(m,2H),1.11(m,2H)。
Example 55.4, 4' -bis (cinchoni-N-methyl) diphenylsulfoxide dibromide (27)
In a 25mL round bottom flask, 4-sulfinylbis (bromomethyl) benzene (200mg, 0.543mmol) was added to (-) -hydrogenated cinchonil (272mg, 0.924mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: chloroform (5: 6: 2) in 3mL of a mixed solvent and stirred at 110 ℃ under reflux for 4.5 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (20mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a light orange solid (388mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.76(d,J＝4.5Hz,2H),8.27-8.07(m,2H),7.87(m,2H),7.80-7.32(m,10H),7.30-7.17(m,4H),6.68(m,2H),6.30(m,2H),5.93-5.65(m,2H),5.13-4.66(m,8H),4.02(m,2H),3.94-3.61(m,4H),3.25(m,6H),2.19-1.86(m,2H),1.58(m,6H),0.89-0.73(m,2H)。
Example 56.4, 4' -bis (O (9) -allylcinchoni-N-methyl) diphenylsulfoxide dibromide (28)
After compound 27(50mg, 0.052mmol) obtained by the method of example 55 was suspended in chloroform (2.0mL), 50% potassium hydroxide solution (0.15mL, 1.32mmol) and allyl bromide (45mg, 0.369mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (2mL) and the organic layer was extracted with chloroform (2X 2 mL). The chloroform solution was dried over anhydrous magnesium sulfate and filtered. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (52mg) which was the desired product.
1H NMR(300MHz,DMSO-d6)δ9.02(d,J＝4.5Hz,2H),8.40(d,J＝7.5Hz,2H),8.13(d,J＝8.6Hz,2H),7.90-7.71(m,8H),7.57(m,2H),7.53-7.37(m,2H),6.39(m,2H),6.17(m,Hz,2H),5.99(m,2H),5.44(d,J＝17.1Hz,3H),5.35-5.19(m,7H),4.66(d,J＝12.4Hz,2H),4.28(m,2H),4.14-3.92(m,8H),3.57(m,2H),3.03(m,2H),2.82-2.60(m,2H),2.43-2.29(m,2H),1.93-1.70(m,6H),1.21(m,2H)。
Example 57.4, 4' -bis (cinchoni-N-methyl) diphenylsulfone dibromide (29)
In a 25mL round bottom flask, 4-sulfonylbis (bromomethyl) benzene (500mg, 1.24mmol) was added to (+) -cinchonil (656mg, 2.23mmol) and the mixture was stirred in ethanol: n, N-dimethylformamide: chloroform (5: 6: 2) in a mixed solvent (8mL) at 110 ℃ under stirring and refluxing for 4 hours. The reaction mixture was cooled to room temperature and added dropwise to diethyl ether (40mL) to precipitate a solid, which was then filtered under reduced pressure. The resulting solid was isolated and purified by column chromatography (dichloromethane/methanol) to give a pale yellow solid (321mg) as the desired product.
1H NMR(300MHz,DMSO-d6)δ8.98(d,J＝4.5Hz,2H),8.33(d,J＝8.4Hz,2H),8.24(d,J＝8.1Hz,2H),8.15-7.97(m,8H),7.90-7.80(m,4H),7.74(m,2H),6.85(m,2H),6.48(m,2H),5.98(m,2H),5.22(m,6H),5.00(m,2H),4.23(m,2H),4.00-3.84(m,4H),3.52(m,2H),2.99(m,2H),2.63(m,2H),2.27(m,2H),1.93-1.59(m,6H),1.04(m,2H)
Example 58.4, 4' -bis (O (9) -allylcinchoni-N-methyl) diphenylsulfone dibromide (30)
After compound 29(50mg, 0.06mmol) obtained by the method of example 57 was suspended in dichloromethane (2mL), 50% potassium hydroxide solution (0.20mL, 1.78mmol) and allyl bromide (47mg, 0.39mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (3mL) and the organic layer was extracted with dichloromethane (2X 10 mL). The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered, then evaporated in vacuo. The resulting product was isolated and purified by column chromatography (dichloromethane/methanol) to give a light orange solid (55mg) which was the desired product.
1H NMR(300MHz,DMSO-d6)δ9.01(d,J＝4.5Hz,2H),8.96(d,J＝4.5Hz,1H),8.24(d,J＝8.3Hz,4H),8.10(m,10H),7.79(m,6H),6.16(m,2H),5.96(m,2H),5.47-5.39(m,2H),5.26(m,6H),4.72(m,2H),4.27(m,2H),4.01(m,8H),3.57(m,2H),3.02(m,2H),2.68(m,2H),2.34(m,2H),1.90(m,4H),1.51(m,2H),1.19(m,2H)。
Experimental example 1N- (diphenylmethylene) glycine tert-butyl ester alkylation under chiral phase transfer catalysis Radication of
To measure the efficiency of the synthesized phase transfer catalyst, benzylation was performed using tert-butyl N- (diphenylmethylene) glycinate as a substrate, and the optical purity of the resulting product was measured using chiral High Performance Liquid Chromatography (HPLC), as shown in reaction scheme 4 below. Specifically, a mixed solvent of toluene/chloroform (volume ratio ═ 7: 3, 0.75mL) and 50% potassium hydroxide solution (0.25mL, 13.0mmol) were added to N- (diphenylmethylene) glycine tert-butyl ester (30mg, 0.102mmol) and chiral phase transfer catalyst (1% eq., 0.0010mmol), and the reaction solution was cooled to 15 ℃. Then, benzyl bromide (1.2eq., 14.5 μ L, 0.123mmol) was added to the reaction solution, and the reaction mixture was stirred at room temperature until no substrate remained. The reaction mixture was diluted with ether (20mL) and the organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The resulting product was subjected to column separation (mobile phase; hexane: ethyl acetate ═ 50: 1) to give a colorless liquid, tert-butyl 2- (diphenylmethyleneamino) -3-phenylpropionate as desired product. The optical purity of the product obtained was measured by asymmetric HPLC, the operating conditions of the HPLC apparatus were as follows: column: DAICEL Chiralcel OD, mobile phase: hexane: 2-propanol ═ 100: (iii) flow velocity: 0.5mL/min, measuring temperature: 20 ℃, detector: UV spectrophotometer (254nm), and retention time: (R) -enantiomer (minority) 12.2min, (S) -enantiomer (majority) 20.5min.
[ reaction scheme 4]
Figure BDA0001918549330000391
The results of each catalytic reaction are shown in tables 1 and 2.
[ Table 1]
Figure BDA0001918549330000392
Figure BDA0001918549330000401
Figure BDA0001918549330000411
(comparative examples 1, 2: O' Donnell, M.J.; Bennett, W.D.; Wu, S.J.am. chem. Soc.1989,111,2353.)
[ Table 2]
Figure BDA0001918549330000412
Figure BDA0001918549330000421
(comparative example 3: O' Donnell, M.J.; Bennett, W.D.; Wu, S.J.Am. chem. Soc.1989,111, 2353).
Comparative example 4: o' Donnell, m.j.; wu, s.; esikova, i.; mi, A.WO 9506029A 119950302)
As shown in tables 1 and 2, the monobenzylammonium catalysts of comparative examples 1 and 2 (10% equivalent) exhibited optical purities (S) of 80% ee under conditions of 1% equivalent of the catalyst and 1.2 equivalents of benzyl bromide, while the catalysts of the present invention exhibited high optical purities of 95% ee to 99% ee. In addition, the monobenzylammonium catalysts of comparative examples 3 and 4 (10% equiv.) exhibited an (R) optical purity of about 70% ee. On the other hand, the catalyst of the present invention exhibits high optical purity with a maximum of 95% ee at 1% equivalent of catalyst and 1.2 equivalents of benzyl bromide. From the above results, it can be seen that the catalyst of the present invention exhibits high optical purity with only a low catalyst usage amount and using almost the same amount of reagents, and the catalyst can be prepared by a simple process, and thus it can be seen that the catalyst can be widely applied to the preparation of α -amino acids on an industrial level.
It will be appreciated by those of ordinary skill in the art that the foregoing description of the present invention is exemplary and that the exemplary embodiments disclosed herein can be readily modified into other specific forms without departing from the technical spirit or essential characteristics thereof. Accordingly, the exemplary embodiments described above should be construed as illustrative and not limiting in any way.

Claims (9)

1. A cinchona alkaloid compound represented by the following formula 1:
[ formula 1]
Figure FDA0003355076230000011
Wherein
X represents-CH2-, -C (oh) H-, -C (═ O), -O-, -S-, or-S (═ O) -; and R represents
Figure FDA0003355076230000012
Figure FDA0003355076230000013
Wherein R is1Represents hydrogen or C1To C5An alkoxy group;
R2represents a vinyl group or an ethyl group;
R3represents hydrogen, allyl, or C5To C10An aryl group; and
Y-represents a halogen anion selected from fluorine, chlorine, bromine and iodine; and if X is-CH2-, -C (oh) H-, -C (═ O) -, or-S (═ O) -, excluding R3Is C5To C10A compound of an aryl group.
2. The compound of claim 1, wherein when X of the compound represented by formula 1 is-CH2-, -C (OH) H-or-C (═ O) -,
R1represents hydrogen or methoxy;
R2represents a vinyl group or an ethyl group;
R3represents hydrogen or allyl; and is
Y-Represents a halogen anion selected from fluorine, chlorine, bromine and iodine.
3. The compound of claim 2, wherein the compound is selected from the group consisting of:
4, 4' -bis (cinchonidine-N-methyl) benzophenone dibromide;
4, 4' -bis (O (9) -allylcinchonidine-N-methyl) benzophenone dibromide;
4, 4' -bis (hydrogenated cinchonidine-N-methyl) benzophenone dibromide;
4, 4' -bis (O (9) -allylhydridocinnidine-N-methyl) benzophenone dibromide;
3, 4' -bis (cinchonidine-N-methyl) benzophenone dibromide;
3, 4' -bis (O (9) -allylcinchonidine-N-methyl) benzophenone dibromide;
3, 3' -bis (cinchonidine-N-methyl) benzophenone dibromide;
3, 3' -bis (O (9) -allylcinchonidine-N-methyl) benzophenone dibromide;
4, 4' -bis (cinchonidine-N-methyl) diphenylmethane dibromide;
4, 4' -bis (O (9) -allylcinchonidine-N-methyl) diphenylmethane dibromide;
4, 4' -bis (hydrogenated cinchonidine-N-methyl) diphenylmethane dibromide;
4, 4' -bis (O (9) -allylhydridocinnidine-N-methyl) diphenylmethane dibromide;
4, 4' -bis (quinine-N-methyl) diphenylmethane dibromide;
4, 4' -bis (O (9) -allylquinine-N-methyl) diphenylmethane dibromide;
4, 4' -bis (cinchonidine-N-methyl) benzhydrol dibromide;
4, 4' -bis (O (9) -allylcinchonidine-N-methyl) benzhydrol dibromide;
4, 4' -bis (hydrogenated cinchonidine-N-methyl) benzhydrol dibromide;
4, 4' -bis (O (9) -allylhydridocinnidine-N-methyl) benzhydrol dibromide;
4, 4' -bis (cinchoni-N-methyl) benzophenone dibromide;
4, 4' -bis (O (9) -allylcinchoni-N-methyl) benzophenone dibromide;
4, 4' -bis (cinchoni-N-methyl) diphenylmethane dibromide;
4, 4' -bis (O (9) -allylcinchoni-N-methyl) diphenylmethane dibromide;
4, 4' -bis (quinidine-N-methyl) diphenylmethane dibromide;
4, 4' -bis (O (9) -allylquinidine-N-methyl) diphenylmethane dibromide;
4, 4' -bis (cinchoni-N-methyl) benzhydrol dibromide; and
4, 4' -bis (O (9) -allylcinchoni-N-methyl) benzhydrol dibromide.
4. The compound according to claim 1, wherein when X in the compound represented by formula 1 is-O-, -S-or-S (═ O) -,
R1represents hydrogen or methoxy;
R2represents a vinyl group or an ethyl group;
R3represents hydrogen, allyl or benzyl; and is
Y represents a halogen anion selected from fluorine, chlorine, bromine and iodine.
5. The compound of claim 4, wherein the compound is selected from the group consisting of:
4, 4' -bis (cinchonidine-N-methyl) diphenyl ether dibromide;
4, 4' -bis (O (9) -allylcinchonidine-N-methyl) diphenyl ether dibromide;
4, 4' -bis (O (9) -benzyl-cinchonidine-N-methyl) diphenyl ether dibromide;
4, 4' -bis (hydrogenated cinchonidine-N-methyl) diphenyl ether dibromide;
4, 4' -bis (O (9) -allylhydridoconconidine-N-methyl) diphenyl ether dibromide;
4, 4' -bis (quinine-N-methyl) diphenyl ether dibromide;
4, 4' -bis (O (9) -allylquinine-N-methyl) diphenylether dibromide;
3, 3' -bis (cinchonidine-N-methyl) diphenyl ether dibromide;
3, 3' -bis (O (9) -allylcinchonidine-N-methyl) diphenyl ether dibromide;
4, 4' -bis (cinchonidine-N-methyl) diphenyl sulfide dibromide;
4, 4' -bis (O (9) -allylcinchonidine-N-methyl) diphenyl sulfide dibromide;
4, 4' -bis (hydrogenated cinchonidine-N-methyl) diphenyl sulfide dibromide;
4, 4' -bis (O (9) -allylhydridocinnidine-N-methyl) diphenyl sulfide dibromide;
4, 4' -bis (quinine-N-methyl) diphenyl sulfide dibromide;
4, 4' -bis (O (9) -allylquinine-N-methyl) diphenyl sulfide dibromide;
3, 3' -bis (cinchonidine-N-methyl) diphenyl sulfide dibromide;
3, 3' -bis (O (9) -allylcinchonidine-N-methyl) diphenyl sulfide dibromide;
4, 4' -bis (cinchonidine-N-methyl) diphenylsulfoxide dibromide;
4, 4' -bis (O (9) -allylcinchonidine-N-methyl) diphenylsulfoxide dibromide;
4, 4' -bis (hydrogenated cinchonidine-N-methyl) diphenylsulfoxide dibromide;
4, 4' -bis (O (9) -allylhydridocinnidine-N-methyl) diphenylsulfoxide dibromide;
4, 4' -bis (cinchoni-N-methyl) diphenyl ether dibromide;
4, 4' -bis (O (9) -allylcinchoni-N-methyl) diphenyl ether dibromide;
4, 4' -bis (quinidine-N-methyl) diphenyl ether dibromide;
4, 4' -bis (O (9) -allylquinidine-N-methyl) diphenylether dibromide;
4, 4' -bis (cinchoni-N-methyl) diphenyl sulfide dibromide;
4, 4' -bis (O (9) -allylcinchoni-N-methyl) diphenyl sulfide dibromide;
4, 4' -bis (quinidine-N-methyl) diphenyl sulfide dibromide;
4, 4' -bis (cinchoni-N-methyl) diphenylsulfoxide dibromide; and
4, 4' -bis (O (9) -allylcinchoni-N-methyl) diphenylsulfoxide dibromide.
6. A method of synthesizing an α -amino acid using the compound of any one of claims 1 to 5 as a chiral phase transfer catalyst.
7. The process of claim 6, as shown in the following reaction scheme 1, comprising:
preparing a compound represented by formula III by reacting a compound represented by formula I with a compound represented by formula II in the presence of the cinchona alkaloid compound of any one of claims 1 to 5 as a chiral phase transfer catalyst; and
preparing a compound represented by formula IV by hydrolyzing the compound represented by formula III prepared in the above step under acidic conditions,
[ reaction scheme 1]
Figure FDA0003355076230000041
In reaction scheme 1, R' is C2-C6Alkyl and R' is C2-C6Alkyl or C5-C10And (4) an aryl group.
8. The method according to claim 7, wherein the reaction of the compound represented by formula I with the compound represented by formula II is carried out at 10 ℃ to 20 ℃.
9. The process according to claim 7, wherein the chiral phase transfer catalyst is used in the range of 0.0005 to 0.012 equivalents per equivalent of the compound of formula I.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101411996A (en) * 2008-11-28 2009-04-22 上海第二工业大学 Macromolecule supported Cinchona bases compound, production method and application
CN102397793A (en) * 2010-08-25 2012-04-04 帝斯曼知识产权资产管理有限公司 A kind of cinchona base-squaramide hydrogen bond catalyst, its synthesis method and its application in asymmetric reaction
CN104220433A (en) * 2011-11-22 2014-12-17 爱尔兰皇家外科医学院 Process for the preparation of gamma amino acids and intermediates for said process
CN105131032A (en) * 2015-07-28 2015-12-09 西安近代化学研究所 Synthetic method for L-phosphinothricin

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20030044364A (en) * 2001-11-29 2003-06-09 주식회사 아미노젠 Novel phase transfer catalyst and its application for the synthesis of α-amino acid
KR101130818B1 (en) * 2009-07-10 2012-04-12 성균관대학교산학협력단 Method for preparing chiral amino acid from azlactones using bifunctional bis-cinchona alkaloid thiourea organo catalysts

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101411996A (en) * 2008-11-28 2009-04-22 上海第二工业大学 Macromolecule supported Cinchona bases compound, production method and application
CN102397793A (en) * 2010-08-25 2012-04-04 帝斯曼知识产权资产管理有限公司 A kind of cinchona base-squaramide hydrogen bond catalyst, its synthesis method and its application in asymmetric reaction
CN104220433A (en) * 2011-11-22 2014-12-17 爱尔兰皇家外科医学院 Process for the preparation of gamma amino acids and intermediates for said process
CN105131032A (en) * 2015-07-28 2015-12-09 西安近代化学研究所 Synthetic method for L-phosphinothricin

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
A new class of bifunctional chiral phase transfer catalysts for highly enantioselective asymmetric epoxidation of α，β-unsaturated ketonesat ambient temperature;Veeramanoharan Ashokkumar et al.;《Journal of Molecular Catalysis A: Chemical》;20150821;第409卷;第128页Scheme 2 *
Recent Advances in Asymmetric Phase-Transfer Catalysis;Takashi Ooi et al.;《Angew. Chem. Int. Ed.》;20071231;第46卷;第4228-4229页 *

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