阅读说明：本技术 轴手性联苯环-链异构化合物及其制备方法与应用 (Axial chiral biphenyl ring-chain isomerization compound and preparation method and application thereof ) 是由 尤磊 查代君 于 2018-07-20 设计创作，主要内容包括：本发明属于手性化合物识别和纯度测定技术领域,具体涉及轴手性联苯环-链异构化合物及其制备方法与应用。本发明设计合成了轴手性联苯化合物,所述化合物具有环-链互变异构体。本发明的制备方法无需复杂的分离提纯、操作简单、产物易纯化、重现性好,且产品的化学性质稳定。而且,本发明化合物在高通量手性醇、伯胺、仲胺的光学纯度检测方面有巨大的应用前景。此外,本发明测定手性醇、伯胺、仲胺光学纯度的方法克服了常规测量方法的缺点,具有测试精度高、耗时短、成本低、易推广等优点。本发明提供了一种全新的可用于单官能团的手性醇、胺光学纯度的测定手段。并且,本发明测定方法的检出限低。(The invention belongs to the technical field of chiral compound identification and purity determination, and particularly relates to an axial chiral biphenyl ring-chain isomer compound, a preparation method and application thereof.)

1, an axial chiral biphenyl ring-chain isomerization compound, wherein the structure of the compound is shown as the following formula (A) or formula (B):

wherein X, Y, R are the same or different and independently represent H, F, Cl, Br, I, -NO₂Unsubstituted or optionally or more R_aSubstituted of the following groups: c_1-40Alkyl radical, C_1-40Alkoxy radical, C_3-20Cycloalkyl, 3-20 membered heterocyclyl, C_6-20Aryl, 5-20 membered heteroaryl;

every R_aIdentical or different, independently of one another, from the group-F, -Cl, -Br, -I, -OH, -SH, -CN, -NH₂、＝O、-NO₂、-NH₂Unsubstituted or optionally or more R_nSubstituted of the following groups: c_1-40Alkyl radical, C_1-40Alkyloxy, C_1-40Alkylthio radical, C_2-40Alkenyl radical, C_2-40Alkenyloxy radical, C_2-40Alkenylthio radical, C_2-40Alkynyl, C_2-40Alkynyloxy, C_2-40Alkynylthio, C_3-20Cycloalkyl radical, C_3-20Cycloalkyl oxy, C₃-₂₀Cycloalkylthio, 3-20 membered heterocyclyl, 3-20 membered heterocyclyloxy, 3-20 membered heterocyclylthio, C_6-20Aryl radical, C_6-20Aryloxy radical, C_6-20Arylthio, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy, 5-20 membered heteroarylthio;

every R_nIdentical or different, independently of one another, from the group consisting of H, -NH₂、＝O、C_1-40Alkyl radical, C_2-40Alkenyl radical, C_2-40Alkynyl, C_3-20Cycloalkyl, 3-20 membered heterocyclyl, C_6-20Aryl, 5-20 membered heteroaryl.

2. The axial chiral biphenyl cyclo-chain isomeric compound of claim 1 wherein said X, Y, R are the same or different and are independently selected from H, C_1-40An alkyl group; for example, X, Y is selected from H and R is selected from CH₃、C₂H₅、C₃H₇Or C₄H₉；

Preferably, the compounds of formula (a) and (B) are each an axial chiral biphenyl ring-chain isomer, in particular an axial chiral biphenyl ring-chain tautomer.

3. The process for preparing an axial chiral biphenyl cyclo-chain isomeric compound as claimed in claim 1 or 2, comprising reacting a compound of formula (I) with a compound of formula (II) to obtain a compound of formula (a) or (B);

wherein X, Y, R has the definition of claim 1 or 2.

4. The method of claim 3, wherein the reaction is carried out under an inert gas blanket, such as nitrogen blanket;

the reaction may be carried out in the presence of a tetradentate palladium catalyst, which may be Pd (PPh)₃)₄；

The reaction may further be carried out at step in the presence of a base and/or fluoride, where the base may be an alkali metal salt, for example an alkali metal carbonate such as Cs₂CO₃、K₂CO₃、Na₂CO₃、Li₂CO₃ or more fluoride can be or more of tetrabutylammonium fluoride, cesium fluoride and potassium fluoride;

the molar ratio of the compound of formula (I) to the compound of formula (II) may be 1 (1-3), preferably 1 (1.5-2.5), for example 1: 2;

the molar ratio of the catalyst to the compound of formula (I) may be (0.03-0.07):1, preferably (0.04-0.06):1, for example 0.05: 1;

the molar ratio of the base and/or fluoride to the compound of formula (I) may be (1-5) to 1, preferably (2-4) to 1, for example 3: 1;

the reaction may be carried out in a solvent, and the solvent for the reaction may be a mixed solvent of an ether solvent and water, for example, a mixed solvent of 1, 4-dioxane and water;

the temperature of the reaction may be from 25 to 100 ℃, preferably from 60 to 100 ℃, for example 80 ℃;

the reaction time may be 6 to 24 hours, preferably 18 to 24 hours.

5. The method for preparing according to claim 3 or 4, characterized in that it comprises the following steps:

1) reacting the compound of the formula (III) with thionyl chloride to obtain a compound of a formula (IV);

2) compounds of formula (IV) and RNH₂Reacting to obtain a compound shown in a formula (I);

wherein X, R has the definition of claim 1 or 2.

6. The method according to claim 5, wherein, in step 1),

the reaction time may be 4 to 8 hours, preferably 5 to 7 hours, for example 6 hours;

the reaction may be carried out under heating, for example under reflux;

in the step 2), the step (c) is carried out,

the reaction may be carried out with the addition of a base, which may be an inorganic base such as sodium carbonate;

the molar ratio of the compound of formula (IV) to the base may be 1 (1-5), preferably 1 (2-4), for example 1: 3;

the reaction time may be 1 to 3 hours, for example 2 hours;

the reaction may be carried out in a solvent, which may be a halogenated hydrocarbon solvent, such as dichloromethane.

7. The use of the axial chiral biphenyl cyclo-chain isomeric compound according to claim 1 or 2, wherein the axial chiral biphenyl cyclo-chain isomeric compound is used for determining the optical purity of the chiral compound.

8. The use according to claim 7, wherein the chiral compound is selected from the group consisting of chiral alcohols, chiral amines;

preferably, the chiral amine may be a chiral primary amine or a chiral secondary amine; the chiral amine is for example selected from 1-phenylethylamine, chiral 2- (methoxymethyl) pyrrolidine;

preferably, the chiral alcohol may be a chiral compound containing hydroxyl groups, such as chiral 3, 3-dimethyl-2-butanol, 3-methyl-2-butanol, menthol, 1-phenylethanol, methyl mandelate.

A method for measuring optical purity of chiral compound, wherein the method uses the axial chiral biphenyl cyclo-chain isomeric compound of claim 1 or 2, the method comprising the steps of:

(1) preparing an axial chiral biphenyl compound solution;

(2) adding series chiral compound solution with known optical purity into the axial chiral biphenyl compound solution prepared in the step (1) for reaction, detecting a signal of the obtained product through a Circular Dichroism (CD), and establishing a calibration curve, namely establishing a relation between the CD signal and the optical purity of the chiral compound;

(3) adding a chiral compound solution with unknown optical purity into the axial chiral biphenyl compound solution prepared in the step (1), reacting, detecting signals of the obtained product through a Circular Dichroism (CD), and determining the optical purity of the chiral compound solution based on the relation between the CD signals established in the step (2) and the optical purity of the chiral compound.

10. The method for measuring optical purity of a chiral compound according to claim 9, wherein in the step (1), the solution of the axial chiral biphenyl compound is a solution prepared by dissolving the axial chiral biphenyl compound in a nitrile solvent, for example, a solution prepared by dissolving the axial chiral biphenyl compound in acetonitrile;

the concentration of the axial chiral biphenyl compound solution can be 17mmol/L to 29mmol/L, preferably 20mmol/L to 26mmol/L, such as 23 mmol/L;

preferably, when the method is used for determining the optical purity of a chiral alcohol, an acidic catalyst and/or a dehydrating agent may be added to the solution of step (1);

the acidic catalyst is selected from methanesulfonic acid;

the mass ratio of the acidic catalyst to the axial chiral biphenyl compound may be (0.1-0.7) to 1, preferably (0.2-0.6) to 1, e.g. 0.375: 1;

the dehydrating agent is selected from molecular sieves;

preferably, 1-5 molecular sieves, preferably 1 molecular sieve;

preferably, when the method is used to determine the optical purity of chiral amines, a dehydrating agent, and optionally a basic compound;

the dehydrating agent is selected from molecular sieves;

preferably, 1-5 molecular sieves, preferably 1 molecular sieve;

the basic compound is selected from triethylamine;

the mass ratio of the basic compound to the axial chiral biphenyl compound may be (0-0.5):1, preferably (0-0.1):1, e.g. 0, 0.875: 1;

in step (2), the optical purity of the chiral compound solution of known optical purity is selected from, for example, -100%, -66.67%, -33.33%, 0, 33.33%, 66.67%, 100%;

the temperature of the reaction may be 0-60 ℃;

the reaction time may be 6-12 hours;

preferably, a linear plot of optical purity versus CD intensity may be established taking the CD intensity values at peaks 225nm-285nm, preferably at peaks 245nm-265nm, for example at 245nm, 260nm, 265 nm.

Technical Field

The invention belongs to the technical field of chiral compound identification and purity determination, and particularly relates to an axial chiral biphenyl ring-chain isomerization compound and a preparation method and application thereof.

Background

In nature, the two enantiomers of a chiral compound exist in different amounts, with significant differences in metabolic and pharmacological actions between them in the field of organic synthesis, the degree of enantiomeric excess (e.e.%) in the product is a key problem for asymmetric syntheses.

For chiral compounds, when no external chiral environment exists, two enantiomers have completely the same chemical and physical properties except optical activity, show the same melting point, solubility, infrared spectrum and nuclear magnetic resonance spectrum, and have the same retention time on chromatography (gas phase and liquid phase). for many years, scholars at home and abroad establish a plurality of methods for qualitatively or quantitatively analyzing the enantiomeric excess, mainly including means such as chromatography (including high performance liquid chromatography, gas chromatography and supercritical fluid chromatography), nuclear magnetic resonance analysis, spectroscopy (including optical rotation and circular dichroism), and the like.

The bifunctional chiral molecules, such as amino acid, diamine, amino alcohol and the like, can react with chiral reagents at multiple sites through abundant chelation to form diastereoisomer intermediate compounds, and further achieve the purpose of analyzing the content of enantiomers by utilizing different CD signals. For many monofunctional chiral alcohols and chiral amines (especially chiral secondary amines, which have greater steric hindrance), it is difficult to form diastereoisomers by reaction with chiral reagents, and analysis of their enantiomeric contents is therefore more challenging.

Disclosure of Invention

To improve the above problems, the present invention provides kinds of compounds represented by the following formula (A) or formula (B):

wherein X, Y, R are the same or different and independently represent H, F, Cl, Br, I, -NO₂Unsubstituted or optionally or more R_aSubstituted of the following groups: c_1-40Alkyl radical, C_1-40Alkoxy radical, C_3-20Cycloalkyl, 3-20 membered heterocyclyl, C_6-20Aryl, 5-20 membered heteroaryl;

every R_aIdentical or different, independently of one another, from the group-F, -Cl, -Br, -I, -OH, -SH, -CN, -NH₂、＝O、-NO₂、-NH₂Unsubstituted or optionally or more R_nSubstituted of the following groups: c_1-40Alkyl radical, C_1-40Alkyloxy, C_1-40Alkylthio radical, C_2-40Alkenyl radical, C_2-40Alkenyloxy radical, C_2-40Alkenylthio radical, C_2-40Alkynyl, C_2-40Alkynyloxy, C_2-40Alkynylthio, C_3-20Cycloalkyl radical, C_3-20Cycloalkyl oxy, C₃-₂₀Cycloalkylthio, 3-20 membered heterocyclyl, 3-20 membered heterocyclyloxy, 3-20 membered heterocyclylthio, C_6-20Aryl radical, C_6-20Aryloxy radical, C_6-20Arylthio, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy, 5-20 membered heteroarylthio;

every R_nIdentical or different, independently of one another, from the group consisting of H, -NH₂、＝O、C_1-40Alkyl radical, C_2-40Alkenyl radical, C_2-40Alkynyl, C_3-20Cycloalkyl, 3-20 membered heterocyclyl, C_6-20Aryl, 5-20 membered heteroaryl.

According to an embodiment of the invention, said X, Y, R are the same or different and are independently selected from H, C_1-40An alkyl group. For example, X, Y is selected from H and R is selected from CH₃、C₂H₅、C₃H₇Or C₄H₉。

According to an embodiment of the invention, the compounds of formula (a) and (B) are each an axial chiral biphenyl ring-chain isomer, in particular an axial chiral biphenyl ring-chain tautomer.

The invention also provides a preparation method of the compound shown in the formula (A) or the formula (B), which comprises the steps of reacting the compound shown in the formula (I) with the compound shown in the formula (II) to obtain the compound shown in the formula (A) or the formula (B);

wherein X, Y, R has the definitions described above.

According to the invention, the reaction can be carried out under an inert gas blanket, such as a nitrogen blanket;

the reaction may be carried out in the presence of a tetradentate palladium catalyst, which may be Pd (PPh)₃)₄；

The reaction may further be carried out at step in the presence of a base and/or fluoride, where the base may be an alkali metal salt, for example an alkali metal carbonate such as Cs₂CO₃、K₂CO₃、Na₂CO₃、Li₂CO₃ or more fluoride can be or more of tetrabutylammonium fluoride, cesium fluoride and potassium fluoride;

the molar ratio of the compound of formula (I) to the compound of formula (II) may be 1 (1-3), preferably 1 (1.5-2.5), for example 1: 2;

the molar ratio of the catalyst to the compound of formula (I) may be (0.03-0.07):1, preferably (0.04-0.06):1, for example 0.05: 1;

the molar ratio of the base and/or fluoride to the compound of formula (I) may be (1-5) to 1, preferably (2-4) to 1, for example 3: 1;

the reaction may be carried out in a solvent, and the solvent for the reaction may be a mixed solvent of an ether solvent and water, for example, a mixed solvent of 1, 4-dioxane and water;

the temperature of the reaction may be from 25 to 100 ℃, preferably from 60 to 100 ℃, for example 80 ℃;

the reaction time may be 6 to 24 hours, preferably 18 to 24 hours.

According to the invention, the preparation method further comprises the following steps:

1) reacting the compound of the formula (III) with thionyl chloride to obtain a compound of a formula (IV);

2) compounds of formula (IV) and RNH₂Reacting to obtain a compound shown in a formula (I);

wherein X, R has the definitions described above.

According to the present invention, in step 1),

the reaction time may be 4 to 8 hours, preferably 5 to 7 hours, for example 6 hours.

The reaction may be carried out under heating, for example under reflux.

According to the present invention, in step 2),

the reaction may be carried out with the addition of a base, which may be an inorganic base such as sodium carbonate;

the molar ratio of the compound of formula (IV) to the base may be 1 (1-5), preferably 1 (2-4), for example 1: 3;

the reaction time may be 1 to 3 hours, for example 2 hours.

The reaction may be carried out in a solvent, which may be a halogenated hydrocarbon solvent, such as dichloromethane.

The invention also provides application of the axial chiral biphenyl compound, and the axial chiral biphenyl compound can be used for measuring the optical purity of the chiral compound.

According to the invention, the chiral compound may be a chiral alcohol, a chiral amine;

according to the invention, the chiral amine may be a chiral primary or a chiral secondary amine; the chiral amine is for example selected from 1-phenylethylamine, chiral 2- (methoxymethyl) pyrrolidine.

According to the invention, the chiral alcohol may be a chiral compound containing hydroxyl groups, such as chiral 3, 3-dimethyl-2-butanol, 3-methyl-2-butanol, menthol, 1-phenylethanol, methyl mandelate.

The present invention also provides methods for determining the optical purity of a chiral compound, using the above axial chiral biphenyl compound, the method comprising the steps of:

(1) preparing an axial chiral biphenyl compound solution;

(2) adding series chiral compound solution with known optical purity into the axial chiral biphenyl compound solution prepared in the step (1) for reaction, detecting a signal of the obtained product through a Circular Dichroism (CD), and establishing a calibration curve, namely establishing a relation between the CD signal and the optical purity of the chiral compound;

(3) adding a chiral compound solution with unknown optical purity into the axial chiral biphenyl compound solution prepared in the step (1), reacting, detecting signals of the obtained product through a Circular Dichroism (CD), and determining the optical purity of the chiral compound solution based on the relation between the CD signals established in the step (2) and the optical purity of the chiral compound.

According to the present invention, in the step (1), the solution of the axial chiral biphenyl compound is preferably a solution prepared by dissolving the axial chiral biphenyl compound in a nitrile solvent, for example, a solution prepared by dissolving the axial chiral biphenyl compound in acetonitrile.

The concentration of the axial chiral biphenyl compound solution can be 17mmol/L to 29mmol/L, preferably 20mmol/L to 26mmol/L, such as 23 mmol/L.

According to the present invention, when the method is used for measuring the optical purity of a chiral alcohol, an acid catalyst and/or a dehydrating agent may be added to the solution of step (1);

the acidic catalyst is selected from methanesulfonic acid;

the mass ratio of the acidic catalyst to the axial chiral biphenyl compound may be (0.1-0.7) to 1, preferably (0.2-0.6) to 1, e.g. 0.375: 1;

the dehydrating agent is selected from molecular sieves.

The amount of the dehydrating solvent used in the present invention is not particularly limited, and for example, 1 to 5 molecular sieves, preferably 1 molecular sieve, can be used.

According to the present invention, when the method is used for measuring the optical purity of chiral amines, a dehydrating agent, and optionally a basic compound, may be added to the solution of step (1);

the dehydrating agent is selected from molecular sieves;

the amount of the dehydrating solvent used in the present invention is not particularly limited, and for example, 1 to 5 molecular sieves, preferably 1 molecular sieve, can be used.

The basic compound is selected from triethylamine.

The mass ratio of the basic compound to the axial chiral biphenyl compound may be (0-0.5):1, preferably (0-0.1):1, e.g. 0, 0.875: 1.

According to the invention, in step (2), the optical purity of the solution of chiral compound of known optical purity is selected, for example, from-100%, -66.67%, -33.33%, 0, 33.33%, 66.67%, 100%.

According to the invention, the axial chiral biphenyl compound reacted with the chiral compound may be a compound of formula (a) or a compound of formula (B), preferably a compound of formula (B);

the temperature of the reaction may be 0-60 ℃;

the reaction time may be 6-12 hours;

according to the invention, a linear relation graph of optical purity and CD intensity can be established by taking the CD intensity value at the position of a peak of 225nm-285nm, preferably the CD intensity value at the position of 245nm-265nm, such as the CD intensity values at the positions of 245nm, 260nm and 265 nm.

The invention has the advantages of

(1) The axial chiral biphenyl compound is designed and synthesized, and has a ring-chain tautomer, the preparation method of the invention does not need complicated separation and purification, is simple to operate, and has the advantages of easy product purification, good stability, good reproducibility and stable chemical properties of the product.

(2) The biphenyl axis chiral compound has excellent reactivity with chiral alcohol, primary amine and secondary amine with single functional group, and high conversion rate. The diastereoisomer formed after the reaction has stronger CD signal and is easy to detect. Has great application prospect in the aspect of optical purity detection of high-throughput chiral alcohol, primary amine and secondary amine.

(3) The method for determining the optical purity of chiral alcohol, primary amine and secondary amine overcomes the defects of the conventional measuring methods (such as chromatography, nuclear magnetic method and optical rotation method), has the advantages of high measuring precision, short time consumption, low cost, easy extrapolation of and the like, provides brand-new measuring methods for the optical purity of chiral alcohol and amine with single functional groups, has low detection limit, and can determine the optical purity of chiral 3-methyl-2-butanol, 1-phenylethylamine and 2- (methoxymethyl) pyrrolidine when the concentration is only 23 mM.

Definition and description of terms

Unless otherwise indicated, the definitions of radicals and terms set forth in the specification and claims of this application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions of particular compounds in the examples, and the like, may be combined with one another in any combination and permutation. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present specification.

The term "C_1-40Alkyl is understood to preferably mean a straight-chain or branched, saturated -valent hydrocarbon radical having from 1 to 40 carbon atoms, preferably C_1-10An alkyl group. "C_1-10Alkyl "is understood to preferably denote a straight-chain or branched, saturated -valent hydrocarbon radical having 1,2, 3,4, 5,6, 7, 8, 9 or 10 carbon atoms, the alkyl radical being, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-butylPropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, and the like, or isomers thereof. In particular, the radicals have 1,2, 3,4, 5,6 carbon atoms ("C)_1-6Alkyl groups) such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly groups having 1,2 or 3 carbon atoms ("C)_1-3Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.

The term "C_2-40Alkenyl "is understood to preferably mean a linear or branched -valent hydrocarbon radical which contains or more double bonds and has from 2 to 40 carbon atoms, preferably" C_2-10Alkenyl ". "C_2-10Alkenyl "is understood to preferably mean a straight-chain or branched -valent hydrocarbon radical which contains or more double bonds and has 2,3, 4,5, 6, 7, 8, 9 or 10 carbon atoms, in particular 2 or 3 carbon atoms (" C)_2-3Alkenyl "), it being understood that in the case where the alkenyl comprises more than double bonds, which may be separated from one another or conjugated, the alkenyl is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -hex-2-enyl, (Z) -hex-2-enyl, (E) -hex-1-enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, (Z) -but-3-2-enyl, methyl-1-3-propenyl, (Z) -but-2-3-2-enyl, methyl-1-3-butenyl, (Z) -but-2-3-2-enyl, methyl-3-2-enyl, Z-2-propenyl, Z-3-2-methyl-2-propenyl, 2--2-alkenyl, (E) -1-methylbut-2-enyl, (Z) -1-methylbut-2-enyl, (E) -3-methylbut-1-enyl, (Z) -3-methylbut-1-enyl, (E) -2-methylbut-1-enyl, (Z) -2-methylbut-1-enyl, (E) -1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

The term "C_2-40Alkynyl "is understood to mean a linear or branched -valent hydrocarbon radical which contains or more triple bonds and has from 2 to 40 carbon atoms, preferably" C₂-C₁₀Alkynyl ". The term "C₂-C₁₀Alkynyl "is understood as preferably meaning a straight-chain or branched -valent hydrocarbon radical which contains or more triple bonds and has 2,3, 4,5, 6, 7, 8, 9 or 10 carbon atoms, in particular 2 or 3 carbon atoms (" C)₂-C₃-alkynyl "). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, prop-2-ynyl, but-3-methylbut-1-ynyl, and so-1-ethylprop, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2-dimethylbut-3-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-1-ynyl, 3-methylpent-1-, 1, 1-dimethylbut-3-ynyl, 1-dimethylbut-2-ynyl or 3, 3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

The term "C_3-20Cycloalkyl is understood to mean a saturated -valent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C_3-10Cycloalkyl groups ". The term "C_3-10Cycloalkyl "is understood to mean a saturated -valent monocyclic or bicyclic hydrocarbon ring having 3,4, 5,6, 7, 8, 9 or 10 carbon atomsAnd (4) adding the active ingredients. Said C is_3-10Cycloalkyl groups may be monocyclic hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbon groups such as decalin rings.

The term "3-20 membered heterocyclyl" means a saturated membered monocyclic or bicyclic hydrocarbon ring containing 1-5 heteroatoms independently selected from N, O and S, preferably "3-10 membered heterocyclyl". the term "3-10 membered heterocyclyl" means a saturated membered monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S. the heterocyclyl may be attached to the remainder of the molecule by any of the carbon atoms or, if present, the heterocyclyl may include, but is not limited to, a 4 membered ring such as azetidinyl, oxetanyl, a 5 membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6 membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl, or a 7 membered ring such as diazepanyl optionally, the heterocyclyl may be benzofused.

The term "C_6-20Aryl "is understood to preferably mean an valent or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably" C_6-14Aryl ". The term "C_6-14Aryl "is to be understood as preferably meaning an valent or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (" C)_6-14Aryl "), in particularHaving 6 carbon atoms in the ring (' C)₆Aryl "), such as phenyl; or biphenyl, or is a ring having 9 carbon atoms ("C₉Aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C₁₀Aryl radicals), such as tetralinyl, dihydronaphthyl or naphthyl, or rings having 13 carbon atoms ("C₁₃Aryl radicals), such as the fluorenyl radical, or a ring having 14 carbon atoms ("C)₁₄Aryl), such as anthracenyl.

The term "5-20 membered heteroaryl" is understood to include membered monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, such as "5-14 membered heteroaryl" the term "5-14 membered heteroaryl" is understood to include membered monocyclic, bicyclic or tricyclic aromatic ring systems having 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S, and further may be benzo-fused in each cases, in particular the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl-4H-pyrazolyl and the like and their benzofuranyl, e, cinnolinyl, quinoxalinyl, cinnolinyl, indolinyl, cinnolinyl, quinoinyl, quinoxalinyl, cinnolinyl, quinoyl, quinoxalinyl, cinnolinyl, quinoxalinyl, cinnolinyl, quinoxalinyl, cinnolinyl and the like, benzoxazinyl derivatives thereof, and the like, benzoxazinyl, and the like, benzoxaz.

Thus, for some illustrative non-limiting examples, pyridyl or pyridylene includes pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and thienyl or thienylene includes thien-2-yl, thien-3-yl, and thien-3-yl.

Drawings

FIG. 1 is a schematic diagram of the synthesis of a biphenyl axis chiral cyclo-chain isomeric compound of example 1.

Fig. 2 is a circular dichroism graph of biphenyl axis chiral cyclo-chain isomeric compound (23mmol/L) after reaction with 3-methyl-2-butanol of different optical purity (e.e.%).

Fig. 3 is a circular dichroism graph of biphenyl axis chiral cyclo-chain isomeric compound (23mmol/L) after reaction with 1-phenylethylamine of different optical purity (e.e.%).

Fig. 4 is a circular dichroism spectrum of biphenyl axis chiral cyclo-chain isomeric compound (23mmol/L) after reaction with 2- (methoxymethyl) pyrrolidine of different optical purity (e.e.%).

Fig. 5 is a calibration curve of biphenyl axis chiral cyclo-chain isomeric compound (23mmol/L) against chiral 3-methyl-2-butanol, 1-phenylethylamine, 2- (methoxymethyl) pyrrolidine of different optical purity (e.e.%).

Detailed Description

The present invention will now be described in further detail in with reference to specific examples, it being understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention.

Instruments and reagents:¹H-NMR was measured using a 400MHz Bruker Biospin amplitude type III NMR spectrometer; circular dichroism was measured using a French Bio-Logic model MOS-450 circular dichroism spectrometer (1cm quartz cuvette); chiral 3-methyl-2-butanol, 1-phenylethylamine, and 2- (methoxymethyl) pyrrolidine were purchased from Alfa Aesar for calibration, and all other reagents were commercially available analytical grade reagents.