Preparation method of alpha-chiral carbonyl heterocyclic compound
阅读说明：本技术 α-手性羰基杂环化合物的制备方法 (Preparation method of alpha-chiral carbonyl heterocyclic compound ) 是由 黄湧 陈杰安 黎黎 于 2019-09-29 设计创作，主要内容包括：本发明属于药物合成技术领域,尤其涉及一种α-手性羰基杂环化合物的制备方法。本发明提供的制备方法,包括：提供如式a1和/或式a2所示的羰基底物,如式b1和/或式b2所示的手性胺,如式d1和/或式d2所示的手性磷酸,以及卤化试剂；将所述羰基底物、所述卤化试剂、所述手性胺和所述手性磷酸在反应溶剂中进行混合,并在惰性气体气氛下进行反应,获得如式Ⅰ和/或式Ⅱ所示的α-手性羰基杂环化合物。解决了现有方法存在的需要使用金属催化剂以及羰基底物适用范围局限的问题。<Image he="707" wi="700" file="DDA0002221512420000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of an alpha-chiral carbonyl heterocyclic compound. The preparation method provided by the invention comprises the following steps: providing a carbonyl substrate as shown in formula a1 and/or formula a2, a chiral amine as shown in formula b1 and/or formula b2, a chiral phosphate as shown in formula d1 and/or formula d2, and a halogenating agent; and mixing the carbonyl substrate, the halogenating reagent, the chiral amine and the chiral phosphoric acid in a reaction solvent, and reacting in an inert gas atmosphere to obtain the alpha-chiral carbonyl heterocyclic compound shown as the formula I and/or the formula II. Solves the existing problemThe method has the problems of needing to use metal catalysts and limiting the application range of carbonyl substrates.)
1. A method for preparing an alpha-chiral carbonyl heterocyclic compound, which is characterized by comprising the following steps:
providing a carbonyl substrate as shown in formula a1 and/or formula a2, a chiral amine as shown in formula b1 and/or formula b2, a chiral phosphate as shown in formula d1 and/or formula d2, and a halogenating agent;
mixing the carbonyl substrate, the halogenating reagent, the chiral amine and the chiral phosphoric acid in a reaction solvent, and reacting in an inert gas atmosphere to obtain an alpha-chiral carbonyl heterocyclic compound shown as a formula I and/or a formula II;
wherein n is 1 or 2;
y is selected from O, S or NH;
R1、R5、R6、R5' and R6' each is independently selected from any one of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkoxy, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, alkyloxycarbonyl, cyanoalkyl groups having 1 to 20 hydrogen atoms or carbon atoms;
R7、R8、R7'、R8' are each independently selected from any one of a hydrogen atom, or an alkyl group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group, an alkenyl group, a heteroalkenyl group, a cycloalkenyl group, and a heterocycloalkenyl group having a carbon number of 1 to 20;
R9、R10、R9'、R10' each is independently selected from alkyl, alkynyl, phenyl or phenylsilyl with a carbon number of 1-20;
in a carbonyl substrate of formula a1, R2And/or R3Is connected with the alpha-carbon atom of Y by an unsaturated carbon-carbon bond; in a carbonyl substrate of formula a2, R4Linked to Y with an alkenyl group;
in the alpha-chiral carbonyl heterocyclic compound shown as the formula I, R2' and/or R3' is linked to the β -carbon atom of Y by an unsaturated carbon-carbon bond; in the alpha-chiral carbonyl heterocyclic compound shown as the formula II, R4' is linked to the alpha-carbon atom of Y with an alkenyl group.
2. The method according to claim 1, wherein in the step of mixing the carbonyl substrate, the halogenating agent, the chiral amine and the chiral phosphoric acid in a reaction solvent, the molar ratio of the chiral amine to the chiral phosphoric acid is (0.1-20): (0.1-20).
3. The method according to claim 1, wherein the reaction is carried out at a temperature of 0 to 35 ℃ for 1 to 12 hours in the step of carrying out the reaction under an inert gas atmosphere.
4. The production method according to any one of claims 1 to 3, characterized in that in the step of mixing the carbonyl substrate, the halogenating agent, the chiral amine and the chiral phosphoric acid in a reaction solvent, the molar ratio of the chiral amine, the chiral phosphoric acid, the carbonyl substrate and the halogenating agent is (0.1-20): (1-100).
5. The method according to any one of claims 1 to 3, wherein the step of mixing the carbonyl substrate, the halogenating agent, the chiral amine and the chiral phosphoric acid in a reaction solvent further comprises: adding an acid reagent;
the molar ratio of the chiral amine to the acid reagent is (0.1-20) to (0.1-30).
6. The method according to claim 5, wherein the acid reagent is any one selected from the group consisting of acetic acid, trifluoroacetic acid, benzoic acid, p-methoxybenzoic acid and m-nitrobenzoic acid.
7. The method according to any one of claims 1 to 3, wherein R is9、R10、R9'、R10' are each independently selected from triethylphenyl, triisopropylphenyl, tricyclohexylphenyl, triphenylsilyl, or substituted alkynyl; and/or
R5、R6、R5' and R6' each is independently selected from a hydrogen atom, a methyl group or a phenyl group; and/or
R7、R8、R7'、R8' are each independently selected from a hydrogen atom, a methyl group or an isopropyl group.
8. The method according to any one of claims 1 to 3, wherein the carbonyl substrate is selected from any one or two or more compounds selected from the group consisting of: 5- (allylthio) pentanal; 6- (allylthio) hexanal; 5- (prop-2-yn-1-ylthio) pentanal; 1-phenyl-5- (prop-2-yn-1-ylsulfanyl) pent-1-one; at least one of 5- ((2-phenylallyl) thio) pentanal.
9. The production method according to any one of claims 1 to 3, wherein the α -chiral carbonyl heterocyclic compound is selected from any one or two or more of the following compounds:
10. an α -chiral carbonyl heterocyclic compound produced by the production method according to any one of claims 1 to 9.
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of an alpha-chiral carbonyl heterocyclic compound.
Background
"chiral" means that the left and right hand of a person have the same structure, and the sequence from thumb to little finger is the same, but the sequence is different, the left hand is from left to right, and the right hand is from right to left. A pair of molecules cannot coincide with each other like the two hands of a human being, and are called chiral compounds (chiral compounds), that is, compounds having the same molecular weight and molecular structure but arranged in opposite directions (e.g., an enantiomer in a mirror thereof).
The alpha-chiral carbonyl heterocyclic compound is an important one of chiral compounds, and the alpha-chiral carbonyl heterocyclic compound is an important construction unit for synthesis of a drug intermediate, particularly a compound containing a chiral structure and preparation of a functional material. At present, the method for synthesizing the alpha-chiral carbonyl heterocyclic compound comprises the following steps: generating a chiral substrate under the catalytic action of a metal catalyst; cyclizing rearrangement of a racemic substrate under the condition of equivalent chiral metal auxiliary agent; racemic substrate is subjected to ylide cyclization rearrangement reaction mediated by chiral metal catalyst. However, the above methods all have the following drawbacks to varying degrees: 1) most asymmetric reactions use metal catalysts, which are not favorable for the subsequent application of products in the aspects of medicinal chemistry and chemical biology; 2) for metal catalyzed reactions, carbonyl substrates are limited to stable ketones, amides, or esters; for the aldehyde functional group which is more active, the active carbonyl compound can be obtained only by hydrolyzing or reducing and oxidizing the product; 3) as for the final product, esters, carboxylic acids, amides, which are essentially alpha-chiral, have certain limitations for subsequent functional group transformations and are not suitable as a leading compound for chiral transfer; 4) at present, no universal small molecular catalytic means is available for realizing asymmetric bifunctional of alpha carbonyl.
Disclosure of Invention
The invention mainly aims to provide a preparation method of an alpha-chiral carbonyl heterocyclic compound, and aims to solve the problems that a metal catalyst needs to be used and the application range of a carbonyl substrate is limited in the existing method.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for preparing an alpha-chiral carbonyl heterocyclic compound, comprising the steps of:
providing a carbonyl substrate as shown in formula a1 and/or formula a2, a chiral amine as shown in formula b1 and/or formula b2, a chiral phosphate as shown in formula d1 and/or formula d2, and a halogenating agent;
mixing the carbonyl substrate, the halogenating reagent, the chiral amine and the chiral phosphoric acid in a reaction solvent, and reacting in an inert gas atmosphere to obtain an alpha-chiral carbonyl heterocyclic compound shown as a formula I and/or a formula II;
wherein n is 1 or 2;
y is selected from O, S or NH;
R1、R5、R6、R5' and R6' each is independently selected from any one of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkoxy, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, alkyloxycarbonyl, cyanoalkyl groups having 1 to 20 hydrogen atoms or carbon atoms;
R7、R8、R7'、R8' are each independently selected from any one of a hydrogen atom, or an alkyl group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group, an alkenyl group, a heteroalkenyl group, a cycloalkenyl group, and a heterocycloalkenyl group having a carbon number of 1 to 20;
R9、R10、R9'、R10' each is independently selected from alkyl, alkynyl, phenyl or phenylsilyl with a carbon number of 1-20;
in a carbonyl substrate of formula a1, R2And/or R3Is connected with the alpha-carbon atom of the Y by an unsaturated carbon-carbon bond; in the carbonyl substrate of formula a2,R4linked to said Y with an alkenyl group;
in the alpha-chiral carbonyl heterocyclic compound shown as the formula I, R2' and/or R3' is linked to the β -carbon atom of said Y by an unsaturated carbon-carbon bond; in the alpha-chiral carbonyl heterocyclic compound shown as the formula II, R4' is attached to the alpha-carbon atom of said Y with an alkenyl group.
The preparation method of the alpha-chiral carbonyl heterocyclic compound provided by the invention takes chiral amine and chiral phosphoric acid with specific molecular structures as chiral catalysts, and synthesizes the alpha-chiral carbonyl heterocyclic compound with a specific configuration in one step by reacting a carbonyl substrate, a halogenating reagent, the chiral amine and the chiral phosphoric acid under an inert gas atmosphere. During the synthesis of the alpha-chiral carbonyl heterocyclic compound, chiral amine reacts with a carbonyl substrate to form a strong electrophilic intermediate; then, a halogenating agent is used as a nucleophilic reagent to attack alpha-carbon atoms of the compound to construct tertiary carbon centers to form alpha-halogenated intermediates which are used as carbene equivalents, then heteroatom salts such as sulfonium salts are generated with the assistance of chiral amine, then [2,3] -sigma rearrangement is carried out under the catalytic action of chiral phosphoric acid, and finally the alpha-chiral carbonyl heterocyclic compound shown as the formula I is obtained.
Compared with the prior art, the preparation method of the alpha-chiral carbonyl heterocyclic compound provided by the invention has the following advantages:
1) the carbonyl substrate has wide selectable range, can be selected from ketone and ester with stable structure, can also be selected from active aldehyde, breaks through the limitation that the prior method can not directly synthesize the alpha-chiral aldehyde heterocyclic compound, and greatly expands the designability and application prospect of the compound;
2) the configuration of the synthesized alpha-chiral carbonyl heterocyclic compound is strictly controlled by adopting a synergistic asymmetric catalytic system of chiral amine and chiral phosphoric acid, so that the chiral heterocyclic compound has high enantioselectivity, realizes the strict non-metallization of a reaction system, is safe and controllable in reaction process, and is beneficial to the subsequent application of a product in the aspects of pharmaceutical chemistry and chemical biology;
3) the reaction raw materials are easy to obtain, and no additional modification protection is needed to be carried out on a reaction substrate, so that the method can be directly used for preparation production, the operation steps are simplified, and the reaction route is shortened; the forward reaction rate is high, the reaction efficiency is obviously improved, the utilization rate of the substrate is high, and the production cost is greatly reduced.
Drawings
FIG. 1 is a schematic diagram showing the reaction mechanism of compound I1 in the example of the present invention.
Detailed Description
In the description of the present invention, the compounds and derivatives thereof are named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, colombia, ohio) naming system, and the groups of the compounds specifically referred to are illustrated and described as follows:
"alkyl" refers to a class of saturated chain hydrocarbon radicals containing only two atoms of carbon and hydrogen, having a straight and/or branched carbon chain, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and the like. The number of carbon atoms in the alkyl group is 1-20, and in some embodiments, the number of carbon atoms in the alkyl group is 1,2, 3,4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"Heteroalkyl" refers to alkyl groups containing at least one heteroatom in the molecule, including O, N, S, P and the like, such as methylaminoethyl. The number of carbon atoms of the heteroalkyl group is from 1 to 20, and in some embodiments, the number of carbon atoms of the heteroalkyl group is 1,2, 3,4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"cycloalkyl" refers to a group of saturated hydrocarbon groups containing cyclic structures in the molecule, such as monocyclic, bicyclic, fused, spiro, and bridged rings, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl, tetrahydronaphthyl, adamantyl, and the like. The number of carbon atoms of the cycloalkyl group is 3 to 20, and in some embodiments, the number of carbon atoms of the cycloalkyl group is 3,4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom in the molecule, including, but not limited to, azepanyl, azetidinyl, indolinyl, morpholinyl, pyrazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroindazolyl, tetrahydroindolyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinoxalinyl, tetrahydrothiopyranyl, thiazolidinyl, thiomorpholinyl, thioxanthyl, thiaxanyl, and the like. The number of carbon atoms in the heterocycloalkyl group is from 3 to 20, and in some embodiments, the number of carbon atoms in the heterocycloalkyl group is 3,4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"alkenyl" refers to a class of alkyl groups containing at least one carbon-carbon double bond, such as ethenyl, propenyl, and the like. The number of carbon atoms of the alkenyl group is 2 to 20, and in some embodiments, the number of carbon atoms of the alkenyl group is 2,3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"Heteroalkenyl" refers to alkenyl groups containing at least one heteroatom in the molecule, such as vinylaminoethyl. The heteroalkenyl group has a carbon number of 2 to 20, and in some embodiments, the heteroalkyl group has a carbon number of 2,3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"cycloalkenyl" refers to a class of alkenyl groups containing at least one or more cyclic carbon chains, such as cyclic ethenyl, cyclopropenyl, and the like. The number of carbon atoms of the cycloalkenyl group is 3-20, and in some embodiments, the number of carbon atoms of the cycloalkenyl group is 3,4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"heterocycloalkenyl" refers to a cycloalkenyl group that contains at least one heteroatom in the molecule. The number of carbon atoms of the heterocycloalkenyl group is 3-20, and in some embodiments, the number of carbon atoms of the heterocycloalkenyl group is 3,4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"alkoxy" refers to a class of alkyl groups directly bonded to an oxygen atom, including but not limited to, methoxy, ethoxy, propoxy, butoxy, isobutoxy, t-butoxy, and the like. The number of carbon atoms of the alkoxy group is 1 to 20, and in some embodiments, the number of carbon atoms of the alkoxy group is 1,2, 3,4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"aryl" refers to an organic group formed by an aromatic hydrocarbon lacking a hydrogen and can be a monocyclic aryl, polycyclic aryl, or fused ring aryl, including but not limited to phenyl, naphthyl, anthryl, phenanthryl, and the like. The number of carbon atoms of the aryl group is 6 to 20, and in some embodiments, the number of carbon atoms of the aryl group is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. The aryl is substituted or unsubstituted, and the substituent is hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxy, nitro, halogen, amino, oxyamido, aminoamido, phosphino, sulfinyl, sulfonyl, silyl, boryl and the like. When there is more than one substituent on the aryl group, the substitution position of the substituent includes, but is not limited to, ortho, meta, or para substitution.
"heteroaryl" refers to a class of aryl groups containing at least one heteroatom in the molecule, including, but not limited to, benzofuranyl, thienyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyranyl, furanyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine [3,4-b ] indolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolizyl, quinolyl, quinoxalyl, thiadiazolyl, thiatriazolyl, thiazolyl, thienyl, triazinyl, triazolyl, xanthenyl, and the like. The number of carbon atoms of the heteroaryl group is from 6 to 20, and in some embodiments, the number of carbon atoms of the heteroaryl group is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"aryloxy" refers to a class of aryl groups directly bonded to an oxygen atom, such as phenoxy, naphthoxy, anthracenoxy, phenanthroxy, and the like. The number of carbon atoms of the aryloxy group is 6 to 20, and in some embodiments, the number of carbon atoms of the aryloxy group is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"heteroaryloxy" refers to a class of aryloxy groups that contain at least one heteroatom in the aromatic ring. The heteroaryloxy group has a carbon number of 6 to 20, and in some embodiments, the heteroaryloxy group has a carbon number of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"arylalkyl" refers to a group of aryl groups directly bonded to an alkyl group, such as phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylisobutyl, phenylpentyl, phenylisopentyl, phenylneopentyl, and the like. The number of carbon atoms in the arylalkyl group is from 6 to 20, and in some embodiments the number of carbon atoms in the arylalkyl group is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"heteroarylalkyl" refers to a class of heteroaryl groups bonded directly to an alkyl group, the heteroarylalkyl group having from 6 to 20 carbon atoms, and in some embodiments 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms.
"Alkyloxycarbonyl" refers to a class of oxycarbonyl groups that are directly bonded to an alkyl group, such as acetoxymethylene. The number of carbon atoms of the alkyloxycarbonyl group is 6 to 20, and in some embodiments, the number of carbon atoms of the alkyloxycarbonyl group is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"cyanoalkyl" refers to a group of cyano groups directly bonded to an alkyl group, such as cyanomethylene. The cyanoalkyl group has from 1 to 20 carbon atoms, and in some embodiments, the cyanoalkyl group has 1,2, 3,4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms.
"phenylsilyl" refers to a class of phenyl groups bonded directly to a silyl group, such as trimethylsilylphenyl. The number of carbon atoms of the phenylsilyl group is 1-20, and in some specific embodiments, the number of carbon atoms of the phenylsilyl group is 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"alkynyl" refers to a class of alkyl groups containing at least one carbon-carbon triple bond, such as ethynyl, propynyl, and the like. The number of carbon atoms of the alkynyl group is 2 to 20, and in some embodiments, the number of carbon atoms of the alkynyl group is 2,3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"cycloalkynyl" refers to a class of alkynyl groups that contain at least one or more cyclic carbon chain. The number of carbon atoms of the cycloalkynyl group is 3 to 20, and in some embodiments, the number of carbon atoms of the cycloalkynyl group is 3,4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"Heterocycloalkynyl" refers to cycloalkynyl groups that contain at least one heteroatom in the molecule. The number of carbon atoms of the heterocycloalkynyl group is 3 to 20, and in some embodiments, the number of carbon atoms of the heterocycloalkynyl group is 3,4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.
"halogen" refers to elements of group VIIA of the periodic Table of the elements, including chlorine (Cl), bromine (Br), iodine (I), and the like.
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
A method for preparing an alpha-chiral carbonyl heterocyclic compound, comprising the steps of:
s01, providing carbonyl substrates shown as a formula a1 and/or a formula a2, chiral amines shown as a formula b1 and/or a formula b2, chiral phosphoric acids shown as a formula d1 and/or a formula d2, and a halogenating reagent;
s02, mixing the carbonyl substrate, the halogenating reagent, the chiral amine and the chiral phosphoric acid in a reaction solvent, and reacting in an inert gas atmosphere to obtain an alpha-chiral carbonyl heterocyclic compound shown in formula I and/or formula II;
wherein n is 1 or 2;
y is selected from O, S or NH;
R1、R5、R6、R5' and R6' each is independently selected from any one of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkoxy, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, alkyloxycarbonyl, cyanoalkyl groups having 1 to 20 hydrogen atoms or carbon atoms;
R7、R8、R7'、R8' are each independently selected from any one of a hydrogen atom, or an alkyl group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group, an alkenyl group, a heteroalkenyl group, a cycloalkenyl group, and a heterocycloalkenyl group having a carbon number of 1 to 20;
R9、R10、R9'、R10' each is independently selected from alkyl, alkynyl, phenyl or phenylsilyl with a carbon number of 1-20;
in a carbonyl substrate of formula a1, R2And/or R3Is connected with the alpha-carbon atom of the Y by an unsaturated carbon-carbon bond; in a carbonyl substrate of formula a2, R4Linked to said Y with an alkenyl group;
in the alpha-chiral carbonyl heterocyclic compound shown as the formula I, R2' and/or R3' is linked to the β -carbon atom of said Y by an unsaturated carbon-carbon bond; in the alpha-chiral carbonyl heterocyclic compound shown as the formula II, R4' with alkenyl andthe alpha-carbon atom of the Y is bonded.
According to the preparation method of the alpha-chiral carbonyl heterocyclic compound provided by the embodiment of the invention, chiral amine and chiral phosphoric acid with specific molecular structures are used as chiral catalysts, and a carbonyl substrate, a halogenating reagent, the chiral amine and the chiral phosphoric acid are reacted under an inert gas atmosphere to synthesize the alpha-chiral carbonyl heterocyclic compound with a specific configuration in one step.
In step S01, the carbonyl substrate is specifically a substrate for synthesizing an α -chiral carbonyl heterocyclic compound, and has any one of the following structural formulas:
wherein n is 1 or 2;
y is selected from O, S or NH;
R1any one selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkoxy, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, alkyloxycarbonyl, and cyanoalkyl groups having 1 to 20 hydrogen atoms or carbon atoms;
in a carbonyl substrate of formula a1, R2And/or R3Is connected with the alpha-carbon atom of the Y by an unsaturated carbon-carbon bond; in a carbonyl substrate of formula a2, R4An alkenyl group is attached to said Y.
It will be appreciated that in the carbonyl substrate of formula a1, R2And R3The same or different. When R is2And R3Wherein when one of the groups is bonded to the α -carbon atom of Y via an unsaturated carbon-carbon bond, the other group is selected from any of alkyl groups, cycloalkyl groups, heteroalkyl groups, heterocycloalkyl groups, alkoxy groups, alkenyl groups, heteroalkenyl groups, cycloalkenyl groups, heterocycloalkenyl groups, aryl groups, heteroaryl groups, aryloxy groups, heteroaryloxy groups, arylalkyl groups, heteroarylalkyl groups, alkyloxycarbonyl groups, and cyanoalkyl groups, each of which has 1 to 20 hydrogen atoms or carbon atoms. When R is2And R3When the same, R2And R3Are not necessarily a hydrogen atom, a cyano group andalkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkoxy, aryloxy, heteroaryloxy, alkyloxycarbonyl, cyanoalkyl groups having 1 to 20 carbon atoms.
In one embodiment, in the carbonyl substrate, R2And R3Are identical or different, and R2And/or R3Is selected from
In some embodiments, R2And/or R3Selected from any one of phenyl, propenyl, propynyl, butynyl, alkenyl, substituted or unsubstituted cyclopentenyl.
In a carbonyl substrate of formula a2, R4Linked to said Y with a linking group. The alkenyl refers to a group containing a pair of adjacent carbon-carbon double bonds in a molecule, and in some embodiments, the R group4Is selected from-CH ═ C ═ CH2、-CH＝C＝CMe2-CH ═ C ═ CCy and-CMe ═ C ═ CH2Any one of the above.
R1Selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkoxy, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, alkyloxycarbonyl, and combinations thereof, each of which has 1 to 20 hydrogen or carbon atoms,Any of cyanoalkyl groups. When R is1When selected from hydrogen atoms, the carbonyl substrate is an aldehyde substrate; when R is1When the carbonyl substrate is selected from alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyloxycarbonyl and cyanoalkyl groups having 1 to 20 carbon atoms, the carbonyl substrate is a ketone substrate; when R is1Selected from alkoxy, aryloxy, and heteroaryloxy groups having 1 to 20 carbon atoms, the carbonyl substrate is an ester substrate. In some embodiments, R1Selected from hydrogen atoms.
The R is1The group types of the alpha-chiral heterocyclic carbonyl compounds are in one-to-one correspondence with the types of carbonyl groups in the subsequently generated alpha-chiral heterocyclic carbonyl compounds, for example, when the carbonyl substrate is an aldehyde substrate, the alpha-chiral heterocyclic carbonyl compounds synthesized by the method contain active aldehyde groups, the limitation that the alpha-chiral heterocyclic carbonyl compounds cannot be directly synthesized by the existing method is broken through, the application range of the carbonyl substrate is wide, the carbonyl substrate can be selected from ketone and ester with stable structures, and can also be selected from active aldehyde, and the designability and the application prospect of the compounds are greatly expanded.
As an embodiment, the carbonyl substrate is selected from any one or two or more of the following compounds: 5- (allylthio) pentanal; 6- (allylthio) hexanal; 5- (prop-2-yn-1-ylthio) pentanal; 1-phenyl-5- (prop-2-yn-1-ylsulfanyl) pent-1-one; 5- ((2-phenylallyl) thio) pentanal.
In particular, the halogenating agent is used to provide a halogen atom for nucleophilic substitution of the α -H of the carbonyl substrate to form an α -halogenated intermediate. In one embodiment, the halogenating agent is selected from at least one of N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS) and N-iodosuccinimide (NIS). In some embodiments, the halogenating agent is selected from N-iodosuccinimide (NIS), which is more reactive in the synthesis of the alpha-chiral carbonyl heterocyclic compound.
Specifically, the chiral amine is taken as one of chiral catalysts and has any one of the following structural general formulas:
wherein R is5、R6、R5' and R6' each is independently selected from any one of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkoxy, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, alkyloxycarbonyl, cyanoalkyl groups having 1 to 20 hydrogen atoms or carbon atoms;
R7、R8、R7'、R8' are each independently selected from any one of a hydrogen atom, or an alkyl group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group, an alkenyl group, a heteroalkenyl group, a cycloalkenyl group, and a heterocycloalkenyl group having a carbon number of 1 to 20.
As an embodiment, in the chiral amine of formula b, R5And R6The same or different, and each is independently selected from any one of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyloxycarbonyl, cyanoalkyl with 1-20 carbon atoms.
As an embodiment, in the chiral amine of formula b2, R5' and R6' the same or different, and each is independently selected from any one of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyloxycarbonyl, cyanoalkyl groups having a carbon number of 1 to 20.
As an embodiment, R5、R6、R5' and R6' each is independently selected from a hydrogen atom, a methyl group or a phenyl group; r7、R8、R7'、R8' are each independently selected from a hydrogen atom, a methyl group or an isopropyl group. In some embodiments, the chiral amine is selected from any one or two or more of the following compounds: (1S,2S) -cyclohexane-1, 2-diamine, (1S,2S) -1, 2-diphenylethane-1, 2-diamine, (1S,2S) -bicyclo [2.2.2]Octane2, 3-diamine, (1S,2S) -N1 methylcyclohexane-1, 2-diamine. Specifically, the chiral phosphoric acid is taken as one of chiral catalysts and has any one of the following structural general formulas:
wherein R is9、R10、R9'、R10' are each independently selected from alkyl, alkynyl, phenyl or phenylsilyl groups of 1-20 carbon atoms.
As an embodiment, in chiral phosphoric acid of formula d1, R9And R10Identical or different and are each independently selected from triisopropylphenyl, triphenylsilyl, triethylphenyl, tricyclohexylphenyl or substituted alkynyl. In some embodiments, the triisopropylphenyl is selected from 1- (2,4, 6-triisopropylphenyl), 1- (3,4, 5-triisopropylphenyl), 1- (2,3, 4-triisopropylphenyl), or 1- (2,3, 6-triisopropylphenyl); in other embodiments, the triethylphenyl is selected from 1- (2,4, 6-triethylphenyl), 1- (3,4, 5-triethylphenyl), 1- (2,3, 4-triethylphenyl), or 1- (2,3, 6-triethylphenyl); in some other embodiments, the tricyclohexylphenyl is selected from 1- (2,4, 6-tricyclohexylphenyl), 1- (3,4, 5-tricyclohexylphenyl), 1- (2,3, 4-tricyclohexylphenyl), or 1- (2,3, 6-tricyclohexylphenyl).
As an embodiment, in chiral phosphoric acid of formula d2, R9' and R10' are the same or different and are each independently selected from triisopropylphenyl, triphenylsilyl, triethylphenyl, tricyclohexylphenyl, or substituted alkynyl. In some embodiments, the triisopropylphenyl is selected from 1- (2,4, 6-triisopropylphenyl), 1- (3,4, 5-triisopropylphenyl), 1- (2,3, 4-triisopropylphenyl), or 1- (2,3, 6-triisopropylphenyl); in other embodiments, the triethylphenyl is selected from 1- (2,4, 6-triethylphenyl), 1- (3,4, 5-triethylphenyl), 1- (2,3, 4-triethylphenyl), or 1- (2,3, 6-triethylphenyl); in other embodiments, the tricyclohexylphenyl group is selected from the group consisting of 1- (2,4, 6-tricyclohexylphenyl), 1- (3,4, 5-tricyclohexylphenyl),1- (2,3, 4-tricyclohexylphenyl) or 1- (2,3, 6-tricyclohexylphenyl). .
In the early period of research, the chiral carbon configuration, mother nucleus structure and substituent type of the chiral amine and the chiral phosphoric acid directly influence the chiral configuration of the alpha-carbon atom of the synthesized alpha-chiral carbonyl heterocyclic compound. Through a large number of experimental researches, the applicant finds that the alpha-chiral carbonyl heterocyclic compound shown as the formula I can be synthesized with high enantioselectivity by synergistically adopting the chiral amine with the specific molecular structure and the chiral phosphoric acid. Compared with the prior art, the preparation method of the alpha-chiral carbonyl heterocyclic compound provided by the invention adopts a synergistic asymmetric catalytic system of chiral amine and chiral phosphoric acid, on one hand, the high-efficiency catalytic efficiency is achieved, the target product with almost single absolute configuration can be obtained by reaction under mild conditions, the configuration of the synthesized alpha-chiral carbonyl heterocyclic compound is strictly controlled, and the high enantioselectivity is achieved; on the other hand, the toxicity is low, the use of a metallization reagent in a reaction system is avoided, the reaction process is safe and controllable, and the subsequent application of the product in the aspects of medicinal chemistry and chemical biology is facilitated; in another aspect, the catalytic system improves atom utilization rate and reaction efficiency, and has few byproducts and high production efficiency.
As an embodiment, the molar ratio of chiral amine to chiral phosphoric acid is (0.1-20): (0.1-20), preferably 20:20, which makes it possible to achieve very well highly selective, highly enantioselective products.
In step S02, specifically, the carbonyl substrate, the halogenating agent, the chiral amine and the chiral phosphoric acid are mixed in a reaction solvent, so that the carbonyl substrate, the halogenating agent, the chiral amine and the chiral phosphoric acid are uniformly mixed to promote the subsequent reaction. The step of mixing the carbonyl substrate, the halogenating agent, the chiral amine and the chiral phosphoric acid in the reaction solvent can be performed by referring to the conventional operation in the art, for example, a mechanical stirring method can be used to promote the thorough and uniform mixing of the raw materials. In some embodiments, the stirring speed is 300-; in other embodiments, stirring is for 1 to 3 hours; in still other embodiments, the mixing and stirring are performed under an inert gas atmosphere in order to avoid the influence of, for example, oxygen in the environment on the reaction raw materials.
As an embodiment, in the step of mixing the carbonyl substrate, the halogenating agent, the chiral amine and the chiral phosphoric acid in a reaction solvent, the molar ratio of the chiral amine, the chiral phosphoric acid, the carbonyl substrate and the halogenating agent is (0.1-20): (1-100), and this strategy can satisfy high yield and high selectivity and also have good atom economy.
As an embodiment, the step of mixing the carbonyl substrate, the halogenating agent, the chiral amine, and the chiral phosphoric acid in a reaction solvent further comprises: adding an acid reagent to mix with the carbonyl substrate, the halogenating reagent, the chiral amine, and the chiral phosphoric acid; the molar ratio of the chiral amine to the acid reagent is (0.1-20) to (0.1-30). The acid reagent with the specific molar dosage is added into the reaction system, so that the enantioselectivity of the reaction can be further improved, and the yield is improved. In some embodiments, the acid reagent is selected from any one of acetic acid, trifluoroacetic acid, benzoic acid, p-methoxybenzoic acid and m-nitrobenzoic acid.
The reaction solvent is used for dissolving each reaction raw material and for constructing a reaction system. The reaction solvent should dissolve each reaction raw material well and be inert to the subsequent reaction, including but not limited to toluene, diethyl ether, tetrahydrofuran, dichloromethane, etc. In some embodiments, the molar ratio of the reaction solvent to the sum of the chiral amine and the chiral phosphoric acid is (1000-: 1.
specifically, the reaction is carried out in an inert gas atmosphere to synthesize the alpha-chiral carbonyl heterocyclic compound shown as the formula I. As an embodiment, in the step of performing the reaction under an inert gas atmosphere, the reaction temperature is 0 to 35 ℃ and the reaction time is 1 to 12 hours. In some embodiments, the reaction temperature is 0, 5, 8, 10, 13, 15, 16, 18, 19, 20, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 ℃; in other embodiments, the reaction time is 1,2, 3,4,5, 6, 7, 8, 9, 10, 11, 12 hours. According to the preparation method of the alpha-chiral carbonyl heterocyclic compound provided by the embodiment of the invention, the carbonyl substrate with a specific molecular structure, the chiral amine and the chiral phosphoric acid are optimally selected as reaction raw materials, the alpha-chiral carbonyl heterocyclic compound is synthesized at room temperature while high enantioselectivity is maintained, heating or high pressure conditions are avoided, the operation in the preparation and production process is simplified, the reaction efficiency is improved, the production cost is reduced, and the preparation method is suitable for large-scale synthesis of the alpha-chiral carbonyl heterocyclic compound. In some embodiments, the inert gas atmosphere is at least one of nitrogen, argon, helium.
Specifically, the molecular structure of the alpha-chiral carbonyl heterocyclic compound synthesized by the preparation method provided by the embodiment of the invention is shown as formula I and/or formula II:
wherein n is 1 or 2;
y is selected from O, S or NH;
R1any one selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkoxy, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, alkyloxycarbonyl, and cyanoalkyl groups having 1 to 20 hydrogen atoms or carbon atoms;
in the alpha-chiral carbonyl heterocyclic compound shown as the formula I, R2' and/or R3' is linked to the β -carbon atom of said Y by an unsaturated carbon-carbon bond;
in the alpha-chiral carbonyl heterocyclic compound shown as the formula II, R4' is attached to the alpha-carbon atom of said Y with an alkenyl group.
In the alpha-chiral carbonyl heterocyclic compound with the structure shown in the formula I, the alpha-carbon atom is in an S configuration, and the S configurations of the two chiral carbons in the chiral amine correspond to one another, so that the preparation method provided by the embodiment of the invention has high enantioselectivity.
In the alpha-chiral carbonyl heterocyclic compound, n is 1 or 2, and Y is selected from O, S or NH. When n is 1 and Y is selected from S, the alpha-chiral carbonyl heterocyclic compound is a tetrahydrothiophene compound; when n is 2 and Y is selected from NH, the alpha-chiral carbonyl heterocyclic compound is a piperidine compound.
In the alpha-chiral carbonyl heterocyclic compound, R2' and R2Correspond to each other, R3' and R3Correspond to each other. When R is2By reaction of [2,3]]In-sigma rearrangement, R2' is R2By reaction of [2,3]]Group formed after sigma rearrangement, R3' and R3The same; when R is3By reaction of [2,3]]In-sigma rearrangement, R3' is R3By reaction of [2,3]]Group formed after sigma rearrangement, R2' and R2The same is true.
As an embodiment, the α -chiral carbonyl heterocyclic compound is selected from any one or two or more of the following compounds:
in the above provided method for preparing an α -chiral carbonyl heterocyclic compound, a chiral amine reacts with a carbonyl substrate to form a strongly electrophilic intermediate; then, a halogenating agent is used as a nucleophilic reagent to attack alpha-carbon atoms of the compound to construct tertiary carbon centers to form alpha-halogenated intermediates which are used as carbene equivalents, then heteroatom salts such as sulfonium salts are generated with the assistance of chiral amine, then [2,3] -sigma rearrangement is carried out under the catalytic action of chiral phosphoric acid, and finally the alpha-chiral carbonyl heterocyclic compound shown as the formula I is obtained.
In order to more clearly express the specific processes of the preparation method of the alpha-chiral carbonyl heterocyclic compound and to facilitate a clearer understanding of the role of each reaction raw material in the reaction, the following is further explained in combination with the reaction mechanism of the compound i 1:
as shown in fig. 1, halogenation reagent NIS and carbonyl substrate M1 generate α -iodo intermediate M2 under the catalysis of chiral amine; isomerizing the alpha-iodo intermediate M2 to form an imine intermediate, and accelerating cyclization to form a sulfonium salt intermediate M3; under the catalytic action of chiral phosphoric acid, sulfonium salt intermediate M3 is isomerized into intermediate M4 by enamine, then [2,3] -sigma rearrangement of allyl connected with sulfur positive ion is accelerated, alpha-carbon atom of sulfur positive ion is attacked and connected from small steric hindrance direction, thereby intermediate M5 is generated, and then amino group is removed to generate compound I1 with stable structure.
Compared with the prior art, the preparation method of the alpha-chiral carbonyl heterocyclic compound provided by the embodiment of the invention does not need to use a metal catalyst; the selectable range of the carbonyl substrate is wide, and the limitation that the prior method can not directly synthesize the alpha-chiral aldehyde heterocyclic compound is broken through; the alpha-chiral carbonyl heterocyclic compound with almost single absolute configuration can be obtained, the chiral configuration of the synthesized alpha-chiral carbonyl heterocyclic compound is strictly controlled, and the high enantioselectivity is realized; the reaction substrate does not need to be subjected to additional modification protection before reaction, and can be directly used for preparation production, so that the operation steps are simplified, and the reaction route is shortened; the method has the advantages of easily obtained reaction raw materials, high forward reaction rate, higher reaction efficiency and substrate utilization rate and greatly reduced production cost.
According to experimental detection, the alpha-chiral carbonyl heterocyclic compound prepared by the preparation method provided by the embodiment of the invention has the enantioselectivity of 95% ee and the yield of 90%.
In order that the details of the above-described implementation and operation of the present invention will be clearly understood by those skilled in the art, and the improved performance of the method for preparing an α -chiral carbonyl heterocyclic compound according to the embodiments of the present invention will be apparent, the implementation of the present invention will be illustrated by the following examples.