Preparation method of gem-difluoroolefin

Abstract

The invention relates to the technical field of organic synthesis, in particular to a preparation method of gem-difluoroolefin. The preparation method comprises the following steps: contacting a trifluoroacetic acid derivative with a compound R1-MgX1, and carrying out primary reaction to obtain an intermediate 1; contacting the intermediate 1 with a compound R2-MgX2, and carrying out a secondary reaction to obtain an intermediate 2; enabling the intermediate 2 to be in contact with a hydroxyl protective agent, and carrying out three-time reaction to obtain a compound as shown in a formula I; and contacting the compound as shown in the formula I with an azacyclo-phosphorus reagent for four times of reaction to obtain the gem-difluoroolefin as shown in a formula II. The preparation method has good universality, i.e., various gem-difluoroolefins can be synthesized under mild conditions through nitrogen heterocyclic phosphorus reagent mediation and module assembly (the combination of the trifluoroacetic acid derivative, two Grignard reagents and a hydroxyl protective agent), and the used raw materials (such as the trifluoroacetic acid derivative) are simple in structure, low in price and easy to obtain commercially. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing gem-difluoroolefins. Background Art

[0002] Gem-difluoroolefins are an important class of fluorinated organic compounds and have attracted much attention due to their wide applications in medicinal chemistry, pesticide science, and materials science. Such compounds can not only serve as bioisosteres of carbonyl groups to enhance the metabolic stability of drugs, but also become key structural units in drug molecule optimization due to their high liposolubility and low metabolic rate. They can also act as versatile intermediates for the synthesis of many other complex fluorinated compounds. However, traditional synthesis methods have many problems, such as harsh reaction conditions, the use of sensitive reagents, and limited substrate scope. Given the limitations of the prior art, it is particularly important to develop a new method for synthesizing gem-difluoroolefins that is green, efficient, mild in conditions, and has a wide substrate applicability. This new method should be able to start from cheap and readily available substrates to achieve the efficient synthesis of gem-difluoroolefins, while improving the selectivity and yield of the reaction.

[0003] Traditional methods for synthesizing gem-difluoroolefins include the following: (1) Wittig reaction: First, a difluoromethyl ylide is generated by reacting a phosphorus compound with a halogenated hydrocarbon containing a difluoromethyl group, and then it reacts with a carbonyl compound to form a gem-difluoroolefin. However, the limitation of this method is that it requires multiple steps to prepare intermediates, and the carbonyl compound generally needs to be activated (converting a ketone to a hydrazone); (2) Nucleophilic / radical addition-elimination reaction: This strategy starts from a substrate containing a trifluoromethyl vinyl fragment, and uses methods such as photocatalysis / transition metal catalysis to first functionalize the substrate, and then promotes the fluorine ion elimination of the precursor molecule containing a trifluoromethyl group through the E1cb process to form a gem-difluoroolefin. Although such methods are simple, the reaction conditions are relatively complex and the substrates are limited. In recent years, photocatalytic reactions, radical reactions, etc. have been booming, and the synthesis of gem-difluoroolefins is waiting for new breakthroughs and is developing towards the direction of greenness, high selectivity, and wide applicability. Summary of the Invention

[0004] The present invention aims to solve at least one of the technical problems in the related art to some extent. To this end, the present invention provides a method for preparing gem-difluoroolefins. This preparation method has good versatility, that is, it can synthesize a variety of gem-difluoroolefins under mild conditions through the mediation of aza-cyclic phosphorus reagents and modular assembly (a combination of trifluoroacetic acid derivatives, two Grignard reagents, and a hydroxyl protecting agent), and the raw materials used (such as trifluoroacetic acid derivatives) have simple structures and are cheap and readily available commercially.

[0005] To this end, in a first aspect of the present invention, there is provided a method for preparing gem-difluoroolefins, and the preparation method includes the following steps:

[0006] The trifluoroacetic acid derivative is reacted with compound R 1 -MgX1 contact, a reaction is carried out to obtain intermediate 1;

[0007] The intermediate 1 is mixed with compound R 2 -MgX2 contact, secondary reaction, to obtain intermediate 2;

[0008] The intermediate 2 is contacted with a hydroxyl protecting agent and reacted three times to obtain a compound represented by formula I;

[0009] The compound represented by formula I is contacted with an azacyclic phosphorus reagent and reacted four times to obtain a geminal difluoroolefin represented by formula II;

[0010]

[0011] Among them, R 1 、R 2 are independently selected from unsubstituted or optionally substituted with at least one R a Substituted with the following groups: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, benzene ring, naphthalene ring, 3-10 membered heterocyclic group;

[0012] The at least one R a Each of the same or different and independently selected from C1-C 10 Alkyl, C1-C 10 Alkoxy, C6-C 20 aryl;

[0013] X1 and X2 are each independently selected from halogen;

[0014] The hydroxyl protecting agent is used to provide the group R 3 , R 3 Selected from Boc, Tf, Ts, Ac.

[0015] The preparation method provided by the present invention has good versatility. That is, it can synthesize a variety of geminal difluoroolefins under mild conditions through the mediation of nitrogen heterocyclic phosphorus reagents and modular assembly (a combination of trifluoroacetic acid derivatives, two Grignard reagents and a hydroxyl protecting agent). In addition, the raw materials used (such as trifluoroacetic acid derivatives) are simple in structure, commercially inexpensive and easily available.

[0016] According to an embodiment of the present invention, the R 1 、R 2 are independently selected from unsubstituted or optionally substituted with at least one R aThe following substituted groups: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, benzene ring, naphthalene ring, 3-7 membered heterocyclic group;

[0017] Said at least one R a Each is the same or different and is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 aryl.

[0018] According to an embodiment of the present invention, said R 1 , R 2 Are independently selected from the following groups which are unsubstituted or optionally substituted by at least one R a : C1-C4 alkyl, C2-C4 alkenyl, C2-C3 alkynyl, C5-C6 cycloalkyl, benzene ring, naphthalene ring, 4-6 membered heterocyclic group;

[0019] Said at least one R a Each is the same or different and is independently selected from C1-C3 alkyl, C1-C3 alkoxy, C6-C7 aryl.

[0020] According to an embodiment of the present invention, said R 1 , R 2 Are independently selected from C1 alkyl, C4 alkyl, C4 alkenyl, C3 alkynyl, C6 cycloalkyl, benzene ring, -CH2-Ph, -Ph-CH3, -Ph-OCH3, naphthalene ring, 6 membered nitrogen heterocyclic group, 5 membered sulfur heterocyclic group.

[0021] According to an embodiment of the present invention, the trifluoroacetic acid derivative includes at least one of trifluoroacetic anhydride, methyl trifluoroacetate, trifluoroacetyl chloride, N-methoxy-N-methyl-2,2,2-trifluoroacetamide.

[0022] According to an embodiment of the present invention, the azacyclic phosphorus reagent has the following structure:

[0023]

[0024] According to an embodiment of the present invention, the temperatures of the primary reaction and the secondary reaction are independently -20°C to 40°C.

[0025] According to an embodiment of the present invention, the times of the primary reaction and the secondary reaction are independently 2 h to 10 h.

[0026] According to an embodiment of the present invention, the temperature of the tertiary reaction is -20°C to 40°C.

[0027] According to an embodiment of the present invention, the time of the tertiary reaction is 2 h to 10 h.

[0028] According to an embodiment of the present invention, the temperature of the four - time reaction is 60°C - 120°C.

[0029] According to an embodiment of the present invention, the time of the four - time reaction is 12 h - 48 h.

[0030] According to an embodiment of the present invention, the trifluoroacetic acid derivative and the compound R 1 -MgX1 have a molar ratio of 1:(1 - 5).

[0031] According to an embodiment of the present invention, the trifluoroacetic acid derivative and the compound R 2 -MgX2 have a molar ratio of 1:(1 - 5).

[0032] According to an embodiment of the present invention, the preparation method further includes: contacting the intermediate 2 with a hydroxyl - protecting agent and a catalyst to carry out a three - time reaction to obtain the compound shown in formula I.

[0033] According to an embodiment of the present invention, the catalyst includes at least one of 4 - dimethylaminopyridine, pyridine, and 1,8 - diazabicyclo[5.4.0]undec - 7 - ene.

[0034] According to an embodiment of the present invention, the trifluoroacetic acid derivative and the hydroxyl - protecting agent have a molar ratio of 1:(1 - 5).

[0035] According to an embodiment of the present invention, the trifluoroacetic acid derivative and the catalyst have a molar ratio of 1:(0.1 - 0.5).

[0036] According to an embodiment of the present invention, the preparation method further includes:

[0037] Contacting the compound shown in formula I with an azacyclic phosphorus reagent and a reducing agent to carry out a four - time reaction to obtain the gem - difluoroalkene.

[0038] According to an embodiment of the present invention, the reducing agent includes at least one of Mn, Zn, and Mg.

[0039] According to an embodiment of the present invention, the trifluoroacetic acid derivative and the azacyclic phosphorus reagent have a molar ratio of 1:(0.1 - 1.5).

[0040] According to an embodiment of the present invention, the trifluoroacetic acid derivative and the reducing agent have a molar ratio of 1:(1 - 5).

[0041] Additional aspects and advantages of the present invention will be given in part in the following description, become apparent in part from the following description, or be learned through the practice of the present invention. Detailed embodiments

[0042] Embodiments of the present invention will be described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as a limitation of the present invention.

[0043] It should be noted that the terms "first" and "second" are only used for descriptive purposes and should not be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, features defined with "first" and "second" may explicitly or implicitly include one or more of such features. Further, in the description of the present invention, unless otherwise specified, the meaning of "a plurality" is two or more.

[0044] In the ranges disclosed herein, the endpoints and any value are not limited to the exact range or value, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and individual point values, and between individual point values, they can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

[0045] To make the present invention easier to understand, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which the present invention pertains.

[0046] In this document, the term "comprising" or "including" is an open expression, that is, it includes the content specified by the present invention, but does not exclude other aspects.

[0047] In this document, the terms "optionally", "optional" or "option" generally mean that the subsequent events or conditions may or may not occur, and this description includes the cases where such events or conditions occur, as well as the cases where such events or conditions do not occur.

[0048] Term Definitions and Explanations

[0049] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in embodiments, etc., can be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination should fall within the scope recorded in the specification of this application.

[0050] The term "C1-C 10"Alkyl" should be understood to mean a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Examples of said alkyl include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; "C1-C6 alkyl" should be understood to mean a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6 carbon atoms.

[0051] The term "C1-C 10 Alkoxy" should be understood as -O-(C1-C 10 alkyl), where "C1-C 10 alkyl" has the above definition.

[0052] The term "C2-C 10 Alkenyl" should be understood to preferably mean a straight-chain or branched-chain monovalent hydrocarbon group which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0053] The term "C2-C 10 Alkynyl" should be understood to preferably mean a straight-chain or branched-chain monovalent hydrocarbon group which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0054] The term "C3-C 10 Cycloalkyl" should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 - 10 carbon atoms. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decahydronaphthalene ring.

[0055] The term "3- to 10-membered heterocyclic group" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1 to 5, preferably 1 to 3 heteroatoms selected from N, O, and S. In particular, the heterocyclic group may include, but is not limited to: a 4-membered ring such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolanyl, 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 heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, for example but not limited to a 5,5-membered ring such as hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The ring containing a nitrogen atom may be partially unsaturated, i.e., it may contain one or more double bonds, for example but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example but not limited to dihydroisoquinolinyl.

[0056] The term "C6-C 20 aryl" should be understood to preferably denote a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl"), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl"), such as anthracenyl.

[0057] The term "halogen" is fluorine, chlorine, bromine, iodine.

[0058] According to an embodiment of the present invention, a first aspect of the present invention provides a method for preparing gem-difluoroolefins, the preparation method comprising the following steps:

[0059] (1) contacting a trifluoroacetic acid derivative with a compound R 1 -MgX1 to carry out a first reaction to obtain intermediate 1;

[0060] wherein R 1 is selected from the following groups which are unsubstituted or optionally substituted by at least one R a : C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C10 Cycloalkyl, benzene ring, naphthalene ring, 3- to 10-membered heterocyclic group;

[0061] Said at least one R a Each of which is the same or different and is independently selected from C1-C 10 Alkyl, C1-C 10 Alkoxy, C6-C 20 Aryl;

[0062] X1 is selected from fluorine, chlorine, bromine, iodine.

[0063] According to a specific embodiment of the present invention, said R 1 Is selected from the following groups which are unsubstituted or optionally substituted by at least one R a Substituted: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, benzene ring, naphthalene ring, 3- to 7-membered heterocyclic group;

[0064] Said at least one R a Each of which is the same or different and is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 Aryl.

[0065] According to a specific embodiment of the present invention, said R 1 Is selected from the following groups which are unsubstituted or optionally substituted by at least one R a Substituted: C1-C4 alkyl, C2-C4 alkenyl, C2-C3 alkynyl, C5-C6 cycloalkyl, benzene ring, naphthalene ring, 4- to 6-membered heterocyclic group;

[0066] Said at least one R a Each of which is the same or different and is independently selected from C1-C3 alkyl, C1-C3 alkoxy, C6-C7 aryl.

[0067] According to a specific embodiment of the present invention, said R 1 Is selected from C1 alkyl, C4 alkyl, C4 alkenyl, C3 alkynyl, C6 cycloalkyl, benzene ring, -CH2-Ph, -Ph-CH3, -Ph-OCH3, naphthalene ring, 6-membered nitrogen heterocyclic group, 5-membered sulfur heterocyclic group.

[0068] According to a specific embodiment of the present invention, the type of the trifluoroacetic acid derivative is not particularly limited. As some specific examples, the trifluoroacetic acid derivative includes at least one of trifluoroacetic anhydride, methyl trifluoroacetate, trifluoroacetyl chloride, N-methoxy-N-methyl-2,2,2-trifluoroacetamide.

[0069] According to specific embodiments of the present invention, the temperature of the primary reaction is -20°C to 40°C. As some specific examples, the temperature of the primary reaction can be -20°C, 0°C, 10°C, 20°C, etc.

[0070] According to specific embodiments of the present invention, the time of the primary reaction is 2 h to 10 h. As some specific examples, the time of the primary reaction can be 2 h, 4 h, 6 h, 8 h, 10 h, etc.

[0071] According to specific embodiments of the present invention, the trifluoroacetic acid derivative and the compound R 1 -MgX1 have a molar ratio of 1:(1–5). As some specific examples, the molar ratio of the trifluoroacetic acid derivative and the compound R 1 -MgX1 can be 1:1, 1:2, 1:3, 1:5, etc.

[0072] According to specific embodiments of the present invention, the solvent for the primary reaction is not particularly limited. As some specific examples, it includes but is not limited to tetrahydrofuran (THF).

[0073] (2) Contact the intermediate 1 with the compound R 2 -MgX2 to carry out a secondary reaction to obtain intermediate 2;

[0074] Wherein, R 2 is selected from the following groups which are unsubstituted or optionally substituted by at least one R a : C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 cycloalkyl, benzene ring, naphthalene ring, 3- to 10-membered heterocyclic group;

[0075] Each of the at least one R a is the same or different and is independently selected from C1-C 10 alkyl, C1-C 10 alkoxy, C6-C 20 aryl;

[0076] X2 is selected from fluorine, chlorine, bromine, iodine.

[0077] According to specific embodiments of the present invention, R 2 is selected from the following groups which are unsubstituted or optionally substituted by at least one R a : C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, benzene ring, naphthalene ring, 3- to 7-membered heterocyclic group;

[0078] Each of the at least one R aEach of which is the same or different and is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 aryl.

[0079] According to a specific embodiment of the present invention, the R 2 is selected from the following groups which are unsubstituted or optionally substituted by at least one R a : C1-C4 alkyl, C2-C4 alkenyl, C2-C3 alkynyl, C5-C6 cycloalkyl, benzene ring, naphthalene ring, 4-6 membered heterocyclic group;

[0080] Each of the at least one R a is the same or different and is independently selected from C1-C3 alkyl, C1-C3 alkoxy, C6-C7 aryl.

[0081] According to a specific embodiment of the present invention, the R 2 is selected from C1 alkyl, C4 alkyl, C4 alkenyl, C3 alkynyl, C6 cycloalkyl, benzene ring, -CH2-Ph, -Ph-CH3, -Ph-OCH3, naphthalene ring, 6 membered nitrogen heterocyclic group, 5 membered sulfur heterocyclic group.

[0082] According to a specific embodiment of the present invention, the temperature of the secondary reaction is -20°C to 40°C. As some specific examples, the temperature of the secondary reaction can be -20°C, 0°C, 10°C, 20°C, etc.

[0083] According to a specific embodiment of the present invention, the time of the secondary reaction is 2 h to 10 h. As some specific examples, the time of the secondary reaction can be 2 h, 4 h, 6 h, 8 h, 10 h, etc.

[0084] According to a specific embodiment of the present invention, the molar ratio of the trifluoroacetic acid derivative to the compound R 2 -MgX2 is 1:(1 - 5). As some specific examples, the molar ratio of the trifluoroacetic acid derivative to the compound R 2 -MgX2 can be 1:1, 1:2, 1:3, 1:5, etc.

[0085] According to a specific embodiment of the present invention, the solvent for the secondary reaction is not particularly limited. As some specific examples, it includes but is not limited to THF.

[0086] (3) Contact the intermediate 2 with a hydroxyl protecting agent to carry out a third reaction to obtain the compound shown in formula I;

[0087]

[0088] The hydroxyl protecting agent is used to provide the group R 3 , R 3Selected from Boc, Tf, Ts, Ac.

[0089] According to a specific embodiment of the present invention, the temperature of the three - time reaction is - 20°C to 40°C. As some specific examples, the temperature of the three - time reaction can be - 20°C, 0°C, 10°C, 20°C, etc.

[0090] According to a specific embodiment of the present invention, the time of the three - time reaction is 2h to 10h. As some specific examples, the time of the three - time reaction can be 2h, 4h, 6h, 8h, 10h, etc.

[0091] According to a specific embodiment of the present invention, the preparation method further includes: contacting the intermediate 2 with a hydroxyl - protecting agent and a catalyst, and performing a three - time reaction to obtain the compound shown in formula I.

[0092] According to a specific embodiment of the present invention, the type of the catalyst is not particularly limited. As some specific examples, the catalyst includes at least one of 4 - dimethylaminopyridine, pyridine, 1,8 - diazabicyclo[5.4.0]undec - 7 - ene (DBU).

[0093] According to a specific embodiment of the present invention, the molar ratio of the trifluoroacetic acid derivative to the hydroxyl - protecting agent is 1:(1 - 5). As some specific examples, the molar ratio of the trifluoroacetic acid derivative to the hydroxyl - protecting agent can be 1:1, 1:2, 1:3, 1:5, etc.

[0094] According to a specific embodiment of the present invention, the molar ratio of the trifluoroacetic acid derivative to the catalyst is 1:(0.1 - 0.5). As some specific examples, the molar ratio of the trifluoroacetic acid derivative to the catalyst can be 1:0.1, 1:0.2, 1:0.3, 1:0.5, etc.

[0095] According to a specific embodiment of the present invention, the solvent for the three - time reaction is not particularly limited. As some specific examples, it includes but is not limited to dichloromethane (DCM).

[0096] (4) Contacting the compound shown in formula I with an azacyclic phosphorus reagent, and performing a four - time reaction to obtain the gem - difluoroalkene shown in formula II;

[0097]

[0098] The compound shown in formula I undergoes reductive coupling with the azacyclic phosphorus reagent and then β - F elimination at the P center to generate the gem - difluoroalkene.

[0099] According to a specific embodiment of the present invention, the azacyclic phosphorus reagent has the following structure:

[0100]

[0101] According to specific embodiments of the present invention, the temperature of the four - time reaction is 60°C - 120°C. As some specific examples, the temperature of the four - time reaction can be 60°C, 80°C, 100°C, 120°C, etc.

[0102] According to specific embodiments of the present invention, the time of the four - time reaction is 12h - 48h. As some specific examples, the time of the four - time reaction can be 12h, 24h, 36h, 48h, etc.

[0103] According to specific embodiments of the present invention, the preparation method further includes:

[0104] Contacting the compound shown in Formula I with an azacyclic phosphorus reagent and a reducing agent, and performing a four - time reaction to obtain the gem - difluoroalkene.

[0105] According to specific embodiments of the present invention, the type of the reducing agent is not particularly limited. As some specific examples, the reducing agent includes at least one of Mn, Zn, and Mg.

[0106] According to specific embodiments of the present invention, the molar ratio of the trifluoroacetic acid derivative to the azacyclic phosphorus reagent is 1:(0.1 - 1.5). As some specific examples, the molar ratio of the trifluoroacetic acid derivative to the azacyclic phosphorus reagent can be 1:0.1, 1:0.3, 1:1.0, 1:1.5, etc.

[0107] According to specific embodiments of the present invention, the molar ratio of the trifluoroacetic acid derivative to the reducing agent is 1:(1 - 5). As some specific examples, the molar ratio of the trifluoroacetic acid derivative to the reducing agent can be 1:1, 1:2, 1:3, 1:5, etc.

[0108] According to specific embodiments of the present invention, the solvent for the four - time reaction is not particularly limited. As some specific examples, it includes but is not limited to acetonitrile.

[0109] Specifically, when trifluoroacetic anhydride is used as the reaction raw material, Boc2O is used as the hydroxyl protecting agent, 4 - dimethylaminopyridine (DMAP) is used as the catalyst, and Mn is used as the reducing agent, the preparation method can be represented by the following reaction formula:

[0110]

[0111] Among them, "[P - Br]" is the azacyclic phosphorus reagent, and its structural formula is

[0112] The solution of the present invention will be explained below in conjunction with embodiments. Those skilled in the art will understand that the following embodiments are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. For those without specific techniques or conditions noted in the embodiments, the techniques or conditions described in the literature in this field or according to the product specifications are followed. For reagents or instruments without the manufacturer noted, they are all conventional products that can be obtained through commercial purchases.

[0113] "Room temperature" in the following embodiments all refers to 25 °C.

[0114] Example 1

[0115] This example provides a method for preparing a compound represented by the following formula:

[0116]

[0117] (1) Add 15 mL of THF and trifluoroacetic anhydride (TFAA, 10.0 mmol) to a Schlenk tube in sequence. After cooling the mixture to 0 °C in an ice bath, add compound PhMgBr (10.0 mmol) dropwise, and then restore to room temperature and react for 6 hours;

[0118] (2) After monitoring by NMR / TLC, cool the mixture to 0 °C in an ice bath, then add compound (4-OMe)Ph-MgBr (10.0 mmol) dropwise, and restore to room temperature and react for 10 hours;

[0119] (3) After monitoring by NMR / TLC, cool the mixture to 0 °C in an ice bath, then add a mixed solution of Boc2O (11.0 mmol) and DMAP (1.0 mmol) in DCM (5 mL) dropwise, restore to room temperature and react for 10 hours. After monitoring by NMR / TLC, evaporate the reaction solution to dryness, add about 15 mL of deionized water to quench it, extract the aqueous phase with ether, dry the organic solvent with anhydrous sodium sulfate, evaporate to dryness, and separate by silica gel column chromatography to obtain the precursor;

[0120] (4) Add the precursor (0.3 mmol), azacyclophosphorus reagent (0.3 mmol, the structural formula is ) and Mn (0.9 mmol) to a sealed reaction tube, and add 2 mL of MeCN solution. React at 80 °C for 12 hours. Stop the reaction after monitoring by NMR that the reaction is complete. Monitor the reaction yield (using PhCF3 as the internal standard) by 19F NMR, and the yield is 80%. The 1H NMR and 19F NMR data are as follows: 19 19F NMR) to monitor the reaction yield (using PhCF3 as the internal standard), and the yield is 80%. The 1H NMR and 19F NMR data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.37 - 7.32 (m, 5H), 6.96 (dd, J = 7.0, 1.7 Hz, 2H), 6.22 (dd, J = 7.4, 1.6 Hz, 2H), 3.71 (s, 3H).19 19F NMR (376 MHz, CDCl3) δ -87.5, -87.7.

[0121] Example 2

[0122] This example provides a method for preparing a compound represented by the following formula:

[0123]

[0124] The preparation method is basically the same as that of Example 1, except that:

[0125] The compound R 2 -MgX2 used is PhMgBr;

[0126] Using 19 19F NMR to monitor the reaction yield (PhCF3 as the internal standard), the yield is 90%, and the proton nuclear magnetic resonance spectrum and fluorine nuclear magnetic resonance spectrum data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.35 - 7.30 (m, 10H). 19 19F NMR (376 MHz, CDCl3) δ -87.2.

[0127] Example 3

[0128] This example provides a method for preparing a compound represented by the following formula:

[0129]

[0130] The preparation method is basically the same as that of Example 1, except that:

[0131] The compound R 2 -MgX2 used is (2-Me)PhMgBr;

[0132] Using 19 19F NMR to monitor the reaction yield (PhCF3 as the internal standard), the yield is 77%, and the proton nuclear magnetic resonance spectrum and fluorine nuclear magnetic resonance spectrum data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.30 - 7.22 (m, 5H), 7.13 - 6.99 (m, 4H), 2.48 (s, 3H). 19 19F NMR (376 MHz, CDCl3) δ -84.1, -89.5.

[0133] Example 4

[0134] This example provides a method for preparing a compound represented by the following formula:

[0135]

[0136] The preparation method is basically the same as that of Example 1, except that:

[0137] The compound R 2 -MgX2 used is MeC≡CMgBr;

[0138] Using 19 19F NMR was used to monitor the reaction yield (PhCF3 as the internal standard), and the yield was 79%. The 1H NMR and 19F NMR data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.64 - 7.45 (s, 5H), 1.84 (s, 3H). 19 19F NMR (376 MHz, CDCl3) δ -89.9, -90.0.

[0139] Example 5

[0140] This example provides a method for preparing a compound represented by the following formula:

[0141]

[0142] The preparation method is basically the same as that of Example 1, except that:

[0143] The compound R 2 -MgX2 used is MeMgBr;

[0144] Using 19 19F NMR was used to monitor the reaction yield (PhCF3 as the internal standard), and the yield was 82%. The 1H NMR and 19F NMR data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.17 - 7.03 (m, 5H), 2.32 (s, 3H). 19 19F NMR (376 MHz, CDCl3) δ -89.0, -89.1, -89.3, -89.4 (dd, J = 112.8 Hz, 3.8 Hz).

[0145] Example 6

[0146] This example provides a method for preparing a compound represented by the following formula:

[0147]

[0148] The preparation method is basically the same as that of Example 1, except that:

[0149] The compound R 2 -MgX2 used is 2-methyl-1-propenylmagnesium bromide;

[0150] Using 19The reaction yield was monitored by 19F NMR (using PhCF3 as the internal standard), and the yield was 84%. The 1H NMR and 19F NMR data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.37 - 7.28 (m, 5H), 5.56 (m, 1H), 2.40 (s, 3H), 2.13 (s, 3H). 19 19F NMR (376 MHz, CDCl3) δ -80.8, -87.9.

[0151] Example 7

[0152] This example provides a method for preparing the compound shown by the following formula:

[0153]

[0154] The preparation method is basically the same as that of Example 1, except that:

[0155] The compound R 2 -MgX2 used is t BuMgCl;

[0156] Using 19 19F NMR to monitor the reaction yield (using PhCF3 as the internal standard), the yield was 44%. The 1H NMR and 19F NMR data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.22 - 7.19 (m, 5H), 1.13 (s, 9H). 19 19F NMR (376 MHz, CDCl3) δ -80.7, -80.8.

[0157] Example 8

[0158] This example provides a method for preparing the compound shown by the following formula:

[0159]

[0160] The preparation method is basically the same as that of Example 1, except that:

[0161] The compound R 2 -MgX2 used is 1-NaphthMgBr;

[0162] Using 19 19F NMR to monitor the reaction yield (using PhCF3 as the internal standard), the yield was 79%. The 1H NMR and 19F NMR data are as follows: 11H NMR (400 MHz, CDCl3) δ 8.10 - 7.97 (m, 2H), 7.90 - 7.87 (m, 2H), 7.84 - 7.67 (m, 3H), 7.30 - 7.27 (m, 5H). 19 19F NMR (376 MHz, CDCl3) δ -83.5, -88.5。

[0163] Example 9

[0164] This example provides a method for preparing a compound represented by the following formula:

[0165]

[0166] The preparation method is basically the same as that of Example 1, except that:

[0167] The compound R 2 -MgX2 used is 2-pyridylmagnesium bromide;

[0168] Using 19 19F NMR to monitor the reaction yield (PhCF3 as the internal standard), the yield is 71%, and the 1H NMR and 19F NMR data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 8.14 (m, 1H), 7.45 - 7.40 (m, 3H), 7.32 - 7.29 (m, 5H). 19 19F NMR (376 MHz, CDCl3) δ -84.2, -88.4。

[0169] Example 10

[0170] This example provides a method for preparing a compound represented by the following formula:

[0171]

[0172] The preparation method is basically the same as that of Example 1, except that:

[0173] The compound R 2 -MgX2 used is 2-thienylmagnesium bromide;

[0174] Using 19 19F NMR to monitor the reaction yield (PhCF3 as the internal standard), the yield is 65%, and the 1H NMR and 19F NMR data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.53 (m, 1H), 7.22 - 7.12 (m, �H), 7.10 - 7.04 (m, 2H). 19 19F NMR (376 MHz, CDCl3) δ -85.5, -89.2。

[0175] Example 11

[0176] This example provides a method for preparing the compound shown by the following formula:

[0177]

[0178] The preparation method is basically the same as that of Example 1, except that:

[0179] The compound R 2 -MgX2 used is BnMgCl;

[0180] Using 19 19F NMR to monitor the reaction yield (PhCF3 as the internal standard), the yield is 73%, and the 1H NMR and 19F NMR data are as follows: 1 1H NMR(400MHz,CDCl3)δ7.33 - 7.06(m,10H),3.95(m,2H). 19 19F NMR(376MHz,CDCl3)δ - 87.9, - 88.2.

[0181] Example 12

[0182] This example provides a method for preparing the compound shown by the following formula:

[0183]

[0184] The preparation method is basically the same as that of Example 1, except that:

[0185] The compound R 1 -MgX1 used is BnMgCl;

[0186] The compound R 2 -MgX2 used is MeC≡CMgBr;

[0187] Using 19 19F NMR to monitor the reaction yield (PhCF3 as the internal standard), the yield is 88%, and the 1H NMR and 19F NMR data are as follows: 1 1H NMR(400MHz,CDCl3)δ7.30 - 7.25(s,5H),4.02(m,2H),1.90(s,3H). 19 19F NMR(376MHz,CDCl3)δ - 79.0, - 82.9.

[0188] Example 13

[0189] This example provides a method for preparing the compound shown by the following formula:

[0190]

[0191] The preparation method is basically the same as that of Example 1, except that:

[0192] The compound R used 1 -MgX1 is CyMgBr;

[0193] The compound R used 2 -MgX2 is MeC≡CMgBr;

[0194] Using 19 19F NMR to monitor the reaction yield (PhCF3 as the internal standard), the yield is 77%, and the 1H NMR and 19F NMR data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 2.55 (m, 1H), 1.90 (s, 3H), 1.55 (m, 2H), 1.54 - 1.50 (m, 2H), 1.38 - 1.28 (m, 2H), 1.24 - 1.20 (m, 2H), 1.18 (m, 1H), 1.09 (m, 1H). 19 19F NMR (376 MHz, CDCl3) δ -81.0, -85.8.

[0195] Example 14

[0196] This example provides a method for preparing the compound shown by the following formula:

[0197]

[0198] The preparation method is basically the same as that of Example 1, except that:

[0199] The compound R used 1 -MgX1 is t BuMgCl;

[0200] The compound R used 2 -MgX2 is MeC≡CMgBr;

[0201] Using 19 19F NMR to monitor the reaction yield (PhCF3 as the internal standard), the yield is 65%, and the 1H NMR and 19F NMR data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 2.01 (s, 3H), 1.29 (s, 9H). 19 19F NMR (376 MHz, CDCl3) δ -80.9, -88.8.

[0202] Example 15

[0203] This example provides a method for preparing the compound shown by the following formula:

[0204]

[0205] The preparation method is basically the same as that of Example 1, except that:

[0206] The compound R used 1 -MgX1 is BnMgCl;

[0207] The compound R used 2 -MgX2 is 2-methyl-1-propenylmagnesium bromide;

[0208] Using 19 19F NMR was used to monitor the reaction yield (PhCF3 as the internal standard), and the yield was 90%. The 1H NMR and 19F NMR data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.37 - 7.30 (m, 5H), 5.56 (m, 2H), 4.86 (m, 1H), 2.44 (s, 3H), 2.30 (s, 3H). 19 19F NMR (376 MHz, CDCl3) δ -88.2, -88.9.

[0209] Example 16

[0210] This example provides a method for preparing the compound shown by the following formula:

[0211]

[0212] The preparation method is basically the same as that of Example 1, except that:

[0213] The compound R used 1 -MgX1 is CyMgBr;

[0214] The compound R used 2 -MgX2 is 2-methyl-1-propenylmagnesium bromide;

[0215] Using 19 19F NMR was used to monitor the reaction yield (PhCF3 as the internal standard), and the yield was 71%. The 1H NMR and 19F NMR data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 5.23 (m, 1H), 2.65 (m, 1H), 2.14 (s, 3H), 2.00 (s, 3H), 1.75 (m, 2H), 1.64 - 1.59 (m, 2H), 1.48 - 1.33 (m, 2H), 1.21 - 1.20 (m, 2H), 1.15 (m, 1H), 1.09 (m, 1H). 1919F NMR (376 MHz, CDCl3) δ -88.8, -89.9.

[0216] Example 17

[0217] This example provides a method for preparing a compound represented by the following formula:

[0218]

[0219] The preparation method is basically the same as that of Example 1, except that:

[0220] The compound R 1 -MgX1 used is t BuMgCl;

[0221] The compound R 2 -MgX2 used is 2-methyl-1-propenylmagnesium bromide;

[0222] Using 19 19F NMR to monitor the reaction yield (PhCF3 as the internal standard), the yield is 70%, and the 1H NMR and 19F NMR data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 5.06 (m, 1H), 2.64 (s, 3H), 2.55 (s, 3H), 1.30 (s, 9H). 19 19F NMR (376 MHz, CDCl3) δ -87.5, -90.0.

[0223] In the description of this specification, the description referring to terms such as "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials, or characteristics described in connection with that embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0224] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for preparing gem-difluoroolefins, characterized in that, The preparation method comprises the following steps: React a trifluoroacetic acid derivative with compound R 1 -MgX1 to carry out a first reaction to obtain intermediate 1; React the intermediate 1 with compound R 2 -MgX2 to carry out a secondary reaction to obtain intermediate 2; Contacting the intermediate 2 with a hydroxyl protecting agent and carrying out three reactions to obtain the compound shown in Formula I; Contacting the compound shown in Formula I with an azacyclophosphorus reagent and carrying out four reactions to obtain the gem-difluoroalkene shown in Formula II; wherein, R 1 and R 2 are each independently selected from the following groups which are unsubstituted or optionally substituted by at least one R a : C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 cycloalkyl, benzene ring, naphthalene ring, 3- to 10-membered heterocyclic group; Said at least one R a each of which is the same or different and is independently selected from C1-C 10 alkyl, C1-C 10 alkoxy, C6-C 20 aryl; X1 and X2 are each independently selected from halogen; The hydroxyl protecting agent is used to provide the group R 3 , R 3 is selected from Boc, Tf, Ts, Ac.

2. The preparation method according to claim 1, wherein, The said R 1 , R 2 are each independently selected from the following groups which are unsubstituted or optionally substituted by at least one R a : C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, benzene ring, naphthalene ring, 3- to 7-membered heterocyclic group; Said at least one R a each of which is the same or different and is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 aryl.

3. The preparation method according to claim 1, wherein The R 1 , R 2 are each independently selected from the following groups which are unsubstituted or optionally substituted by at least one R a : C1-C4 alkyl, C2-C4 alkenyl, C2-C3 alkynyl, C5-C6 cycloalkyl, benzene ring, naphthalene ring, 4-6 membered heterocyclic group; Said at least one R a each of which is the same or different and is independently selected from C1-C3 alkyl, C1-C3 alkoxy, C6-C7 aryl.

4. The preparation method according to claim 1, characterized in that, The R 1 , R 2 are each independently selected from C1 alkyl, C4 alkyl, C4 alkenyl, C3 alkynyl, C6 cycloalkyl, benzene ring, -CH2-Ph, -Ph-CH3, -Ph-OCH3, naphthalene ring, 6-membered nitrogen heterocyclic group, 5-membered sulfur heterocyclic group.

5. The preparation method according to claim 1, characterized in that, The trifluoroacetic acid derivative includes at least one of trifluoroacetic anhydride, methyl trifluoroacetate, trifluoroacetyl chloride, and N-methoxy-N-methyl-2,2,2-trifluoroacetamide; Optionally, the azacyclophosphorus reagent has the following structure:

6. The preparation method according to claim 1, wherein The temperatures of the first reaction and the second reaction are independently -20°C to 40°C; Optionally, the times of the first reaction and the second reaction are independently 2 h to 10 h.

7. The preparation method according to claim 1, characterized in that, The temperature of the third reaction is -20°C to 40°C; Optionally, the time of the third reaction is 2 h to 10 h; Optionally, the temperature of the fourth reaction is 60°C to 120°C; Optionally, the time of the fourth reaction is 12 h to 48 h.

8. The preparation method according to claim 1, characterized in that, The trifluoroacetic acid derivative and the compound R 1 The molar ratio of -MgX1 is 1:(1–5); Optionally, the molar ratio of the trifluoroacetic acid derivative to the compound R 2 -MgX2 is 1:(1–5).

9. The preparation method according to claim 1, characterized in that, The preparation method further comprises: contacting the intermediate 2 with a hydroxyl protecting agent and a catalyst and carrying out three reactions to obtain the compound shown in Formula I; Optionally, the catalyst includes at least one of 4-dimethylaminopyridine, pyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene; Optionally, the molar ratio of the trifluoroacetic acid derivative to the hydroxyl protecting agent is 1:(1 - 5); Optionally, the molar ratio of the trifluoroacetic acid derivative to the catalyst is 1:(0.1 - 0.5).

10. The preparation method according to claim 1, characterized in that, The preparation method further comprises: Contacting the compound shown in Formula I with an azacyclophosphorus reagent and a reducing agent and carrying out four reactions to obtain the gem-difluoroalkene; Optionally, the reducing agent includes at least one of Mn, Zn, and Mg; Optionally, the molar ratio of the trifluoroacetic acid derivative to the azacyclophosphorus reagent is 1:(0.1 - 1.5); Optionally, the molar ratio of the trifluoroacetic acid derivative to the reducing agent is 1:(1 - 5).

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