WO2018232777A1 - Synthesis method for difluorodeuteromethoxy(thio) functional group-containing aromatic compound - Google Patents

Abstract

A synthesis method for an aromatic compound containing a difluorodeuteromethoxy functional group or a difluorodeuterothio functional group. In the presence of an alkali, a difluorocarbene donor and Ar-(XH)n and heavy water undergo a reaction to produce a deuterated product Ar-(XCF2D)n, the difluorocarbene donor being BrCF2PO(OR)2 or (chlorodifluoromethyl)trimethylsilane or (bromodifluoromethyl)trimethylsilane, and the alkali being selected from Na, K, Li, Mg, Zn, Al, NaH, KH, LiH, LiAlH4, KOD, NaOD, NaOMe, NaOEt, NaOBu, sodium carbonate, potassium carbonate and cesium carbonate. The method has the advantages of cheap and easily available raw materials, simple and mild reaction, high yield, high deuteration rate, and production amplification easiness.

Description

Method for synthesizing aromatic compound containing difluorodeuteromethoxy (thio) group functional group Technical field

The invention relates to the technical field of ruthenium-containing compound synthesis, in particular to a method for synthesizing an aromatic compound containing a difluoro-deuterated methoxy functional group or a difluoro-deuterated methylthio functional group.

Background technique

In April 2017, the US FDA approved the first deuterated drug, Tiva's deuterated tetrabenazine (trade name Austedo), mainly used to treat Huntington's disease, which marks the arrival of the era of deuterated drugs. Difluoromethoxy-containing compounds, especially aromatic compounds, have a wide range of uses in the pharmaceutical field. There have been many reports on the synthesis of difluoromethoxy groups, but the synthesis of deuterated difluoromethoxy aromatic compounds has rarely been reported so far.

Our company, in the patent CN 106083736, discloses the synthesis of a nitro-containing deuterated difluoromethoxy aromatic compound by radical reaction using sodium phenolate, ethyl bromodifluoroacetate and heavy water. This method is difficult to control by verifying that the applicability is poor and the reaction temperature is high.

The literature (Huaxue Xuebao 1986, 1, 92-96) reports the preparation of deuterated difluoromethoxybenzene using deuterated ethanol as a solvent and fluorosulfonyl difluoro compound to produce difluorocarbene. The disadvantage is that the ethanol cost of the deuterated generation is relatively high and it is not suitable for amplifying production.

The literature (Tetrahedron 2009, 65, 5278–5283) reports the use of diethyl bromodifluoromethylphosphonate as a source of carbenes, using 20 equivalents of potassium hydroxide, acetonitrile and water as solvent to prepare difluoromethoxy (sulfur). Base aromatic compound, the method has high yield, good applicability and mild conditions. Referring to the literature, the solvent was replaced with heavy water, and the synthesis experiment was carried out. As a result, only a lower deuteration rate (less than 80%) of the difluorodeuterated methoxy aromatic compound could not be obtained, which could not meet the purity requirements of the deuterated drug. . The reason for the analysis is that the potassium hydroxide and acetonitrile used in the reaction system will seriously affect the abundance of the strontium isotope in the product, so it is not applicable. Synthesis of aromatic compounds of difluorodeuterated methoxy(thio)-functional groups.

For the above reasons, it is necessary to provide a synthesis method suitable for an aromatic compound containing a difluorodeuteromethoxy (thio) group functional group to increase the deuteration rate of the synthesized product.

Summary of the invention

The technical problem to be solved by the present invention is to provide a method for synthesizing an aromatic compound containing a difluorodeuterated methoxy functional group or a difluorodeuterated methylthio functional group, which has the advantages of high deuteration rate.

In order to solve the above technical problems, a technical solution adopted by the present invention is: a method for synthesizing an aromatic compound containing a difluorodeuterated methoxy (thio) group functional group, and the reaction formula is as follows:

In the presence of a base, the difluorocarbene donor and

Reacts with heavy water to produce deuterated products

among them:

n is an integer from 1 to 3;

Ar is an aryl or heteroaryl group, or Ar is an optionally substituted aryl or heteroaryl group having from 1 to 4 hetero atoms selected from O, S, N, P;

X is an O atom or an S atom;

The difluorocarbene donor is BrCF ₂ PO(OR) ₂ or (chlorodifluoromethyl)trimethylsilane or (bromodifluoromethyl)trimethylsilane, and R in BrCF ₂ PO(OR) ₂ is C. _{1 to 5} alkyl groups;

The base is optionally selected from the group consisting of Na, K, Li, Mg, Zn, Al, NaH, KH, LiH, LiAlH ₄ , KOD, NaOD, NaOMe, NaOEt, NaOBu, sodium carbonate, potassium carbonate, cesium carbonate;

The organic solvent solver is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, and diethyl ether. Diol dimethyl ether.

Preferably, the synthesis of an aromatic compound containing a difluorodeuteromethoxy (thio) group functional group Method, including the steps:

will

Dissolved in an organic solvent to obtain a concentration of 0.05 to 1.0 mol/L

Solution

Under inert gas protection, will

Cooling the solution to -78 ° C ~ 30 ° C, then to the

The alkali is added to the solution in batches, the amount of the base is 1.0 to 30.0 equivalents, and the internal temperature of the reaction is controlled to be lower than 25 ° C during the addition of the alkali, and then the reaction is 0.5 to 18 hours;

Then, heavy water is added dropwise to the reaction system, the amount of heavy water is 5.0 to 200.0 equivalents, and the reaction temperature is kept below 40 ° C during the dropwise addition of heavy water, and after the completion of the dropwise addition, the reaction is 0.1 to 18 hours;

Then add the difluorocarbene donor, the amount of the difluorocarbene donor is 1.0-5.0 equivalent, and the reaction temperature is lower than 30 ° C during the addition of the difluorocarbene donor, and then the reaction is 10 min to 18 h, and the reaction is completed, and the reaction is completed. Product

After further processing, the deuterated product can be obtained.

Pure.

The amount of the base described above is 1.0 to 30.0 equivalents, the amount of heavy water is 5.0 to 200.0 equivalents, and the amount of difluorocarbene donor is 1.0 to 5.0 equivalents, both relative to

The amount is calculated.

Alternatively, Ar is phenyl, naphthyl, binaphthyl, anthracenyl, phenanthryl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, 1,10-phenanthroline, fluorene Mercapto, carbazolyl, pyrrolyl, thienyl, furyl, imidazolyl,

Azolyl, different

Azyl, thiazolyl, isothiazolyl,

Diazolyl, thiadiazolyl, pyranyl, pyrazolyl, isoquinolinyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzo

Azolyl, benzo

Diazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, isodecyl, triazolyl, triazinyl, quinoxalinyl, fluorenyl, quinazolinyl, quinolizine Base, naphthyridinyl, pteridinyl, carbazolyl, aza

Base, diaza

Alkyl, acridinyl, fluorenyl; or substituted phenyl, naphthyl, binaphthyl, anthracenyl, phenanthryl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, 1,10 -phenanthroline, fluorenyl, carbazolyl, pyrrolyl, thienyl, furyl, imidazolyl,

Azolyl, different

Azyl, thiazolyl, isothiazolyl,

Diazolyl, thiadiazolyl, pyranyl, pyrazolyl, isoquinolinyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzo

Azolyl, benzo

Diazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, isodecyl, triazolyl, triazinyl, quinoxalinyl, fluorenyl, quinazolinyl, quinolizine Base, naphthyridinyl, pteridinyl, carbazolyl, aza

Base, diaza

a substituent, a pyridyl group, a steroid group, the substituent being a mono-, di-, tri-, tetra- or penta-substituted group, the substituent being a halogen, a cyano group, a nitro group, an ester group, a C _1-6 alkyl group, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _1-6 alkylthio, C _1-6 haloalkyl, C _1-6 acyl, C _1-6 Alkylamino, phenyl or C _3-6 cycloalkylamino.

Unless otherwise stated, the following terms used in this application (including the specification and claims) have the definitions given below.

"Alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon group containing from 1 to 12 carbon atoms consisting solely of carbon and hydrogen atoms. The "alkyl group" is preferably an alkyl group of 1 to 6 carbon atoms, that is, a C ₁ -C ₆ alkyl group, more preferably a C ₁ -C ₄ alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

"Alkoxy" refers to a radical of the formula -OR wherein R is alkyl as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, t-butoxy, and the like.

"Halogen (halo)" means a fluorine, chlorine, bromine or iodine substituent.

"Haloalkyl" refers to an alkyl group, as defined herein, wherein one or more hydrogens are replaced by the same or different halogens. Examples of the haloalkyl group include -CH ₂ Cl, -CH ₂ CF ₃ , -CH ₂ CCl ₃ , a perfluoroalkyl group (for example, -CF ₃ ), and the like.

"Haloalkoxy" refers to a radical of the formula -OR wherein R is haloalkyl as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.

"Cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of a mono- or bicyclic ring having from 3 to 12, preferably from 3 to 10, more preferably from 3 to 6 ring atoms. The cycloalkyl group can be optionally substituted by one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino or dialkylamino. Cycloalkyl group Examples of groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

"Cycloalkoxy" refers to a radical of the formula -OR wherein R is cycloalkyl as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

"Acyl" refers to a radical of the formula -C(O)R wherein R is alkyl as defined herein. Exemplary acyl groups include acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, t-butyryl and the like.

Ester group refers to a group of the formula -C(O)OR wherein R is alkyl as defined herein. Exemplary ester groups include -C(O)OMe, -C(O)OEt, and the like.

"Alkylthio" refers to _a radical of the formula -SR _a where R _a is H or alkyl as defined herein.

"Alkylamino" refers to _a radical of the formula -NR _a R _b wherein R _a is H or alkyl as defined herein and R _b is alkyl as defined herein.

"Cycloalkylamino" refers to _a radical of the formula -NR _a R _b wherein R _a is H, alkyl as defined herein or cycloalkyl as defined herein, and R _b is cycloalkane as defined herein base.

Further optionally, Ar is phenyl, naphthyl, binaphthyl, benzothienyl, fluorenyl, pyridyl, indolyl, pyrimidinyl, pyridazinyl, quinolinyl; or substituted phenyl, Naphthyl, binaphthyl, benzothienyl, fluorenyl, pyridyl, fluorenyl, pyrimidinyl, pyridazinyl, quinolyl, said substituent being monosubstituted or disubstituted, the substituent being halogen, cyanide Base, phenyl, nitro, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxy.

Preferably, when

When n is taken as 1, Ar is a phenyl group, a naphthyl group, a benzothienyl group, a fluorenyl group, a pyridyl group, a fluorenyl group, a pyrimidinyl group, a pyridazinyl group, a quinolyl group; or a substituted phenyl group, a naphthyl group, a benzothienyl group, a fluorenyl group, a pyridyl group, a fluorenyl group, a pyrimidinyl group, a pyridazinyl group, a quinolyl group, the substituent is a mono- or di-substituted group, and the substituent is a halogen, a cyano group, a phenyl group, a nitro group C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxy.

Preferably, when

When n is 2, Ar is a binaphthyl group or a substituted binaphthyl group.

Preferably, R in the difluorocarbene donor BrCF ₂ PO(OR) ₂ is methyl or ethyl.

Preferably, the base base is NaH and the organic solvent solver is tetrahydrofuran and/or 1,4-dioxane.

Preferably,

The concentration of the solution is 0.25mol / L, under the protection of inert gas, will

The solution was cooled to 0 ° C ~ 25 ° C.

Preferably, the base is used in an amount of 10.0 equivalents.

The amount of heavy water used was 50.0 equivalents.

The amount of the difluorocarbene donor was 2.0 equivalents.

The invention has the beneficial effects that the synthesis method provided by the invention adopts an aprotic solvent, in the presence of a base, such as a metal or a metal hydride,

The hydrogen in the phenolic hydroxyl or sulfhydryl group is converted to hydrogen, and then the cheap heavy water is used as the source of cesium. The commercial difluorocarbene donor is used as the source of difluorocarbene. Under mild reaction conditions, it can be obtained by one step reaction. Deuterated fluorinated methoxy(thio) aryl compounds

The method has the advantages that the raw materials are cheap and easy to obtain, the reaction is simple and mild, the yield is high, the generation rate is high, and the production is easy to be enlarged.

Detailed ways

The technical solution of the present invention will be described in detail below through specific embodiments.

Example 1

The compound 2-naphthol (144 mg, 1 mmol) was dissolved in 4.0 ml of 1,4-dioxane which was dried (metal sodium was dried in water), cooled under argon, and cooled to 15 ° C in an ice water bath. NaH (60%, 400mg, 10mmol), ensure the temperature of the reaction system is lower than 25 ° C during the addition process, then react for 0.5 h, then slowly add 1 ml (50 mmol) of heavy water, and ensure the temperature of the reaction system is lower than 40 ° C during the dropwise addition. After the completion of the dropwise addition, the reaction was carried out for 0.5 h, and diethyl bromodifluoromethyl phosphate (534 mg, 2 mmol) was added dropwise. During the dropwise addition, the temperature of the reaction system was kept below 30 ° C, and the reaction was allowed to rise to room temperature for 0.5 h. After the reaction is completed, 20 ml of diethyl ether is added, the organic phase and the aqueous phase are separated, and the organic phase is washed with a saturated ammonium chloride solution. Polyester (20ml × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated at 30 ° C, and then subjected to silica gel column chromatography. The eluent was petroleum ether to give a colorless oil. , yield 80%, deuteration rate 98.7%). The analytical data information of the obtained compound is:

_{^{1 H NMR (400MHz, CDCl 3}} , ppm): δ = 7.85-7.42 (m, 3H), 7.50-7.42 (m, 3H), 7.25 (dd, J = 2.4Hz, 8.9Hz, 1H);

¹⁹ F NMR (376 MHz, CDCl ₃ , ppm): δ = -81.32 (t, J = 11.6 Hz);

¹³ C NMR (100 MHz, CDCl ₃ , ppm): δ = 149.0 (t, J _CF = 2.6 Hz), 133.8, 131.1, 130.1, 127.8, 127.5, 127.0, 125.7, 119.7, 115.9 (tt, J _CD = 33.7 Hz , J _CF = 256.6 Hz), 115.4.

The above data information was analyzed and identified as the target compound.

Example 2 - Example 9

The following are the examples 2-9, and the other conditions of the reaction are the same as those in the first embodiment. The only difference is that the amount of the alkali NaH is adjusted, and the effects on the yield of the target compound and the deuteration rate under different conditions of the amount of the base are examined.

As can be seen from the above table data, the amount of alkali has a great influence on the yield, in 8-15 equivalents. When the yield is high, the amount of alkali has little effect on the rate of deuteration. With the adjustment of the amount of alkali, the fluctuation rate of deuteration is extremely small, and the deuteration rate is ≥98.5%.

Example 10 - Example 16

The following are the examples 10-16. The other conditions of the reaction are the same as those in the first embodiment. The only difference is that the amount of heavy water is adjusted, and the effects on the yield and the yield of the target compound under different heavy water dosage conditions are investigated.

It can be seen from the above table data that the amount of heavy water has a great influence on the yield. When 40 equivalents, the yield reaches 65%, and when it is 100 equivalents or more, it reaches 80% or more. Considering the cost problem, about 50 equivalents can be selected; The amount of heavy water had little effect on the rate of deuteration. With the increase of heavy water consumption, the deuteration rate increased from 95% to 98.7%, and above 30 equivalents, the deuteration rate was ≥98.5%.

Example 17 - Example 20

The following are the examples 17-20, and the other conditions of the reaction are the same as those in the first embodiment. The only difference is that the reaction time after the dropwise addition of diethyl bromodifluoromethyl phosphate to the room temperature reaction is adjusted, and the reaction time is considered for the target. The effect of compound yield and deuteration rate.

It can be seen from the above table data that the reaction time has little effect on the yield, the reaction time is extended from 10 minutes to 18 hours, the yield is increased by 10%, and the reaction is 10%, the reaction is 70%, and the reaction is carried out for 20 minutes. The rate was increased to 78%, the reaction time was extended to 18 hours, and the yield was 80%. The reaction time had no significant effect on the rate of deuteration, and the rate of deuteration was 98.7%.

Example 21 - Example 23

The following are the examples 21-23, the other conditions of the reaction are the same as in the first embodiment, the only difference is that the different difluorocarbene donors are replaced, and the yield and the yield of the target compound using different difluorocarbene donors are investigated. influences.

It can be seen from the above data that different difluorocarbene donors have a slight effect on the yield and have little effect on the rate of deuteration.

Example 24 - Example 44

In the following, in the manner of Example 24-44, referring to the synthesis method of Example 1, a series of different target compounds were prepared by replacing different starting compounds, specifically as follows, and the deuteration rates were all above 98%.

Example 45

The amount of the difluorocarbene donor diethyl bromodifluoromethyl phosphate in Example 1 was changed to 4 mmol, i.e., 4.0 equivalent, to complete Example 45.

The analytical data information of the target compounds prepared in Examples 24-45 are as follows.

The above description is only an embodiment of the present invention, and is not intended to limit the scope of the invention.

Claims (10)

1. A method for synthesizing an aromatic compound containing a difluorodeuteromethoxy (thio) group functional group, characterized in that the reaction formula is as follows:

   

   In the presence of a base, the difluorocarbene donor and

   

   Reacts with heavy water to produce deuterated products

   

   among them:

   n is an integer from 1 to 3;

   Ar is an aryl or heteroaryl group, or Ar is an optionally substituted aryl or heteroaryl group having from 1 to 4 hetero atoms selected from O, S, N, P;

   X is an O atom or an S atom;

   The difluorocarbene donor is BrCF ₂ PO(OR) ₂ or (chlorodifluoromethyl)trimethylsilane or (bromodifluoromethyl)trimethylsilane, and R in BrCF ₂ PO(OR) ₂ is C. _{1 to 5} alkyl groups;

   The base is optionally selected from the group consisting of Na, K, Li, Mg, Zn, Al, NaH, KH, LiH, LiAlH ₄ , KOD, NaOD, NaOMe, NaOEt, NaOBu, sodium carbonate, potassium carbonate, cesium carbonate;

   The organic solvent solver is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, and diethyl ether. Diol dimethyl ether.
2. The method for synthesizing a difluoro-deuterated methoxy (thio)-functional group-containing aromatic compound according to claim 1, comprising the steps of:

   will

   

   Dissolved in an organic solvent to obtain a concentration of 0.05 to 1.0 mol/L

   

   Solution

   Under inert gas protection, will

   

   Cooling the solution to -78 ° C ~ 30 ° C, then to the

   

   The alkali is added to the solution in batches, the amount of the base is 1.0 to 30.0 equivalents, and the internal temperature of the reaction is controlled to be lower than 25 ° C during the addition of the alkali, and then the reaction is 0.5 to 18 hours;

   Then, heavy water is added dropwise to the reaction system, the amount of heavy water is 5.0 to 200.0 equivalents, and the reaction temperature is kept below 40 ° C during the dropwise addition of heavy water, and after the completion of the dropwise addition, the reaction is 0.1 to 18 hours;

   Then add the difluorocarbene donor, the amount of the difluorocarbene donor is 1.0-5.0 equivalent, and the reaction temperature is lower than 30 ° C during the addition of the difluorocarbene donor, and then the reaction is 10 min to 18 h, and the reaction is completed, and the reaction is completed. Product

   
3. The method for synthesizing a difluoro-deuterated methoxy (thio)-functional group-containing aromatic compound according to claim 2, wherein Ar is a phenyl group, a naphthyl group, a binaphthyl group, an anthracenyl group, a phenanthryl group or a pyridine group. , pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, 1,10-phenanthroline, fluorenyl, oxazolyl, pyrrolyl, thienyl, furyl, imidazolyl,

   

   Azolyl, different

   

   Azyl, thiazolyl, isothiazolyl,

   

   Diazolyl, thiadiazolyl, pyranyl, pyrazolyl, isoquinolinyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzo

   

   Azolyl, benzo

   

   Diazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, isodecyl, triazolyl, triazinyl, quinoxalinyl, fluorenyl, quinazolinyl, quinolizine Base, naphthyridinyl, pteridinyl, carbazolyl, aza

   

   Base, diaza

   

   Alkyl, acridinyl, fluorenyl; or substituted phenyl, naphthyl, binaphthyl, anthracenyl, phenanthryl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, 1,10 -phenanthroline, fluorenyl, carbazolyl, pyrrolyl, thienyl, furyl, imidazolyl,

   

   Azolyl, different

   

   Azyl, thiazolyl, isothiazolyl,

   

   Diazolyl, thiadiazolyl, pyranyl, pyrazolyl, isoquinolinyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzo

   

   Azolyl, benzo

   

   Diazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, isodecyl, triazolyl, triazinyl, quinoxalinyl, fluorenyl, quinazolinyl, quinolizine Base, naphthyridinyl, pteridinyl, carbazolyl, aza

   

   Base, diaza

   

   a substituent, a pyridyl group, a steroid group, the substituent being a mono-, di-, tri-, tetra- or penta-substituted group, the substituent being a halogen, a cyano group, a nitro group, an ester group, a C _1-6 alkyl group, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _1-6 alkylthio, C _1-6 haloalkyl, C _1-6 acyl, C _1-6 Alkylamino, phenyl or C _3-6 cycloalkylamino.
4. The method for synthesizing a difluoro-deuterated methoxy (thio)-containing functional group-containing aromatic compound according to claim 3, wherein Ar is a phenyl group, a naphthyl group, a binaphthyl group, a benzothienyl group, or an anthracene. , pyridyl, steroidal, pyrimidinyl, pyridazinyl, quinolyl; or substituted phenyl, naphthyl, binaphthyl, benzothienyl, fluorenyl, pyridyl, steroidal, pyrimidine a pyridyl group, a quinolyl group, the substituent being a mono- or di-substituted group, the substituent being a halogen, a cyano group, a phenyl group, a nitro group, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, C _1-6 alkylamino, C _1-6 alkoxy.
5. The method for synthesizing an aromatic compound containing a difluoro-deuterated methoxy (thio) group-containing functional group according to claim 4, wherein

   

   When n is taken as 1, Ar is a phenyl group, a naphthyl group, a benzothienyl group, a fluorenyl group, a pyridyl group, a fluorenyl group, a pyrimidinyl group, a pyridazinyl group, a quinolyl group; or a substituted phenyl group, a naphthyl group, a benzothienyl group, a fluorenyl group, a pyridyl group, a fluorenyl group, a pyrimidinyl group, a pyridazinyl group, a quinolyl group, the substituent is a mono- or di-substituted group, and the substituent is a halogen, a cyano group, a phenyl group, a nitro group C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkylamino, C _1-6 alkoxy.
6. The method for synthesizing an aromatic compound containing a difluoro-deuterated methoxy (thio) group-containing functional group according to claim 4, wherein

   

   When n is 2, Ar is a binaphthyl group or a substituted binaphthyl group.
7. The method for synthesizing a difluoro-deuterated methoxy (thio)-functional group-containing aromatic compound according to any one of claims 1 to 6, wherein the base base is NaH, and the organic solvent solver is tetrahydrofuran and/or 1, 4-dioxane.
8. The method for synthesizing a difluoro-deuterated methoxy (thio)-functional group-containing aromatic compound according to claim 7, wherein the base is used in an amount of 10.0 equivalent.
9. The method for synthesizing a difluorodeuteromethoxy (thio) group-containing aromatic compound according to claim 8, wherein the amount of heavy water is 50.0 equivalents.
10. The method for synthesizing a difluoro-deuterated methoxy (thio)-functional group-containing aromatic compound according to claim 9, wherein the difluorocarbene donor is used in an amount of 2.0 equivalents.