阅读说明：本技术 一种手性α-氟代烷氧基醇及其制备方法 (Chiral alpha-fluoroalkoxy alcohol and preparation method thereof ) 是由 周海峰 赵蓉蓉 彭琛琛 刘祈星 于 2021-08-10 设计创作，主要内容包括：本发明涉及一种手性α-氟代烷氧基醇(式I)及其制备方法。本发明所涉及的制备方法为一锅法不对称串联反应,包括步骤1)：α-溴代苯乙酮(式II)为原料,氟代烷基醇(式III)既是溶剂又是反应原料,添加1当量的磷酸钾为碱,50℃反应2小时,反应生成中间体(式IV)；步骤2)：直接往反应体系中加入手性二胺金属络合物做催化剂,甲酸和三乙胺做氢源,在氮气保护下,经不对称转移氢化得到手性α-氟代烷氧基醇(式I)。该方法具有反应条件简单、温和,步骤经济性、原子经济性等绿色合成优点,而且底物适应范围广,对映选择性高,合成扥手性α-氟代烷氧基醇在医药中间体以及和精细化工原料方面具有广阔的应用前景。(The invention relates to chiral alpha-fluoroalkoxy alcohol (formula I) and a preparation method thereof. The preparation method related by the invention is a one-pot asymmetric series reaction and comprises the following steps of 1): alpha-bromoacetophenone (formula II) is used as a raw material, fluoroalkyl alcohol (formula III) is used as a solvent and a reaction raw material, 1 equivalent of potassium phosphate is added as a base, and the mixture is reacted for 2 hours at 50 ℃ to generate an intermediate (formula IV); step 2): directly adding a chiral diamine metal complex as a catalyst into a reaction system, using formic acid and triethylamine as hydrogen sources, and carrying out asymmetric transfer hydrogenation under the protection of nitrogen to obtain the chiral alpha-fluoroalkoxy alcohol (shown in a formula I). The method has the advantages of simple and mild reaction conditions, economic steps, economic atoms and the like, is green and has wide substrate application range and high enantioselectivity, and the synthesized chiral alpha-fluoroalkoxy alcohol has wide application prospect in the aspects of medical intermediates and fine chemical raw materials.)

1. A method for preparing chiral alpha-fluoroalkoxy alcohol is characterized by comprising the following steps: step (1): adding alkali and C into alpha-bromoacetophenone II_xF_yPerforming nucleophilic substitution reaction on OH and III to prepare an intermediate IV;

adding a hydrogen source and an asymmetric transfer hydrogenation catalyst into the intermediate IV in the step (2) to carry out asymmetric transfer hydrogenation to prepare the chiral alpha-fluoroalkoxy alcohol I, wherein the reaction formula is as follows:

wherein, R is any one of alkyl, alkyloxy, trifluoromethyl, aryl and halogen;

C_xF_yin OH, x is 2-6, y is 2-8, and x and y are integers;

in the definitions of the compounds given above, the terms used, whether used alone or in compound words, represent the following substituents:

alkyl groups: refers to straight or branched chain alkyl;

aryl: is phenyl, substituted phenyl;

halogen: refers to fluorine, chlorine, bromine, iodine.

2. The method according to claim 1, wherein the solvent for the nucleophilic substitution reaction in step (1) is: c_xF_yAnd (2) OH solution, wherein x is 2-6, y is 2-8, and x and y are integers.

3. The method of claim 2, wherein C is_xF_yOH comprises C₂H₃F₂OH、C₂H₂F₃OH、C₃HF₆OH、C₄H₃F₆OH、C₄H₂F₇OH、C₅H₃F₈Any one of OH.

4. The method according to claim 1, wherein the base for the nucleophilic substitution reaction in step (1) is potassium phosphate, cesium carbonate, or potassium carbonate.

5. The method according to claim 1, wherein the catalyst for asymmetric transfer hydrogenation in step (2) is: and (3) complexes of monosulfonyl chiral diamine and ruthenium, rhodium and iridium.

6. The asymmetric transfer hydrogenation catalyst as claimed in claim 5, wherein the chiral catalyst is a complex of (R, R) or (S, S) chiral ethylenediamine and ruthenium or rhodium or iridium as transition metal, and the structural formula is shown as formula V,

in the general structural formula V, M is Ru, Rh or Ir;

ar is phenyl or p-methoxy, methyl substituted phenyl, naphthyl;

r is-CH₃、-CF₃、-C₆H₅、4-CH₃C₆H₄、4-CF₃C₆H₄、4-(t-Bu)-C₆H₄-、3,4-(CH₃)₂-C₆H₃-、2,4,6-(CH₃)₃-C₆H₂-、2,6-Cl₂-C₆H₃-、2,4,6-(i-Pr)₃-C₆H₂-、C₆F₅Or naphthyl;

r is H, CH₃、i-Pr；

L is benzene, 1, 4-dimethylbenzene, 1-methyl-4-isopropylbenzene, 1,3, 5-trimethylbenzene, 1,2,3,4, 5-pentamethylbenzene, 1,2,3,4,5, 6-hexamethylbenzene or pentamethylcyclopentadiene;

x is Cl-, [ OTf ]]-、[PF₆]-、[BF₄]-、[SbF₆]-or a chiral phosphate anion.

7. The preparation method according to claim 1, wherein the hydrogen source for the asymmetric transfer hydrogenation reaction in the step (2) is: sodium formate, formic acid/triethylamine mixtures.

8. The method according to claim 1, wherein the reaction temperature is 25 to 60 ℃.

9. The method according to claim 8, wherein the reaction temperature is 50 ℃.

Technical Field

The invention belongs to the technical field of green catalytic asymmetric synthesis, and particularly relates to chiral alpha-fluoroalkoxyl and an asymmetric tandem synthesis method thereof.

Background

Chiral alpha-fluoroalkoxy alcohol is an important medical intermediate and chemical raw material, and in medicinal chemistry, compounds containing the functional group can enhance the medicinal effect and reduce side reactions. The inventor starts from alpha-bromoaryl ethanone, uses fluoroalkyl alcohol as a raw material and a solvent to directly synthesize the chiral alpha-fluoroalkoxy alcohol through asymmetric tandem reaction, and has the advantages of simple and mild reaction conditions, wide substrate application range, high enantioselectivity and the like.

Disclosure of Invention

A chiral alpha-fluoro alkoxy alcohol and its preparation method, regard alpha-bromo acetophenone and fluoro alkyl alcohol as raw materials, adopt the tactics of "two-step one pot" method, does not need to separate and purify the midbody, synthesize the chiral alpha-fluoro alkoxy alcohol directly; step 1): alpha-bromoacetophenone (formula II) and C_xF_yPreparing an intermediate IV by nucleophilic substitution reaction of OH (formula III); step 2): asymmetric transfer hydrogenation of intermediate IV produces chiral alpha-fluoroalkoxy alcohols I.

Wherein R is any one of alkyl, alkyloxy, trifluoromethyl, aryl and halogen.

C_xF_yIn OH, x is 2-6, y is 2-8, and x and y are integers.

C_xF_yOH is selected from C₂H₃F₂OH、C₂H₂F₃OH、C₃HF₆OH、C₄H₃F₆OH、C₄H₂F₇OH、C₅H₃F₈Any one of OH.

In the definitions of the compounds given above, the terms used, whether used alone or in compound words, represent the following substituents:

alkyl groups: refers to straight or branched chain alkyl;

aryl: is phenyl, substituted phenyl;

halogen: fluorine, chlorine, bromine, iodine;

the step 1): the solvent for nucleophilic substitution reaction is fluoroalkyl alcohol solution, C_xF_yAnd (2) OH solution, wherein x is 2-6, y is 2-8, and x and y are integers.

C_xF_yOH comprises C₂H₃F₂OH、C₂H₂F₃OH、C₃HF₆OH、C₄H₃F₆OH、C₄H₂F₇OH、C₅H₃F₈Any one of OH.

The base for nucleophilic substitution reaction in step 1) is cesium carbonate, potassium phosphate, etc., and more preferably: potassium phosphate.

The step 1): the nucleophilic substitution reaction temperature is 25-60 ℃, the preferable reaction temperature is 50 ℃, and the reaction time is 2-3 hours;

the step 2): the catalyst used in the asymmetric transfer hydrogenation reaction is a complex of (R, R) -or (S, S) -N-monosulfonyl-diaryl chiral ethylenediamine and transition metal ruthenium or rhodium or iridium; the general formula of the structure is shown as formula V,

in the general structural formula V, M is Ru, Rh or Ir;

ar is phenyl or p-methoxy, methyl substituted phenyl, naphthyl;

r is-CH₃、-CF₃、-C₆H₅、4-CH₃C₆H₄、4-CF₃C₆H₄、4-(t-Bu)-C₆H₄-、3,4-(CH₃)₂-C₆H₃-、2,4,6-(CH₃)3-C₆H₂-、2,6-Cl₂-C₆H₃-、2,4,6-(i-Pr)₃-C₆H₂-、C₆F₅-, or naphthyl;

r is H, CH₃Or i-Pr;

l is benzene, 1, 4-dimethylbenzene, 1-methyl-4-isopropylbenzene, 1,3, 5-trimethylbenzene, 1,2,3,4, 5-pentamethylbenzene, 1,2,3,4,5, 6-hexamethylbenzene or pentamethylcyclopentadiene;

x is Cl^-、[OTf]^-、[PF₆]^-、[BF₄]^-、[SbF₆]^-Or a chiral phosphate anion;

the step 2): the catalyst used in the asymmetric transfer hydrogenation reaction, further preferably, has a representative catalyst structure of any one of the following:

the step 2): asymmetric transfer hydrogenation, hydrogen source is formic acid triethylamine, preferably: the volume ratio is 1.1:1, 5 equivalents.

The step 2): asymmetric transfer hydrogenation, the reaction temperature is 35-60 ℃, and more preferably: at 50 ℃.

The invention relates to chiral alpha-fluoroalkoxy alcohol (formula I) and a preparation method thereof. The preparation method related by the invention is a one-pot asymmetric series reaction and comprises the following steps of 1): alpha-bromoacetophenone (formula II) as raw material, C_xF_yOH (formula III) is used as a solvent and a reaction raw material, 1 equivalent of potassium phosphate is added as alkali, and the reaction is carried out for 2 hours at 50 ℃ to generate an intermediate (formula IV); step 2): directly adding 1 mol% of chiral diamine metal ruthenium complex as a catalyst into a reaction system, and adding 5 equivalents of formic acid: triethylamine (1.1:1) is used as hydrogen source, the reaction is carried out for 6 hours at 50 ℃ under the protection of nitrogen, and chiral alpha-fluoroalkoxy alcohol (formula I) is obtained by asymmetric transfer hydrogenation. The method has the advantages of simple and mild reaction conditions, economic steps, high atom economy and the like, is green and has wide substrate application range and high enantioselectivity, and has wide application prospect in the aspects of synthesizing chiral alpha-fluoroalkoxy alcohol medical intermediates and fine chemical raw materials.

Detailed Description

The present invention will be further described with reference to the following examples, but the present invention is not limited to the following examples.

The chiral catalyst used in the invention is prepared by a general preparation method, taking a catalyst 5i as an example: 0.05mmol of (S, S) -N- (4-trifluoromethyl) benzenesulfonyl diphenyl chiral ethylenediamine, 0.025mmol of [ Ru (cymene)]₂Cl₂Dissolving in 0.5ml dichloromethane, adding 0.05mmol triethylamine, reacting for 30 minutes at room temperature, washing with water, extracting the water phase with 1ml dichloromethane for 3 times, combining and concentrating to dry to obtain catalyst 5i, which is directly used for catalytic reaction.

The same process conditions as for 5i were used for catalysts 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5 h.

Example 1: asymmetric synthesis of (S) -1-phenyl-2- (2,2, 2-trifluoroethoxy) ethane-1-ol

Adding 0.25mmol of 2-bromoacetophenone into a test tube, and sequentially adding 0.25mmol of tripotassium phosphate, 1ml of trifluoroethanol solution and N₂Then, the reaction was carried out at 50 ℃ for 2 hours, and 1.25mmol of formic acid: triethylamine (1.1:1, molar ratio), 0.0l of catalyst (S, S-5e) were added, nitrogen was substituted for 3 times, reaction was carried out at 50 ℃ for 6h, after completion, water was washed, aqueous phase was extracted 3 times with ethyl acetate, organic phases were combined and concentrated to dryness, and the yield was isolated: 47% (petroleum ether: ethyl acetate: 5:1) with an ee value of 92%. HPLC separation conditions: chiral column OD-H column, mobile phase: n-hexane/isopropyl alcohol 98:2 (volume ratio), flow rate: 1.0ml/min, wavelength: 220nm, temperature, 25 ℃, t₁＝20.728min(minor),t₂＝24.766min(major).；¹H NMR(400MHZ,CDCl₃):δ＝7.41-7.32(m,5H),4.94(dt,J₁＝2.4HZ,J₂＝8.8HZ,1H),4.00-3.88(m,2H),3.81(dd,J₁＝3.2HZ,J₂＝10HZ,1H),3.67(t,J＝8.8HZ,1H)；¹³C NMR(100MHZ,CDCl₃):δ＝139.52,128.56,128.18,126.17,124.00(q,J＝278HZ,1C),76.75,72.93,69.27(q,J＝34HZ,1C)；HRMS(ESI)m/zcalcd for C₁₀H₁₁F₃O₂[M+Na]⁺＝243.0610,found＝243.0609.

Taking the process steps of the embodiment 1 as an example, the stepwise optimization of the process conditions is carried out, which specifically comprises the following steps:

the method comprises the following steps of screening conditions of the 1-phenyl-2- (2,2, 2-trifluoroethoxy) ethanone, and optimizing the types of alkali, a hydrogen source and a catalyst, reaction time, temperature and the using amount of the catalyst. Namely the relevant process steps of asymmetric transfer hydrogenation by taking intermediate ketone as a substrate without adding a catalyst.

1) Synthesis of 1-phenyl-2- (2,2, 2-trifluoroethoxy) ethanone^a

From Table 1, it is found that₃PO₄As a base, CF₃CH₂OH as a solvent, N at 50 DEG C₂And the yield is better after the reaction is carried out for 2 hours.

Further screening the chiral catalyst and hydrogen source for the second step reaction^a：

^a Reaction conditions:Step1:2-Bromoacetophenone(1a；0.25mmol),1mL of CF₃CH₂OH,50℃,2h,under N₂ atmosphere.Step2:1mol％catalyst,[H]source(5eq.),50℃,under N₂,6h,isolated yield；^b 0.1mol％of(S,S)-5e.

Example 2: asymmetric synthesis of (S) -1-phenyl-2- (2,2, 2-trifluoroethoxy) ethane-1-ol

Adding 0.25mmol of 2-bromoacetophenone into a test tube, and sequentially adding 0.25mmol of tripotassium phosphate, 1ml of trifluoroethanol solution and N₂Then, the reaction was carried out at 50 ℃ for 2 hours, and 5 equivalents of formic acid: triethylamine (1.1:1, molar ratio), 0.0l of catalyst (S, S-5e) were added, nitrogen was substituted for 3 times, reaction was carried out at 50 ℃ for 6h, after completion, water was washed, aqueous phase was extracted 3 times with ethyl acetate, organic phases were combined and concentrated to dryness, and the yield was isolated: 90% (petroleum ether: ethyl acetate: 5:1), ee value 98%. HPLC separation conditions: chiral column OD-H column, mobile phase: n-hexane/isopropyl alcohol 98:2 (volume ratio), flow rate: 1.0ml/min, wavelength: 220nm, temperature, 25 ℃, t₁＝20.728min(minor),t₂＝24.766min(major).；¹H NMR(400MHZ,CDCl₃):δ＝7.41-7.32(m,5H),4.94(dt,J₁＝2.4HZ,J₂＝8.8HZ,1H),4.00-3.88(m,2H),3.81(dd,J₁＝3.2HZ,J₂＝10HZ,1H),3.67(t,J＝8.8HZ,1H)；¹³C NMR(100MHZ,CDCl₃):δ＝139.52,128.56,128.18,126.17,124.00(q,J＝278HZ,1C),76.75,72.93,69.27(q,J＝34HZ,1C)；HRMS(ESI)m/z calcd for C₁₀H₁₁F₃O₂[M+Na]⁺＝243.0610,found＝243.0609。

Example 3: asymmetric Synthesis of (S) -1- (p-tolyl) -2- (2,2, 2-Trifluoroxy) ethan-1-ol

Adding 0.25mmol of 2-bromo-p-methylacetophenone into a test tube, and sequentially adding 0.25mmol of tripotassium phosphate, 1ml of trifluoroethanol solution and N₂Then, the reaction was carried out at 50 ℃ for 2 hours, and 1.25mmol of formic acid: triethylamine (1.1:1, molar ratio), 0.0l of catalyst (S, S-5e) were added, nitrogen was substituted for 3 times, reaction was carried out at 50 ℃ for 6h, after completion, water was washed, aqueous phase was extracted 3 times with ethyl acetate, organic phases were combined and concentrated to dryness, and the yield was isolated: 87% (petroleum ether: ethyl acetate: 5:1) with an ee value of 94%. HPLC separation conditions: chiral column AD-H column, mobile phase: n-hexane/isopropyl alcohol 95:5 (volume ratio), flow rate: 1.0ml/min, wavelength: 220nm, temperature, 25 ℃, t₁＝10.594min(minor),t₂＝12.571min(major)；¹H NMR(400MHz,CDCl₃):δ＝7.31(d,J＝8Hz,2H),7.22(d,J＝7.6Hz,2H),4.93(dd,J₁＝3.2Hz,J₂＝5.6Hz,1H),4.01-3.89(m,2H),3.78(dd,J₁＝2.8Hz,J₂＝10Hz,1H),3.68(t,J＝8.4Hz,1H),2.40(s,3H)；¹³C NMR(100MHz,CDCl₃):δ＝137.92,136.68,129.24,126.15,123.95(q,J＝278Hz,1C),78.02,72.79,67.76(q,J＝33Hz,1C),HRMS(ESI)m/z calcd for C₁₁H₁₃F₃O₂[M+Na]⁺＝257.0765,found＝257.0770。

Example 4: asymmetric synthesis of (S) -1- (2-methoxyphenyl) -2- (2,2, 2-trifluoroethoxy) ethan-1-ol

Adding 0.25mmol of 2-bromo-1- (2-methoxyphenyl) ethane-1-ketone into a test tube, and sequentially adding 0.25mmol of tripotassium phosphate and C₂H₂F₃OH alcohol solution 1ml, N₂Then, the reaction was carried out at 50 ℃ for 2 hours, and 1.25mmol of formic acid: triethylamine (1.1:1, molar ratio), 0.0l of catalyst (S, S-5e) were added, nitrogen was substituted for 3 times, reaction was carried out at 50 ℃ for 6 hours, and after completion, reaction was carried outWashing with water, extracting the aqueous phase with ethyl acetate 3 times, combining the organic phases, concentrating to dryness, separating the yield: 83% (petroleum ether: ethyl acetate: 5:1) with an ee value of 88%. HPLC separation conditions: chiral column AD-H column, mobile phase: n-hexane/isopropyl alcohol 95:5 (volume ratio), flow rate: 1.0ml/min, wavelength: 220nm, temperature, 25 ℃, t₁＝15.691min(minor),t₂＝18.832min(major)；¹H NMR(400MHZ,CDCl₃):δ＝7.51(dd,J₁＝2HZ,J₂＝7.8HZ,1H),7.34-7.30(m,1H),7.18-7.13(m,2H),7.02(t,J＝7.2HZ,1H),6.91(dd,J₁＝0.8HZ,J₂＝8.0HZ,1H),5.29(dd,J₁＝3.2HZ,J₂＝6.4HZ,1H),3.99-3.86(m,3H),3.85(s,3H),3.66(dd,J₁＝8.0HZ,J₂＝10.0HZ,1H),3.66(t,J＝8.8HZ,1H)；¹³C NMR(100MHZ,CDCl₃):δ＝¹³C NMR(101MHZ,CDCl₃)δ156.22,128.86,128.01,127.05,124.14(q,J＝278HZ,1C),120.80,110.29,76.62,68.56(q,J＝34HZ,1C),68.43,55.16；；HRMS(ESI)m/z calcd for C₁₁H₁₃F₃O₃[M+Na]⁺＝273.0714,found＝273.0722。

Example 5: asymmetric synthesis of (S) - -2- (2,2, 2-trifluoroethoxy) -1- (4- (trifluoromethyl) phenyl) ethan-1-ol

Adding 0.25mmol of 2-bromo-1- (4- (trifluoromethyl) phenyl) ethane-1-ketone into a test tube, and sequentially adding 0.25mmol of tripotassium phosphate, 1ml of trifluoroethanol solution and N₂Then, the reaction was carried out at 50 ℃ for 2 hours, and 1.25mmol of formic acid: triethylamine (1.1:1, molar ratio), 0.0l of catalyst (S, S-5e) were added, nitrogen was substituted for 3 times, reaction was carried out at 50 ℃ for 6h, after completion, water was washed, aqueous phase was extracted 3 times with ethyl acetate, organic phases were combined and concentrated to dryness, and the yield was isolated: 60% (petroleum ether: ethyl acetate: 5:1), ee value 94%. HPLC separation conditions: chiral column OD-H column, mobile phase: n-hexane/isopropyl alcohol 90:10 (volume ratio), flow rate: 1.0ml/min, wavelength: 220nm, temperature, 25 DEG C,t₁＝9.146min(minor),t₂＝10.447min(major)；¹H NMR(400MHZ,CDCl₃):δ＝7.66(d,J＝8HZ,2H),7.54(d,J＝8HZ,2H),5.02(dd,J₁＝3.2HZ,J₂＝8.4HZ,1H),4.03-3.91(m,2H),3.84(dd,J₁＝3.2HZ,J₂＝10HZ,1H),3.67(t,J＝8.4HZ,1H)；¹³C NMR(100MHZ,CDCl₃):δ＝143.43,130.83,130.51,130.19,125.49,125.46,123.79(q,J＝278HZ,1C),123.51(q,J＝276HZ,1C),77.59,72.32,69.14(q,J＝34.1HZ,1C)。

Example 6: asymmetric synthesis of (S) -1- (naphthalen-2-yl) -2- (2,2, 2-trifluoroethoxy) ethan-1-ol

Adding 0.25mmol of potassium phosphate into a test tube, and sequentially adding 0.25mmol of potassium phosphate and C₂H₂F₃OH alcohol solution 1ml, N₂Then, the reaction was carried out at 50 ℃ for 2 hours, and 1.25mmol of formic acid: triethylamine (1.1:1, molar ratio), 0.0l of catalyst (S, S-5e) were added, nitrogen was substituted for 3 times, reaction was carried out at 50 ℃ for 6h, after completion, water was washed, aqueous phase was extracted 3 times with ethyl acetate, organic phases were combined and concentrated to dryness, and the yield was isolated: 60% (petroleum ether: ethyl acetate: 5:1), ee value 92%. HPLC separation conditions: chiral column IA-H column, mobile phase: n-hexane/isopropyl alcohol 90:10 (volume ratio), flow rate: 1.0ml/min, wavelength: 220nm, temperature, 25 ℃, t₁＝10.693min(minor),t₂＝11.762；¹H NMR(400MHZ,CDCl₃):δ＝7.88(q,J＝3.6HZ,4H),7.55-7.49(m,3H),5.12(dd,J₁＝3.2HZ,J₂＝8.8HZ,1H),4.03-3.89(m,3H),3.77(t,J＝8.8HZ,1H)；¹³C NMR(100MHZ,CDCl₃):δ＝136.99,133.28,133.23,128.36,128.04,127.76,126.34,126.18,125.33,124.01,123.54(q,J＝278HZ,1C),77.93,77.42,77.10,76.79,73.07,68.83(q,J＝34HZ,1C).HRMS(ESI)m/z calcd for C₁₄H₁₃F₃O₂[M+Na]⁺＝293.0765,found＝293.0768。

Example 7: asymmetric synthesis of (S) -1- ([1,1' -biphenyl ] -4-yl) -2-bromoethane-1-one

0.25mmol of 1- ([1,1' -biphenyl)]Adding the (E) -4-yl) -2-bromoethane-1-ketone into a test tube, and sequentially adding 0.25mmol of tripotassium phosphate, 1ml of trifluoroethanol and N₂Then, the reaction was carried out at 50 ℃ for 2 hours, and 1.25mmol of formic acid: triethylamine (1.1:1), 0.0l of catalyst (S, S-5e) was added, 3 times replaced with nitrogen, reaction was carried out at 50 ℃ for 6h, after completion, washing was carried out with water, aqueous phase was extracted 3 times with ethyl acetate, organic phases were combined and concentrated to dryness, and the yield was isolated: 87% (petroleum ether: ethyl acetate: 5:1) with an ee value of 94%. HPLC separation conditions: chiral column OD-H column, mobile phase: n-hexane/isopropyl alcohol 90:10 (volume ratio), flow rate: 1.0ml/min, wavelength: 220nm, temperature, 25 ℃, t₁＝11.632min(minor),t₂＝13.707min(major)；¹H NMR(400MHZ,CDCl₃):δ＝7.66-7.64(m,4H),7.52-7.48(m,4H),7.44-7.39(m,1H),5.03(dd,J₁＝3.2HZ,J₂＝8.4HZ,1H),4.08-3.92(m,2H),3.88(dd,J₁＝3.2HZ,J₂＝10HZ,1H),3.75(t,J＝9.2HZ,1H)；¹³C NMR(100MHZ,CDCl₃):δ＝141.15,140.71,138.57,128.87,127.48,127.32,127.15,126.68,123.95(q,J＝278HZ,1C),77.96,72.75,69.01(q,J＝34HZ,1C).HRMS(ESI)m/z calcd for C₁₆H₁₅F₃O₂[M+Na]⁺＝319.0922,found＝319.0920。

Example 8: (S) -2- ((1,1,1,3, 3-hexafluoropropan-2-yl) oxy) -1-phenylethane-1-ol

Adding 0.25mmol of 2-bromoacetophenone into a test tube, and sequentially adding 0.25mmol of tripotassium phosphate, 1ml of hexafluoroisopropanol and N₂Then, the reaction was carried out at 50 ℃ for 2 hours, and 1.25mmol of formic acid: triethylamine (1.1:1), then 00l of catalyst (S, S-5e) is replaced by nitrogen for 3 times, the reaction is carried out at 50 ℃ for 6h, after the reaction is finished, water is used for washing, the water phase is extracted by ethyl acetate for 3 times, the organic phases are combined and concentrated to be dry, and the separation yield is as follows: 88% (petroleum ether: ethyl acetate: 5:1), ee value 96%. HPLC separation conditions: chiral column OD-H column, mobile phase: n-hexane/isopropyl alcohol 90:10 (volume ratio), flow rate: 1.0ml/min, wavelength: 220nm, temperature, 25 ℃, t₁＝9.138min(minor),t₂＝11.174min(major)；¹H NMR(400MHZ,CDCl₃):δ＝7.43-7.37(m,5H),5.04(dt,J₁＝2.8HZ,J₂＝8.8HZ,1H),4.35(dt,J₁＝6HZ,J₂＝18HZ,¹H),4.03(dd,J₁＝2.8HZ,J₂＝10.4HZ,1H),3.89(t,J＝8.8HZ,1H),2.75(d,J＝2.8HZ,1H)；¹³C NMR(100MHZ,CDCl₃):δ＝138.80,128.70,128.48,126.17,122.80,120.02,79.73,76.34(dt,J₁＝32HZ,J₂＝97HZ),73.26.HRMS(ESI)m/z calcd for C₁₁H₁₀F₆O₂[M+Na]⁺＝289.0663,found＝289.0669。

Example 9: (S) -2- (2,2,3,3,4, 4-heptafluorobutoxy) -1-phenylethane-1-ol

Adding 0.25mmol of 2-bromoacetophenone into a test tube, and sequentially adding 0.25mmol of tripotassium phosphate, 1ml of heptafluorobutanol and N₂Then, the reaction was carried out at 50 ℃ for 2 hours, and 1.25mmol of formic acid: triethylamine (1.1:1), 0.0l of catalyst (S, S-5e) was added, 3 times replaced with nitrogen, the reaction was carried out at 50 ℃ for 6h, after that, water was used for washing, the aqueous phase was extracted 3 times with ethyl acetate, the combined organic phases were concentrated to dryness, and the isolated yield was 90% (petroleum ether: ethyl acetate ═ 10:1), ee value was 98%. HPLC separation conditions: chiral column OD-H column, mobile phase: n-hexane/isopropyl alcohol 95:5 (volume ratio), flow rate: 1.0ml/min, wavelength: 220nm, temperature, 25 ℃, t₁＝13.938min(minor),t₂＝16.079min(major)；¹H NMR(400MHz,CDCl₃):δ＝7.40-7.33(m,5H),4.95(dt,J₁＝2.8Hz,J₂＝8.8Hz,1H),4.15-3.98(m,2H),3.81(dd,J₁＝3.2Hz,J₂＝13.2Hz,1H),3.67(t,J＝9.2Hz,1H)；¹³C NMR(100MHz,CDCl₃):δ＝139.37,128.57,128.21,126.16,119.09,114.81,108.61,78.33,72.94,68.16(t,J＝25Hz)；HRMS(ESI)m/zcalcd for C₁₂H₁₁F₇O₂[M+Na]⁺＝321.0726,found＝321.0731。

Example 10: (S) -2- (2,2,3,4, 4-hexafluorobutoxy) -1-phenylethane-1-ol

Adding 0.25mmol of 2-bromoacetophenone into a test tube, and sequentially adding 0.25mmol of tripotassium phosphate, 1ml of hexafluorobutanol and N₂Then, the reaction was carried out at 50 ℃ for 2 hours, and 1.25mmol of formic acid: triethylamine (1.1:1), 0.0l of catalyst (S, S-5e) was added, 3 times replaced with nitrogen, the reaction was carried out at 50 ℃ for 6h, after that, water was used for washing, the aqueous phase was extracted 3 times with ethyl acetate, the combined organic phases were concentrated to dryness, and the isolated yield was 87% (petroleum ether: ethyl acetate ═ 10:1), ee value was 97%. HPLC separation conditions: chiral column OD-H column, mobile phase: n-hexane/isopropyl alcohol 95:5 (volume ratio), flow rate: 1.0ml/min, wavelength: 220nm, temperature, 25 ℃, t₁＝18.909min(minor),t₂＝21.458min(major)；¹H NMR(400MHZ,CDCl₃):δ＝7.40-7.32(m,5H),5.08-4.88(m,2H),4.02-3.64(m,4H),2.57(s,1H)；¹³C NMR(100MHZ,CDCl₃):δ＝139.62,128.61,1128.29,126.11,77.78,77.65,72.91,69.31,68.97,68.71；HPLC(Chiralcel OD-H,n-hexane/i-PrOH＝95/5(v/v),220nm,1.0mL/min,25℃),HRMS(ESI)m/zcalcd for C₁₂H₁₂F₆O₂[M+Na]⁺＝325.0639,found＝325.0642。

Example 11: (S) -2- (2, 2-difluoroethoxy) -1-phenylethane-1-ol

Adding 0.25mmol of 2-bromoacetophenone into a test tube, and sequentially adding 0.25mmol of tripotassium phosphate, 1ml of difluoroethanol solution and N₂Then, the reaction was carried out at 50 ℃ for 2 hours, and 1.25mmol of formic acid: triethylamine (1.1:1), 0.0l of catalyst (S, S-5e) was added, 3 times replaced with nitrogen, the reaction was carried out at 50 ℃ for 6h, after that, water was used for washing, the aqueous phase was extracted 3 times with ethyl acetate, the combined organic phases were concentrated to dryness, and the isolated yield was 90% (petroleum ether: ethyl acetate ═ 10:1), ee value was 96%. HPLC separation conditions: chiral column AD-H column, mobile phase: n-hexane/isopropyl alcohol 98:2 (volume ratio), flow rate: 1.0ml/min, wavelength: 220nm, temperature, 25 ℃, t₁＝28.760min(minor),t₂＝34.347min(major)；¹H NMR(400MHZ,CDCl₃):δ＝7.40-7.31(m,5H),6.07-5.77(m,1H),4.93(dt,J1＝2.4HZ,J2＝8.8HZ,1H),3.81-3.70(m,3H),3.61(t,J＝8.8HZ,1H),2.86(s,1H)；¹³C NMR(100MHZ,CDCl₃):δ＝139.70,128.53,128.11,126.17,116.68,114.28,111.88,77.61,72.85,70.51(t,J＝27 HZ,1C)；HPLC(ChiralcelAD-H,n-hexane/i-PrOH＝98/2(v/v),220 nm,1.0 mL/min,25℃),HRMS(ESI)m/z calcd forC₁₀H₁₂F₂O₂[M+Na]⁺＝225.0703,found＝225.0713。