Method for synthesizing gem-difluorocyclopropane through asymmetric hydrogenation of gem-difluorocyclopropene under catalysis of rhodium

Abstract

The invention discloses a method for synthesizing gem-difluorocyclopropane through asymmetric hydrogenation of gem-difluorocyclopropene under catalysis of rhodium, gem-difluorocyclopropene ester or ketone is used as a reaction substrate 1, a chiral diphosphorus ligand of rhodium is used as a catalyst, gem-difluorocyclopropane 2 is synthesized through asymmetric hydrogenation, and the enantiomeric excess can reach 97.9%. The method is simple, convenient and practical to operate, high in enantioselectivity and good in yield, and the reaction has green atom economy and is environment-friendly.

Description

Technical Field

[0001] The invention belongs to the field of asymmetric hydrogenation synthesis, and particularly relates to a method for synthesizing gem-difluorocyclopropane by catalytic hydrogenation of gem-difluorocyclopropene in a homogeneous system using rhodium with high enantioselectivity. Background Art

[0002] Chiral geminal difluorocyclopropanes are the core building blocks of many pesticides, pharmaceutical intermediates, and natural products. Therefore, the synthesis and biological activity of these compounds have attracted widespread attention from organic chemists and the pharmaceutical community. The following are active molecules containing chiral geminal difluorocyclopropane building blocks:

[0003]

[0004] Given the importance of chiral geminal difluorocyclopropanes and their derivatives in the fields of medicine and synthetic chemistry, chemists have developed some methods to synthesize such compounds, which are usually synthesized by substrate induction. Until 2022, the Xu group first used hydrosilylation to synthesize geminal difluorocyclopropylsilanes with high enantioselectivity (Reference 1: Xu, H.; Fang, X.-J.; Huang, W.-S.; Xu, Z.; Li, L.; Ye, F.; Cao, J.; Xu, L.-W. Org. Chem. Fron. 2022, 9, 5272.), and subsequently developed some enzyme-catalyzed methods (Reference 2: Villada, JD; Majhi, J.; Lehuédé, V.; Hendricks, ME; Neufeld, K.; Tona, V.; Fasa n, R.Angew.Chem.Int.Ed.2024,63,1.), kinetic resolution (Reference 3: Jiang, Z.-T.; Chen, Z.; Zeng, Y.; Shi, J.-L.; Xia, Y.Org.Lett.2022,24,6176.) or transfer hydrogenation (Reference 4: Li, X.; Li, L.; Tang, Y.; Zhong, L.; Cun, L.; Zhu, J.; Liao, J.; Deng, J.Org.Chem.2010,75,2981.) strategies have achieved the synthesis of chiral geminal difluorocyclopropanes. However, due to the diversity of substrates, the development of new asymmetric hydrogenation reduction catalytic systems is still very meaningful.

[0005] Asymmetric hydrogenation reactions using hydrogen as a hydrogen source have advantages such as good atom economy, environmental friendliness, ease of operation, and convenient product separation. Currently, many asymmetric hydrogenation systems have been applied industrially. Therefore, the present invention relates to the synthesis of gem-difluorocyclopropanes via asymmetric catalytic hydrogenation of gem-difluorocyclopropenes. Summary of the Invention

[0006] The present invention aims to provide a method for synthesizing gem-difluorocyclopropane by rhodium-catalyzed asymmetric hydrogenation of gem-difluorocyclopropene. The method is simple and practical to operate, has readily available raw materials, high enantioselectivity, good yield, and the reaction has the advantages of green atom economy, environmental friendliness, and the like.

[0007] To achieve the above object, the technical solution of the present invention is as follows:

[0008] A method for synthesizing gem-difluorocyclopropane by rhodium-catalyzed asymmetric hydrogenation of gem-difluorocyclopropene, wherein the method uses a gem-difluorocyclopropene ester or ketone as a reaction substrate 1 and a chiral diphosphorus ligand of rhodium as a catalyst to synthesize gem-difluorocyclopropane 2 through asymmetric hydrogenation, and the reaction formula is as follows:

[0009]

[0010] Where:

[0011] R is a phenyl group or a phenyl ring containing a substituent, wherein the substituent includes MeO, CF3, halogen, heteroaryl, naphthyl and C1-C 20 at least one of the alkyl substituents of

[0012] R' is one of an alkoxy group, a phenyl group, and a benzene ring containing a substituent, and the substituent includes at least one of MeO, CF3, a halogen, a heteroaryl group, and a naphthyl group.

[0013] Based on the above technical solution, further, the chiral geminal difluorocyclopropane compound 2 is one of the following compounds:

[0014]

[0015] Based on the above technical solution, further, the catalyst is one of the following compounds: cyclooctadienyl rhodium chloride dimer, bis(1,5-cyclooctadiene) rhodium tetrafluoroborate, bis(norbornadiene) rhodium tetrafluoroborate, bis(1,5-cyclooctadiene) rhodium hexafluoroantimonate as a combination of metal precursors and chiral phosphine ligands.

[0016] Optionally, the method comprises the following steps:

[0017] (1) Catalyst preparation: a rhodium metal precursor and a chiral bisphosphine ligand were added to a reaction flask, the atmosphere was replaced with nitrogen, dichloromethane was added, and the mixture was stirred at room temperature for 10 minutes to obtain the catalyst;

[0018] (2) Under nitrogen atmosphere, a solvent is added to the reaction flask containing the catalyst, and then the solution in the reaction flask is transferred to a reactor containing the reaction substrate 1. Hydrogen gas is introduced at 14.8-1000 psi and the reaction is carried out at 0-60°C for 1-24 hours to obtain chiral gem-difluorocyclopropane 2.

[0019] Optionally, the molar ratio of the rhodium metal precursor, the chiral bisphosphine ligand and the reaction substrate 1 is 1:1.0:150-1:2.0:200.

[0020] Optionally, the molar ratio of the reaction substrate 1 to the catalyst is 50:1-10:1.

[0021] Optionally, the solvent includes one or a mixed solvent of two of dichloromethane, ethyl acetate, toluene, and tetrahydrofuran.

[0022] Optionally, the chiral bisphosphine ligand includes one of (R)-PhanePhos, (R)-JosiPhos, (R)-SegPhos, (R)-BINAP, (S,S)-Ph-BPE, and (S)-Xyl-SDP.

[0023] Optionally, the reaction substrate 1 is p-difluorocyclopropene ester, the chiral bisphosphine ligand is (R)-PhanePhos, the solvent is dichloromethane, R is Ph, and R' is MeO; the temperature is 40°C, the reaction time is 16 hours, the hydrogen pressure is 600 psi, and the enantiomeric excess can reach 91.7%.

[0024] Optionally, the reaction substrate 1 is p-difluorocyclopropenone, the chiral bisphosphine ligand is (R)-PhanePhos, the solvent is dichloromethane, R is Ph, R' is 4-MeO-C6H4; the temperature is 8°C, the reaction time is 1 hour, the hydrogen pressure is 600 psi, and the enantiomeric excess can reach 97.9%.

[0025] Optionally, the metal precursor of rhodium is bis(1,5-cyclooctadiene)rhodium hexafluoroantimonate, bis(1,5-cyclooctadiene)rhodium tetrafluoroborate, bis(norbornadiene)rhodium tetrafluoroborate or cyclooctadienyl rhodium chloride dimer.

[0026] The present invention has the following advantages

[0027] 1. The reaction activity and enantioselectivity are high, the reaction is complete, and cis-specific products are generated.

[0028] 2. The catalyst is easy to prepare and the reaction operation is simple and practical.

[0029] 3. The hydrogenation reaction conditions are mild and can also be carried out at room temperature.

[0030] 4. The catalytic system has a wide range of substrates and is suitable not only for the asymmetric reduction of geminal difluorocyclopropene esters but also for the asymmetric reduction of geminal difluorocyclopropenones.

[0031] 5. The obtained chiral gem-difluorocyclopropane can be further converted into biologically active molecules. DETAILED DESCRIPTION

[0032] The present invention is described in detail below by way of examples, but the present invention is not limited to the following examples.

[0033] The reaction substrate 1 used in the following examples was synthesized according to the literature method (Literature 5: Yamani, K.; Pierre, H.; Archambeau, A.; Meyer, C.; Cossy, J. Angew. Chem. Int. Ed. 2020, 59, 18505.).

[0034] Examples 1-10: Optimization of conditions

[0035] The ligand structure is as follows:

[0036] To an ampoule, weighed amounts of rhodium precursor (5 mol% of the substrate, 5.6 mg, 0.010 mmol) and chiral ligand were added. After nitrogen displacement, 1 ml of solvent was added and stirred at room temperature for 10 minutes. The catalyst was then rinsed with 2.0 ml of solvent into an ampoule containing gem-difluorocyclopropene ester 1a (42.0 mg, 0.2 mmol). The ampoule was then placed in a stainless steel autoclave, hydrogen was introduced, and the reaction was allowed to proceed at the set temperature for 16 hours. The hydrogen was slowly released, the solvent was removed using a rotary evaporator, and the pure product was isolated directly by column chromatography (eluent: petroleum ether and ethyl acetate in a volume ratio of 30:1). The reaction formula is as follows:

[0037]

[0038] The yield is the isolated yield, and the enantiomeric excess of the product is determined by chiral liquid chromatography, see Table 1.

[0039] Table 1

[0040]

[0041] Examples 10-24

[0042] Rhodium-catalyzed asymmetric hydrogenation to synthesize various gem-difluorocyclopropane compounds 2.

[0043] Weighed amounts of bis(1,5-cyclooctadiene)rhodium hexafluoroantimonate (5 mol% of substrate, 0.02 mmol) and chiral (R)-PhanePhos ligand (6 mol% of substrate, 0.024 mmol) were added to an ampoule. Stirring was continued for 10 minutes with 2.0 mL of solvent. The mixture was then rinsed with 4.0 mL of solvent into an ampoule containing gem-difluorocyclopropene ester or ketone 1 (0.4 mmol). The ampoule was then placed in a stainless steel autoclave and introduced with hydrogen at 14.8-1000 psi. The reaction was allowed to proceed at 1-40°C for 1-16 hours. The hydrogen was gradually released, and the solvent was removed using a rotary evaporator. The pure product was then isolated by column chromatography (eluent: petroleum ether and ethyl acetate, 30:1 by volume). The reaction formula is as follows:

[0044]

[0045] The corresponding products obtained in Examples 10-24 are 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, and 2o, respectively. The enantiomeric excess of the products was determined by chiral liquid chromatography.

[0046] Methyl(1S,3R)-2,2-difluoro-3-phenylcyclopropane-1-carboxylate(2a):40℃,16h,78.1mg,92%yield,colorless oil,R f =0.45(hexanes / ethyl acetate 30 / 1),91.7%ee,[α] 20 D = +39.16 (c 0.98, CHCl3). 1 HNMR (400MHz, CDCl3) δ7.36-7.26(m,5H),3.55(s,3H),3.26(ddd,J=14.3,12.1,2.5Hz,1H),2.81(td,J=12.1,1.4Hz,1H). 13 C NMR (100MHz, CDCl3) δ165.2,129.6,129.5,128.4,128.0,111.2(dd, 1 J C-F =289.6Hz and 1 J C-F =283.4Hz),52.0,32.0(dd, 2 J C-F =11.9,9.6Hz),30.3(dd, 2 J C-F=13.8,9.0Hz). 19 FNMR(376MHz,CDCl3)δ-118.0(d, 2 J F-F =158.5Hz),-146.2(d, 2 J F-F =158.1Hz).HPLC:OJ-Hcolumn,220nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=0.8mL / min,retention time15.3min(major)and 27.5min.

[0047] Isopropyl(1S,3R)-2,2-difluoro-3-phenylcyclopropane-1-carboxylate(2b):40℃,16h,90.2mg,94%yield,colorless oil,new compound,R f =0.50(hexanes / ethylacetate 30 / 1),91.8%ee,[α] 20 D =+29.38(c0.97,CHCl3). 1 H NMR(400 MHz,CDCl3)δ7.36-7.26(m,5H),4.84(hept,J=6.3Hz,1H),3.24(ddd,J=14.2,12.2,2.3Hz,1H),2.76(td,J=12.3,1.3Hz,1H),1.07(d,J=6.2Hz,3H),0.94(d,J=6.3Hz,3H). 13 C NMR(100 MHz,CDCl3)δ164.4,129.8,129.6,128.3,127.8,111.3(dd, 1 J C-F =291.8Hz and 1 J C-F =284.3Hz),68.6,31.8(dd, 2 J C-F =12.1,9.6Hz),30.8(dd, 2 J C-F =13.6,9.2Hz),21.6,21.3. 19 F NMR(376MHz,CDCl3)δ-117.6(d, 2 J F-F=158.8Hz),-146.0(d, 2 J F-F =158.8Hz).HPLC:OJ-H column,220nm,30℃,n-Hexane / i-PrOH=97 / 3,flow=1.0 mL / min,retention time 7.9 min(major)and 9.0 min.HRMS:Calculated for C 13 H 15 F2O2[M+H] + 241.1035,found:241.1036.

[0048] Benzyl(1S,3R)-2,2-difluoro-3-phenylcyclopropane-1-carboxylate(2c):40℃,16h,110.3mg,96%yield,colorless oil,R f =0.30(hexanes / ethyl acetate 50 / 1),87.2%ee,[α] 20 D =-2.70(c 0.92,CHCl3). 1 H NMR(400 MHz,CDCl3)δ7.32-7.28(m,8H),7.17-7.10(m,2H),4.98(q,J=12.3Hz,2H),3.27(ddd,J=14.2,12.2,2.5Hz,1H),2.85(td,J=12.1,1.3Hz,1H). 13 C NMR(100 MHz,CDCl3)δ164.7,135.2,129.6,129.4,128.5,128.5,128.4,128.3,128.0,111.2(dd, 1 J C-F =289.9Hz and 1 J C-F =283.5Hz),66.8,32.1(dd, 2 J C-F =11.9,9.5Hz),30.4(dd, 2 J C-F =13.9,9.0Hz). 19 F NMR(376 MHz,CDCl3)δ-118.0(d, 2 J F-F =158.2Hz),-146.0(d,2 J F-F =158.7Hz).HPLC:OJ-H column,220 nm,30℃,n-Hexane / i-PrOH=95 / 5,flow=1.0 mL / min,retention time 19.3 min(major)and 24.6 min.

[0049] Methyl(1S,3R)-2,2-difluoro-3-(4-fluorophenyl)cyclopropane-1-carboxylate(2d):40℃,16h,86.5mg,94%yield,colorless oil,R f =0.50(hexanes / ethyl acetate 30 / 1),89.3%ee,[α] 20 D =+74.46(c 0.97,CHCl3). 1 H NMR(400 MHz,CDCl3)δ7.34-7.25(m,2H),7.08-6.97(m,2H),3.57(s,3H),3.28-3.16(m,1H),2.81(td,J=12.1,1.4Hz,1H). 13 C NMR(100 MHz,CDCl3)δ165.0,162.3(d, 1 J C-F =247.1Hz),131.3(d, 3 J C-F =8.1Hz),125.2(d, 4 J C-F =3.4Hz),115.5(d, 4 J C-F =21.7Hz),111.1(dd, 1 J C-F =291.0Hz and 1 J C-F =285.6Hz),52.0,31.2(dd, 2 J C-F =12.1,9.5Hz),30.2(dd, 2 J C-F =13.7,9.0Hz). 19 F NMR(376MHz,CDCl3) 19 F NMR(376 MHz,CDCl3)δ-113.6,-118.2(d,2 J F-F =158.7Hz),-146.3(d, 2 J F-F =158.3Hz).GC:β-255 chiral column,1.8 mL / min;120℃,5 min;3℃ / min,150℃,0min;10℃ / min,180℃,10min,retention time 16.3 min(major)and 16.5 min.

[0050] Methyl(1S,3R)-3-(4-chlorophenyl)-2,2-difluorocyclopropane-1-carboxylate(2e):40℃,16h,88.5mg,90%yield,colorless oil,new compound,R f =0.30(hexanes / ethyl acetate 30 / 1),87.4%ee,[α] 20 D =+22.66(c 0.88,CHCl3). 1 H NMR(400MHz,CDCl3)δ7.35-7.28(m,2H),7.28-7.22(m,2H),3.58(s,3H),3.21(td,J=12.8,2.4Hz,1H),2.82(td,J=12.1,1.4Hz,1H). 13 C NMR(100 MHz,CDCl3)δ165.0,134.0,130.9(t, 4 J C-F =2.0Hz),128.7,127.9,110.9(dd, 1 J C-F =289.2Hz and 1 J C-F =284.2Hz),52.1,31.3(dd,J=12.1,9.5Hz),30.2(dd,J=13.7,9.0Hz). 19 F NMR(376 MHz,CDCl3)δ-118.3(d, 2 J C-F =158.8Hz),-146.2(d, 2 J C-F=158.8Hz).The HPLC:OJ-H column,220 nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=1.0 mL / min,retention time 10.2 min(major)and 13.1 min.HRMS:Calculated for C 11 H 10 ClF2O2[M+H] + 247.0332( 35 Cl),249.0305( 37 Cl),found:247.0332( 35 Cl),249.0305( 37 Cl).

[0051] Methyl(1S,3R)-3-(4-bromophenyl)-2,2-difluorocyclopropane-1-carboxylate(2f):40℃,16h,104.8mg,90%yield,colorless oil,new compound,R f =0.30(hexanes / ethyl acetate 30 / 1),85.4%ee,[α] 20 D =+23.69(c 1.01,CHCl3). 1 H NMR(400 MHz,CDCl3)δ7.51-7.43(m,2H),7.20(d,J=8.4Hz,2H),3.58(s,3H),3.28-3.10(m,1H),2.82(td,J=12.1,1.4Hz,1H). 13 C NMR(100 MHz,CDCl3)δ164.9,131.6,131.2,128.4,122.2,110.9(dd, 1 J C-F =291.0Hz and 1 J C-F =285.9Hz),52.1,31.3(dd, 2 J C-F =12.1,9.5Hz),30.2(dd, 2 J C-F =13.6,9.0Hz). 19 F NMR(376 MHz,CDCl3)δ-118.3(d, 2 JF-F =158.9Hz),-146.2(d, 2 J F-F =158.8Hz).HPLC:OJ-H column,220 nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=1.0 mL / min,retention time 11.4(major)min and 13.4 min.HRMS:Calculated for C 11 H7BrF2O2[M+H]+290.9827( 79 Br),292.9807( 81 Br),found:290.9824( 79 Br),292.9803( 81 Br).

[0052] Methyl(1S,3R)-3-(4-(t-butyl)phenyl)-2,2-difluorocyclopropane-1-carboxylate(2g):40℃,16h,97.0mg,90%yield,colorless oil,R f =0.30(hexanes / ethyl acetate 30 / 1),83.4%ee,[α] 20 D =+23.41(c 0.91,CHCl3). 1 H NMR(400 MHz,CDCl3)δ7.35(d,J=8.2Hz,2H),7.24(d,J=8.1Hz,2H),3.55(s,3H),3.20(ddd,J=14.3,12.1,2.6Hz,1H),2.82-2.73(m,1H),1.30(s,9H). 13 C NMR(100 MHz,CDCl3)δ165.3,150.8,129.2,126.3,125.4,111.4(dd, 1 J C-F =290.9Hz and 1 J C-F =285.4Hz),51.9,34.6,31.9(dd, 2 J C-F =11.8,9.7Hz),31.3,30.2(dd, 2 J C-F =13.8,8.9Hz). 19F NMR(376 MHz,CDCl3)δ-118.1(d, 2 J F-F =158.0Hz),-146.4(d, 2 J F-F =157.7Hz).HPLC:OJ-H column,220 nm,30℃,n-Hexane / i-PrOH=97 / 3,flow=0.8 mL / min,retention time 8.4 min and 9.5 min(major).

[0053] Methyl(1S,3R)-2,2-difluoro-3-(p-tolyl)cyclopropane-1-carboxylate(2h):40℃,16h,78.3mg,87%yield,colorless oil,new compound,R f =0.40(hexanes / ethylacetate 30 / 1),90.0%ee,[α] 20 D =+42.38(c0.88,CHCl3). 1 H NMR(400 MHz,CDCl3)δ7.20(d,J=8.0Hz,2H),7.13(d,J=8.0Hz,2H),3.56(s,3H),3.23(ddd,J=14.3,11.9,2.4Hz,1H),2.78(td,J=12.2,1.3Hz,1H),2.33(s,3H). 13 C NMR(100 MHz,CDCl3)δ165.3,137.7,129.4,129.2,126.2,111.3(dd, 1 J C-F =291.3Hz and 1 J C-F =285.1Hz),52.0,31.9(dd, 2 J C-F =11.7,9.6Hz),30.2(dd, 2 J C-F =13.8,9.0Hz),21.3. 19 F NMR(376 MHz,CDCl3)δ-118.0(d, 2 J F-F =158.1Hz),-146.3(d, 2 J F-F=157.5Hz).HPLC:OJ-H column,220 nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=1.0 mL / min,retention time 10.9(major)min and 19.9min.HRMS:Calculated for C 12 H 13 F2O2[M+H] + 227.0878,found:227.0878

[0054] Methyl(1S,3R)-2,2-difluoro-3-(o-tolyl)cyclopropane-1-carboxylate(2i):40℃,16h,81.5mg,90%yield,colorless oil,new compound,R f =0.40(hexanes / ethylacetate 30 / 1),82.1%ee,[α] 20 D =+63.39(c0.94,CHCl3). 1 H NMR(400 MHz,CDCl3)δ7.33(d,J=7.4Hz,1H),7.26-7.13(m,3H),3.56(s,3H),3.14(ddd,J=14.2,11.7,2.6Hz,1H),2.86(t,J=12.2Hz,1H),2.29(s,3H). 13 C NMR(100 MHz,CDCl3)δ165.4,138.0(d, 4 J C-F =2.1Hz),130.1,129.4(d, 4 J C-F =2.9Hz),128.2,127.9,125.8,111.6(dd, 1 J C-F =291.8Hz and 1 J C-F =284.8Hz),52.0,31.1(dd, 2 J C-F =11.6,9.2Hz),29.9(dd, 2 J C-F =13.6,9.2Hz),19.5. 19 F NMR(376 MHz,CDCl3)δ-117.7(d, 2J F-F =156.8Hz),-145.0(d, 2 J F-F =156.8Hz).HPLC:OJ-H column,220 nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=1.0 mL / min,retention time 8.9(major)min and20.8 min.HRMS:Calcula-ted for C 12 H 13 F2O2[M+H] + 227.0878,found:227.0875.

[0055] Methyl(1S,3R)-2,2-difluoro-3-(m-tolyl)cyclopropane-1-carboxylate(2j):40℃,16h,87.3mg,96%yield,colorless oil,new compound,R f =0.30(hexanes / ethylacetate 30 / 1),93.5%ee,[α] 20 D =+44.99(c0.89,CHCl3). 1 H NMR(400 MHz,CDCl3)δ7.22(t,J=7.5Hz,1H),7.16-7.04(m,3H),3.56(s,3H),3.23(ddd,J=14.4,12.0,2.5Hz,1H),2.80(td,J=12.2,1.3Hz,1H),2.34(s,3H). 13 C NMR(100 MHz,CDCl3)δ165.3,138.1,130.2,129.3,128.8,128.3,126.5,111.2(dd, 1 J C-F =291.4Hz and 1 J C-F =284.9Hz),52.0,32.0(dd, 2 J C-F =11.8,9.6Hz),30.2(dd, 2 J C-F =13.8,9.0Hz),21.4. 19 F NMR(376 MHz,CDCl3)δ-118.0(d, 2 JF-F =158.0Hz),-146.2(d, 2 J F-F =158.1Hz).HPLC:OJ-H column,220 nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=1.0 mL / min,reten-tion time 8.5(major)min and 11.1min.HRMS:Calculated for C 12 H 13 F2O2[M+H] + 227.0878,found:227.0878.

[0056] Methyl(1S,3R)-2,2-difluoro-3-(3-fluorophenyl)cyclopropane-1-carboxylate(2k):40℃,16h,83.8mg,91%yield,colorless oil,R f =0.35(hexanes / ethyl acetate 30 / 1),91.1%ee,[α] 20 D =+37.77(c 0.83,CHCl3). 1 H NMR(400 MHz,CDCl3)δ7.37-7.27(m,1H),7.12-7.08(m,1H),7.07-6.97(m,2H),3.58(s,3H),3.33-3.15(m,1H),2.83(td,J=12.1,1.4Hz,1H). 13 C NMR(100 MHz,CDCl3)δ164.9,162.5(d, 1 J C-F =246.0Hz),131.7(d, 3 J C-F =8.3Hz),129.9(d, 3 J C-F =8.5Hz),125.3,116.7(d, 2 J C-F =22.5Hz),115.1(d, 2 J C-F =20.9Hz),110.8(dd, 1 J C-F =289.2Hz and 1 J C-F=284.2Hz),52.1,31.4(t, 2 J C-F =10.7Hz),30.3(dd, 2 J C-F =13.8,9.1Hz). 19 F NMR(376 MHz,CDCl3)δ-112.7,-118.3(d, 2 J F-F =159.5Hz),-146.3(d, 2 J F-F =159.5Hz).HPLC:OJ-H column,220 nm,30℃,n-Hexane / i-PrOH=97 / 3,flow=1.0 mL / min,retention time 13.5(major)min and 14.7 min.

[0057] Methyl(1S,3R)-2,2-difluoro-3-(thiophen-3-yl)cyclopropane-1-carboxylate(2l):40℃,16h,64.8mg,74%yield,colorless oil,R f =0.40(hexanes / ethyl acetate 30 / 1),70.5%ee,[α] 20 D =+14.93(c 1.00,CHCl3). 1 H NMR(400 MHz,CDCl3)δ7.34-7.26(m,2H),7.06(d,J=4.9Hz,1H),3.58(s,3H),3.27-3.11(m,1H),2.77(td,J=12.1,1.6Hz,1H). 13 C NMR(100 MHz,CDCl3)δ164.9,128.6,128.4(t, 4 J C-F =2.0Hz),125.3,124.8(t, 4 J C-F =2.0Hz),111.1(dd, 1 J C-F =290.9Hz and 1 J C-F =286.4Hz),52.0,30.4(dd, 2 J C-F =13.7,8.9Hz),28.4(dd,2 J C-F =12.7,10.2Hz). 19 F NMR(376 MHz,CDCl3)δ-119.2(d, 2 J F-F =158.8Hz),-146.1(d, 2 J F-F =158.8Hz).HPLC:AD-H column,220 nm,30℃,n-Hexane / i-PrOH=92 / 8,flow=1.0 mL / min,retention time 5.0 min and 5.6 min(major).HRMS:Calculated for C9H9F2O2S[M+H] + 219.0286,found:219.0289.

[0058] Methyl(1S,3S)-3-(4-(benzyloxy)butyl)-2,2-difluorocyclopropane-1-carboxylate(2m):40℃,16h,67.1mg,56%yield,colorless oil,R f =0.55(hexanes / diethyl ether 4 / 1),90.9%ee,[α] 20 D =-50.00(c 0.80,CHCl3). 1 H NMR(400 MHz,CDCl3)δ7.36-7.32(m,4H),7.30-7.27(m,1H),4.50(s,2H),3.70(s,3H),3.48(t,J=6.4Hz,2H),2.40(ddd,J=12.7,11.5,1.3Hz,1H),2.01-1.77(m,3H),1.70-1.58(m,2H),1.52-1.42(m,2H). 13 C NMR(100 MHz,CDCl3)δ166.5,138.6,128.4,127.7,127.6,112.1(t, 1 J C-F =288.1Hz),72.9,70.0,52.0,29.2(dd, 2 J C-F =11.0,9.0Hz),29.1,27.3(dd, 2 J C-F=13.7,9.3Hz),25.4(d, 4 J C-F =1.4Hz),20.4(d, 3 J C-F =3.3Hz). 19 F NMR(376 MHz,CDCl3)δ-121.2(td, 2 J F-F =155.3,3.3Hz),-150.2(dd, 2 J F-F =154.6,3.2Hz).HPLC:OD-H column,220 nm,30℃,n-Hexane / i-PrOH=97 / 3,flow=0.8mL / min,retention time 11.7 min and 12,5 min(major).

[0059] ((1S,3R)-2,2-Difluoro-3-phenylcyclopropyl)(4-methoxyphenyl)methanone(2n):8℃,1h,78.3mg,68%yield,colorless oil,new compound,R f =0.25(hexanes / ethyl acetate 30 / 1),97.9%ee,[α] 20 D =-128.71(c 0.86,CHCl3). 1 H NMR(400 MHz,CDCl3)δ7.91(d,J=8.9Hz,2H),7.26(s,5H),6.93(d,J=8.9Hz,2H),3.87(s,3H),3.69-3.52(m,1H),3.40(td,J=12.9,2.6Hz,1H). 13 C NMR(100MHz,CDCl3)δ188.5,163.8,130.9,130.5,129.8,129.5,128.3,127.7,113.9,112.8(dd, 1 J C-F =291.7and 1 J C-F =286.6Hz),55.6,33.9(dd, 2 J C-F =11.9,9.3Hz),32.7(dd, 2 J C-F=11.9Hz,9.3Hz). 19 F NMR(376MHz,CDCl3)δ-115.9(d, 2 J F-F =156.1Hz),-147.4(d, 2 J F-F =156.1Hz).The HPLC:AD-H column,254nm,30℃,n-Hexane / i-PrOH=80 / 20,flow=1.0mL / min,retention time 11.0min(minor)and 13.1min(major).The HRMS:Calculated for C 17 H 15 F2O2[M+H] + 289.1035,found:289.1030.

[0060] ((1S,3S)-2,2-Difluoro-3-phenethylcyclopropyl)(4-methoxyphenyl)methanone(2o):8℃,1h,94.7mg,72%yield,colorless oil,new compound,R f =0.20(hexanes / ethyl acetate 30 / 1),93.0%ee,[α] 20 D =+21.46(c 0.80,CHCl3), 1 H NMR(400MHz,CDCl3)δ7.94-7.90(m,2H),7.28-7.23(m,2H),7.19-7.14(m,3H),9.96-6.92(m,2H),3.85(s,3H),3.16(ddd,J=13.1,10.9,1.8Hz,1H),2.72-2.64(m,2H),2.12-2.10(m,1H),2.09-2.03(m,2H). 13 C NMR(100MHz,CDCl3)δ190.3,163.9,140.9,131.0,130.5,128.6,128.5,126.1,113.9,113.4(dd, 1 J C-F =287.8and 1 J C-F =286.3Hz),55.6,35.1,30.3(dd, 2 JC-F =11.4,9.5Hz),30.0(dd, 2 J C-F =10.5,8.9Hz),23.0(d, 3 J C-F =3.2Hz). 19 F NMR(376MHz, CDCl3)δ-119.7(d, 2 J F-F =153.2Hz),-150.1(d, 2 J F-F =153.2Hz).The HPLC:AD-H column,254nm,30℃,n-Hexane / i-PrOH=80 / 20,flow=1.0mL / min,retention time 6.1min and7.6min(major).HRMS:Calculated for C 19 H 19 F2O2[M+H] + 317.1348,found:317.1349.

[0061] N-benzimidazole-3-phenyl-difluorocyclopropanecarboxamide derivatives can effectively block the proliferation, survival and invasion signaling pathways of tumor cells by inhibiting LPA receptors, thereby significantly inhibiting tumor growth and metastasis. Compared with traditional treatments, these compounds have high specificity, multi-target mechanisms of action, and can reduce the development of drug resistance, so they are expected to provide new and effective means for cancer treatment. On this basis, the above-mentioned hydrogenation product cis-(1S,3R)-2a was epimerized and converted into trans-(1R,3R)-3. Further attempts were made to hydrolyze compound 3 under alkaline reflux conditions and condense it with 5-chloro-1H-benzimidazole-2-amine. Finally, the biologically active molecule (1R,3R)-4 was successfully obtained with a yield of 62% in two steps. The reaction formula is as follows:

[0062]

[0063] (1R,3R)-(-)-N-(1,6-Dichloro-1H-benzo[d]imidazol-2-yl)-2,2-difluoro-3-phenylcyclopropane-1-carbo xamide(4):52.2mg,56%yield(3 steps),yellow oil,R f =0.20(hexane / ethyl acetate 5 / 1),[α]20 D =-109.32(c 0.68,THF). 1 H NMR(400 MHz,CDCl3) 1 H NMR(400 MHz,DMSO)δ12.33(s,1H),12.19(s,1H),7.50-7.35(m,7H),7.14(dd,J=8.5,2.1Hz,1H),3.76-3.70(m,1H),3.41(dd,J=12.7,8.2Hz,1H). 19 F NMR(376 MHz,DMSO)δ-132.8(d, 2 J F-F =147.1Hz),-133.4(d, 2 J F-F =147.2Hz).The HRMS:Calculated forC 11 H 10 ClF2O2[M+H] + 348.0710( 35 Cl),348.0714( 37 Cl),found:350.0685( 35 Cl),350.0685( 37 Cl).

Claims

1. A method for synthesizing gem-difluorocyclopropane by rhodium-catalyzed asymmetric hydrogenation of gem-difluorocyclopropene, characterized in that: The method uses gem-difluorocyclopropene ester or ketone as reaction substrate 1 and chiral diphosphorus ligand of rhodium as catalyst to synthesize gem-difluorocyclopropane 2 through asymmetric hydrogenation. The reaction formula is as follows: Where: R is a phenyl group or a phenyl ring containing a substituent, wherein the substituent includes MeO, CF3, halogen, heteroaryl, naphthyl and C1-C 20 at least one of the alkyl substituents of R' is one of an alkoxy group, a phenyl group, and a benzene ring containing a substituent, and the substituent includes at least one of MeO, CF3, a halogen, a heteroaryl group, and a naphthyl group.

2. The method for synthesizing gem-difluorocyclopropane by rhodium-catalyzed asymmetric hydrogenation of gem-difluorocyclopropene according to claim 1, characterized in that: The steps of the method are as follows: (1) Catalyst preparation: a rhodium metal precursor and a chiral bisphosphine ligand were added to a reaction flask, the atmosphere was replaced with nitrogen, dichloromethane was added, and the mixture was stirred at room temperature for 10 minutes to obtain the catalyst; (2) Under nitrogen atmosphere, add solvent to the reaction flask containing the catalyst, then transfer the solution in the reaction flask to a reactor containing the reaction substrate 1, introduce hydrogen at 14.8-1000 psi, and react at 0-60° C. for 1-24 hours to obtain the product.

3. The method for synthesizing gem-difluorocyclopropane by rhodium-catalyzed asymmetric hydrogenation of gem-difluorocyclopropene according to claim 2, characterized in that: The molar ratio of the rhodium metal precursor, the chiral bisphosphine ligand and the reaction substrate 1 is 1:1.2:150-1:1.2:200; the molar ratio of the reaction substrate 1 and the catalyst is 50:1-10:1; the solvent includes one or a mixed solvent of two of dichloromethane, ethyl acetate, toluene and tetrahydrofuran; and the chiral bisphosphine ligand includes one of (R)-PhanePhos, (R)-JosiPhos, (R)-SegPhos, (R)-BINAP, (S,S)-Ph-BPE and (S)-Xyl-SDP.

4. The method for synthesizing gem-difluorocyclopropane by rhodium-catalyzed asymmetric hydrogenation of gem-difluorocyclopropene according to claim 3, characterized in that The reaction substrate 1 is geminal difluorocyclopropene ester, the chiral bisphosphine ligand is (R)-PhanePhos, the solvent is dichloromethane, R is Ph, and R' is MeO; the temperature is 0-60° C., the reaction time is 1-24 hours, and the hydrogen pressure is 14.8-1000 psi.

5. The method for synthesizing gem-difluorocyclopropane by rhodium-catalyzed asymmetric hydrogenation of gem-difluorocyclopropene according to claim 3, characterized in that: The reaction substrate 1 is gem-difluorocyclopropenone, the chiral bisphosphine ligand is (R)-PhanePhos, the solvent is dichloromethane, R is Ph, and R' is 4-MeO-C6H4; the temperature is 0-60°C, the reaction time is 1-24 hours, and the hydrogen pressure is 14.8-1000 psi.

6. The method for synthesizing gem-difluorocyclopropane by rhodium-catalyzed asymmetric hydrogenation of gem-difluorocyclopropene according to claim 3, characterized in that: The metal precursor of rhodium is bis(1,5-cyclooctadiene)rhodium hexafluoroantimonate, bis(1,5-cyclooctadiene)rhodium tetrafluoroborate, bis(norbornadiene)rhodium tetrafluoroborate or chlorinated cyclooctadienyl rhodium dimer.

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