A synthesis 13 Methods and applications of C-labeled aryl 4-trifluoromethylformate

Abstract

The application discloses a kind of synthesis 13 The application discloses a method for synthesizing C-labeled 4-trifluoromethyl aryl formate and application thereof.The method has mild reaction conditions and simple preparation process.Further, the method uses aryl iodide, epoxide or aziridine as raw materials, and reacts with 13 C-labeled 4-trifluoromethyl aryl formate is used as a starting material, and under the action of a palladium catalyst, a phosphine ligand, a norbornene derivative, a base and an additive, a series of C-labeled isochromane ketone compounds and dihydroisoquinoline ketone compounds can be synthesized by stirring at 60 DEG C in an organic solvent. 13 C-labeled isochromane ketone compounds and dihydroisoquinoline ketone compounds have important theoretical value and application potential.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method based on H 13 CO2Na reagent synthesis 13 Methods and applications of C-labeled aryl 4-trifluoromethylformate. Background Technology

[0002] Stable isotope-labeled reagents are high-value-added and high-tech scientific research reagents. 11 C 13 C and 14 Carbon isotopes are ideal tools for labeling small organic molecules, allowing for seamless insertion of stable or radioactive labels without altering their properties or activity. (This is in contrast to radioactive carbon isotopes...) 11 C and 14 Compared to C), 13 C is a stable isotope that does not require specialized operating equipment and has advantages such as being non-radioactive, non-polluting to the environment, and requiring no radiation equipment or protection measures. 13 C isotopes are widely used in synthetic chemistry, food safety, environmental science, and life science research.

[0003] Aryl formate can release carbon monoxide molecules in a mild manner under the action of alkali. Using phenyl formate as a CO substitute source, carbonylation reactions achieved under palladium catalysis have been reported one after another ([1] Org. Lett. 2012, 14, 3100; [2] Org. Lett. 2012, 14, 5370; [3] Org. Lett. 2014, 16, 186; [4] Angew. Chem. Int. Ed. 2014, 53, 3183.). 13 There are only two reported cases of C-labeled aryl formate participating in the synthesis of isotopically labeled products ([5] Org. Biomol. Chem. 2015, 13, 10341–10347; [6] Org. Biomol. Chem. 2016, 14, 3047–3052.), indicating that there is much room for improvement and development in this field. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a method based on H... 13 CO2Na reagent synthesis 13 A method for synthesizing C-labeled aryl 4-trifluoromethylformate. This method uses mild reaction conditions, has a simple preparation process, and provides a new synthetic route.

[0005] The technical solution provided by this invention is as follows:

[0006] Firstly, this invention provides a method based on H 13 CO2Na reagent synthesis 13 A method for C-labeled aryl 4-trifluoromethylformate includes the following steps:

[0007] With base A, methanesulfonyl chloride B, p-trifluoromethylphenol, H 13 Using CO2Na as the starting material, the reaction is stirred in organic solvent C until complete. After the reaction is complete, the reactants are filtered, separated, and purified to obtain the product shown in formula D. 13 C-labeled aryl 4-trifluoromethylformate compounds.

[0008] Furthermore, the method includes the following more specific steps: dissolving base A and methanesulfonyl chloride B in organic solvent C, and mixing them under low temperature with stirring; adding 4-trifluoromethylphenol and H 13 CO2Na is reacted at a low temperature. After the reaction is complete, the reactants are filtered and purified to obtain the product shown in formula D. 13 C-labeled aryl p-trifluoromethylformate compounds.

[0009] The reaction equation is as follows:

[0010]

[0011] Furthermore, the base A is any one or more of sodium formate, sodium acetate, potassium acetate, sodium tert-butoxide, sodium carbonate, sodium methoxide, and sodium hydroxide. Preferred base A is sodium acetate.

[0012] Furthermore, solvent C is any one or more of tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, toluene, and acetonitrile. Preferably, solvent C is acetonitrile.

[0013] Furthermore, the molar ratio of each raw material is: alkali A: methanesulfonyl chloride B: 4-trifluoromethylphenol: H 13 CO2Na = 1.0:1.0:1.0:1.0. Preferably, base A: methanesulfonyl chloride, B: 4-trifluoromethylphenol, H... 13 CO2Na=1.0:1.0:1.0:1.0.

[0014] Furthermore, the reaction takes place in an air environment.

[0015] Furthermore, the reaction temperature is below 5°C. Preferably, the reaction temperature is between 0°C and 5°C.

[0016] Furthermore, the reaction time is 12-24 hours. Preferably, the reaction time is 12 hours.

[0017] Furthermore, the method for separating the reactants involves filtering, concentrating, and purifying the reaction mixture by column chromatography.

[0018] Furthermore, the filtration method involves washing with dichloromethane; the concentration process can employ methods such as low-temperature vacuum distillation, for example, low-temperature vacuum concentration using a rotary evaporator; and the purification method can employ column chromatography for separation and purification.

[0019] Secondly, the present invention provides 13 Methods for synthesizing C-labeled isochoric ketone compounds, including the synthesis described in the first aspect. 13 The method for C-labeled aryl 4-trifluoromethylformate further includes the following steps:

[0020] Under a protective gas atmosphere, aryl iodide and compound M are used as starting materials. In the presence of palladium catalyst E, phosphine ligand F, norbornene derivative G and base H, compound D and base J are stirred in organic solvent I with carbon monoxide generated in solvent K until complete. The reaction temperature is 40-100℃. After the reaction is completed, the reactants are separated to obtain the heterochromatic ketone compound shown in formula L.

[0021] The reaction equation is as follows:

[0022]

[0023] Among them, R 1 R is one or more of alkyl, aryl, ester, amide, alkoxy, benzyloxy, tert-butoxycarbonyl, and halogen. 1 The substitution positions on the aromatic ring are limited to positions 2-5; R 2 It is one or more of the following: hydrogen, alkyl, aryl, ester, hydroxyl, amide, alkoxy, benzyloxy, halogen, haloalkyl, tert-butyldimethylsiloxy, and natural product derivatives such as gibberellin and estradiol; R 3 It is one or more of alkyl, aryl, and sulfonyl groups.

[0024] Furthermore, the protective gas is selected from argon or nitrogen. Argon is preferred.

[0025] Furthermore, R 1 R 2 and R 3 In the group, the alkyl group is an alkyl group having 1 to 16 carbon atoms, including methyl, ethyl, isopropyl, decyl, hexadecyl, etc.; the aryl group is phenyl, fused-ring aromatic ring, and substituted aromatic hydrocarbon, and the substituent includes C1-C6 alkyl, C1-C6 alkoxy, halogen, etc.; the ester group is -COOR, where R is an alkyl group having 1 to 3 carbon atoms, including methyl, etc.; the alkoxy group refers to an alkoxy group having 1 to 10 carbon atoms, including methoxy, etc.; the halogen refers to fluorine, chlorine, bromine, iodine; the haloalkyl group is a C1-C6 haloalkyl group; the sulfonyl group includes p-toluenesulfonyl, etc.

[0026] Furthermore, the palladium catalyst E is any one or more of Pd(PPh3)4, Pd(dba)2, Pd2(dba)3, Pd(OAc)2, Pd(PhCN)2Cl2, Pd(MeCN)2Cl2, PdCl2, PdI2, and [Pd(allyl)Cl]2. Preferably, the palladium catalyst E is Pd(OAc)2.

[0027] Further, the phosphine ligand F is any one or more of 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl, 2-di-tert-butylphosphine-2-(N,N-dimethylamino)biphenyl, triarylphosphine, tris(2-furanyl)phosphine, and bis(2-diphenylphosphine) ether. Preferably, the phosphine ligand F is 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl or 2-dicyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl.

[0028] Furthermore, the structural formula of the norbornene derivative G is as follows:

[0029]

[0030] in:

[0031] i)R 3 The substituents on the left five-membered ring, p represents the number of substituents, 0≤p≤8; R 4 q represents the substituents on the double bond, where q represents the number of substituents, and 0 ≤ q ≤ 2;

[0032] ii) When the number of substituents on the left five-membered ring is two or more, they can be the same or different; when the number of substituents on the double bond is two, they can be the same or different.

[0033] iii)R 3 and R 4 The types of substituents can be the same or different;

[0034] iii) Each R 3 and R 4 It is independently one or more of ester, carboxyl, cyano, amide, alkoxy, aryl, heterocyclic aryl, alkyl or halogen.

[0035] Furthermore, the R 3 and R 4The ester group is COOR, where R is an alkyl group with 1 to 2 carbon atoms, including methyl and ethyl; the alkoxy group is an alkoxy group with 1 to 10 carbon atoms; the aryl group is a phenyl group, a fused-ring aromatic ring, or a substituted aromatic hydrocarbon, and the substituents include C1-C6 alkyl groups, C1-C6 alkoxy groups, halogens, etc.; the alkyl group has 1 to 6 carbon atoms, including methyl, ethyl, isopropyl, hexyl, etc.; and the halogen is fluorine or chlorine. Preferred norbornene derivative G is (1S,2S,4S)-2-norbornene-5-formylaniline, (1S,2S,4S)-2-norbornene-5,6-ethylenediamide biphenyl, or (1S,2S,4S)-2-norbornene-5,6-ethylenediamide quinoline as a co-catalyst.

[0036] Further, the alkali H is any one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, cesium acetate, tripotassium phosphate, potassium formate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, and potassium tert-butoxide. Preferably, the alkali H is potassium acetate.

[0037] Further, solvent I is methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dimethyl ethylenediether, methyl tert-butyl ether, 1,4-dioxane, 1,3-dioxane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, C 4-12 Saturated alkanes, C 3-12 Fluorinated or chlorinated alkanes, benzene, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, N-methylpyrrolidone, acetonitrile, C 3-12 Solvent I is any one or more of saturated alkyl nitriles. Preferably, solvent I is N-methylpyrrolidone.

[0038] Furthermore, the base J is any one or more of sodium bicarbonate, sodium acetate, cesium carbonate, potassium phosphate, triethylamine, triethylenediamine, pyridine, and 4-dimethylaminopyridine; preferably, the base J is triethylamine.

[0039] Furthermore, solvent K is methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dimethyl ethylenediether, methyl tert-butyl ether, 1,4-dioxane, 1,3-dioxane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, C 4-12 Saturated alkanes, C 3-12 Fluorinated or chlorinated alkanes, benzene, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, N-methylpyrrolidone, acetonitrile, C 3-12 The solvent K is any one or more of saturated alkyl nitriles. Preferably, the solvent K is 1,4-dioxane.

[0040] Furthermore, the ratio of aryl iodide:epoxide:4-trifluoromethylphenol C:catalyst E:phosphine ligand F:norbornene derivative G:base H = 1.0:3.0:1.2:0.05~0.1:0.12~0.24:0.2~0.5:1.5.

[0041] Furthermore, the reaction mixture is separated by extraction, concentration, and column chromatography purification. The extraction is performed using ethyl acetate and a saturated sodium chloride solution. The concentration process can be achieved using methods such as vacuum distillation, for example, vacuum concentration using a rotary evaporator. The purification method can be column chromatography separation and purification.

[0042] The method of the present invention can synthesize 13 Compared with the prior art, the present invention has the following advantages regarding C-labeled aryl 4-trifluoromethylformate, isochoronone compounds, and dihydroisoquinolinone compounds:

[0043] i) First use of H 13 CO2Na reagent synthesis 13 C-labeled aryl 4-trifluoromethylformate is a currently available synthetic 13 An important supplement to the C-labeled aryl formate method, releasing 13 C-labeled carbon monoxide molecules participate in the reaction. The reaction takes place in air, requires no protective gas, is simple to operate, and is conducted under mild conditions.

[0044] ii) In synthesis 13 Based on the C-labeled aryl 4-trifluoromethylformate, further synthesis was carried out. 13 C-labeled isochloroquinones and dihydroisoquinolineones. Detailed Implementation

[0045] The present invention will be further illustrated by the following examples. It is worth noting that the present invention is not limited to the following embodiments.

[0046] Example 1: Preparation of compound D

[0047]

[0048] Take a 10 mL Schlenk reaction tube and add sodium acetate (82 mg, 1.0 mmol), methanesulfonyl chloride (114.6 mg, 1.0 mmol), and 0.2 mL of MeCN. Stir at 5 °C for 2 h, then add 4-trifluoromethylphenol (162 mg, 1.0 mmol) and H2O. 13CO2Na (69 mg, 1.0 mmol) was reacted at 0℃-5℃ for 12 h. The reaction solution was filtered, washed with dichloromethane, concentrated under reduced pressure at low temperature, and purified by column chromatography to obtain compound D (yellow oily liquid). 1 H NMR (400MHz, CDCl3) δ8.60 (s, 0.5H), 8.02 (s, 0.5H), 7.69 (d, J = 8.5Hz, 2H), 7.28 (d, J = 8.4Hz, 2H); 13 C NMR (100MHz, CDCl3) δ 158.5 ( 13 C-enriched), 127.2 (d, J = 3.8Hz), 121.9 (d, J = 1.7Hz); 19 F NMR (377MHz, CDCl3) δ-62.4.

[0049] Based on Example 1, synthesized 13 The reaction equation for C-labeled isochromatic ketones is as follows:

[0050]

[0051] Example 2: Preparation of compound L-1

[0052]

[0053] In a glove box, palladium acetate (2.3 mg, 0.01 mmol), 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl (11.5 mg, 0.024 mmol), potassium acetate (29.4 mg, 0.3 mmol), and (1S,2S,4S)-2-norbornene-5-carboxyaniline (8.6 mg, 0.04 mmol) were added to the carbon monoxide consumption chamber of a dry, magnetically stirred two-chamber reaction tube. Then, 2-methyliodobenzene (43.6 mg, 0.2 mmol), S-benzyl glycidyl ether (98.5 mg, 0.6 mmol), and dry N-methylpyrrolidone (1.0 mL) were added; in the carbon monoxide generation chamber, palladium acetate (2.3 mg, 0.01 mmol), 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl (11.5 mg, 0.024 mmol), potassium acetate (29.4 mg, 0.3 mmol), and (1S,2S,4S)-2-norbornene-5-carboxylaniline (8.6 mg, 0.04 mmol) were added. 13 C-labeled phenyl 4-trifluoromethylformate (45.6 mg, 0.24 mmol), triethylamine (24.3 mg, 0.24 mmol), and dried 1,4-dioxane (1.0 mL) were reacted at 60 °C under an argon atmosphere for 16 hours. The mixture in the carbon monoxide consumption chamber was extracted with ethyl acetate and saturated sodium chloride solution, dried over anhydrous sodium sulfate, the solvent was removed by vacuum distillation, and the compound L-1 was purified by column chromatography (pale yellow oily liquid, 78% yield, 99% ee). 1H NMR (400MHz, CDCl3) δ7.40–7.28 (m, 6H), 7.19 (d, J = 7.7Hz, 1H), 7.08 (d, J=7.5Hz,1H),4.67–4.57(m,3H),3.79(dd,J=10.2,4.8Hz,1H),3.72(dd,J=10.3,5. 3Hz, 1H), 3.11 (dd, J=16.1, 11.6Hz, 1H), 2.94 (dd, J=16.1, 3.0Hz, 1H), 2.67 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 164.5 ( 13 C-enriched),143.2(d,J=3.0Hz),140.0(d,J=1.9Hz),137.9,132.9, 131.2(d,J=4.6Hz),128.7,128.0,127.9,125.5(d,J=3.6Hz),123.8(d,J=68.4Hz),76.7 (d,J=1.8Hz),73.8,71.3(d,J=2.8Hz),31.6(d,J=3.3Hz),22.4; HRMS(ESI-TOF):calc'd for C 18 [ 13 C]H 18 NaO3[M+Na + ]306.1182, found 306.1183; HPLC: DaicelChiralpak IG column, 10% i PrOH in n hexane, 1 mL / min, λ = 230 nm, t R (major) = 19.382 min, t R (minor) = 20.910 min; -99.057 (c=0.61, CHCl3).

[0054] Example 3: Preparation of compound L-2

[0055]

[0056] The procedure was the same as in Example 2, except that the iodides used were methyl o-iodophenylacetate (55.2 mg), palladium acetate (4.5 mg, 0.1 mmol), 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (23.0 mg, 0.24 mmol), and (1S,2S,4S)-2-norbornene-5,6-ethylenediamide-biphenyl (31.5 mg, 0.5 mmol), yielding compound L-2 (yellow oily liquid, 50% yield). 1 H NMR(400MHz, CDCl3)δ7.46(t,J=7.6Hz,1H),7.39–7.27(m,5H),7.20(dd,J=7.8,3.5 Hz,2H),4.72–4.64(m,1H),4.62(d,J=1.3Hz,2H),4.22(d,J=16.8Hz,1H),3.95(d,J=16.9H z,1H),3.79(dd,J=10.4,4.7Hz,1H),3.75–3.71(m,1H),3.70(s,3H),3.16(dd,J=16.2,11.5 Hz,1H),2.98(dd,J=16.2,3.1Hz,1H); 13 C NMR(100MHz,CDCl3)δ172.0,164.5 ( 13 C-enriched),140.3(d,J=1.8Hz),138.2(d,J=2.6Hz),137.9,133.2,131.7(d,J=4.6Hz), 128.6,128.0,127.9,127.3(d,J=3.6Hz),124.2(d,J=68.5Hz),76.8(d,J=2.2Hz), 73.8,71.1(d,J=2.7Hz),52.1,40.6,31.3(d,J=3.2Hz); HRMS(ESI-TOF):calc'dfor C 20 [ 13 C]H 20 NaO5[M+Na + ]364.1236, found 364.1237.

[0057] Example 4: Preparation of compound L-3

[0058]

[0059] The operation steps are the same as in Example 2, except that the iodide used is 2-methyl-3-chloroiodobenzene (50.4 mg), yielding compound L-3 (pale yellow solid, 70% yield). 1H NMR (400MHz, CDCl3) δ7.49 (d, J = 8.1Hz, 1H), 7.39 –7.28(m,5H),7.03(d,J=8.1Hz,1H),4.66–4.54(m,3H),3.78(dd,J=10.3,4.8Hz,1H),3.71( dd,J=10.3,5.2Hz,1H),3.07(dd,J=16.2,11.5Hz,1H),2.92(dd,J=16.2,3.0Hz,1H),2.72(s, 3H); 13 C NMR (100MHz, CDCl3) δ 163.7 ( 13 C-enriched),140.5(d,J=3.4Hz),138.6(d,J=1.8 Hz),137.8,135.5(d,J=6.4Hz),133.7,128.6,128.1,127.9,125.89(d,J=68.6Hz),126.0 4(d,J=4.1Hz),76.7(d,J=1.8Hz),73.8,71.0(d,J=2.8Hz),31.4(d,J=3.3Hz),18.1; HRMS (ESI-TOF):calc'd for C 18 [ 13 C]H 17 ClNaO3[M+Na + ]340.0792,found340.0793.

[0060] Example 5: Preparation of compound L-4

[0061]

[0062] The procedure was the same as in Example 2, except that the iodides used were methyl 3-methyl-4-iodobenzoate (55.2 mg), palladium acetate (4.5 mg, 0.1 mmol), 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (23.0 mg, 0.24 mmol), and (1S,2S,4S)-2-norbornene-5,6-ethylenediamide-biphenyl (31.5 mg, 0.5 mmol), yielding compound L-4 (white solid, 60% yield). 1H NMR(400MHz, CDCl3)δ7.84(s,1H),7.74(s,1H),7.39–7.28(m,5H),4.62(s,3H), 3.94(s,3H),3.79(dd,J=10.3,4.8Hz,1H),3.72(dd,J=10.3,5.2Hz,1H),3.15(dd,J=16.2,11.4Hz,1H),3.01(dd,J=16.2,3.1Hz,1H),2.71(s,3H); 13 C NMR(100MHz,CDCl3)δ166.3, 163.8( 13 C-enriched),143.5,140.2,137.8,133.5,131.9(d,J=4.7Hz),128.7,128.1,127.9,127.4 (d,J=68.2Hz),126.4(d,J=3.6Hz),73.9,71.0(d,J=2.9Hz),52.7,31.5(d,J=3.1Hz),22.3; HRMS(ESI-TOF):calc'd for C 20 [ 13 C]H 20 NaO5[M+Na + ]364.1236, found 364.1233.

[0063] Example 6: Preparation of compound L-5

[0064]

[0065] The procedure was the same as in Example 2, except that the iodides used were 2-chloro-3,4-dimethoxyiodobenzene (59.6 mg), palladium acetate (4.5 mg, 0.1 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (23.0 mg, 0.24 mmol), and (1S,2S,4S)-2-norbornene-5,6-ethylenediamide-biphenyl (31.5 mg, 0.5 mmol), yielding compound L-5 (white solid, 49% yield). 1 H NMR (400MHz, CDCl3) δ7.40–7.30(m,5H),6.66(s,1H),4.65–4.54(m,3H),3.93(s, 3H), 3.85 (s, 3H), 3.78 (dd, J = 10.2, 4.6Hz, 1H), 3.71 (dd, J = 10.2, 5.7Hz, 1H), 3.09 (dd, J = 16.1, 11.5Hz, 1H), 2.92 (dd, J = 16.2, 3.0Hz, 1H);13 C NMR (100MHz, CDCl3) δ 161.5 ( 13 C-enriched),157.4,146.1(d,J=4.6Hz),138.1,137.8,131.8,128.7,128.1,128.0,115.9(d,J= 73.7Hz), 109.1 (d, J = 4.3Hz), 76.3 (d, J = 1.8Hz), 73.9, 70.9 (d, J = 3.0Hz), 60.8, 56.4, 31.9 (d, J = 3.2Hz); HRMS (ESI-TOF): calc'd for C 19 [ 13 C]H 19 ClNaO5[M+Na + ]386.0847,found386.0843.

[0066] Example 7: Preparation of compound L-6

[0067]

[0068] The procedure was the same as in Example 2, except that the iodides used were 4-bromo-1-iodonaphthalene (66.4 mg), palladium acetate (4.5 mg, 0.1 mmol), 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (23.0 mg, 0.24 mmol), and (1S,2S,4S)-2-norbornene-5,6-ethylenediamide-biphenyl (31.5 mg, 0.5 mmol), yielding compound L-6 (brownish-yellow solid, 45% yield). 1 H NMR (400MHz, CDCl3) δ9.22(d,J=8.6Hz,1H),8.31(d,J=8.4Hz,1H),7.70(d,J=7.0Hz,2H), 7.64(t,J=7.6Hz,1H),7.40–7.28(m,5H),4.74–4.59(m,3H),3.84(dd,J=10.4,4.7Hz,1H), 3.78(dd,J=10.3,5.3Hz,1H), 3.31(dd,J=16.6,11.7Hz,1H), 3.04(dd,J=16.7,3.1Hz,1H); 13 C NMR (100MHz, CDCl3) δ 163.8 ( 13C-enriched),140.7(d,J=1.7Hz),137.8,133.1(d,J= 3.7Hz),131.9(d,J=4.3Hz),130.6,129.7,129.4(d,J=4.1Hz),128.7,128.1,128.0,127.9, 127.8,126.8,120.0(d,J=69.7Hz),76..1(d,J=1.8Hz),73.9,70.9(d,J=2.8Hz),31.6(d,J= 3.5Hz); HRMS(ESI-TOF):calc'd for C 21 [ 13 C]H 17 BrNaO3[M+Na + ]420.0287,found 420.0286.

[0069] Example 8: Preparation of compound L-7

[0070]

[0071] The operating steps are the same as in Example 2, except that the iodide used is as shown. (81.0 mg), palladium acetate (4.5 mg, 0.1 mmol), 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (23.0 mg, 0.24 mmol), (1S,2S,4S)-2-norbornene-5,6-ethylenediamide-biphenyl (31.5 mg, 0.5 mmol), yielded compound L-7 (colorless oily liquid, 37% yield). 1 H NMR (400MHz, CDCl3) δ7.43–7.26(m,10H),7.05(s,1H),6.91(s,1H),5.01(d,J= 8.2Hz,1H),4.68–4.49(m,6H),3.98(s,1H),3.77(dd,J=10.4,4.8Hz,1H),3.72(m,4H),3.5 8(m,2H),3.48(d,J=5.1Hz,1H),3.33(dd,J=13.2,3.4Hz,1H),3.18–3.06(m,3H),2.99(dd,J =13.7,6.6Hz,1H),2.88(dd,J=16.2,2.9Hz,1H),1.40(s,9H); 13 C NMR(100MHz,CDCl3)δ 172.1,165.6( 13C-enriched),155.1,144.0,142.1,140.5,138.5,137.8,132.9,128.7,128.6,128.1, 127.9,127.8,127.1,80.4,74.8,73.8,73.6,72.6,71.0(d,J=2.9Hz),54.2,52.6,38.5,31.6,28.4; HRMS(ESI-TOF):calc'd for C 36 [ 13 C]H 43 NNaO9[M+Na + ]657.2863, found 657.2853.

[0072] Example 9: Preparation of compound L-8

[0073]

[0074] The operation steps are the same as in Example 2, except that the iodide used is 2-methyliodobenzene (43.6 mg) and the epoxide is propylene oxide (34.9 mg), yielding compound L-8 (colorless oily liquid, 58% yield). 1 H NMR (400MHz, CDCl3) δ7.36(t,J=7.6Hz,1H),7.19(d,J=7.7Hz,1H),7.05(d,J=7.5Hz,1H),4.64–4.51(m,1H),2 .94(dd,J=16.0,11.0Hz,1H),2.86(dd,J=16.1,3.4Hz,1H),2.67(s,3H),1.49(d,J=6.3Hz, 3H); 13 C NMR (100MHz, CDCl3) δ 165.2 ( 13 C-enriched),143.1(d,J=2.9Hz),140.4(d,J=2.0 Hz), 132.7, 131.2 (d, J = 4.7Hz), 125.3 (d, J = 3.6Hz), 123.8 (d, J = 67.9Hz), 74.5 ( d,J=1.8Hz),36.3(d,J=3.2Hz),22.4,21.0(d,J=2.5Hz); HRMS(ESI-TOF):calc'd forC 11 [ 13 C]H 12 NaO2[M+Na + ]200.0763, found 200.0762.

[0075] Example 10: Preparation of compound L-9

[0076]

[0077] The operation steps are the same as in Example 2, except that the iodide used is 2-methyliodobenzene (43.6 mg) and the epoxide is glycidyl ether (44.5 mg), yielding compound L-9 (colorless oily liquid, 59% yield). 1 H NMR (400MHz, CDCl3) δ7.38(t,J=7.6Hz,1H),7.20(d,J=7.6Hz,1H),7.09(d,J=7.5Hz,1H),4.53(ddt,J=12.0,5. 8,3.1Hz,1H),3.93(dd,J=12.2,3.4Hz,1H),3.82(dd,J=12.3,5.2Hz,1H),3.18(dd,J=16.1, 12.4Hz, 1H), 2.81 (dd, J=16.1, 2.9Hz, 1H), 2.67 (s, 3H); 13 C NMR (100MHz, CDCl3) δ164.7 ( 13 C-enriched),143.3(d,J=2.9Hz),140.1(d,J=1.9Hz),133.1,131.3(d,J=4.7Hz), 125.6 (d, J = 3.6Hz), 123.5 (d, J = 68.6Hz), 78.5 (d, J = 1.8Hz), 64.4 (d, J = 2.6Hz), 30.5 (d, J = 3.2Hz), 22.4; HRMS (ESI-TOF): calc'd for C 11 [ 13 C]H 12 NaO3[M+Na + ]215.0678,found215.0672.

[0078] Example 11: Preparation of compound L-10

[0079]

[0080] The procedure was the same as in Example 2, except that the iodide used was 2-methyliodobenzene (43.6 mg), the epoxy compound was epichlorohydrin (55.5 mg), palladium acetate (4.5 mg, 0.1 mmol), 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (23.0 mg, 0.24 mmol), and (1S,2S,4S)-2-norbornene-5,6-ethylenediamide-biphenyl (31.5 mg, 0.5 mmol), yielding compound L-10 (colorless oily liquid, 60% yield). 1 H NMR (400MHz, CDCl3) δ7.40 (t, J=7.6Hz, 1H), 7.22 (d,J=7.7Hz,1H),7.11(d,J=7.5Hz,1H),4.64(dddd,J=10.0,7.8,4.6,1.0Hz,1H),3.81 (dd,J=11.4,4.7Hz,1H),3.71(dd,J=11.5,6.8Hz,1H),3.18–3.04(m,2H),2.67(s,3H); 13 C NMR (100MHz, CDCl3) δ 163.8 ( 13 C-enriched),143.4,139.1(d,J=2.2Hz),133.2,131.6(d,J=4.7 Hz), 125.7 (d, J = 3.7Hz), 123.4 (d, J = 68.6Hz), 76.6 (d, J = 1.7Hz), 44.9 (d, J = 3.1Hz), 32.0 (d, J = 3.2Hz), 22.3; HRMS (ESI-TOF): calc'd for C 11 [ 13 C]H 11 ClNaO2[M+Na + ]233.0339,found233.0335.

[0081] Example 12: Preparation of compound L-11

[0082]

[0083] The procedure was the same as in Example 2, except that the iodide used was 2-methyliodobenzene (43.6 mg), the epoxy compound was N-(2,3-epoxypropyl)phthalamide (121.9 mg), palladium acetate (4.5 mg, 0.1 mmol), 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl (23.0 mg, 0.24 mmol), and (1S,2S,4S)-2-norbornene-5,6-ethylenediamide-biphenyl (31.5 mg, 0.5 mmol), yielding compound L-11 (white solid, 58% yield). 1 H NMR (400MHz, CDCl3) δ7.87 (dd, J=5.5, 3.0Hz, 2H), 7.74 (dd, J=5.5, 3.1Hz, 2H), 7.35 (t, J=7.6Hz, 1H), 7.18 (d, J=7.7Hz, 1H),7.06(d,J=7.5Hz,1H),4.87–4.75(m,1H),4.14(dd,J=14.1,7.3Hz,1H),3.91(dd,J=14.1,5.6Hz,1H),3.03(d,J=6.7Hz,2H),2.65(s,3H); 13 C NMR(100MHz,CDCl3)δ168.2, 163.8( 13 C-enriched), δ143.3(d,J=2.9Hz),139.0(d,J=2.0Hz),134.4,133.0,132.1,131.5(d,J =4.7Hz), 125.6 (d, J = 3.6Hz), 123.8 (d, J = 70.7Hz), 123.7, 74.4 (d, J = 1.7Hz), 41.1 (d, J = 2.5Hz), 32.4 (d, J = 3.3Hz), 22.3; HRMS (ESI-TOF): calc'd for C 19 [ 13 C]H 15 NNaO4[M+Na + ]344.0893, found 344.0889.

[0084] Example 13: Preparation of compound L-12

[0085]

[0086] The procedure was the same as in Example 2, except that the iodide used was 2-benzyloxy-4-methoxyiodobenzene (68.0 mg), and the epoxides were S-propylene oxide (34.9 mg), palladium acetate (4.5 mg, 0.1 mmol), 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl (23.0 mg, 0.24 mmol), and (1S,2S,4S)-2-norbornene-5,6-ethylenediamide-biphenyl (31.5 mg, 0.5 mmol), yielding compound L-12 (pale yellow oily liquid, 45% yield, 99% ee). 1 H NMR (400MHz, CDCl3) δ7.55(d,J=7.0Hz,2H),7.37(t,J=7.6Hz,2H),7.30(d,J=7.2Hz,1H),6.43(s,1H),6.30(s, 1H),5.29–5.17(m,2H),4.52(ddt,J=12.2,6.6,4.5Hz,1H),3.80(s,3H),2.88(dd,J=16.0, 10.9Hz, 1H), 2.79 (dd, J=16.0, 3.2Hz, 1H), 1.47 (d, J=6.3Hz, 3H); 13 C NMR(100MHz, CDCl3)δ164.3,162.6( 13 C-enriched),162.2,144.0,136.7,128.8,127.9,126.9,107.7,104.5(d,J =3.6Hz),99.8(d,J=3.1Hz),73.7,70.7,55.7,36.8,20.9(d,J=2.6Hz); HRMS(ESI-TOF):calc'd for C 18 [ 13 C]H 18 NaO4[M+Na + ]322.1131, found 322.1133; HPLC: Daicel Chiralpak OD column, 20% i PrOH in n hexane, 1 mL / min, λ = 230 nm, t R (major) = 13.721 min, t R (minor) undetected; 62.342 (c 0.12, CHCl3).

[0087] Example 14: Preparation of compound L-13

[0088]

[0089] The procedure was the same as in Example 2, except that the iodide used was 2-benzyloxyiodobenzene (62.0 mg), and the epoxy compounds were R-propylene oxide (34.9 mg), palladium acetate (4.5 mg, 0.1 mmol), 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl (23.0 mg, 0.24 mmol), and (1S,2S,4S)-2-norbornene-5,6-ethylenediamide-biphenyl (31.5 mg, 0.5 mmol), yielding compound L-13 (colorless oily liquid, 55% yield, 99% ee). 1 H NMR (400MHz, CDCl3) δ7.54(d,J=7.5Hz,2H),7.41–7.34(m,3H),7.30(d,J=7.3Hz,1H),6.93(d,J=8.5Hz,1H ),6.79(d,J=7.5Hz,1H),5.32–5.19(m,2H),4.57(dqd,J=9.9,6.3,3.3Hz,1H),2.96–2.81(m,2H),1.49(d, J=6.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ 162.6 ( 13 C-enriched),160.2,142.2,136.7,134.4, 128.7,127.9,126.9,119.7(d,J=3.6Hz),114.6(d,J=70.2Hz),113.0(d,J=3.0Hz),7 4.2(d,J=1.9Hz),70.7,36.3(d,J=3.2Hz),20.9(d,J=2.6Hz); HRMS(ESI-TOF):calc'd for C 17 [ 13 C]H 16 NaO3[M+Na + ]292.1025, found 292.1025; HPLC: Daicel ChiralpakAD column, 25% i PrOH in n hexane, 1 mL / min, λ = 320 nm, t R (major) = 15.264 min, t R (minor)undetected; -149.01 (c 0.20, CHCl3).

[0090] Based on Example 1, synthesized 13The reaction equation for C-labeled dihydroisoquinolinones is as follows:

[0091]

[0092] Example 15: Preparation of compound L-14

[0093]

[0094] In a glove box, palladium acetate (4.5 mg, 0.02 mmol), 2-biscyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl (15.6 mg, 0.04 mmol), and dried N-methylpyrrolidone (0.5 mL) were added to the carbon monoxide consumption chamber of a dry, magnetically stirred double-chamber reaction tube. After pre-stirring the catalyst and ligands for half an hour, potassium carbonate (27.6 mg, 0.2 mmol), (1S,2S,4S)-2-norbornene-5,6-ethylenediamidequinoline (29.4 mg, 0.1 mmol), and 2-methyliodobenzene (43.6 mg, 0.2 mmol) were added. In the carbon monoxide generation chamber, palladium acetate (4.5 mg, 0.02 mmol), 2-biscyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl (15.6 mg, 0.04 mmol), and dried N-methylpyrrolidone (0.5 mL) were added. 13 C-labeled phenyl 4-trifluoromethylformate (76 mg, 0.4 mmol), triethylamine (24.3 mg, 0.24 mmol), and dried 1,4-dioxane (1.0 mL) were added to the carbon monoxide consumption chamber. Finally, aziridine (47 mg, 0.6 mmol) was dissolved in dried N-methylpyrrolidone (1.0 mL) and slowly added to the chamber using a syringe pump with parameters set for 5 h. The mixture was reacted at 60 °C under an argon atmosphere for 16 h. The mixture in the carbon monoxide consumption chamber was extracted with ethyl acetate and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The final product was purified by column chromatography to give compound L-14 (pale yellow solid, 72% yield). 1 H NMR (400MHz, CDCl3) δ7.96 (d, J=8.4Hz, 2H), 7.30 (dd, J= 17.4,7.9Hz,3H),7.10(d,J=7.6Hz,1H),7.03(d,J=7.5Hz,1H),4.20–4.16(m,2H),3.04(t,J=6.1Hz,2H),2.54(s,3H),2.42(s,3H); 13 C NMR (100MHz, CDCl3) δ 164.0 ( 13C-enriched), 144.6,142.7(d,J=2.7Hz),140.5(d,J=1.7Hz),136.9,132.5,131.4(d,J=4.4Hz),129.5, 128.6, 126.9 (d, J = 65.9Hz), 125.4 (d, J = 3.6Hz), 44.8, 30.3 (d, J = 2.7Hz), 22.6, 21.8; HRMS (ESI-TOF):calc'd for C 17 [ 13 C]H 17 NaNO3S[M+Na + ]339.0852, found 339.0856.

[0095] Example 16: Preparation of compound I-15

[0096]

[0097] The procedure was the same as in Example 15, except that the aziridine used was as shown (50.7 mg), and trifluoroethanol (60 mg, 3.0 equiv) was added to give compound L-15 (white solid, 53% yield). 1 H NMR (400MHz, CDCl3) δ7.98(d,J=8.4Hz,2H),7.31(t,J=7.9Hz,3H),7.10(d,J=7.6Hz,1H),7.02(d,J=7.5Hz,1H),5.06(ddt,J=10.6,8.6,3. 3Hz,1H),3.39(dd,J=15.8,5.6Hz,1H),2.76(dd,J=15.7,2.1Hz,1H),2.55(s,3H),2.42(s,3H),1.31(d,J=6.7Hz,3H); 13 C NMR (100MHz, CDCl3) δ 163.4 ( 13 C-enriched),144.5,142.3(d,J=2.8Hz),138.0(d,J=1.7Hz),137.3,132.7,131.4(d,J=4.5 Hz),129.5,128.7,126.7-126.2(m),51.4,36.4(d,J=3.1Hz),22.5,21.8,20.2; HRMS(ESI-TOF):calc'd for C 12 [ 13 C]H 15 NaNO3S[M+Na +]353.1009, found 353.1012.

[0098] Example 17: Preparation of compound L-16

[0099]

[0100] The procedure was the same as in Example 15, except that the aziridine used was as shown (81.9 mg), and trifluoroethanol (60 mg, 3.0 equiv) was added to give compound L-16 (white solid, 54% yield). 1 H NMR (400MHz, CDCl3) δ7.98(d,J=8.4Hz,2H),7.30(dd,J=18.0,7.8Hz,3H),7.08(d,J=7.6Hz,1H),7.01(d,J=7.5H z,1H),4.86(tt,J=8.0,4.2Hz,1H),3.81(dd,J=9.8,4.7Hz,1H),3.45(t,J=9.5Hz,1H),3.20 (d,J=3.8Hz,2H),2.55(s,3H),2.42(s,3H),0.82(s,9H),-0.06(d,J=38.6Hz,6H); 13 C NMR (100MHz, CDCl3) δ 163.6 ( 13 C-enriched),144.6,142.0(d,J=2.8Hz),137.8(d,J=1.9Hz), 137.3, 132.6, 131.3 (d, J = 4.7Hz), 129.5, 128.7, 126.7 (d, J = 66.0Hz), 126.4 (d, J = 3.7Hz), 62.8,55.8,30.6(d,J=3.2Hz),25.9,22.5,21.8,18.3,-5.3,-5.5; HRMS(ESI-TOF):calc'd for C 24 [ 13 C]H 33 NaNO4SSi[M+Na + ]483.1818, found 483.1819.

[0101] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any modifications, equivalent substitutions, and improvements made by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the invention.

Claims

1. A kind 13 A method for synthesizing C-labeled isochoric ketone compounds, characterized in that: Includes the following steps: Under a protective gas atmosphere, aryl iodide and compound M are used as starting materials. In the presence of palladium catalyst E, phosphine ligand F, norbornene derivative G and base H, compound D and base J are stirred in organic solvent I with carbon monoxide generated in solvent K until complete. The reaction temperature is 40-100℃. After the reaction is completed, the reactants are separated to obtain the isochromic ketone compound or dihydroisoquinoline ketone compound shown in formula L. The reaction equation is as follows: Among them, R 1 R is one or more of alkyl, aryl, ester, amide, alkoxy, benzyloxy, tert-butoxycarbonyl, and halogen. 1 The substitution positions on the aromatic ring are limited to positions 2-5; R 2 It is one or more of hydrogen, alkyl, aryl, ester, hydroxyl, amide, alkoxy, benzyloxy, halogen, haloalkyl, and tert-butyldimethylsiloxy; R 3 It is one or more of alkyl, aryl, and sulfonyl groups; Wherein, the palladium catalyst E is any one or more of Pd(PPh3)4, Pd(dba)2, Pd2(dba3), Pd(OAc)2, Pd(PhCN)2Cl2, Pd(MeCN)2Cl2, PdCl2, PdI2, and [Pd(allyl)Cl]2; The phosphine ligand F is 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl or 2-bicyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl; The norbornene derivative G is (1S,2S,4S)-2-norbornene-5-formylaniline or (1S,2S,4S)-2-norbornene-5,6-ethylenediamide biphenyl or (1S,2S,4S)-2-norbornene-5,6-ethylenediamide quinoline. The base H is potassium acetate or potassium carbonate; The organic solvent I is N-methylpyrrolidone; The base J is triethylamine.

2. The method according to claim 1, characterized in that: Solvent K is methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dimethyl ethylenediether, methyl tert-butyl ether, 1,4-dioxane, 1,3-dioxane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, C 4-12 Saturated alkanes, C 3-12 Fluorinated or chlorinated alkanes, benzene, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, N , N -Dimethylformamide, N , N -Dimethylacetamide, acetone, N -Methylpyrrolidone, acetonitrile, C 3-12 Any one or more of the saturated alkyl nitriles.

3. The synthesis method according to claim 1, characterized in that, It also includes the following steps: In an air environment, base A, methanesulfonyl chloride B, 4-trifluoromethylphenol, and H... 13 Using CO2Na as the starting material, the reaction is carried out in organic solvent C with low-temperature stirring until complete. After the reaction is completed, the reactants are filtered, separated, and purified to obtain the product shown in formula D. 13 C-labeled p-trifluoromethylformate arylate compound; the reaction temperature is below 5°C, and the reaction time is 12-24 h; the molar ratio of each raw material is alkali A: methanesulfonyl chloride B: 4-trifluoromethylphenol: H 13 CO2Na = 1.0:1.0:1.0:1.0; The D is .

4. The synthesis method according to claim 3, characterized in that, The base A is any one or more of sodium formate, sodium acetate, potassium acetate, sodium tert-butoxide, sodium carbonate, sodium methoxide, and sodium hydroxide.

5. The synthesis method according to claim 3, characterized in that: The solvent C is tetrahydrofuran, 1,4-dioxane, N , N - any one or more of dimethylformamide, toluene, and acetonitrile.

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