Preparation methods of unsaturated nitrile, N-15 labeled unsaturated nitrile and N-15 labeled rilpivirine

Abstract

The invention discloses a method for preparing an unsaturated nitrile, an N-15 labeled unsaturated nitrile and an N-15 labeled rilpivirine, using an N-15 ammonium salt or a common ammonium salt as a nitrogen source, and directly oxidizing to obtain an unsaturated nitrile or an N-15 labeled unsaturated nitrile in the presence of an oxidant; 2,6-dimethylaniline is synthesized using the synthesis method of the unsaturated nitrile, and starting from 2,6-dimethylaniline, N-15 labeled rilpivirine is synthesized using a five-step reaction. The present invention can achieve the synthesis of N-15 labeled unsaturated nitrile and N-15 labeled rilpivirine, and the raw materials used by the method are all simple and easy to obtain, and can be synthesized in a public commercial channel or according to the synthetic method reported in the literature, and the method is simple to operate, has a short reaction time, is easy to post-process, and is insensitive to water and air.

Description

Technical Field

[0001] The invention belongs to the field of organic compound synthesis, and particularly relates to a preparation method of an unsaturated nitrile, an N-15 labeled unsaturated nitrile and an N-15 labeled rilpivirine. Background Art

[0002] Numerous methods for the synthesis of α,β-unsaturated nitriles have been reported, including oxidation of phenylpropenylamine (Org. Lett. 2014, 16, 6484–6487); oxidation of phenylpropenol with ammonia in the presence of ruthenium (ACS Catal. 2020, 10, 6299–6308); and reaction of cinnamaldehyde with NH₂OH·HCl (Tetrahedron Lett. 2012, 53, 882–885). A number of other methods have been reported, but none are suitable for the synthesis of N-15-labeled substrates.

[0003] Rilpivirine, also known as Eckmmt, is a non-nucleoside reverse transcriptase inhibitor that is usually used in combination with other antiretroviral drugs for the treatment of human immunodeficiency virus (HIV) infection (anti-AIDS drugs). Its molecular structure is as follows:

[0004]

[0005] As an unsaturated nitrile, rilpivirine has been reported in many synthetic methods. In 2016, Liu Xinyong et al. reported a method for synthesizing rilpivirine via Heck reaction and microwave irradiation (201610352775.4). The synthetic route is as follows:

[0006]

[0007] In 2021, Strotman et al. discovered that, under the catalysis of metallic nickel, C-13-labeled Zn(CN)2 could exchange with CN in organic structures, thereby synthesizing C-13-labeled rilpivirine (J.Am.Chem.Soc.2021,143,4817-4823). However, there are currently no reports on N-15-labeled rilpivirine. Summary of the Invention

[0008] The present invention is proposed to overcome the shortcomings of the prior art, and its purpose is to provide a preparation method of an unsaturated nitrile, an N-15 labeled unsaturated nitrile and an N-15 labeled rilpivirine.

[0009] The present invention is achieved through the following technical solutions:

[0010] A method for preparing an unsaturated nitrile comprises: mixing a conjugated diene, a nitrogen source, a base, a solvent and water, adding an oxidant, and separating, purifying and drying the unsaturated nitrile after the reaction is completed;

[0011] The structure of the conjugated diene is as follows:

[0012]

[0013] The structure of the unsaturated nitrile is as follows:

[0014]

[0015] In the above technical solution, the R 1 、R 2 、R 3 phenyl, hydrogen, o-methylphenyl, m-methylphenyl, p-methylphenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, o-iodophenyl, m-iodophenyl, p-iodophenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl, p-trifluoromethylphenyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, dimethyl Phenyl, difluorophenyl, dichlorophenyl, dibromophenyl, trimethylphenyl, trifluorophenyl, trichlorophenyl, tribromophenyl, naphthalene-1-yl, naphthalene-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, 1-phthalamidophenyl, 2-phthalamidophenyl, 3-phthalamidophenyl, p-benzyloxyamidobenzene, methyl, phenethyl, phenylpropyl, straight-chain or branched alkyl groups having 1 to 20 carbon atoms, cyclopentyl or cyclohexyl.

[0016] In the above technical solution, the nitrogen source is an ammonium salt; the ammonium salt is ammonium chloride, ammonium formate, ammonium carbonate, ammonium sulfate, urea, ammonium nitrate or ammonium phosphate.

[0017] In the above technical solution, the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide or potassium phosphate, preferably cesium carbonate, sodium hydride, potassium tert-butoxide or potassium carbonate.

[0018] In the above technical solution, the oxidant is a hypervalent iodine compound; the hypervalent iodine compound is diacetoxyphenyl iodide (PIDA) or bis(trifluoroacetoxyphenyl iodide) (PIFA).

[0019] In the above technical solution, the solvent is trifluoroethanol, methanol, ethanol, isopropanol, tetrahydrofuran or acetonitrile, preferably an alcohol solvent.

[0020] In the above technical solution, the molar ratio of the oxidant to the conjugated diene is 1:(1-10), preferably 1:(2-4); the molar ratio of the nitrogen source to the conjugated diene is 1:(1-10), preferably 1:(1-6); the molar ratio of the base to the conjugated diene is 1:(1-10), preferably 1:(2-6); the molar ratio of the water to the conjugated diene is (0-1):10, preferably 1:(1-5); the amount of the solvent is 2-20 mL (corresponding to a conjugated diene concentration of 0.04 mol / L to 0.4 mol / L).

[0021] In the above technical solution, the reaction temperature is -20°C to 50°C, preferably 0°C; and the reaction time is 1h to 10h.

[0022] A method for preparing an N-15 labeled unsaturated nitrile comprises: mixing a conjugated diene, an N-15 labeled nitrogen source, a base, a solvent, and water; adding an oxidant; and separating, purifying, and drying to obtain the N-15 labeled unsaturated nitrile after the reaction is completed.

[0023] The structure of the conjugated diene is as follows:

[0024]

[0025] The structure of the unsaturated nitrile is as follows:

[0026]

[0027] In the above technical solution, the R 1 、R 2 、R 3 phenyl, hydrogen, o-methylphenyl, m-methylphenyl, p-methylphenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, o-iodophenyl, m-iodophenyl, p-iodophenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl, p-trifluoromethylphenyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, dimethyl Phenyl, difluorophenyl, dichlorophenyl, dibromophenyl, trimethylphenyl, trifluorophenyl, trichlorophenyl, tribromophenyl, naphthalene-1-yl, naphthalene-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, 1-phthalamidophenyl, 2-phthalamidophenyl, 3-phthalamidophenyl, p-benzyloxyamidobenzene, methyl, phenethyl, phenylpropyl, straight-chain or branched alkyl groups having 1 to 20 carbon atoms, cyclopentyl or cyclohexyl.

[0028] In the above technical solution, the N-15 labeled nitrogen source is an N-15 labeled ammonium salt; the N-15 labeled ammonium salt is N-15 labeled ammonium chloride, N-15 labeled urea, N-15 labeled ammonium formate, N-15 labeled ammonium carbonate, N-15 labeled ammonium sulfate, N-15 labeled ammonium nitrate or N-15 labeled ammonium phosphate, preferably N-15 labeled ammonium chloride.

[0029] In the above technical solution, the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide or potassium phosphate, preferably cesium carbonate, sodium hydride, potassium tert-butoxide or potassium carbonate.

[0030] In the above technical solution, the oxidant is a hypervalent iodine compound; the hypervalent iodine compound is diacetoxyphenyliodide (PIDA) or bis(trifluoroacetoxyphenyliodide) (PIFA);

[0031] In the above technical solution, the solvent is trifluoroethanol, methanol, ethanol, isopropanol, tetrahydrofuran or acetonitrile, preferably an alcohol solvent.

[0032] In the above technical solution, the molar ratio of the oxidant to the conjugated diene is 1:(1-10), preferably 1:(2-4); the molar ratio of the N-15 labeled nitrogen source to the conjugated diene is 1:(1-10), preferably 1:(1-6); the molar ratio of the base to the conjugated diene is 1:(1-10), preferably 1:(2-6); the molar ratio of the water to the conjugated diene is (0-1):10, preferably 1:(1-5); and the concentration of the conjugated diene after the solvent is added is 0.04 mol / L to 0.4 mol / L.

[0033] In the above technical solution, the reaction temperature is -20°C to 50°C, preferably 0°C; and the reaction time is 1h to 10h.

[0034] A method for preparing N-15 labeled rilpivirine is synthesized according to the following synthetic route:

[0035]

[0036] In the above technical solution, the protecting group R is tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-methoxybenzyl (PMB), fluorenylmethyloxycarbonyl (Fmoc), phthaloyl (Pht), p-toluenesulfonyl (Tos), trityl (Trt) or trifluoroacetyl, preferably Cbz protection.

[0037] In the above technical solution, the compound (IV) is prepared by the method described in claim 4.

[0038] In the above technical scheme, the compound (V) is obtained by reacting the compound (IV) with a catalyst in an acidic solvent; the acidic solvent is any one of sulfuric acid, hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, acetic acid, formic acid, propionic acid or oxalic acid; the catalyst is a palladium-carbon catalyst or hydrobromic acid; when a palladium-carbon catalyst is used, the reaction is carried out under a hydrogen atmosphere; the reaction temperature is room temperature; the molar ratio of the compound (IV) to the acidic reagent is 1:(1 to 20); and the reaction time is 1 hour to 24 hours.

[0039] In the above technical scheme, the compound (VII) is obtained by heating the compound (V) and the compound (VI) under the action of an auxiliary agent; the auxiliary agent is an inorganic base or an organic amine, and the inorganic base is any one of potassium carbonate, cesium carbonate, lithium carbonate, potassium phosphate or lithium phosphate; the organic amine is any one of triethylamine, tributylamine or diisopropylethylamine; the heating method is electric heating or microwave heating; the reaction temperature is 10°C to 100°C; when the heating method is electric heating, the reaction time is 1h to 24h; when the heating method is microwave heating, the reaction time is 1h to 6h; the molar ratio of compound (V) to compound (VI) in the reaction is 1:(0.1 to 10); the molar ratio between the auxiliary agent and compound (V) is (1 to 10):1.

[0040] The beneficial effects of the present invention are:

[0041] The present invention provides a method for preparing an unsaturated nitrile, an N-15-labeled unsaturated nitrile, and an N-15-labeled rilpivirine. The method comprises using an N-15 ammonium salt or a common ammonium salt as a nitrogen source, and directly oxidizing the unsaturated nitrile or the N-15-labeled unsaturated nitrile in the presence of a certain oxidant. 2,6-dimethylaniline is synthesized using the method for synthesizing the unsaturated nitrile, and starting from 2,6-dimethylaniline, N-15-labeled rilpivirine is synthesized in a five-step reaction. The raw materials used in the method of the present invention are all simple and easily available and can be synthesized from public commercial channels or according to synthesis methods reported in the literature. The method of the present invention is simple to operate, has a good preparation yield, a short reaction time, simple post-processing, and is insensitive to water and air. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 This is the H NMR spectrum of the N-15 labeled unsaturated nitrile prepared in Example 1 of the present invention;

[0043] Figure 2 This is the NMR carbon spectrum of the N-15 labeled unsaturated nitrile prepared in Example 1 of the present invention;

[0044] Figure 3 This is the NMR nitrogen spectrum of the N-15 labeled unsaturated nitrile prepared in Example 1 of the present invention;

[0045] Figure 4 This is the H NMR spectrum of the N-15 labeled p-trifluoromethyl unsaturated nitrile prepared in Example 2 of the present invention;

[0046] Figure 5 This is the NMR fluorine spectrum of the N-15 labeled trifluoromethyl unsaturated nitrile prepared in Example 2 of the present invention;

[0047] Figure 6 This is the NMR carbon spectrum of the N-15 labeled trifluoromethyl unsaturated nitrile prepared in Example 2 of the present invention;

[0048] Figure 7 This is the NMR nitrogen spectrum of the N-15 labeled trifluoromethyl unsaturated nitrile prepared in Example 2 of the present invention;

[0049] Figure 8 This is the H NMR spectrum of the N-15 labeled p-bromounsaturated nitrile prepared in Example 3 of the present invention;

[0050] Figure 9 This is the NMR carbon spectrum of the N-15 labeled p-bromounsaturated nitrile prepared in Example 3 of the present invention;

[0051] Figure 10 This is the NMR nitrogen spectrum of the N-15 labeled p-bromounsaturated nitrile prepared in Example 3 of the present invention;

[0052] Figure 11 This is the H NMR spectrum of N-15 labeled rilpivirine prepared in Example 4 of the present invention;

[0053] Figure 12 This is the NMR carbon spectrum of N-15 labeled rilpivirine prepared in Example 4 of the present invention;

[0054] Figure 13 This is the nuclear magnetic nitrogen spectrum of N-15 labeled rilpivirine prepared in Example 4 of the present invention. DETAILED DESCRIPTION

[0055] In order to enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be further described below with reference to the accompanying drawings and through specific implementation methods.

[0056] Example 1: Synthesis of N-15 labeled unsaturated nitrile

[0057] In a 15 mL pressure tube, 65 mg of phenylbutadiene (0.5 mmol), 54 mg of N-15 labeled ammonium chloride (1 mmol), and 326 mg of cesium carbonate (1 mmol) were added. 6 mL of trifluoroethanol and 18 μL of water (1 mmol) were then added. Under an ice-water bath, 322 mg of PIDA (1 mmol) was added and stirred at 0°C for 4 h. After the reaction, 15 mL of trifluoroethanol was added to wash the reaction mixture. The mixture was extracted with dichloromethane (5 mL x 2), and the organic phase was dried over anhydrous sodium sulfate. Column chromatography was performed to remove PhI using PE, followed by purification using n-pentane / diethyl ether. After concentration under reduced pressure at low temperature, 38 mg of N-15 labeled cinnamonitrile was obtained with a molar yield of 58%.

[0058] like Figure 1 As shown: 1 H NMR (400MHz, CDCl3) δ (ppm): 7.48-7.35 (m, 6H), 5.87 (dd, J = 16.8, 1.6Hz, 1H).

[0059] like Figure 2 As shown: 13 C NMR (101MHz, CDCl3) δ (ppm): 150.6, 133.5, 131.2, 129.1, 127.4, 118.1 (d, J = 18.2Hz), 96.3 (d, J = 3.4Hz).

[0060] like Figure 3 Shown: 15N NMR (71MHz, CDCl3) δ (ppm): 257.0.

[0061] Example 2: Synthesis of N-15 labeled p-trifluoromethylcinnamonitrile

[0062] In a 15 mL pressure tube, 99 mg of phenylbutadiene (0.5 mmol), 54 mg of N-15 labeled ammonium chloride (1 mmol), and 326 mg of cesium carbonate (1 mmol) were added. 6 mL of trifluoroethanol and 18 μL of water (1 mmol) were then added. 322 mg of PIDA (1 mmol) was then added under ice-water bath and stirred at 0°C for 4 h. After the reaction, 15 mL of trifluoroethanol was added to wash the reaction mixture, followed by extraction with dichloromethane (5 mL x 2). The organic phase was dried over anhydrous sodium sulfate. Purification by column chromatography was performed, first using PE to remove PhI, followed by purification using n-pentane / diethyl ether as the eluent. After concentration under reduced pressure at low temperature, 45 mg of N-15 labeled p-trifluoromethylphenyl acrylonitrile was obtained, yielding 45% molar yield.

[0063] like Figure 4Shown: 1H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.73-7.67 (m, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 16.8 Hz, 1H), 5.98 (dd, J = 16.8, 1.6 Hz, 1H).

[0064] like Figure 5 Shown: 19F NMR (377 MHz, CDCl3) δ (ppm): -63.0.

[0065] like Figure 6 As shown: 13C NMR (101 MHz, CDCl 3 ) δ (ppm): 148.8, 134.2, 131.7 (q, J = 32.8 Hz), 130.4, 129.8, 127.6 (q, J = 4.1 Hz), 124.0 (q, J = 4.1 Hz), 123.5 (q, J = 273.4 Hz), 117.4 (d, J = 18.1 Hz), 98.6 (d, J = 3.4 Hz).

[0066] like Figure 7 Shown: 15N NMR (71MHz, CDCl3) δ (ppm): 259.5.

[0067] Example 3: Synthesis of N-15 labeled p-bromounsaturated nitrile

[0068] In a 200 mL pressure tube, 1.05 g of p-bromophenylbutadiene (5 mmol), 540 mg of N-15 labeled ammonium chloride (10 mmol), and 3.26 g of cesium carbonate (10 mmol) were added. 60 mL of trifluoroethanol and 180 μL of water (10 mmol) were then added. Under an ice-water bath, 3.22 g of PIDA (1 mmol) was added and stirred at 0°C for 4 h. After the reaction, 100 mL of trifluoroethanol was added to wash the reaction mixture. The mixture was extracted with dichloromethane (5 mL x 2), and the organic phase was dried over anhydrous sodium sulfate. Purification by column chromatography, first using PE to remove PhI, was followed by purification using n-pentane / diethyl ether as the eluent. After concentration under reduced pressure at low temperature, 428 mg of N-15 labeled p-bromophenyl acrylonitrile was obtained with a molar yield of 41%.

[0069] like Figure 8 Shown: 1H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.54 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 16.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 5.88 (dd, J = 16.4, 1.6 Hz, 1H).

[0070] like Figure 9As shown: 13C NMR (101 MHz, CDCl 3 ) δ (ppm): 149.2, 132.4, 128.7, 125.7, 117.8 (d, J = 18.2 Hz), 97.1 (d, J = 3.4 Hz).

[0071] like Figure 10 Shown: 15N NMR (71MHz, CDCl3) δ (ppm): 258.3.

[0072] Example 4: Synthesis of N-15 labeled rilpivirine

[0073] (1) Synthesis of N-15 labeled 2-(3,5-dimethyl-4-benzyloxyamido)phenylacrylonitrile (IV)

[0074]

[0075] 215 mg of 4-butadienyl-2,6-dimethylcarbamic acid benzyl ester (0.7 mmol, 1.0 equiv) and 76 mg of 15 N-labeled ammonium chloride (1.4 mmol, 2.0 equiv) and 456 mg of cesium carbonate (1.4 mmol, 1.0 equiv) were added to 9 mL of trifluoroethanol and 25 μL of water (25 mg, 1.4 mmol, 2.0 equiv). Then, 451 mg of PIDA (1.4 mmol, 2.0 equiv) was added under ice-water bath and stirred at 0°C for 6 h. After the reaction, 15 mL of water was added to wash the trifluoroethanol, followed by extraction with dichloromethane (5 mL x 2). The organic phase was dried over anhydrous sodium sulfate. Purification by column chromatography, first with PE to remove PhI, then with PE / EtOAc (8 / 1) as the eluent, afforded 85 mg of N-15-labeled 2-(3,5-dimethyl-4-benzyloxyamido)phenylacrylonitrile as a white solid in a 35% yield.

[0076] HRMS(ESI)calcd for [M+H,C 19 H 18 N 15 NO2] + :308.1412,found 308.1413.

[0077] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.45-7.30 (m, 5H), 7.28 (d, J = 16.4Hz, 1H), 7.14 (s,2H),6.26(s,1H),5.79(dd,J=16.8,1.6Hz,1H),5.18(s,2H),2.25(s,6H).

[0078] 13 C NMR (101MHz, CDCl3) δ (ppm): 150.0, 136.6, 136.5, 136.5, 136.1, 132.1, 128.6, 128.4, 128.2, 127.3, 118.2 (d, J = 18.3Hz), 96.2, 67.4, 18.5.

[0079] 15 N NMR (71MHz, CDCl3) δ (ppm): 256.8.

[0080] (2) Synthesis of N-15 labeled 2-(3,5-dimethyl-4-amino)phenyl acrylonitrile

[0081]

[0082] 71 mg of N-15 labeled 2-(3,5-dimethyl-4-benzyloxyamido)phenylacrylonitrile (0.23 mmol) was added to the reaction tube and N2 was replaced. 0.31 mL of glacial acetic acid and 0.52 mL of acetic acid solution of hydrogen bromide (33%) were added in sequence. The mixture was stirred at room temperature for 1.5 h. After the reaction was completed, filtration was performed to obtain 30 mg of a light yellow solid with a yield of 52%.

[0083] (3) Synthesis of N-15-labeled rilpivirine

[0084]

[0085] Add 24 mg of N-15-labeled 2-(3,5-dimethyl-4-amino)phenylacrylonitrile (0.094 mmol) and 24 mg of 4-(4-chloropyrimidin-2-amino)benzonitrile (0.1 mmol) to a microwave-safe tube and heat at 140°C for 2 h. After reaction, cool to room temperature, adjust pH to 8 with 10% K2CO3 solution, filter, and wash with acetonitrile to obtain 12 mg of a white solid (34% yield). Melting point: 175–177°C.

[0086] like Figure 11 As shown: 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.60 (s, 1H), 9.02 (s, 1H), 8.02 (d, J = 6Hz, 1H), 7.64 (d ,J=16.8Hz,1H),7.49(s,2H),7.42(s,2H),6.47(dd,J=16.8,1.8Hz,1H),2.17(s,6H).

[0087] like Figure 12 As shown: 13C NMR(151MHz,DMSO-d6)δ(ppm):162.17,159.64,150.82,145.99,136.96,133.57,132.98,12 7.89,120.17,119.46(d,J=17.2Hz),119.21,118.54,118.32,101.79,98.95,96.61,18.77.

[0088] like Figure 13 As shown: 15 N NMR(61MHz,DMSO-d6)δ(ppm):258.9.

[0089] Reaction principle of the present invention:

[0090] 1. Synthesis of unsaturated nitriles and N-15 labeled unsaturated nitriles

[0091] Using conjugated diene as raw material, ordinary ammonium salt or N-15 ammonium salt as nitrogen source, direct oxidation in the presence of a certain oxidant to obtain unsaturated nitrile or N-15 labeled unsaturated nitrile, the route is as follows:

[0092]

[0093] 2. Synthesis of N-15-labeled Rilpivirine

[0094] Starting from 2,6-dimethylaniline, N-15-labeled rilpivirine was synthesized in five steps. The route is as follows:

[0095]

[0096] The applicant declares that the above is only a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention fall within the scope of protection and disclosure of the present invention.

Claims

1. A method for preparing an N-15 labeled unsaturated nitrile, characterized in that: The conjugated diene, N-15 labeled nitrogen source, base, solvent and water are mixed, and then an oxidant is added. After the reaction is completed, the N-15 labeled unsaturated nitrile is obtained by separation, purification and drying. The conjugated diene is phenylbutadiene, p-bromophenylbutadiene or 4-butadienyl-2,6-dimethylbenzylcarbamate; The unsaturated nitrile is N-15 labeled cinnamononitrile, N-15 labeled p-bromophenyl acrylonitrile or N-15 labeled 2-(3,5-dimethyl-4-benzyloxyamide)phenyl acrylonitrile; The N-15 labeled nitrogen source is an N-15 labeled ammonium salt; the N-15 labeled ammonium salt is N-15 labeled ammonium chloride, N-15 labeled urea, N-15 labeled ammonium formate, N-15 labeled ammonium carbonate, N-15 labeled ammonium sulfate, N-15 labeled ammonium nitrate or N-15 labeled ammonium phosphate; The base is sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide or potassium phosphate; The oxidant is a hypervalent iodine compound; the hypervalent iodine compound is PIDA or PIFA; The solvent is trifluoroethanol, methanol, ethanol, isopropanol, tetrahydrofuran or acetonitrile.

2. The method for preparing N-15 labeled unsaturated nitrile according to claim 1, wherein: The molar ratio of the oxidant to the conjugated diene is 1:(1-10); the molar ratio of the N-15 labeled nitrogen source to the conjugated diene is 1:(1-10); the molar ratio of the base to the conjugated diene is 1:(1-10); the molar ratio of the water to the conjugated diene is (0-1):10; the concentration of the conjugated diene is 0.04 mol / L-0.4 mol / L; the reaction temperature is -20 o C~50 o C; the reaction time is 1h~10h.

3. A method for preparing N-15 labeled rilpivirine, characterized in that: Synthesized according to the following synthetic route: ； The protecting group R is tert-butyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyl, p-methoxyphenyl, fluorenylmethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trityl or trifluoroacetyl; The hypervalent iodine compound is PIDA or PIFA; The solvent is trifluoroethanol; The compound (IV) is prepared by the method according to claim 1.

4. The method for preparing N-15 labeled rilpivirine according to claim 3, characterized in that: The compound (V) is obtained by reacting the compound (IV) with a catalyst in an acidic solvent; the acidic solvent is any one of sulfuric acid, hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, acetic acid, formic acid, propionic acid or oxalic acid; the catalyst is a palladium-carbon catalyst or hydrobromic acid; when a palladium-carbon catalyst is used, the reaction is carried out under a hydrogen atmosphere; the reaction temperature is room temperature; the molar ratio of the compound (IV) to the acidic reagent is 1:(1-20); and the reaction time is 1h-24h; The compound (VII) is obtained by heating the compound (V) and the compound (VI) in the presence of an auxiliary agent; the auxiliary agent is an inorganic base or an organic amine, and the inorganic base is any one of potassium carbonate, cesium carbonate, lithium carbonate, potassium phosphate or lithium phosphate; the organic amine is any one of triethylamine, tributylamine or diisopropylethylamine; the heating method is electric heating or microwave heating; the reaction temperature is 10°C to 100°C; when electric heating is used, the reaction time is 1h to 24h; when microwave heating is used, the reaction time is 1h to 6h; in the reaction, the molar ratio of the compound (V) to the compound (VI) is 1:(0.1-10); and the molar ratio between the auxiliary agent and the compound (V) is (1-10):1.

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