Deuterated alkenyl furan compound and preparation method thereof

Abstract

The invention provides a deuterated alkenyl furan compound and a preparation method thereof. The deuterated olefin furan compound comprises a furan ring, a deuterated alkenyl group (the deuteration rate is 94%) and a carbonyl group, can be derived and converted in multiple directions, and has structural novelty. The preparation method comprises the following steps: reacting an eneyne ketone compound with deuterated alkenyl azide (the deuteration rate is 94%) under the catalysis of zinc to generate the deuterated alkenyl furan compound. The synthetic method has the advantages of simple and efficient preparation process, no heavy metal residue risk, no need of acid-base assistance, no equipment corrosion hidden danger, 100% deuteration conversion, high deuteration rate (94%) of the product, and potential industrial application value. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and particularly relates to a deuterated alkenylfuran compound and a preparation method thereof. Background Art

[0002] The efficient synthesis of selectively deuterated compounds is a key focus in modern organic synthesis and applied research. The introduction of deuterium into drugs can improve their pharmacokinetic properties and reduce their toxicity. Deuterated tracers play a crucial role in drug metabolism analysis and reaction mechanism studies. Therefore, the development of simple and efficient synthetic methods has important synthetic applications. Traditionally, the synthesis of deuterated alkenyls relies on carbonyl-deuterated Wittig olefination reactions, which require the use of strong bases to form Wittig reagents. These methods are characterized by harsh conditions and poor functional group compatibility. Therefore, the development of novel, mild, and efficient methods for the synthesis of deuterated alkenyls is of great value and significance.

[0003] The present invention provides a simple and rapid method for preparing deuterated alkenylfuran compounds in one step by reacting an enynone compound with a deuterated alkenyl azide. This method is simple and efficient, operates under neutral reaction conditions, eliminates the risk of equipment corrosion, and features a simple purification process. The method also achieves a high deuteration rate, achieving 100% deuterium conversion, and has potential industrial applications. Summary of the Invention

[0004] One of the purposes of the present invention is to disclose a deuterated alkenyl furan compound, which has a furan ring, a carbonyl substituent and a deuterated terminal olefin in its structure, can be multi-directionally derivatized and transformed, and has a novel structure.

[0005] Another object of the present invention is to disclose a method for preparing a deuterated alkenylfuran compound. This method utilizes readily available, inexpensive raw materials and allows for modular preparation, allowing for the one-step construction of a deuterated alkenylfuran compound. Furthermore, the synthesized deuterated alkenylfuran compound is molecule-compatible with carbonyl substituents.

[0006] The present invention is an original method for synthesizing deuterated alkenylfuran compounds, which has not been reported in the literature before the application date.

[0007] A deuterated alkenylfuran compound having the following characteristics:

[0008] Where: R 1 , R 2 All are C1~C 12 Alkyl, aryl, heteroaryl; R 1 Any one or more hydrogen atoms on the aromatic ring may be replaced by a substituent; R 1 , R 2 To connect or not to connect;

[0009] Where: R3 C1~C 12 alkyl, aryl or heteroaryl; wherein R 3 Any one or more hydrogen atoms of the upper aromatic ring may be replaced by a substituent;

[0010] The present invention is achieved through the following technical solutions:

[0011] Under nitrogen protection, the enynone compound 1 is dissolved in a solvent, a catalyst and a deuterated alkenyl azide 2 are added, and after the reaction, the deuterated alkenyl furan compound 3 is separated and purified.

[0012] Where: R 1 , R 2 All are C1~C 12 Alkyl, aryl, heteroaryl; R 1 , R 2 Any one or more hydrogen atoms on the aromatic ring may be replaced by a substituent; R 1 , R 2 To connect or not to connect;

[0013] Where: R 3 C1~C 12 alkyl, aryl or heteroaryl; wherein R 3 Any one or more hydrogen atoms of the upper aromatic ring may be replaced by a substituent;

[0014] Where: R is C1~C 12 Alkyl, aryl and heteroaryl; any one or more hydrogen atoms of the aromatic ring on R may be replaced by a substituent;

[0015] The catalyst is one of Zn(OTf)2, ZnF2, ZnCl2, ZnBr2, and ZnI2; the preferred catalyst is ZnCl2;

[0016] The molar ratio of the metal catalyst to the alkenyl ketone compound is preferably 0.001 to 1:1, preferably 0.1:1.

[0017] The molar ratio of the deuterated alkenyl azide to the alkenyl ketone compound is 1 to 10:1, preferably 1.5:1.

[0018] The solvent is selected from the group consisting of 1,2-dichloroethane, 1,1-dichloromethane, chloroform, carbon tetrachloride, trifluorotoluene, 1,4-dioxane, acetonitrile, toluene, chlorobenzene, and xylene. The preferred solvent is toluene.

[0019] The ratio of the solvent to the enynone compound is 1 to 20 mL:1 mmol, preferably 10 mL:1 mmol.

[0020] The reaction conditions are preferably 25°C to 120°C for 0.5h to 48h, preferably 40°C for 14h.

[0021] The enynone compound can be prepared by referring to known literature (J.Am.Chem.Soc.2013,135,13502-13511).

[0022] Method 1

[0023] Method 2

[0024] Method 3

[0025] The deuterated alkenyl azide compound can be prepared by referring to known literature (Org. Lett. 2014, 16, 3668-3671).

[0026]

[0027] The introduction of deuterium into drugs can significantly improve pharmacokinetic properties and reduce toxicity, playing an important role in drug metabolism analysis and reaction mechanism studies. For example, D5-nifedipine can increase the efficacy of rodents by 34%, while D5-tamoxifen can reduce genotoxicity. In 2017, the FDA approved the first deuterated drug, deutetrabenazine (Austedo, SD-809). The presence of deuterium increases the half-life of the active metabolite and prolongs its pharmacological activity. Therefore, the development of simple and efficient methods for the synthesis of (deuterated) terminal olefins is attractive and important for the further derivatization and functionalization of drug molecules.

[0028]

[0029] Deuterated alkenyl furan compounds that can be prepared by the present invention are exemplified as follows:

[0030]

[0031] Compared with the prior art, the present invention has the following advantages and effects:

[0032] The preparation process of the invention is simple and fast, simple and efficient, uses neutral reaction conditions, has no hidden danger of equipment corrosion, has a simple purification process, has a high deuteration rate, and has 100% deuteration conversion, and has potential industrial application value. DETAILED DESCRIPTION

[0033] The present invention is further described below with reference to specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art and can be directly purchased or synthesized by known literature methods.

[0034] Example 1

[0035] To a dry Schlenk tube with a stirring bar, ZnCl2 (2.7 mg, 0.02 mmol) was added. After nitrogen substitution three times, 1a (42.4 mg, 0.2 mmol), 2a (48.3 mg, 0.3 mmol) and toluene (2 mL) were added and stirred at 40°C for 14 h. After the reaction was complete, the solvent was removed by spun off and the product was purified by flash column chromatography (eluent: petroleum ether:ethyl acetate 20:1 by volume) to obtain product 3a (80% yield, 94% D) as a yellow oily liquid. 1 H NMR (400MHz, Chloroform-d) δ7.45–7.36(m,5H),5.74(s,0.06H),5.23(s,0.06H),6.36(s,1H),2.65(s,3H),2.35(s,3H); 13 C NMR(101MHz, CDCl3)δ194.2,158.6,151.7,139.0,138.4,128.4,122.9,109.2,29.1,14.6; HRMS(ESI)Calcd for C 15 H 12 D2O2(M+Na) + 251.1012, found 251.1006.

[0036] Example 2

[0037]

[0038] To a dry Schlenk tube with a stirring bar, ZnCl2 (2.7 mg, 0.02 mmol) was added. After nitrogen substitution three times, 1b (54.0 mg, 0.2 mmol), 2a (48.3 mg, 0.3 mmol) and toluene (2 mL) were added and stirred at 40°C for 14 h. After the reaction was complete, the solvent was removed and the product was purified by flash column chromatography (eluent: petroleum ether:ethyl acetate 10:1 by volume) to obtain product 3b (53% yield, 94% D) as a yellow solid with a melting point of 120-122°C. 1H NMR(400MHz,Chloroform-d)δ8.07(d,J=8.2Hz,2H),7.51(d,J=8.2Hz,2H),6.35 (s,1H),5.60(s,0.06H),5.29(s,0.06H),3.95(s,3H),2.65(s,3H),2.35(s,3H); 13 C NMR(101MHz, CDCl3)δ194.0,166.8,158.8,151.0,143.5,137.7,130.0,129.8,128.3,122.9,109.4,52.2,29.1,14.6; HRMS(ESI)Calcdfor C 17 H 14 D2O4(M+H) + 287.1247,found287.1244.

[0039] Example 3

[0040]

[0041] To a dry Schlenk tube with a stirring bar, ZnCl2 (2.7 mg, 0.02 mmol) was added. After nitrogen substitution three times, 1c (58.0 mg, 0.2 mmol), 2a (48.3 mg, 0.3 mmol), and toluene (2 mL) were added and stirred at 40°C for 14 h. After the reaction was complete, the solvent was removed by spun-off chromatography. The product 3c (68% yield, 94% D) was obtained as a yellow oily liquid. 1 H NMR (400MHz, Chloroform-d) δ7.52(d,J=8.4Hz,2H),7.30(d,J=8.4Hz,2H),6.34(s,1H),5.73(s,0.06H),5.22(s,0.06H),2.64(s,3H),2.35(s,3H); 13 C NMR(101MHz, CDCl3)δ194.0,158.8,151.2,137.9,137.4,131.6,129.9,122.9,122.3,109.3,29.1,14.6; HRMS(ESI)Calcd for C 15 H 11 D2BrO2(M+H) + 307.0297,found307.0299.

[0042] Example 4

[0043]

[0044] To a dry Schlenk tube with a stirring bar, ZnCl2 (2.7 mg, 0.02 mmol) was added. After nitrogen replacement three times, 1d (50.8 mg, 0.2 mmol), 2a (48.3 mg, 0.3 mmol) and toluene (2 mL) were added and stirred at 40°C for 14 h. After the reaction was complete, the solvent was removed and the product was purified by flash column chromatography (eluent: petroleum ether: ethyl acetate 20:1 by volume) to obtain product 3d (52% yield, 94% D) as a yellow liquid. 1 H NMR(400MHz,Chloroform-d)δ7.99(d,J=8.3Hz,2H),7.53(d,J=8.3Hz,2H),6.3 6(s,1H),5.81(s,0.06H),5.30(s,0.06H),2.65(d,J=4.2Hz,6H),2.36(s,3H); 13 C NMR(101MHz, CDCl3)δ197.6,194.0,158.8,151.0,143.7,137.6,136.9,128.52,128.48,123.0,109.4,29.1,26.7,14.6; HRMS(ESI)Calcd for C 17 H 14 D2O3(M+H) + 271.1298, found 271.1289.

[0045] Example 5

[0046]

[0047] To a dry Schlenk tube with a stirring bar, ZnCl2 (2.7 mg, 0.02 mmol) was added. After nitrogen displacement three times, 1e (52.4 mg, 0.2 mmol), 2a (48.3 mg, 0.3 mmol) and toluene (2 mL) were added and stirred at 40°C for 14 h. After the reaction was complete, the solvent was removed by spun off and the product was purified by flash column chromatography (eluent: petroleum ether:ethyl acetate 20:1 by volume) to obtain product 3e (60% yield, 94% D) as a yellow liquid. 1 H NMR (400MHz, Chloroform-d) δ7.93–7.83(m,4H),7.57–7.48(m,3H),6.39(s,1H),5.82(s,0.06H),5.35(s,0.06H),2.67(s,3H),2.33(s,3H); 13CNMR(101MHz,CDCl3)δ194.2,158.7,151.8,138.4,136.5,133.3,133.2,128.2 ,128.0,127.7,127.2,126.4,126.3,122.9,109.4,29.1,14.6; HRMS(ESI)Calcd for C 19 H 14 D2O2(M+H) + 279.1349, found 279.1347.

[0048] Example 6

[0049]

[0050] To a dry Schlenk tube with a stirring bar, ZnCl2 (2.7 mg, 0.02 mmol) was added. After nitrogen replacement three times, 1f (48.4 mg, 0.2 mmol), 2a (48.3 mg, 0.3 mmol) and toluene (2 mL) were added and stirred at 40°C for 14 h. After the reaction was complete, the solvent was removed and the product was purified by flash column chromatography (eluent: petroleum ether:ethyl acetate 20:1 by volume) to obtain the product 3f (63% yield, 94% D) as a yellow oily liquid. 1 H NMR(400MHz,Chloroform-d)δ7.37(d,J=8.7Hz,2H),6.92(d,J=8.7Hz,2H),6.37 (s,1H),5.66(s,0.06H),5.19(s,0.06H),3.85(s,3H),2.64(s,3H),2.35(s,3H); 13 C NMR(101MHz, CDCl3)δ194.2,159.7,158.5,152.0,137.8,131.4,129.4,122.9,113.8,109.1,55.3,29.1,14.6; HRMS(ESI)Calcd for C 16 H 14 D2O3(M+H) + 259.1298, found 259.1304.

[0051] Example 7

[0052]

[0053] To a dry Schlenk tube with a stirring bar, ZnCl2 (2.7 mg, 0.02 mmol) was added. After nitrogen replacement three times, 1 g (47.6 mg, 0.2 mmol), 2a (47.7 mg, 0.3 mmol) and toluene (2 mL) were added and stirred at 40°C for 14 h. After the reaction was complete, the solvent was removed and the product was purified by flash column chromatography (eluent: petroleum ether: ethyl acetate 20:1 by volume) to obtain 3 g (40%) of the product as a yellow oily liquid. 1 H NMR(400MHz,Chloroform-d)δ7.43–7.39(m,2H),7.37–7.34(m,3H),6.50(s,1H),5.73(s,0.06H),5 .25(s,0.06H),3.08(t,J=6.3Hz,2H),2.75–2.72(m,2H),2.07–2.02(m,2H),1.97–1.92(m,2H);13C NMR(101MHz, CDCl3)δ196.6,161.8,152.5,138.9,138.6,128.3,128.2,125.1,112.6,109.3,44.5,29.8,24.9,22.9; HRMS(ESI)Calcdfor C 17 H 15 D2O2(M+H) + 255.1349, found 255.1347.

[0054] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A deuterated alkenyl furan compound, characterized by: Where: R 1 , R 2 All are C1~C 12 Alkyl, aryl, heteroaryl; R 1 ,R 2 Any one or more hydrogen atoms on the aromatic ring may be replaced by a substituent; R 1 , R 2 To connect or not to connect; Where: R 3 C1~C 12 Alkyl, aryl or heteroaryl; wherein, R 3 Any one or more hydrogen atoms on the aromatic ring may be replaced by a substituent.

2. A method for preparing a deuterated alkenyl furan compound, characterized by: Where: R 1 , R 2 All are C1~C 12 Alkyl, aryl, heteroaryl; R 1 ,R 2 Any one or more hydrogen atoms on the aromatic ring may be replaced by a substituent; R 1 , R 2 To connect or not to connect; Where: R 3 C1~C 12 Alkyl, aryl or heteroaryl; wherein, R 3 Any one or more hydrogen atoms of the upper aromatic ring may be replaced by a substituent; Where: R is C1~C 12 Alkyl, aryl and heteroaryl; any one or more hydrogen atoms of the aromatic ring on R may be replaced by a substituent.

3. The method for preparing the deuterated alkenyl furan compound according to claim 2, wherein: The steps include: Under nitrogen protection, the enynone compound is dissolved in a solvent, a catalyst and deuterated alkenyl azide are added, and after the reaction, the deuterated alkenyl furan compound is separated and purified to obtain the deuterated alkenyl furan compound.

4. The preparation method according to claim 3, wherein: The catalyst is one of Zn(OTf)2, ZnF2, ZnCl2, ZnBr2 and ZnI2.

5. The preparation method according to claim 3, wherein: The molar ratio of the catalyst to the enynone compound is 0.001:1 to 1:

1.

6. The preparation method according to claim 3, wherein: The reaction temperature is 0°C-120°C.

7. The preparation method according to claim 3, wherein: The reaction time is 0.5h to 48h.

8. The preparation method according to claim 3, wherein: The solvent is selected from one of 1,1-dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, trifluorotoluene, 1,4-dioxane, acetonitrile, toluene, chlorobenzene, and xylene. 9 . The molar ratio of the deuterated alkenyl azide to the alkenyl ketone compound according to claim 3 is 0.1:1 to 10:1.

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