CN111635312B - Synthesis method of (E) -2-fluoroalkyl-3-butenoate compound - Google Patents
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Abstract
The invention belongs to the technical field of chemical organic synthesis, and discloses a one-step synthesis method of copper-catalyzed alkyne, diazo compound and 2-fluoro malonic acid dialkyl ester derivative through alkyne 1, 1-bifunctional reactionE) -2-fluoroalkyl-3-butenoate compound: introducing a monofluoroalkyl group into a terminal alkyne using a dialkyl 2-fluoromalonate derivative as a monofluoroalkylating agent to form a compound having a quaternary C-F centerE) -2-fluoroalkyl-3-butenoate compound. The one-step synthesis method is direct and efficient, has simple reaction steps, good selectivity and higher product purity; the reaction substrates used are readily available from industry, and is environment-friendly, low in cost, wide in range and capable of being used for synthesizing various medicinesE) The (E) -2-fluoroalkyl-3-butenoate compound is high in economical efficiency and environment-friendly, and is suitable for industrial mass production.
Description
Technical Field
The invention relates to the technical field of chemical organic synthesis, in particular to a method for synthesizing an (E) -2-fluoroalkyl-3-butenoate compound.
Background
In chemical organic synthesis, crotonate compounds are important organic synthesis intermediates, and derivatives thereof are widely found in natural products. The introduction of fluorine atoms or fluorine-containing functional groups into organic molecules can obviously improve the lipophilicity and metabolic stability of the organic molecules and improve the drug effect of biological medicines. Therefore, the development of a practical and effective method for synthesizing fluorine-containing butenoate compounds is of great significance to the development of medicines, agrochemicals and organic materials. However, due to the few and difficult research methods, fluorocrotonate-containing compounds, especially fluorocrotonate-containing drug molecules containing quaternary C-F centers, currently account for a very low proportion of fluorine-containing drugs in the market and clinical development.
Due to the unique properties of fluorine-containing compounds, methods of introducing fluorine or fluorine-containing groups into organic molecules have attracted extensive attention in drug design. Despite the significant advances currently made in fluorination, trifluoromethylation and difluoroalkylation, the mono-fluoroalkyl reagents remain quite scarce, and few are available, especially in the synthesis of trifluoride compounds. Thus, there remains a need to develop efficient methods for synthesizing fluorides that utilize existing monofluoroalkylation reagents.
Alkynes have a wide range of functionalities and are readily available, and thus, bifunctional of alkynes has become a powerful new method for synthesizing a large number of chemicals, particularly multi-substituted alkenes. In this context, the 1, 2-bifunctional reaction of alkynes, whether transition metal-catalyzed or metal-free, always predominates. In contrast, 1-difunctionalization is much less for alkynes than for 1, 2-difunctionalization. In recent years, 1-difunctionalization of alkynes has been of interest, especially for reactions with diazo compounds. However, three-component selective 1, 1-difunctionalization of alkynes has been less explored due to competition for 1, 2-difunctionalization and coupling reactions of any two of the three components. Therefore, studies on 1, 1-bifunctional alkynes are very necessary.
Disclosure of Invention
The invention aims to provide a method for directly synthesizing (E) -2-fluoroalkyl-3-butenoate compounds in one step by three components of alkyne and diazo compounds catalyzed by CuI and 2-fluoro-malonic acid dialkyl ester derivatives through alkyne 1, 1-bifunctional reaction: taking a 2-fluoro dialkyl malonate derivative as a monofluoroalkyl reagent, introducing monofluoroalkyl into terminal alkyne, and generating the (E) -2-fluoroalkyl-3-butenoate compound containing a quaternary C-F center.
The technical scheme of the invention is as follows:
a synthetic method of (E) -2-fluoroalkyl-3-butenoate compound comprises the following synthetic route:
the compound 1 is a phenylacetylene compound with various substituents on an aromatic ring, 2-ethynyl pyridine, 2-ethynyl thiophene, 3-ethynyl thiophene, propargyl methyl ether, cyclopropyl acetylene or 1-hexyne.
The compound 2 is a diazo compound, including but not limited to the following compounds: ethyl diazoacetate and ethyl diazophenylacetate.
The compound 3 is a dialkyl 2-fluoro malonate derivative, including but not limited to the following compounds: dimethyl-2-fluoromalonate and diethyl-2-fluoromalonate.
The synthesis method of the (E) -2-fluoroalkyl-3-butenoate compound comprises the following synthesis steps: adding a solvent into a sealed tube provided with a stirrer, adding a diazo compound, alkyne and 2-fluoro-malonic acid dialkyl ester derivatives, and uniformly mixing; adding cuprous iodide and alkali into a sealing tube, filling nitrogen into a glass guide tube connected with the nitrogen, and sealing the tube opening by using a cock after air is fully expelled; stirring and reacting for 2.0 hours at the temperature of 80-100 ℃; cooling the reacted system to room temperature, adding distilled water into the system, extracting and combining organic phases; distilling under reduced pressure to remove the solvent of the organic phase, and carrying out silica gel column chromatography to obtain the product.
Further, the molar ratio of the alkyne, the diazo compound and the dialkyl 2-fluoromalonate derivative is 1.2 to 1.5.
Further, the amount of the cuprous iodide is 10mol%.
Further, the base is K 2 CO 3 、Na 2 CO 3 、K 3 PO 4 Or Et 3 N, preferably K 2 CO 3 (ii) a The amount of the base is 1.5equiv.
Further, the solvent is acetone or tetrahydrofuran.
Compared with the prior art, the invention has the following advantages:
(1) The invention fills the blank of the method for directly and effectively synthesizing the (E) -2-fluoroalkyl-3-butenoate compound by taking the diazo compound and the 2-fluoro dialkyl malonate derivative as coupling components and carrying out alkyne 1, 1-bifunctional reaction. The one-step synthesis method is direct and efficient, and the reaction steps are simple.
(2) The reaction substrates used in the invention are all easy to obtain from industry, are environment-friendly, low in price and wide in range, and can be used for synthesizing various (E) -2-fluoroalkyl-3-butenoate compounds. Therefore, the synthesis method is high in economy and environment-friendly, and is suitable for industrial mass production.
(3) The selectivity is excellent. The interference of 1, 2-double-group functionalization and coupling reaction between two substrates is avoided as much as possible, and the obtained 1, 1-double-functionalization reaction product has higher purity.
Drawings
FIG. 1 is a scheme showing that (E) -2-fluoroalkyl-3-butenoate compound 4a 1 H NMR spectrum.
FIG. 2 is a diagram of (E) -2-fluoroalkyl-3-butenoate compound 4a 13 C NMR spectrum.
FIG. 3 is a diagram of (E) -2-fluoroalkyl-3-butenoate compound 4a 19 F NMR spectrum.
FIG. 4 is a diagram of (E) -2-fluoroalkyl-3-butenoate compound 4c 1 H NMR spectrum.
FIG. 5 is a diagram of (E) -2-fluoroalkyl-3-butenoate compound 4c 13 C NMR spectrum.
FIG. 6 is a diagram of (E) -2-fluoroalkyl-3-butenoate compound 4c 19 F NMR spectrum.
FIG. 7 is a schematic representation of (E) -2-fluoroalkyl-3-butenoate compound 4f 1 H NMR spectrum.
FIG. 8 is a drawing showing a scheme for preparing (E) -2-fluoroalkyl-3-butenoate compound 4f 13 C NMR spectrum.
FIG. 9 is a diagram of (E) -2-fluoroalkyl-3-butenoate compound 4f 19 F NMR spectrum.
Detailed Description
To further illustrate the technical means and effects of the present invention, the following detailed description is given with reference to the accompanying drawings and the specific embodiments.
Example 1
First, ethyl diazoacetate (66. Mu.L, 0.6 mmol), phenylacetylene (57. Mu.L, 0.50 mmol), dimethyl 2-fluoromalonate (117.3mg, 0.75mmol) were added to a sealed tube containing a stirrer and an acetone (1.0 mL) solvent, and mixed well. Then, cuI (9.5mg, 0.05mmol) and K were added 2 CO 3 (103.6 mg, 0.75mmol), the reaction mixture was purged with nitrogen for about 3 minutes through a glass tube to which nitrogen was connected, and the reaction mixture was stirred at 80 ℃ for 2.0 hours while sufficiently purging the air. After the reaction, the system was cooled to room temperature, 3.0ml of distilled water was added to the reaction system, extracted with ethyl acetate, the organic phases were combined, the solvent of the organic phase was removed by distillation under reduced pressure, and 146.0mg of the product 4a was obtained by silica gel column chromatography with a yield of 86%. The reaction is shown in the following formula:
spectrogram analysis data:
Yellow oil. 1 H NMR(400MHz,CDCl 3 ):δ＝1.24(t,J＝7.2Hz,3H),3.46(d,J＝2.0Hz,2H),3.87(s,6H),4.13(q,J＝7.2Hz,2H),7.11(s,1H),7.27-7.36(m,5H)； 13 C NMR(100MHz,CDCl 3 ):δ＝13.9,33.7(d,J＝5.0Hz),53.5,60.9,94.8(d,J＝201.0Hz),127.1(d,J＝20.0Hz),127.9,128.3,128.4,133.6(d,J＝11.0Hz),135.1,165.5(d,J＝26.0Hz),170.5； 19 F NMR(376MHz,CDCl 3 ):δ＝-159.9.HRMS(ESI-TOF).Calcd for C 17 H 20 FO 6 ,[M+H] + m/z 339.1244,Found 339.1246.
example 2
First, ethyl diazoacetate (66. Mu.L, 0.6 mmol), 4-chlorophenylacetylene (60. Mu.L, 0.50 mmol), and dimethyl 2-fluoromalonate (117.3mg, 0.75mmol) were added to a sealed tube containing a stirrer and an acetone (1.0 mL) solvent, and mixed well. Then, cuI (9.5mg, 0.05mmol) and K were added 2 CO 3 (103.6 mg, 0.75mmol), the reaction mixture was purged with nitrogen for about 3 minutes through a glass tube to which nitrogen was connected, and the reaction mixture was stirred at 80 ℃ for 2.0 hours while sufficiently purging the air. After the reaction, the system was cooled to room temperature, 3.0ml of distilled water was added to the reaction system, extraction was performed with ethyl acetate, the organic phases were combined, the solvent of the organic phase was removed by distillation under reduced pressure, and 150.7mg of the product 4b was obtained by silica gel column chromatography, with a yield of 81%. The reaction is shown in the following formula:
spectrogram analysis data:
Yellow oil. 1 H NMR(400MHz,CDCl 3 ):δ＝1.25(t,J＝7.2Hz,3H),3.43(d,J＝1.6Hz,2H),3.88(s,6H),4.14(q,J＝7.2Hz,2H),7.06(s,1H),7.23(d,J＝8.4Hz,2H),7.33(d,J＝8.4Hz,2H)； 13 C NMR(100MHz,CDCl 3 ):δ＝14.0,33.7(d,J＝5.0Hz),53.6,61.0,94.7(d,J＝201.0Hz),127.8(d,J＝20.0Hz),128.6,129.8,132.5(d,J＝11.0Hz),133.6,133.9,165.4(d,J＝26.0Hz),170.4； 19 F NMR(376MHz,CDCl 3 ):δ＝-160.1.HRMS(ESI-TOF).Calcd for C 17 H 19 ClFO 6 ,[M+H] + m/z 373.0854,Found 373.0847.
example 3
First, ethyl diazoacetate (66. Mu.L, 0.6 mmol), 3-ethynylthiophene (50. Mu.L, 0.50 mmol), and dimethyl 2-fluoromalonate (117.3mg, 0.75mmol) were added to a sealed tube containing a stirrer and an acetone (1.0 mL) solvent, and mixed uniformly. Then, cuI (9.5mg, 0.05mmol) and K were added 2 CO 3 (103.6 mg, 0.75mmol), introducing nitrogen gas through a nitrogen-connected glass tube for about 3 minutes, sufficiently removing air, sealing the tube opening with a cock, and stirring the reaction mixture at 80 ℃ for 2 minutes0 hour. After the reaction, the system was cooled to room temperature, 3.0ml of distilled water was added to the reaction system, extraction was performed with ethyl acetate, the organic phases were combined, the solvent of the organic phase was removed by distillation under reduced pressure, and 132.4mg of the product 4c was obtained by silica gel column chromatography, with a yield of 77%. The reaction is shown in the following formula:
spectrogram analysis data:
Yellow oil. 1 H NMR(400MHz,CDCl 3 ):δ＝1.25(t,J＝7.2Hz,3H),3.54(d,J＝1.6Hz,2H),3.86(s,6H),4.16(q,J＝7.2Hz,2H),7.01(s,1H),7.08-7.09(m,1H),7.30-7.32(m,1H),7.35(s,1H)； 13 C NMR(100MHz,CDCl 3 ):δ＝13.9,34.1(d,J＝5.0Hz),53.4,60.9,94.9(d,J＝201.0Hz),125.0,125.5,125.7,127.6(d,J＝12.0Hz),128.2,135.8,165.4(d,J＝26.0Hz),170.3； 19 F NMR(376MHz,CDCl 3 ):δ＝-159.4.HRMS(ESI-TOF).Calcd for C 15 H 17 FNaO 6 S,[M+Na] + m/z367.0628,Found 367.0622.
example 4
First, ethyl diazoacetate (66. Mu.L, 0.6 mmol), cyclopropylacetylene (45. Mu.L, 0.50 mmol), dimethyl-2-fluoromalonate (117.3mg, 0.75mmol) were added to a sealed tube containing a stirrer and acetone (1.0 mL) solvent and mixed well. Then, cuI (9.5mg, 0.05mmol) and K were added 2 CO 3 (103.6 mg, 0.75mmol), the reaction mixture was purged with nitrogen for about 3 minutes through a glass tube to which nitrogen was connected, and the reaction mixture was stirred at 80 ℃ for 2.0 hours while sufficiently purging the air. After the reaction, the system was cooled to room temperature, 3.0ml of distilled water was added to the reaction system, extraction was performed with ethyl acetate, the organic phases were combined, the solvent of the organic phase was removed by distillation under reduced pressure, and 52.9mg of the product 4d was isolated by silica gel column chromatography, with a yield of 35%. The reaction is shown in the following formula:
spectrogram analysis data:
Yellow oil. 1 H NMR(400MHz,CDCl 3 ):δ＝0.49-0.52(m,2H),0.83-0.88(m,2H),1.24(t,J＝7.2Hz,3H),1.46-1.54(m,1H),3.40(s,2H),3.82(s,6H),4.13(q,J＝7.2Hz,2H),5.34(d,J＝10.0Hz,1H)； 13 C NMR(100MHz,CDCl 3 ):δ＝7.6,10.8,14.1,33.1(d,J＝4.0Hz),53.4,60.8,94.9(d,J＝199.0Hz),122.6(d,J＝20.0Hz),139.5(d,J＝11.0Hz),165.8(d,J＝26.0Hz),170.5； 19 F NMR(376MHz,CDCl 3 ):δ＝-159.0.HRMS(ESI-TOF).Calcd for C 14 H 19 FNaO 6 ,[M+Na] + m/z325.1063,Found 325.1066.
example 5
First, ethyl diazophenylacetate 2b (114mg, 0.6 mmol), phenylacetylene (57. Mu.L, 0.50 mmol), and dimethyl 2-fluoromalonate (117.3mg, 0.75mmol) were added to a sealed tube containing a stirrer and a tetrahydrofuran (1.0 mL) solvent, and mixed well. Then, cuI (9.5mg, 0.05mmol) and K were added 2 CO 3 (103.6 mg, 0.75mmol), the reaction mixture was purged with nitrogen for about 3 minutes through a glass tube to which nitrogen was connected, and the reaction mixture was stirred at 80 ℃ for 2.0 hours while sufficiently purging the air. After the reaction, the system was cooled to room temperature, 3.0ml of distilled water was added to the reaction system, extraction was performed with ethyl acetate, the organic phases were combined, the solvent of the organic phase was removed by distillation under reduced pressure, and 156.0mg of the product 4e was obtained by silica gel column chromatography, with a yield of 39%. The reaction is shown in the following formula:
spectrogram analysis data:
Yellow oil. 1 H NMR(400MHz,CDCl 3 ):δ＝3.52(s,3H),3.69(s,3H),3.88(s,3H),5.14(s,1H),7.11(s,1H),7.18-7.24(m,6H),7.29-7.35(m,4H)； 13 C NMR(100MHz,CDCl 3 ):δ＝50.3(d,J＝2.0Hz),52.2,53.3,53.7,95.5(d,J＝200.0Hz),127.2,128.0,128.5(d,J＝3.0Hz),129.7(d,J＝2.0Hz),132.1,132.3,134.5,134.5,135.3,135.6,165.6(d,J＝26.0Hz),165.9(d,J＝25.0Hz),171.3； 19 F NMR(376MHz,CDCl 3 ):δ＝-160.4.HRMS(ESI-TOF).Calcd for C 22 H 21 FNaO 6 ,[M+Na] + m/z 423.1220,Found 423.1212.
example 6
First, ethyl diazoacetate (66. Mu.L, 0.6 mmol), phenylacetylene (57. Mu.L, 0.50 mmol), and 2-fluoroacetylacetylmorphine 3b (142.0 mg, 0.75mmol) were added to a sealed tube containing a stirrer and an acetone (1.0 mL) solvent, and mixed well. Then, cuI (9.5mg, 0.05mmol) and K were added 2 CO 3 (103.6 mg, 0.75mmol), the reaction mixture was purged with nitrogen for about 3 minutes through a glass tube to which nitrogen was connected, and the reaction mixture was stirred at 80 ℃ for 2.0 hours while sufficiently purging the air. After the reaction, the system was cooled to room temperature, 3.0ml of distilled water was added to the reaction system, extracted with ethyl acetate, the organic phases were combined, the solvent of the organic phase was removed by distillation under reduced pressure, and the product 4f, 132.0mg, was isolated by silica gel column chromatography with a yield of 70%. The reaction is shown in the following formula:
spectrogram analysis data:
Yellow oil. 1 H NMR(400MHz,CDCl 3 ):δ＝1.24(t,J＝7.2Hz,3H),2.36(d,J＝3.6Hz,3H),3.03(dd,J 1 ＝1.6Hz,J 2 ＝16.8Hz,1H),3.44(d,J＝17.2Hz,1H),3.52-3.80(m,8H),4.11-4.17(m,1H),6.86(s,1H),7.30-7.38(m,5H)； 13 C NMR(100MHz,CDCl 3 ):δ＝14.0,26.1,34.0(d,J＝5.0Hz),43.0,46.8(d,J＝9.0Hz),61.1,66.4,66.6,102.3(d,J＝196.0Hz),127.8(d,J＝21.0Hz),128.2,128.4,128.6,134.5(d,J＝8.0Hz),134.9,164.5(d,J＝21.0Hz),171.1,198.9(d,J＝30.0Hz)； 19 F NMR(376MHz,CDCl 3 ):δ＝-157.7.HRMS(ESI-TOF).Calcd for C 20 H 24 FNNaO 5 ,[M+Na] + m/z 400.1536,Found 400.1528.
the above description is only for the specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto, and other modifications or equivalent substitutions made by the technical solutions of the present invention by those skilled in the art should be covered within the scope of the claims of the present invention as long as they do not depart from the spirit and scope of the technical solutions of the present invention.
Claims (5)
1. A method for synthesizing (E) -2-fluoroalkyl-3-butenoate is characterized in that the synthetic route is as follows:
2. The process for the synthesis of (E) -2-fluoroalkyl-3-butenoate according to claim 1, characterized by comprising the following steps: adding a solvent into a sealed tube provided with a stirrer, adding a diazo compound, alkyne and 2-fluoro-malonic acid dialkyl ester derivatives, and uniformly mixing; adding cuprous iodide and alkali into a sealing tube, filling nitrogen into a glass conduit connected with the nitrogen, and sealing the tube opening by using a cock after air is sufficiently expelled; stirring and reacting for 2.0 hours at the temperature of 80-100 ℃, and cooling a system after the reaction to room temperature; adding distilled water into the system, extracting, and combining organic phases; distilling under reduced pressure to remove the solvent of the organic phase, and performing silica gel column chromatography to obtain the product.
3. The method for synthesizing (E) -2-fluoroalkyl-3-butenoate according to claim 2, wherein the molar ratio of the diazo compound to the alkyne to the dialkyl 2-fluoromalonate is 1.2 to 1.5.
4. The method for synthesizing (E) -2-fluoroalkyl-3-butenoic acid ester according to claim 2, wherein K is used as the base 2 CO 3 Substitution to Na 2 CO 3 、K 3 PO 4 Or Et 3 N。
5. The method for synthesizing (E) -2-fluoroalkyl-3-butenoate according to claim 2, wherein acetone is replaced with tetrahydrofuran as the solvent.
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| CN101838240A (en) * | 2010-06-11 | 2010-09-22 | 扬州康伊尔医药科技有限公司 | Preparation method of antiviral compound intermediate pyrazole-3-carboxylic ester |
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| CN101838240A (en) * | 2010-06-11 | 2010-09-22 | 扬州康伊尔医药科技有限公司 | Preparation method of antiviral compound intermediate pyrazole-3-carboxylic ester |
Non-Patent Citations (3)
| Title |
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| Camille Oger等.Are Alkyne Reductions‑, Regio‑, and Stereoselective Enough To Provide Pure ( Z )‑Olefi ns in Polyfunctionalized Bioactive ChemoMolecules?.《Chem. Rev.》.2013,第113卷 * |
| Copper-catalyzed 1,1-arylalalkynes with diazo esters and organoboronic akylation of terminal acids;Yunhe Lv等;《Chem Comm》;20191231;第55卷;第13446-13449页 * |
| Yunhe Lv等.Copper-Catalyzed 1,1-Alkylmonofl uoroalkylation of Terminal Alkynes with Diazo Compounds and 2 ‑Fluoro-1,3-dicarbonyl Compounds: Access toward ( E )‑β-Mono fl uoroalkyl-β, γ-unsaturated Esters or Ketones.《J. Org. Chem. 》.2021,第86卷 * |
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