CN113912468A - Method for preparing 2, 2-difluoro-3-hydroxy-1, 4-diketone compound - Google Patents

Method for preparing 2, 2-difluoro-3-hydroxy-1, 4-diketone compound Download PDF

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CN113912468A
CN113912468A CN202111420794.3A CN202111420794A CN113912468A CN 113912468 A CN113912468 A CN 113912468A CN 202111420794 A CN202111420794 A CN 202111420794A CN 113912468 A CN113912468 A CN 113912468A
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杨健国
刘赛梅
洪鹏
李金山
任君
王治明
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Taizhou University
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Abstract

The invention discloses a method for preparing 2, 2-difluoro-3-hydroxy-1, 4-diketone compounds. The method takes difluorodiluted alcohol silicon ether compounds and substituted glyoxal hydrate as raw materials, and takes toluene as a solvent to react at room temperature under the catalysis of hexafluoroisopropanol to synthesize the target compound. The synthesis method is simple, high in yield, mild in condition, free of metal catalyst and good in application prospect.

Description

Method for preparing 2, 2-difluoro-3-hydroxy-1, 4-diketone compound
Technical Field
The invention relates to a method for synthesizing 2, 2-difluoro-3-hydroxy-1, 4-diketone compounds in a mild reaction system under the conditions of high efficiency, greenness and no metal catalysis.
Background
Fluorine-containing compounds play an increasingly important role in drug synthesis. Introduction of fluorine atoms or fluoroalkyl groups into molecules can significantly change their physicochemical properties and biological activities, and have wide applications in the fields of agrochemicals and material science (chem.Soc.Rev.2008,37, 320-; J.Med.chem.2015,58, 8315-; and 40% of agrochemicals and 25% of pharmaceuticals in the global market contain fluorine atoms (J.Med.chem.2018,61, 5822-; J.Med.chem.2020,63, 6315-; Org.Process Res.Dev.2020,24, 470-) -6386). Therefore, chemists have made efforts to develop new efficient synthetic methods for synthesizing novel fluorinated compounds (chem. Rev.2011,111, 455-529; chem. Rev.2015,115, 826-870; chem. Soc. Rev.2016,45, 5441-5454; Acc. chem. Res.2018,51, 2264-2278).
Like most fluorochemical compounds, α, α -difluoroketone-containing molecules generally exhibit interesting physicochemical and biological properties and have found widespread application in drug research (eur.j.org.chem.2018, 3520-3540; chem. -eur.j.2020,26,7145-7175), e.g., α, α -difluoroketone and α, α -difluoro- β -hydroxyketone have a strong tendency to form stable tetrahedral adducts with water, and have been shown to be potent inhibitors of hydrolytic enzymes and a number of other enzymes, such as serine proteases, HIV proteases, HMG-CoA reductase and GABAB agonists. To date, a number of synthetic methods have been developed for the preparation of compounds containing α, α -difluoro- β -hydroxyketone, including metal-mediated Reformatsky reaction of halodifluoromethyl ketone, 6-triethylborohydride-promoted aldol reaction of iododifluoromethyl ketone (RSCAdv.2017,7, 56034-2pin2And the defluorinated aldol condensation reaction in the presence of NaOtBu (Angew. chem., Int. Ed.2016,55,341- & 344), base-promoted defluorinated acetylated aldol condensation reaction of polyfluoro 1, 3-dione hydrates (J.Am. chem. Soc.2011,133, 5802-5805; Angew. chem., Int. Ed.2013,52,7869- & 7873; Org.Lett.2021,23,5098- & 5101), TBAT-catalyzed aldol condensation reaction of α, α -difluoro- α - (trimethylsilyl) acetamide (J.Org.chem.2001,66,1941- & 1946), thiourea-catalyzed deacylated aldol reaction of 2, 2-difluoro-1, 3-diones (Adv.Synth. Catal.2016, 2811-2816), Cheyne O-Boc ester J.2016, Fluoro. 2016, 85, Fluoro. Chevr. 1946),acylsilane and TMSCF3One-pot conversion with aldehydes (J.org.chem.2001,66, 1941-. In addition to these established methods for the synthesis of α, α -difluoro- β -hydroxyketones, the direct synthesis of this class of compounds by Mukaiyama-aldol reaction using difluoroenolsilyl ether by chemists is considered one of the most efficient and green methods available to many chemists (org. biomol. chem.2015,13, 7351-containing 7380; chem. Commun.2019,55, 13638-containing 13648; J. org. chem.2021,86, 9206-containing 9217). Using difluoroenolsilyl ethers with aldehydes, ketones and active ketones (e.g. isatin, tryptophan, benzo [ b ]]Thiophene-2, 3-diones and β, γ -unsaturated α -ketoesters) in metal-catalyzed, organic-catalyzed or solvent-promoted Mukaiyama-aldol reactions have been achieved (chem. commu.2019, 55, 13638-; chem.2021,86, 9206-9217; angew.chem., int.ed.2014,53, 9512-. However, the use of ketoaldehydes for obtaining 2, 2-difluoro-3-hydroxy-1, 4-diones has been reported only rarely, and to our knowledge, only one example of the use of phenyl groups instead of ketoaldehydes, with H, has been reported2O was synthesized as a solvent to give 2, 2-difluoro-3-hydroxy-1, 4-dione in a yield of only 40% (Angew. chem., int. Ed.2014,53, 9512-one 9516). Therefore, the development of more efficient synthetic methods or catalytic systems for synthesizing such compounds remains one of the challenges to be solved. In view of the excellent properties we have recently investigated in the construction of fluorochemicals (chem. Commun.2021,57, 1050-.
Based on the characteristics, the invention provides a series of novel methods for synthesizing a target compound by taking a difluorohydrinsiloxane compound and a substituted glyoxal hydrate as raw materials and toluene as a solvent to react under the catalysis of hexafluoroisopropanol.
Disclosure of Invention
According to the invention, the method for preparing the 2, 2-difluoro-3-hydroxy-1, 4-diketone compound takes difluorodiluted alcohol silyl ether compound and substituted glyoxal hydrate as raw materials, and takes toluene as a solvent to react at room temperature under the catalysis of hexafluoroisopropanol to synthesize the target compound. The synthesis method is simple, high in yield, mild in condition, free of metal catalyst and good in application prospect. Wherein the synthesis reaction formula of the target compound is as follows:
Figure BDA0003377283560000031
the specific product structure is as follows:
Figure BDA0003377283560000032
the molar ratio of the difluorodiluted alcohol silicon ether compound to the substituted glyoxal hydrate is 2.5: 1, the molar ratio of catalyst hexafluoroisopropanol to substituted glyoxal hydrate is 1: 10, taking toluene as a solvent, and the reaction temperature is room temperature.
By the above synthesis method, 3a-3i, 9 compounds in total, were synthesized.
After the reaction is finished, the reaction product is cooled at room temperature, then the organic solvent is concentrated, and the organic solvent is further purified by column chromatography to obtain a target product.
Detailed Description
The present invention will be further described with reference to the following examples, which are only for illustrating the technical solutions of the present invention and are not to be construed as limiting the present invention.
Example 3a
The crude products were purified by column chromatography with petroleum ether/ethyl acetate(15/1,v/v)as eluent to give compound 3a(white solid,81.9mg,94％yield).M.p.:61–63℃；1H NMR(400MHz,CDCl3)δ8.07–8.03(m,4H),7.69–7.62(m,2H),7.56–7.47(m,4H),5.73(ddd,J＝17.8,7.5,4.0Hz,1H),4.26(d,J＝7.6Hz,1H)；19F NMR(376MHz,CDCl3)δ-100.63(d,J＝279.8Hz,1F),-113.10(dd,J＝278.2,17.9Hz,1F)；13C{1H}NMR(100MHz,CDCl3)δ195.1,189.3(C-F,dd,2JC-F＝30.0,27.0Hz),134.7,134.4,132.6(C-F,d,4JC-F＝1.6Hz),130.1(C-F,dd,3JC-F＝4.1,2.7Hz),129.5(C-F,d,4JC-F＝1.5Hz),128.7,128.6,115.9(C-F,dd,1JC-F＝266.1,261.7Hz),72.3(C-F,t,2JC-F＝27.0Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C16H12F2O3Na 313.0652；Found 313.0655。
Example 3b
The crude products were purified by column chromatography with petroleum ether/ethyl acetate(15/1,v/v)as eluent to give compound 3b(white solid,79.4mg,87％yield).M.p.:69–71℃；1H NMR(400MHz,CDCl3)δ8.06(d,J＝7.6Hz,2H),7.95(d,J＝7.6Hz,2H),7.65–7.61(m,1H),7.48(dd,J＝10.8,4.8Hz,2H),7.33(d,J＝8.0Hz,2H),5.71(ddd,J＝18.3,7.4,3.7Hz,1H),4.30(d,J＝7.6Hz,1H),2.45(s,3H)；19F NMR(376MHz,CDCl3)δ-100.57(d,J＝276.4Hz,1F),-113.71(dd,J＝276.7,18.8Hz,1F)；13C{1H}NMR(100MHz,CDCl3)δ194.4,189.4(C-F,dd,2JC-F＝29.9,26.7Hz),146.1,134.4,132.7,131.9,130.1(C-F,dd,3JC-F＝4.1,2.5Hz),129.6,129.5,128.6,115.9(C-F,dd,1JC-F＝266.1,261.2Hz),72.1(C-F,t,2JC-F＝27.1Hz),21.8；HRMS(ESI)m/z:[M+Na]+Calcd for C17H14F2O3Na327.0809；Found 327.0813。
Example 3c
The crude products were purified by column chromatography with petroleum ether/ethyl acetate(15/1,v/v)as eluent to give compound 3c(white solid,75.7mg,83％yield).M.p.:72–74℃；1H NMR(400MHz,CDCl3)δ8.06(d,J＝7.6Hz,2H),7.84–7.82(m,2H),7.63(dd,J＝10.6,4.3Hz,1H),7.51–7.47(m,3H),7.42(t,J＝7.6Hz,1H),5.71(ddd,J＝17.8,7.6,4.1Hz,1H),4.25(d,J＝7.6Hz,1H),2.44(s,3H)；19F NMR(376MHz,CDCl3)δ-100.65(d,J＝277.6Hz,1F),-113.17(dd,J＝277.5,17.5Hz,1F)；13C{1H}NMR(100MHz,CDCl3)δ195.2,189.3(C-F,dd,2JC-F＝30.0,26.9Hz),138.7,135.6,134.5,134.4,132.7(C-F,d,4JC-F＝1.9Hz),130.1(C-F,dd,3JC-F＝4.1,2.7Hz),129.8(C-F,d,4JC-F＝1.0Hz),128.6,128.6,126.8(C-F,d,4JC-F＝1.6Hz),115.9(C-F,dd,1JC-F＝266.1,261.7Hz),72.3(C-F,t,2JC-F＝26.9Hz),21.3；HRMS(ESI)m/z:[M+Na]+Calcd for C17H14F2O3Na 327.0809；Found 327.0815。
Example 3d
The crude products were purified by column chromatography with petroleum ether/ethyl acetate(15/1,v/v)as eluent to give compound 3d(white solid,67.5mg,74％yield).M.p.:58–60℃；1H NMR(400MHz,CDCl3)δ8.02(d,J＝7.7Hz,2H),7.67–7.61(m,2H),7.50–7.46(m,3H),7.31(t,J＝8.1Hz,2H),5.61(dt,J＝16.3,6.1Hz,1H),4.33(d,J＝6.7Hz,1H),2.57(s,3H)；19F NMR(376MHz,CDCl3)δ-101.09(dd,J＝279.7,5.3Hz,1F),-110.60(dd,J＝279.4,16.5Hz,1F)；13C{1H}NMR(100MHz,CDCl3)δ197.4,189.1(C-F,dd,2JC-F＝30.0,26.9Hz),139.6,134.6,134.4,132.9,132.6(C-F,t,4JC-F＝1.6Hz),130.0(C-F,t,3JC-F＝3.3Hz),129.7,128.6,125.6,116.1(C-F,dd,1JC-F＝264.0,263.1Hz),73.6(C-F,t,2JC-F＝26.3Hz),20.8；HRMS(ESI)m/z:[M+Na]+Calcd for C17H14F2O3Na 327.0809；Found 327.0816。
Example 3e
The crude products were purified by column chromatography with petroleum ether/ethyl acetate(15/1,v/v)as eluent to give compound 3e(white solid,81.2mg,85％yield).M.p.:92–94℃；1H NMR(400MHz,CDCl3)δ8.06(d,J＝7.7Hz,2H),7.98(d,J＝7.8Hz,2H),7.63(t,J＝7.4Hz,1H),7.49(t,J＝7.8Hz,2H),7.36(d,J＝8.3Hz,2H),5.71(ddd,J＝18.2,7.6,3.8Hz,1H),4.30(d,J＝7.6Hz,1H),2.74(q,J＝7.6Hz,2H),1.28(t,J＝7.1Hz,3H)；19F NMR(376MHz,CDCl3)δ-100.54(d,J＝276.2Hz,1F),-113.73(dd,J＝276.7,18.7Hz,1F)；13C{1H}NMR(100MHz,CDCl3)δ194.4,189.4(C-F,dd,2JC-F＝30.1,26.9Hz),152.2,134.4,132.7,132.1,130.1(C-F,dd,3JC-F＝4.2,2.4Hz),129.8,128.6,128.3,115.9(C-F,dd,1JC-F＝266.2,261.5Hz),72.1(C-F,t,2JC-F＝26.3Hz),29.1,14.9；HRMS(ESI)m/z:[M+Na]+Calcd for C18H16F2O3Na 341.0965；Found 341.0960。
Example 3f
The crude products were purified by column chromatography with petroleum ether/ethyl acetate(15/1,v/v)as eluent to give compound 3f(pale yellow solid,86.8mg,79％yield).M.p.:74–76℃；1H NMR(400MHz,CDCl3)δ8.14–8.08(m,4H),7.76(d,J＝8.5Hz,2H),7.67–7.63(m,3H),7.52–7.48(m,4H),7.44(ddd,J＝7.3,3.5,1.2Hz,1H),5.77(ddd,J＝17.9,7.5,3.9Hz,1H),4.31(d,J＝7.6Hz,1H)；19FNMR(376MHz,CDCl3)δ-100.56(d,J＝276.7Hz,1F),-113.21(dd,J＝277.5,17.7Hz,1F)；13C{1H}NMR(100MHz,CDCl3)δ194.5,189.4(C-F,dd,2JC-F＝29.9,26.9Hz),147.5,139.4,134.4,133.0,132.7(C-F,d,4JC-F,J＝1.7Hz),130.2(C-F,d,3JC-F,J＝2.9Hz),130.1,129.0,128.6(C-F,d,3JC-F＝3.0Hz),127.3(C-F,d,3JC-F＝3.6Hz),116.0(C-F,dd,1JC-F＝266.3,261.6Hz),72.3(C-F,dd,2JC-F＝27.5,26.5Hz)；HRMS(ESI)m/z:[M+Na]+Calcd for C22H16F2O3Na 389.0965；Found 389.0969。
Example 3g
The crude products were purified by column chromatography with petroleum ether/ethyl acetate(10/1,v/v)as eluent to give compound 3g(white solid,77.8mg,81％yield).M.p.:82–84℃；1H NMR(400MHz,CDCl3)δ8.07–8.03(m,4H),7.65–7.61(m,1H),7.51–7.47(m,2H),7.02–6.98(m,2H),5.67(ddd,J＝18.7,7.6,3.5Hz,1H),4.32(d,J＝7.7Hz,1H),3.90(s,3H)；19F NMR(376MHz,CDCl3)δ-100.59(d,J＝274.6Hz,1F),-114.41(dd,J＝274.7,19.1Hz,1F)；13C{1H}NMR(100MHz,CDCl3)δ192.8,189.5(C-F,dd,2JC-F＝30.1,26.4Hz),164.9,134.3,132.8,132.0(C-F,d,2JC-F＝2.1Hz),130.1(C-F,dd,3JC-F＝4.3,2.5Hz),128.6,127.2,116.0(C-F,dd,1JC-F＝266.4,260.8Hz),114.1,71.85(C-F,dd,2JC-F＝28.2,26.3Hz),55.6；HRMS(ESI)m/z:[M+Na]+Calcd for C17H14F2O4Na 343.0758；Found 343.0764。
Example 3h
The crude products were purified by column chromatography with petroleum ether/ethyl acetate(10/1,v/v)as eluent to give compound 3h(white solid,75.6mg,72％yield).M.p.:104–106℃；1H NMR(400MHz,CDCl3)δ8.05(d,J＝7.5Hz,2H),7.87(d,J＝8.8Hz,1H),7.63–7.59(m,1H),7.47(dd,J＝10.7,4.9Hz,2H),6.58(dd,J＝8.8,2.3Hz,1H),6.45(d,J＝2.2Hz,1H),6.02(ddd,J＝17.8,7.4,5.1Hz,1H),4.37(d,J＝7.5Hz,1H),3.89(s,3H),3.87(s,3H)；19F NMR(376MHz,CDCl3)δ-103.96--104.70(m,1F),-114.17(dd,J＝275.5,18.0Hz,1F)；13C{1H}NMR(100MHz,CDCl3)δ193.7,189.2(C-F,dd,2JC-F＝29.6,27.5Hz),166.0,161.7,134.1,133.6,132.8,130.0(C-F,dd,3JC-F＝3.4Hz),128.5,118.2,116.4(C-F,dd,1JC-F＝264.1,262.1Hz),106.0,98.4,74.9(C-F,t,2JC-F＝25.8,24.7Hz),55.6,55.5；HRMS(ESI)m/z:[M+Na]+Calcd for C18H16F2O5Na 373.0863；Found373.0863。
Example 3i
The crude products were purified by column chromatography with petroleum ether/ethyl acetate(10/1,v/v)as eluent to give compound 3i(white solid,75.1mg,75％yield).M.p.:123–124℃；1H NMR(400MHz,CDCl3)δ8.06(d,J＝7.7Hz,2H),7.66–7.61(m,2H),7.51–7.47(m,3H),6.92(d,J＝8.2Hz,1H),6.09(s,2H),5.63(ddd,J＝18.3,7.7,3.6Hz,1H),4.28(d,J＝7.8Hz,1H)；19F NMR(376MHz,CDCl3)δ-100.61(d,J＝275.8Hz,1F),-114.14(dd,J＝275.5,18.4Hz,1F)；13C{1H}NMR(100MHz,CDCl3)δ192.6,189.4(C-F,dd,2JC-F＝30.1,26.5Hz),153.4,148.4,134.4,132.8(C-F,d,4JC-F＝2.0Hz),130.1(C-F,dd,3JC-F＝4.4,2.4Hz),128.9,128.6,126.8(C-F,d,3JC-F＝2.9Hz),115.9(C-F,dd,1JC-F＝266.4,261.1Hz),108.8,108.1,102.2,72.0(C-F,dd,2JC-F＝27.8,26.3Hz)；HRMS(ESI)m/z:[M+Na]+Calcd for C17H12F2O5Na 357.0550；Found 357.0553。
It should be noted that the above summary and the detailed description are intended to demonstrate the practical application of the technical solutions provided by the present invention, and should not be construed as limiting the scope of the present invention. Various modifications, equivalent substitutions, or improvements may be made by those skilled in the art within the spirit and principles of the invention. The scope of the invention is to be determined by the appended claims.

Claims (6)

1. The method for preparing the 2, 2-difluoro-3-hydroxy-1, 4-diketone compound is characterized in that the method takes a difluorodiluted alcohol silyl ether compound and a substituted glyoxal hydrate as raw materials, takes toluene as a solvent, and reacts under the catalysis of hexafluoroisopropanol to synthesize a target compound, wherein the chemical reaction formula of the target compound is as follows:
Figure FDA0003377283550000011
the specific product structure is as follows:
Figure FDA0003377283550000012
2. the method for preparing 2, 2-difluoro-3-hydroxy-1, 4-diones as in claim 1, wherein the molar ratio of difluorohydrinsiloxane to substituted glyoxal hydrate is 2.5: 1.
3. the process for preparing 2, 2-difluoro-3-hydroxy-1, 4-diones as in claim 1 wherein the molar ratio of hexafluoroisopropanol catalyst to substituted glyoxal hydrate is 1: 10.
4. the method of claim 1, wherein the reaction of the difluorohydrinsiloxane compound with the substituted glyoxal hydrate is carried out at room temperature.
5. The process for preparing 2, 2-difluoro-3-hydroxy-1, 4-diones as in claim 1, wherein the reaction is carried out without any metal as catalyst.
6. The process for producing 2, 2-difluoro-3-hydroxy-1, 4-diones as described in claim 1, characterized in that the reaction is carried out in toluene as a solvent.
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