CN116199659A - Preparation method of 4, 4-difluoro-3, 4-dihydrocoumarin compound - Google Patents
Preparation method of 4, 4-difluoro-3, 4-dihydrocoumarin compound Download PDFInfo
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- -1 4, 4-difluoro-3, 4-dihydrocoumarin compound Chemical class 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 23
- SXOZXLUKVXWUGL-UHFFFAOYSA-M sodium;formaldehyde;hydrogen sulfate Chemical compound [Na+].O=C.OS([O-])(=O)=O SXOZXLUKVXWUGL-UHFFFAOYSA-M 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 150000007860 aryl ester derivatives Chemical class 0.000 claims abstract description 7
- 150000002989 phenols Chemical class 0.000 claims abstract description 5
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 94
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 90
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- 239000003208 petroleum Substances 0.000 claims description 28
- 239000012046 mixed solvent Substances 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 8
- 238000000034 method Methods 0.000 abstract description 7
- 239000000758 substrate Substances 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 56
- 238000003756 stirring Methods 0.000 description 48
- 239000002904 solvent Substances 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 24
- 238000001816 cooling Methods 0.000 description 20
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 239000007788 liquid Substances 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- NMRLTUDASDOBDX-UHFFFAOYSA-N 3-bromo-3,3-difluoropropanoyl chloride Chemical compound FC(F)(Br)CC(Cl)=O NMRLTUDASDOBDX-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 10
- 239000012295 chemical reaction liquid Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 238000004321 preservation Methods 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DMSHWWDRAYHEBS-UHFFFAOYSA-N dihydrocoumarin Natural products C1CC(=O)OC2=C1C=C(OC)C(OC)=C2 DMSHWWDRAYHEBS-UHFFFAOYSA-N 0.000 description 6
- 125000001153 fluoro group Chemical group F* 0.000 description 6
- ZZUMEZGPHGRMFZ-UHFFFAOYSA-N 3-bromo-3,3-difluoropropanoic acid Chemical compound OC(=O)CC(F)(F)Br ZZUMEZGPHGRMFZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- VMUXSMXIQBNMGZ-UHFFFAOYSA-N 3,4-dihydrocoumarin Chemical group C1=CC=C2OC(=O)CCC2=C1 VMUXSMXIQBNMGZ-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical group C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- IXGFPBMPFILZEP-UHFFFAOYSA-N 3-chloro-3,3-difluoropropanoic acid Chemical compound OC(=O)CC(F)(F)Cl IXGFPBMPFILZEP-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a 4, 4-difluoro-3, 4-dihydrocoumarin compound, which comprises the following steps: (1) Carrying out esterification reaction on a phenolic compound II and 3-halogen-3, 3-difluoropropionyl chloride under the action of alkali to obtain a compound III, namely 3-halogen-3, 3-difluoropropionic acid aryl ester; (2) And (3) performing ring closure reaction on the 3-halogen-3, 3-difluoropropionic acid aryl ester of the compound III and sodium bisulfate formaldehyde to obtain a compound I, 4-difluoro-3, 4-dihydrocoumarin compound. The invention adopts a two-step method to synthesize the target product 4, 4-difluoro-3, 4-dihydrocoumarin compound, and the method has simple operation, wide substrate adaptability and high product yield.
Description
Technical Field
The invention relates to a preparation method of a 4, 4-difluoro-3, 4-dihydrocoumarin compound, belonging to the technical field of organic synthesis.
Background
Fluorine-containing compounds often exhibit unique physicochemical properties, mainly due to the many unique properties of fluorine atoms: such as small volume, strong electronegativity, strong bond force with carbon than halogen atoms except hydrogen and fluorine, no flexibility of bond distance of carbon-fluorine bond, low polarizability, small dispersion force of interaction with molecules of other substances, large hydrophobicity, high lipophilicity, etc. Therefore, after fluorine atoms are connected to the organic micromolecules, the lipophilicity of the organic micromolecules can be improved, and if the organic micromolecules are used as medicines, the metabolism stability and biocompatibility of the organic micromolecules can be improved; in terms of materials science, the introduction of fluorine atoms can also change the characteristics of the material so that the material has unique properties.
The dihydrocoumarin compound widely exists in natural products and bioactive substances and is a core skeleton of many natural products, and has wide physiological activities such as anticoagulation activity, cardiovascular disease resistance, HIV resistance, tumor resistance, oxidation resistance, antimicrobial bacterial activity, anti-inflammatory activity and the like, so that in recent years, the synthesis of the dihydrocoumarin skeleton attracts more and more attention, and a plurality of effective methods for preparing the dihydrocoumarin compound are reported. However, there are few reports of directly introducing fluorine atoms to the dihydropyran ring of the dihydrocoumarin-based skeleton, but all of them introduce fluorine-containing groups to the outside of the structure of the aromatic ring or coumarin-based compound skeleton.
Disclosure of Invention
The invention aims to: the invention aims to provide a simple and efficient method for preparing 4, 4-difluoro-3, 4-dihydrocoumarin compounds, which can obtain target products in two steps.
The technical scheme is as follows: the preparation method of the 4, 4-difluoro-3, 4-dihydrocoumarin compound comprises the following steps:
(1) Carrying out esterification reaction on a phenolic compound II and 3-halogen-3, 3-difluoropropionyl chloride under the action of alkali to obtain a compound III, namely 3-halogen-3, 3-difluoropropionic acid aryl ester;
(2) Carrying out ring closure reaction on the 3-halogen-3, 3-difluoropropionic acid aryl ester of the compound III and sodium bisulfate formaldehyde to obtain a compound I4, 4-difluoro-3, 4-dihydrocoumarin compound;
the synthetic route is as follows:
wherein R is hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl or benzyl; x is Cl, br or I.
Wherein in the step (1), the alkali is pyridine, trialkyl tertiary amine or aromatic tertiary amine; the base is preferably pyridine or triethylamine.
Wherein, in the step (1), the reaction conditions are as follows: the reaction is carried out in an inert gas atmosphere, and the reaction temperature is between 20 ℃ below zero and 20 ℃; the reaction solvent can dissolve the raw materials, and the solvent is preferably toluene; the molar ratio of the reactant 3-halogen-3, 3-difluoropropionyl chloride to the phenol compound II and the alkali is 1-1.6:1:1; the reaction progress was checked by TLC, and the developing solvent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1.
Wherein, in the step (2), the reaction temperature is 40-90 ℃.
Wherein in the step (2), the reaction solvent is a mixed solvent of DMF and water, and the mixing volume ratio of DMF and water is 1-3:1.
Wherein, in the step (2), the molar ratio of the sodium formaldehyde sulfoxylate to the compound III is 1-4:1; the reaction progress was checked by TLC, and the developing solvent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages: according to the invention, 2 fluorine atoms are simultaneously introduced into the 4-position of the dihydropyran ring of the dihydrocoumarin by adopting a two-step method, and the compound can combine the characteristics of the fluorine atoms with the medicinal value of the dihydrocoumarin compound, so that the bioavailability and the pharmaceutical activity of the dihydrocoumarin compound are more effectively improved; the method has the advantages of simple operation, wide substrate adaptability and high product yield.
Detailed Description
Example 1
Preparation of phenyl 3-bromo-3, 3-difluoropropionate: 50mmol of phenol (compound II, R is hydrogen), 50mmol of pyridine and 30mL of toluene are added into a reaction bottle under the protection of nitrogen, and the temperature of the reaction system is reduced to 0 ℃ after stirring for 0.5h at room temperature; 50mmol of 3-bromo-3, 3-difluoropropionyl chloride is dissolved in 20mL of toluene, a toluene solution of 3-bromo-3, 3-difluoropropionyl chloride is slowly dripped into the toluene solution containing phenol, the reaction is stirred at room temperature after dripping, TLC detects the reaction progress, a developing agent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1, 100mL of water and 100mL of toluene are added to the reaction solution after the reaction is completed for about 0.5h, stirring is carried out for 10min, the separated liquid is separated, an organic layer is collected, 30mL of 0.5M diluted hydrochloric acid and 100mL of saturated saline solution are respectively used for washing, anhydrous sodium sulfate is dried, and the solvent is distilled off under reduced pressure to obtain pale yellow compound III, namely 3-bromo-3, 3-difluoropropionic acid phenyl ester, the yield of which is 70%. The obtained product can be directly used for the next reaction without purification.
The structure of phenyl 3-bromo-3, 3-difluoropropionate obtained in example 1 was determined by MS and 1 characterization by H NMR, ESI-LRMS m/z 265.1[ M+H ]] + , 1 H NMR(500MHz,CDCl 3 )δ:7.25～7.47(m,3H),7.05～7.16(m,2H),2.58(t,J＝41.8Hz,2H)。
The 3-bromo-3, 3-difluoropropionyl chloride is prepared by the acyl chlorination reaction of 3-bromo-3, 3-difluoropropionic acid and thionyl chloride, and the specific method is as follows: 100mmol of 3-bromo-3, 3-difluoropropionic acid, 200mL of benzene and 3 drops of DMF are added into a reaction bottle, 15mL of thionyl chloride is added into the mixture after the mixture is stirred uniformly, the mixture is subjected to reflux reaction for 3 hours, and benzene and unreacted thionyl chloride are distilled off under reduced pressure, so that 3-bromo-3, 3-difluoropropionyl chloride is obtained. Wherein, 3-bromo-3, 3-difluoropropionic acid: CAS:130312-65-1, available from Nanjing Shizhou Biotechnology Co. Similarly, 3-chloro-3, 3-difluoropropionyl chloride is prepared by acyl chlorination reaction of 3-chloro-3, 3-difluoropropionic acid and thionyl chloride; the 3-iodine-3, 3-difluoropropionyl chloride is prepared by the acyl chlorination reaction of 3-iodine-3, 3-difluoropropionic acid and thionyl chloride.
Example 2
Preparation of phenyl 3-bromo-3, 3-difluoropropionate: 50mmol of phenol (compound II, R is hydrogen), 50mmol of pyridine and 30mL of toluene are added into a reaction bottle under the protection of nitrogen, and the temperature of the reaction system is reduced to 0 ℃ after stirring for 0.5h at room temperature; 65mmol of 3-bromo-3, 3-difluoropropionyl chloride is dissolved in 20mL of toluene, a toluene solution of 3-bromo-3, 3-difluoropropionyl chloride is slowly dripped into the toluene solution containing phenol, the reaction is stirred at room temperature after dripping, TLC detects the reaction progress, a developing agent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1, 100mL of water and 100mL of toluene are added to the reaction solution after the reaction is completed for about 0.5h, stirring is carried out for 10min, the separated liquid is separated, an organic layer is collected, 30mL of 0.5M diluted hydrochloric acid and 100mL of saturated saline solution are respectively used for washing, anhydrous sodium sulfate is dried, and the solvent is distilled off under reduced pressure to obtain pale yellow compound III 3-bromo-3, 3-difluoropropionic acid phenyl ester, and the yield is 86%. The obtained product can be directly used for the next reaction without purification.
Example 3
Preparation of phenyl 3-bromo-3, 3-difluoropropionate: 50mmol of phenol (compound II, R is hydrogen), 50mmol of pyridine and 30mL of toluene are added into a reaction bottle under the protection of nitrogen, and the temperature of the reaction system is reduced to 0 ℃ after stirring for 0.5h at room temperature; 80mmol of 3-bromo-3, 3-difluoropropionyl chloride is dissolved in 20mL of toluene, a toluene solution of 3-bromo-3, 3-difluoropropionyl chloride is slowly dripped into the toluene solution containing phenol, the reaction is stirred at room temperature after dripping, TLC detects the reaction progress, a developing agent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1, 100mL of water and 100mL of toluene are added to the reaction solution after the reaction is completed for about 0.5h, stirring is carried out for 10min, the separated liquid is separated, an organic layer is collected, 30mL of 0.5M diluted hydrochloric acid and 100mL of saturated saline solution are respectively used for washing, anhydrous sodium sulfate is dried, and the solvent is distilled off under reduced pressure to obtain pale yellow compound III 3-bromo-3, 3-difluoropropionic acid phenyl ester, and the yield is 93%. The obtained product can be directly used for the next reaction without purification.
Example 4
Preparation of phenyl 3-bromo-3, 3-difluoropropionate: 50mmol of phenol (compound II, R is hydrogen), 50mmol of pyridine and 30mL of toluene are added into a reaction bottle under the protection of nitrogen, and the temperature of the reaction system is reduced to 0 ℃ after stirring for 0.5h at room temperature; 70mmol of 3-bromo-3, 3-difluoropropionyl chloride is dissolved in 20mL of ethyl acetate, an ethyl acetate solution of 3-bromo-3, 3-difluoropropionyl chloride is slowly dripped into the toluene solution containing phenol, the reaction is stirred at room temperature after dripping, TLC detects the reaction progress, a developing agent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1, 100mL of water and 100mL of toluene are added to the reaction solution after the reaction is completed for about 0.5h, stirring is carried out for 10min, an organic layer is collected and washed by 30mL of 0.5M dilute hydrochloric acid and 100mL of saturated saline solution respectively, anhydrous sodium sulfate is dried, and the solvent is distilled off under reduced pressure to obtain pale yellow compound III 3-bromo-3, 3-difluoropropionic acid phenyl ester, the yield of which is 92%. The obtained product can be directly used for the next reaction without purification.
As is evident from the yields of the products of examples 1 to 4, the reaction was more complete with increasing molar ratio of 3-bromo-3, 3-difluoropropionyl chloride to phenol, which was advantageous for increasing the yield of the product.
Based on the reaction conditions of example 4 (i.e., the molar ratio of 3-halo-3, 3-difluoropropionyl chloride, phenolic compound II, and base is 1.4:1:1), 3-bromo-3, 3-difluoropropionyl chloride may be replaced with 3-chloro-3, 3-difluoropropionyl chloride, 3-iodo-3, 3-difluoropropionyl chloride; r in the compound II can be halogen, C 1 ～C 4 Alkyl, C of (2) 1 ～C 4 Haloalkyl, C 1 ～C 4 Alkoxy, C3-C6 cycloalkyl, phenyl, benzyl, etc.; thereby obtaining a series of compound III 3-halogen-3, 3-difluoropropionic acid aryl ester; the pyridine can be replaced by tertiary amine such as triethylamine, tributylamine, N-dimethylaniline and the like; the temperature of the reaction system can be adjusted between 20 ℃ below zero and 20 ℃; other reaction conditions were unchanged, and some experimental results are shown in the following table.
Table 1 shows the preparation conditions and results of examples 5 to 49
Example 50
Preparation of compound I4, 4-difluoro-3, 4-dihydrocoumarin: to 50mmol of the phenyl 3-bromo-3, 3-difluoropropionate of the compound III prepared in example 4, 50mmol of sodium bisulfate formaldehyde, 100mL of DMF and 100mL of water were sequentially added, and the reaction system was heated to 90℃with stirring, and the reaction was carried out with heat preservation and stirring; TLC detects the reaction progress, developing agent is mixed solvent of petroleum ether and ethyl acetate in volume ratio of 4:1, after 8 hours, the reaction is completed, heating is stopped, cooling to room temperature, 400mL ethyl acetate and 400mL water are added into the reaction liquid, stirring is carried out for 10 minutes, liquid separation is carried out, the organic layer is collected, 120mL saturated salt water is used for 3 times washing, the organic layer is combined, and dried by anhydrous sodium sulfate, the solvent is distilled off under reduced pressure until about 40mL solvent is left, 200mL petroleum ether is added after cooling, stirring is carried out, standing is carried out for 0.5 hour at room temperature, the precipitated solid is filtered, and the compound I4, 4-difluoro-3, 4-dihydrocoumarin is obtained after the drying under reduced pressure, wherein the yield is 50 percent (calculated by the compound II).
The structure of 4, 4-difluoro-3, 4-dihydrocoumarin obtained in example 50 was obtained by MS and 1 characterization by H NMR, ESI-LRMS m/z 185.2[ M+H ]] + , 1 H NMR(500MHz,CDCl 3 )δ:3.21(t,J＝2.2Hz,2H),7.27～7.41(m,4H)。
Example 51
Preparation of compound I4, 4-difluoro-3, 4-dihydrocoumarin: to 50mmol of the phenyl 3-bromo-3, 3-difluoropropionate of the compound III prepared in example 4, 100mmol of sodium bisulfate formaldehyde, 100mL of DMF and 100mL of water were added in this order, and the reaction system was heated to 90℃with stirring, and the reaction was carried out with heat preservation and stirring; TLC detects the reaction progress, developing agent is mixed solvent of petroleum ether and ethyl acetate in volume ratio of 4:1, after 7 hours, the reaction is completed, heating is stopped, cooling to room temperature, 400mL of ethyl acetate and 400mL of water are added into the reaction liquid, stirring is carried out for 10 minutes, liquid separation is carried out, the organic layer is collected, 120mL of saturated salt water is used for 3 times washing, the organic layer is combined, and dried by anhydrous sodium sulfate, the solvent is distilled off under reduced pressure until about 40mL of solvent is left, 200mL of petroleum ether is added after cooling, stirring is carried out, standing is carried out at room temperature for 0.5 hour, solid is filtered out, and the compound I4, 4-difluoro-3, 4-dihydrocoumarin is obtained after the drying under reduced pressure, and the yield is 61% (calculated by compound II).
Example 52
Preparation of compound I4, 4-difluoro-3, 4-dihydrocoumarin: to 50mmol of the phenyl 3-bromo-3, 3-difluoropropionate of the compound III obtained in example 4, 150mmol of sodium bisulfate formaldehyde, 100mL of DMF and 100mL of water were sequentially added, and the reaction system was heated to 90℃with stirring, and the reaction was carried out with heat preservation and stirring; TLC detects the reaction progress, developing agent is mixed solvent of petroleum ether and ethyl acetate in volume ratio of 4:1, after 6 hours, the reaction is completed, heating is stopped, cooling to room temperature, 400mL of ethyl acetate and 400mL of water are added into the reaction liquid, stirring is carried out for 10 minutes, liquid separation is carried out, the organic layer is collected, 120mL of saturated salt water is used for 3 times washing, the organic layer is combined, and dried by anhydrous sodium sulfate, the solvent is distilled off under reduced pressure until about 40mL of solvent is left, 200mL of petroleum ether is added after cooling, stirring is carried out, standing is carried out at room temperature for 0.5 hour, solid is filtered out, and the compound I4, 4-difluoro-3, 4-dihydrocoumarin is obtained after the drying under reduced pressure, and the yield is 68% (calculated by compound II).
Example 53
Preparation of compound I4, 4-difluoro-3, 4-dihydrocoumarin: to 50mmol of the compound III 3-bromo-3, 3-difluoropropionic acid phenyl ester obtained in example 4, 200mmol of sodium bisulfate formaldehyde, 100mL of LDMF and 100mL of water were sequentially added, and the reaction system was heated to 90℃with stirring, and the reaction was carried out with heat preservation and stirring; TLC detects the reaction progress, developing agent is mixed solvent of petroleum ether and ethyl acetate in volume ratio of 4:1, after 6 hours, the reaction is completed, heating is stopped, cooling to room temperature, 400mL of ethyl acetate and 400mL of water are added into the reaction liquid, stirring is carried out for 10 minutes, liquid separation is carried out, the organic layer is collected, 120mL of saturated salt water is used for 3 times washing, the organic layer is combined, and dried by anhydrous sodium sulfate, the solvent is distilled off under reduced pressure until about 40mL of solvent is left, 200mL of petroleum ether is added after cooling, stirring is carried out, standing is carried out at room temperature for 0.5 hour, solid is filtered out, and the compound I4, 4-difluoro-3, 4-dihydrocoumarin is obtained after the drying under reduced pressure, and the yield is 69% (calculated by compound II).
Example 54
Preparation of compound I4, 4-difluoro-3, 4-dihydrocoumarin: to 50mmol of the compound III 3-bromo-3, 3-difluoropropionic acid phenyl ester obtained in example 4, 150mmol of sodium bisulfate formaldehyde, 100mL of LDMF and 100mL of water were sequentially added, and the reaction system was heated to 40℃with stirring, and the reaction was carried out with heat preservation and stirring; TLC detects the reaction progress, developing agent is mixed solvent of petroleum ether and ethyl acetate in volume ratio of 4:1, after 10 hours, the reaction is completed, heating is stopped, cooling to room temperature, 400mL of ethyl acetate and 400mL of water are added into the reaction liquid, stirring is carried out for 10 minutes, liquid separation is carried out, the organic layer is collected, 120mL of saturated salt water is used for 3 times washing, the organic layer is combined, and dried by anhydrous sodium sulfate, the solvent is distilled off under reduced pressure until about 40mL of solvent is left, 200mL of petroleum ether is added after cooling, stirring is carried out, standing is carried out at room temperature for 0.5 hour, solid is filtered out, and the compound I4, 4-difluoro-3, 4-dihydrocoumarin is obtained after the drying under reduced pressure, and the yield is 39% (calculated by compound II).
Example 55
Preparation of compound I4, 4-difluoro-3, 4-dihydrocoumarin: to 50mmol of the compound III 3-bromo-3, 3-difluoropropionic acid phenyl ester obtained in example 4, 150mmol of sodium bisulfate formaldehyde, 100mL of LDMF and 100mL of water were sequentially added, and the reaction system was heated to 60℃with stirring, and the reaction was carried out with heat preservation and stirring; TLC detects the reaction progress, developing agent is mixed solvent of petroleum ether and ethyl acetate in volume ratio of 4:1, after 8 hours, the reaction is completed, heating is stopped, cooling to room temperature, 400mL of ethyl acetate and 400mL of water are added into the reaction liquid, stirring is carried out for 10 minutes, liquid separation is carried out, the organic layer is collected, 120mL of saturated salt water is used for 3 times washing, the organic layer is combined, and dried by anhydrous sodium sulfate, the solvent is distilled off under reduced pressure until about 40mL of solvent is left, 200mL of petroleum ether is added after cooling, stirring is carried out, standing is carried out at room temperature for 0.5 hour, solid is filtered out, and the compound I4, 4-difluoro-3, 4-dihydrocoumarin is obtained after the drying under reduced pressure, and the yield is 54% (calculated by compound II).
Example 56
Preparation of compound I4, 4-difluoro-3, 4-dihydrocoumarin: to 50mmol of the compound III 3-bromo-3, 3-difluoropropionic acid phenyl ester obtained in example 4, 150mmol of sodium bisulfate formaldehyde, 100mL of LDMF and 100mL of water were sequentially added, and the reaction system was heated to 80℃with stirring, and the reaction was carried out with heat preservation and stirring; TLC detects the reaction progress, developing agent is mixed solvent of petroleum ether and ethyl acetate in volume ratio of 4:1, after 6 hours, the reaction is completed, heating is stopped, cooling to room temperature, 400mL of ethyl acetate and 400mL of water are added into the reaction liquid, stirring is carried out for 10 minutes, liquid separation is carried out, the organic layer is collected, 120mL of saturated salt water is used for 3 times washing, the organic layer is combined, and dried by anhydrous sodium sulfate, the solvent is distilled off under reduced pressure until about 40mL of solvent is left, 200mL of petroleum ether is added after cooling, stirring is carried out, standing is carried out at room temperature for 0.5 hour, solid is filtered out, and the compound I4, 4-difluoro-3, 4-dihydrocoumarin is obtained after the drying under reduced pressure, and the yield is 65% (calculated by compound II).
Example 57
Preparation of compound I4, 4-difluoro-3, 4-dihydrocoumarin: to 50mmol of the phenyl 3-bromo-3, 3-difluoropropionate of the compound III obtained in example 4, 150mmol of sodium bisulfate formaldehyde, 150mL of LDMF and 50mL of water were sequentially added, and the reaction system was heated to 90℃with stirring, and the reaction was carried out with heat preservation and stirring; TLC detects the reaction progress, developing agent is mixed solvent of petroleum ether and ethyl acetate in volume ratio of 4:1, after 6 hours, the reaction is completed, heating is stopped, cooling to room temperature, 400mL of ethyl acetate and 400mL of water are added into the reaction liquid, stirring is carried out for 10 minutes, liquid separation is carried out, the organic layer is collected, 120mL of saturated salt water is used for 3 times washing, the organic layer is combined, and dried by anhydrous sodium sulfate, the solvent is distilled off under reduced pressure until about 40mL of solvent is left, 200mL of petroleum ether is added after cooling, stirring is carried out, standing is carried out at room temperature for 0.5 hour, solid is filtered out, and the compound I4, 4-difluoro-3, 4-dihydrocoumarin is obtained after the drying under reduced pressure, and the yield is 64% (calculated by compound II).
Example 58
Based on the reaction conditions of example 52 (i.e., the reaction temperature is 90 ℃, the reaction solvent is a mixed solution of DMF and water according to the volume ratio of 1:1, and the mole ratio of sodium formaldehyde sulfoxylate to compound III is 3:1), the 3-bromo-3, 3-difluorophenyl propionate prepared in example 4 of compound III is replaced by the 3-bromo-3, 3-difluoroaryl propionate prepared in examples 5-22, and other reaction conditions are unchanged, so that the series of compounds I4, 4-difluoro-3, 4-dihydrocoumarin can be prepared.
Example 59
Preparation of compound I4, 4-difluoro-3, 4-dihydrocoumarin: to 50mmol of the compound III 3-chloro-3, 3-difluoropropionic acid phenyl ester obtained in example 23, 150mmol of sodium bisulfate formaldehyde, 100mL of LDMF and 100mL of water were added in this order, and the reaction system was heated to 90℃with stirring, and the reaction was carried out with heat preservation and stirring; TLC detects the reaction progress, developing agent is mixed solvent of petroleum ether and ethyl acetate in volume ratio of 4:1, after 8 hours, the reaction is completed, heating is stopped, cooling to room temperature, 400mL of ethyl acetate and 400mL of water are added into the reaction liquid, stirring is carried out for 10 minutes, liquid separation is carried out, the organic layer is collected, 120mL of saturated salt water is used for 3 times washing, the organic layer is combined, and dried by anhydrous sodium sulfate, the solvent is distilled off under reduced pressure until about 40mL of solvent is left, 200mL of petroleum ether is added after cooling, stirring is carried out, standing is carried out at room temperature for 0.5 hour, solid is filtered out, and the compound I4, 4-difluoro-3, 4-dihydrocoumarin is obtained after the drying under reduced pressure, and the yield is 31 percent (calculated by the compound II).
Example 60
Preparation of compound I4, 4-difluoro-3, 4-dihydrocoumarin: to 50mmol of the compound III 3-iodo-3, 3-difluoropropionic acid phenyl ester obtained in example 32, 150mmol of sodium bisulfate formaldehyde, 100mL of LDMF and 100mL of water were sequentially added, the reaction system was heated to 90℃with stirring, and the reaction was carried out with heat preservation and stirring; TLC detects the reaction progress, the developing agent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1, after 5 hours, the reaction is completed, heating is stopped, cooling is carried out to room temperature, 400mL of ethyl acetate and 400mL of water are added into the reaction liquid, stirring is carried out for 10 minutes, liquid separation is carried out, the organic layer is collected, 120mL of saturated salt water is used for 3 times for washing, the organic layer is combined, and dried by anhydrous sodium sulfate, the solvent is distilled off under reduced pressure until about 40mL of solvent is left, 200mL of petroleum ether is added after cooling, stirring is carried out, standing is carried out at room temperature for 0.5 hour, solid is filtered out, and the compound I4, 4-difluoro-3, 4-dihydrocoumarin is obtained after the drying under reduced pressure, and the yield is 67% (calculated by the compound II).
Example 61
Based on the reaction conditions of example 60 (i.e., the reaction temperature is 90 ℃, the reaction solvent is a mixed solution of DMF and water according to the volume ratio of 1:1, and the mole ratio of sodium bisulfate formaldehyde to compound III is 3:1), the 3-iodo-3, 3-difluoropropionic acid phenyl ester of compound III prepared in example 32 is replaced by the 3-iodo-3, 3-difluoropropionic acid aryl ester prepared in examples 33-38, and other reaction conditions are unchanged, so that the series of compounds I4, 4-difluoro-3, 4-dihydrocoumarin can be prepared.
Claims (9)
1. The preparation method of the 4, 4-difluoro-3, 4-dihydrocoumarin compound is characterized by comprising the following steps:
(1) Carrying out esterification reaction on a phenolic compound II and 3-halogen-3, 3-difluoropropionyl chloride under the action of alkali to obtain a compound III, namely 3-halogen-3, 3-difluoropropionic acid aryl ester;
(2) Carrying out ring closure reaction on the 3-halogen-3, 3-difluoropropionic acid aryl ester of the compound III and sodium bisulfate formaldehyde to obtain a compound I4, 4-difluoro-3, 4-dihydrocoumarin compound;
the synthetic route is as follows:
wherein R is hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl or benzyl; x is Cl, br or I.
2. The method for producing a 4, 4-difluoro-3, 4-dihydrocoumarin compound according to claim 1, wherein: in the step (1), the alkali is one of pyridine, trialkyl tertiary amine or aromatic tertiary amine.
3. The method for producing a 4, 4-difluoro-3, 4-dihydrocoumarin compound according to claim 1, wherein: in the step (1), the reaction conditions are as follows: the reaction is carried out in an inert gas atmosphere, and the reaction temperature is between-20 ℃ and 20 ℃.
4. The method for producing a 4, 4-difluoro-3, 4-dihydrocoumarin compound according to claim 1, wherein: in the step (1), the molar ratio of the 3-halogen-3, 3-difluoropropionyl chloride to the phenolic compound II to the alkali is 1-1.6:1:1.
5. The method for producing a 4, 4-difluoro-3, 4-dihydrocoumarin compound according to claim 1, wherein: in the step (1), TLC is used for detecting the reaction progress in the reaction process, and the selected developing agent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1.
6. The method for producing a 4, 4-difluoro-3, 4-dihydrocoumarin compound according to claim 1, wherein: in the step (2), the reaction temperature is 40-90 ℃.
7. The method for producing a 4, 4-difluoro-3, 4-dihydrocoumarin compound according to claim 1, wherein: in the step (2), the reaction solvent is a mixed solvent of DMF and water, and the mixing volume ratio of DMF and water is 1-3:1.
8. The method for producing a 4, 4-difluoro-3, 4-dihydrocoumarin compound according to claim 1, wherein: in the step (2), the molar ratio of the sodium formaldehyde sulfoxylate to the compound III is 1-4:1.
9. The method for producing a 4, 4-difluoro-3, 4-dihydrocoumarin compound according to claim 1, wherein: in the step (2), TLC is used for detecting the reaction progress in the reaction process, and the selected developing agent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1.
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| CN105367481A (en) * | 2015-12-03 | 2016-03-02 | 河南工程学院 | Synthetic method for 3,3-difluoro-2-oxindole derivative |
| CN106866608A (en) * | 2017-04-11 | 2017-06-20 | 河南工业大学 | A kind of preparation method of the dihydrocoumarin derivative of fluoro 3,4 |
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| CN105367481A (en) * | 2015-12-03 | 2016-03-02 | 河南工程学院 | Synthetic method for 3,3-difluoro-2-oxindole derivative |
| CN106866608A (en) * | 2017-04-11 | 2017-06-20 | 河南工业大学 | A kind of preparation method of the dihydrocoumarin derivative of fluoro 3,4 |
| CN113584099A (en) * | 2021-07-28 | 2021-11-02 | 南京先进生物材料与过程装备研究院有限公司 | Method for preparing dihydrocoumarin or derivative thereof by adopting micro-flow field reaction technology |
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