CN115925583A - Preparation method of beta-fluoroalkyl-beta-aminovinyl ketone compound - Google Patents
Preparation method of beta-fluoroalkyl-beta-aminovinyl ketone compound Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- -1 amidine hydrochloride Chemical class 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 17
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000001099 ammonium carbonate Substances 0.000 claims abstract description 16
- 235000012501 ammonium carbonate Nutrition 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 238000006115 defluorination reaction Methods 0.000 claims abstract description 9
- 230000009471 action Effects 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- QCMKXHXKNIOBBC-UHFFFAOYSA-N 3-fluoroprop-1-ene Chemical compound FCC=C QCMKXHXKNIOBBC-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 4
- 239000005695 Ammonium acetate Substances 0.000 claims description 4
- 229940043376 ammonium acetate Drugs 0.000 claims description 4
- 235000019257 ammonium acetate Nutrition 0.000 claims description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000005008 perfluoropentyl group Chemical group FC(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(F)* 0.000 claims description 2
- 125000005009 perfluoropropyl group Chemical group FC(C(C(F)(F)F)(F)F)(F)* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 5
- 125000000524 functional group Chemical group 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- OTOATSWKRSNICB-UHFFFAOYSA-N 1,5-diaminopenta-1,4-dien-3-one Chemical class NC=CC(=O)C=CN OTOATSWKRSNICB-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 230000005526 G1 to G0 transition Effects 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- LZCZIHQBSCVGRD-UHFFFAOYSA-N benzenecarboximidamide;hydron;chloride Chemical compound [Cl-].NC(=[NH2+])C1=CC=CC=C1 LZCZIHQBSCVGRD-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- SFFUEHODRAXXIA-UHFFFAOYSA-N 2,2,2-trifluoroacetonitrile Chemical compound FC(F)(F)C#N SFFUEHODRAXXIA-UHFFFAOYSA-N 0.000 description 2
- AJOSDIDPIBJFAI-UHFFFAOYSA-N 4-methoxybenzenecarboximidamide;hydrochloride Chemical compound Cl.COC1=CC=C(C(N)=N)C=C1 AJOSDIDPIBJFAI-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- OTOATSWKRSNICB-ZPUQHVIOSA-N (1e,4e)-1,5-diaminopenta-1,4-dien-3-one Chemical class N\C=C\C(=O)\C=C\N OTOATSWKRSNICB-ZPUQHVIOSA-N 0.000 description 1
- NGMHLSBQVIXGNZ-UHFFFAOYSA-N (2-ethoxybenzenecarboximidoyl)azanium;chloride Chemical compound Cl.CCOC1=CC=CC=C1C(N)=N NGMHLSBQVIXGNZ-UHFFFAOYSA-N 0.000 description 1
- RXAOGVQDNBYURA-UHFFFAOYSA-N (4-chlorobenzenecarboximidoyl)azanium;chloride Chemical compound Cl.NC(=N)C1=CC=C(Cl)C=C1 RXAOGVQDNBYURA-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- UIISHESBWIBGED-UHFFFAOYSA-N 3-cyanobenzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=CC(C#N)=C1 UIISHESBWIBGED-UHFFFAOYSA-N 0.000 description 1
- DKIFMADLURULQV-UHFFFAOYSA-N 4-(trifluoromethyl)benzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=C(C(F)(F)F)C=C1 DKIFMADLURULQV-UHFFFAOYSA-N 0.000 description 1
- IMTHEBSPHHMJOJ-UHFFFAOYSA-N 4-bromobenzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=C(Br)C=C1 IMTHEBSPHHMJOJ-UHFFFAOYSA-N 0.000 description 1
- JQDATBKJKUWNGA-UHFFFAOYSA-N 4-fluorobenzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=C(F)C=C1 JQDATBKJKUWNGA-UHFFFAOYSA-N 0.000 description 1
- LTHONTNMNUUXOD-UHFFFAOYSA-N 4-iodobenzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=C(I)C=C1 LTHONTNMNUUXOD-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- MKJPBOVLAZADQJ-UHFFFAOYSA-N [amino(pyridin-3-yl)methylidene]azanium;chloride Chemical compound Cl.NC(=N)C1=CC=CN=C1 MKJPBOVLAZADQJ-UHFFFAOYSA-N 0.000 description 1
- QEAXZIMXYPAZAX-UHFFFAOYSA-N [amino-(3-methylphenyl)methylidene]azanium;chloride Chemical compound [Cl-].CC1=CC=CC(C(N)=[NH2+])=C1 QEAXZIMXYPAZAX-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- JRYOZJIRAVZGMV-UHFFFAOYSA-N cyclopropanecarboximidamide;hydron;chloride Chemical compound Cl.NC(=N)C1CC1 JRYOZJIRAVZGMV-UHFFFAOYSA-N 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- MTDUPZAXNYELOU-UHFFFAOYSA-N hydron;4-methylbenzenecarboximidamide;chloride Chemical compound Cl.CC1=CC=C(C(N)=N)C=C1 MTDUPZAXNYELOU-UHFFFAOYSA-N 0.000 description 1
- CJXJAUKCHHAJQN-UHFFFAOYSA-N hydron;4-nitrobenzenecarboximidamide;chloride Chemical compound Cl.NC(=N)C1=CC=C([N+]([O-])=O)C=C1 CJXJAUKCHHAJQN-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000003429 reductive ring cleavage reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- URAGJMBGNVOIJC-UHFFFAOYSA-N thiophene-2-carboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=CS1 URAGJMBGNVOIJC-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
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Abstract
The invention discloses a preparation method of a beta-fluoroalkyl-beta-amino vinyl ketone compound, which comprises the step of carrying out defluorination reaction on amidine hydrochloride and a hydroxyl-containing allyl fluoride compound in a solvent under the action of ammonium carbonate and water to obtain the beta-fluoroalkyl-beta-amino vinyl ketone compound. The method has the characteristics of mild reaction conditions, good functional group tolerance, simple post-treatment, green steps, low pollution, high economic benefit and the like.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a preparation method of a beta-fluoroalkyl-beta-amino vinyl ketone compound.
Background
Aminovinyl ketone compounds are present as an important class of structural fragments in a number of pharmaceutical and biologically active molecules (nat. Rev. Drug Discov.2006,5, 821-834), which have been demonstrated to be universal building blocks for the synthesis of different heterocyclic systems by cyclization reactions(adv. Synth. Catal.2022,364, 1508-1521). Although a number of practical strategies have been developed to construct this framework, the direct synthesis of fluoroalkylated β -aminovinyl ketone compounds from readily available and diverse precursors remains challenging. Importantly, introduction of fluoroalkyl groups into aminovinyl ketones can significantly increase biological activity (j. Agric. Food chem.2009,57, 8303-8307) and reactive activity (chem. Commun.2010,46, 2145-2147) due to the unique properties of fluorine atoms. The active methylene compound can be reacted with gaseous trifluoroacetonitrile (CF) 3 CN) to generate beta-trifluoromethylated amino vinyl ketone. This process relies heavily on the use of toxic CF 3 CN, typically requires harsh conditions to achieve the desired conversion. In addition, the intermolecular condensation of the pre-fluorinated diketone or alkynone compound with the ammonium salt is an effective method for obtaining simple enaminones. However, there are some inevitable problems such as the formation of regioisomers and stereoisomers. Recently, a subject group has discovered that the reductive ring cleavage of isoxazole can produce fluoroalkylated enamines where a copper catalyst and stoichiometric amounts of diamine are essential conditions for the success of the reaction (J.Org.chem.2021, 86, 4557-4566). However, metal residues are detrimental to the development of green and sustainable chemistry, particularly in drug development and later derivatization. Therefore, there is a great interest in finding a new green reaction to obtain such β -fluoroalkyl- β -aminovinylketone compounds, which is expected to eliminate the effects of toxic reagents and transition metals.
Therefore, it is a subject to be further explored to develop a reaction system without catalyst and additive, with wide substrate range and simple operation.
Disclosure of Invention
This section is for the purpose of summarizing some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. In this section, as well as in the abstract and the title of the invention of this application, simplifications or omissions may be made to avoid obscuring the purpose of the section, the abstract and the title, and such simplifications or omissions are not intended to limit the scope of the invention.
The present invention has been made keeping in mind the above problems and/or problems occurring in the prior art.
One of the purposes of the invention is to provide a preparation method of a beta-fluoroalkyl-beta-aminovinyl ketone compound, which has the characteristics of mild reaction conditions, good functional group tolerance, simple post-treatment, green steps, low pollution, high economic benefit and the like.
In order to solve the technical problems, the invention provides the following technical scheme: a process for preparing a beta-fluoroalkyl-beta-aminovinyl ketone compound, comprising,
carrying out defluorination reaction on amidine hydrochloride shown in a formula I and allyl fluoride containing hydroxyl shown in a formula II in a solvent under the action of alkali to obtain a compound shown in a formula III;
wherein R is selected from one of phenyl, methoxy substituted phenyl, ethoxy substituted phenyl, methyl substituted phenyl, halogen substituted phenyl, nitro substituted phenyl, cyano substituted phenyl, trifluoromethyl substituted phenyl, thienyl, pyridyl and cyclopropyl;
R 1 、R 2 one selected from methyl, isobutyl, methoxy substituted benzyl, halogen substituted benzyl, cyclobutyl, cyclohexyl and indenyl;
R f selected from perfluoropropyl, perfluoropentyl, perfluoroheptyl, perfluorononyl.
As a preferable embodiment of the method for producing the β -fluoroalkyl- β -aminovinyl ketone compound of the present invention, wherein: the amidine hydrochloride comprises one of benzamidine hydrochloride, 4-methoxybenzamidine hydrochloride, 2-ethoxybenzamidine hydrochloride, 4-methylbenzamidine hydrochloride, 3-methylbenzamidine hydrochloride, 4-fluorobenzamidine hydrochloride, 4-chlorobenzamidine hydrochloride, 4-bromobenzamidine hydrochloride, 4-iodobenzamidine hydrochloride, 4-nitrobenzamidine hydrochloride, 3-cyanobenzamidine hydrochloride, 4-trifluoromethylbenzene-1-formamidine hydrochloride, thiophene-2-formamidine hydrochloride, 3-pyridineamidine hydrochloride and cyclopropylformamidine hydrochloride.
As a preferable embodiment of the method for producing a β -fluoroalkyl- β -aminovinyl ketone compound of the present invention, wherein: the hydroxyl group-containing allylic fluoride compound includes 5,5,6,6,7,7,8,8-nonafluoro-3-iodo-2-methyl-3-octen-2-ol, 5,5,6,6,7,8,8,9,9,10,10,10-tridecafluoro-3-iodo-2-methyl-3-decen-2-ol, 5,5,6,6,7,7,8,8,9,9,10,11,12,12,12-heptadecafluoro-3-iodo-2-methyl-3-dodecen-2-ol, 5,5,6,7,7,8,9,10,11,11,12,13,13,14,14,14-heneicosano-3-iodo-2-methyl-3-tetradecen-2-ol, 7,7,8,8,9,9,10,10,10-nonafluoro-5-iodo-2,4-dimethyl-5-decen-4- ol 5,5,6,6,7,7,8,8, 8-nonafluoro-3-iodo-1- (4-methoxyphenyl) -2-methyl-3-octen-2-ol, 1- (4-chlorophenyl) -5,5,6,6,7,8,8-nonafluoro-3-iodo-2-methyl-3-octen-2-ol, 1- (3,3,4,4,5,6,6, 6-nonafluoro-1-iodo-1-hexen-1-yl) cyclobutyl-1-ol, 1- (3,3,4,4,5,5,6,6-nonafluoro-1-iodo-1-hexen-1-yl) cyclohexyl-1-ol, 2- (3,3,4,4,5,5,6,6-nonafluoro-1-iodo-1-hexen-1-yl) indenyl-2-ol.
As a preferable embodiment of the method for producing a β -fluoroalkyl- β -aminovinyl ketone compound of the present invention, wherein: the molar ratio of the amidine hydrochloride to the hydroxyl-containing allyl fluoride is 1:1 to 2.
As a preferable embodiment of the method for producing a β -fluoroalkyl- β -aminovinyl ketone compound of the present invention, wherein: the alkali is one or more of ammonium carbonate, ammonium chloride, ammonium acetate and cesium carbonate; preferably, the base is ammonium carbonate.
As a preferable embodiment of the method for producing a β -fluoroalkyl- β -aminovinyl ketone compound of the present invention, wherein: the molar ratio of the amidine hydrochloride to the base is 1:2.7 to 8.2; the preferred molar ratio is 1:6.4.
as a preferable embodiment of the method for producing a β -fluoroalkyl- β -aminovinyl ketone compound of the present invention, wherein: the solvent comprises one of acetonitrile, dimethyl sulfoxide and N, N-dimethylacetamide; the preferred solvent is N, N-dimethylacetamide.
As a preferable embodiment of the method for producing a β -fluoroalkyl- β -aminovinyl ketone compound of the present invention, wherein: carrying out defluorination reaction at the temperature of 50-90 ℃; the preferred reaction temperature is 50 ℃.
As a preferable embodiment of the method for producing the β -fluoroalkyl- β -aminovinyl ketone compound of the present invention, wherein: carrying out defluorination reaction for 6-24 h; the preferred reaction time is 24h.
As a preferable embodiment of the method for producing a β -fluoroalkyl- β -aminovinyl ketone compound of the present invention, wherein: also comprises adding water into the reaction system.
As a preferable embodiment of the method for producing a β -fluoroalkyl- β -aminovinyl ketone compound of the present invention, wherein: the molar ratio of the amidine hydrochloride to the water is 1:0 to 10; the preferred molar ratio is 1:5.
in summary, the optimal reaction equation of the present invention is as follows:
compared with the prior art, the invention has the following beneficial effects:
the invention provides a method for generating a series of beta-fluoroalkyl-beta-amino vinyl ketone compounds by defluorination reaction of amidine hydrochloride and hydroxyl-containing allyl fluoride compounds under the action of alkali in a solvent under the condition of no metal; the reaction condition is mild, the functional group tolerance is good, and the method has the characteristics of simple post-treatment, green steps, low pollution, high economic benefit and the like.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the description below are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without inventive labor. Wherein:
FIG. 1 is a hydrogen spectrum of the object product (Z) -5-amino-6, 7, 8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z) -amino (phenyl) methylene) carbamate of example 1 of the present invention;
FIG. 2 is a fluorine spectrum of the objective product (Z) -5-amino-6, 7, 8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z) -amino (phenyl) methylene) carbamate of example 1 of the present invention;
FIG. 3 is a carbon spectrum of the objective product (Z) -5-amino-6, 7, 8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z) -amino (phenyl) methylene) carbamate of example 1 of the present invention;
FIG. 4 is a hydrogen spectrum of the objective product (Z) -5-amino-6, 7, 8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z) -amino (4-methoxyphenyl) methylene) carbamate of example 2 of the present invention;
FIG. 5 is a fluorine spectrum of the objective product (Z) -5-amino-6, 7, 8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z) -amino (4-methoxyphenyl) methylene) carbamate of example 2 of the present invention;
FIG. 6 is a carbon spectrum of the objective product (Z) -5-amino-6, 7, 8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z) -amino (4-methoxyphenyl) methylene) carbamate of example 2 of the present invention;
FIG. 7 is a hydrogen spectrum of the objective product (Z) -7-amino-8, 9, 10-heptafluoro-2, 4-dimethyl-5-oxodec-6-en-4-yl ((Z) -amino (phenyl) methylene) carbamate of example 3 of the present invention;
FIG. 8 is a fluorine spectrum of the objective product (Z) -7-amino-8, 9, 10-heptafluoro-2, 4-dimethyl-5-oxodec-6-en-4-yl ((Z) -amino (phenyl) methylene) carbamate of example 3 of the present invention;
FIG. 9 is a carbon spectrum of the objective product (Z) -7-amino-8, 9, 10-heptafluoro-2, 4-dimethyl-5-oxodec-6-en-4-yl ((Z) -amino (phenyl) methylene) carbamate obtained in example 3 according to the present invention.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention more comprehensible, specific embodiments thereof are described in detail below with reference to examples of the specification.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.
Furthermore, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
The starting hydroxyl-containing allylic fluoride compounds used in the examples were prepared by the methods reported in the literature (Angew. Chem. Int. Ed.2014,53, 4910-4914). Other raw materials are not specifically described and are all purchased commercially.
Example 1
(1) To a 10mL Schlenk tube were added 5,5,6,6,7,7,8,8-nonafluoro-3-iodo-2-methyl-3-octen-2-ol (193.5mg, 0.45mmol,1.5equ v.), benzamidine hydrochloride (47mg, 0.3mmol,1equ v.), ammonium carbonate (184.4mg, 1.92mmol,6.4equ v.), N, N-dimethylacetamide (2 mL), water (27mg, 1.5mmol,5equ v.), and the reaction mixture was stirred at 50 ℃ for 24h in the air.
(2) After the reaction in the step (1) is finished, saturated NH is used 4 The Cl solution was quenched and extracted with ethyl acetate (20 mL. Times.3); the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product; the crude product is purified by a silica gel column chromatography, and the column chromatography separation conditions are as follows: the stationary phase is silica gel powder with 300-400 meshes, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A: B) is 1:7, finally obtaining 98.9mg of the target product a.
The target product a is characterized, as shown in FIGS. 1,2 and 3, and the result is: a yellow solid;
1 H NMR(400MHz,DMSO-d 6 ):δ＝9.22(brs,2H),9.14(brs,2H),7.95(d,J＝7.2Hz,2H),7.60–7.54(m,1H),7.50–7.44(m,2H),5.47(s,1H),1.45(s,6H)ppm.
19 F NMR(376MHz,DMSO-d 6 ):δ＝-80.24(t,J＝9.5Hz,3F),-120.12(q,J＝9.6Hz,2F),-127.11(s,2F)ppm.
13 C NMR(100MHz,DMSO-d 6 ):δ＝199.7,167.3,162.8,147.0(t,J C-F ＝24.0Hz),134.2,132.1,128.4,127.8,88.4,81.5,24.3ppm.
HRMS(m/z):calcd for C 17 H 17 F 7 N 3 O 3 [M+H] + 444.1153,found:444.1154.
from the characterization data, the reaction product obtained was (Z) -5-amino-6, 7, 8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z) -amino (phenyl) methylene) carbamate (> 98% pure), which compound has the formula:
the product yield was calculated to be 74%.
Example 2
(1) To a 10mL Schlenk tube were added 5,5,6,6,7,7,8,8-nonafluoro-3-iodo-2-methyl-3-octen-2-ol (193.5mg, 0.45mmol, 1.5equv.), 4-methoxybenzamidine hydrochloride (56mg, 0.3mmol, 1equv.), ammonium carbonate (184.4mg, 1.92mmol, 6.4equv.), N, N-dimethylacetamide (2 mL), water (27mg, 1.5mmol, 5equv.), and the reaction mixture was stirred in the air at 50 ℃ for 24h.
(2) After the reaction in the step (1) is finished, saturated NH is used 4 The Cl solution was quenched and extracted with ethyl acetate (20 mL. Times.3); the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product; the crude product is purified by a silica gel column chromatography, and the separation conditions of the column chromatography are as follows: the stationary phase is silica gel powder with 300-400 meshes, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A: B) is 1:7, finally obtaining 85.4mg of the target product b.
The target product b was characterized as shown in FIGS. 4,5 and 6, and the results were: a yellow solid;
1 H NMR(400MHz,CDCl 3 ):δ＝9.50(brs,2H),7.85–7.79(m,2H),6.90–6.84(m,2H),6.79(brs,2H),5.76(s,1H),3.81(s,3H),1.54(s,6H)ppm.
19 F NMR(376MHz,CDCl 3 ):δ＝-80.31(s,3F),-120.10(s,2F),-127.13(s,2F)ppm.
13 C NMR(100MHz,CDCl 3 ):δ＝201.6,168.1,163.7,163.1,147.3(t,J C-F ＝24.5Hz),129.3,126.4,114.0,91.2,82.6,55.5,24.1ppm.
HRMS(m/z):calcd for C 18 H 19 F 7 N 3 O 4 [M+H] + 474.1258,found:474.1252.
according to the characterization data, the reaction product obtained was (Z) -5-amino-6, 7, 8-heptafluoro-2-methyl-3-oxooct-4-en-2-yl ((Z) -amino (4-methoxyphenyl) methylene) carbamate (purity > 98%), which has the formula:
the product yield was calculated to be 60%.
Example 3
(1) To a 10mL Schlenk tube were added 7,8, 9, 10-nonafluoro-5-iodo-2, 4-dimethyl-5-decen-4-ol (212.5mg, 0.45mmol, 1.5equv.), benzamidine hydrochloride (47mg, 0.3mmol, 1equv.), ammonium carbonate (184.4mg, 1.92mmol, 6.4equv.), N, N-dimethylacetamide (2 mL), water (27mg, 1.5mmol, 5equv.), and the reaction mixture was stirred at 50 ℃ for 24h in air.
(2) After the reaction in the step (1) is finished, saturated NH is used 4 The Cl solution was quenched and extracted with ethyl acetate (20 mL. Times.3); the combined organic phases were washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product; the crude product is purified by a silica gel column chromatography, and the column chromatography separation conditions are as follows: the stationary phase is silica gel powder with 300-400 meshes, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A: B) is 1:4, 93.6mg of the target product c are finally obtained.
The above target product c was characterized as shown in FIGS. 7,8 and 9, and the results were: a yellow solid;
1 H NMR(400MHz,CDCl 3 ):δ＝9.50(brs,2H),7.86–7.80(m,2H),7.54–7.48(m,1H),7.45–7.38(m,2H),6.70(brs,2H),5.80(s,1H),1.94–1.87(m,1H),1.82–1.71(m,2H),1.61(s,3H),0.95(d,J＝6.4Hz,3H),0.88(d,J＝6.4Hz,3H)ppm.
19 F NMR(376MHz,CDCl 3 ):δ＝-80.26(t,J＝9.1Hz,3F),-120.07(q,J＝9.5Hz,2F),-127.09(s,2F)ppm.
13 C NMR(100MHz,CDCl 3 ):δ＝201.6,168.6,163.7,147.1(t,J C-F ＝24.4Hz),134.7,132.4,128.8,127.4,91.9,85.5,46.0,24.5,24.3,23.8,20.8ppm.
HRMS(m/z):calcd for C 20 H 23 F 7 N 3 O 3 [M+H] + 486.1622,found:486.1622.
from the characterization data, the reaction product obtained was (Z) -7-amino-8, 9, 10-heptafluoro-2, 4-dimethyl-5-oxodec-6-en-4-yl ((Z) -amino (phenyl) methylene) carbamate (> 98% pure), which compound had the formula:
the product yield was calculated to be 64%.
Example 4
Example 4 is essentially the same as example 1, except that in step (1), the base is different, as shown in table 1 below:
TABLE 1
| Alkali | Yield (%) |
| Ammonium chloride/cesium carbonate =2 | 66 |
| Ammonium acetate/cesium carbonate =2 | 12 |
| Ammonia/cesium carbonate =2 | trace |
| Ammonium carbonate | 74 |
As can be seen from table 1, under the same reaction conditions, a base is used, such as: ammonium acetate/cesium carbonate =2, ammonia/cesium carbonate =2, with lower yields; the yield was 66% with ammonium chloride/cesium carbonate =2 as base, and the highest reaction yield was 74% with ammonium carbonate as base.
Example 5
Example 5 is substantially the same as example 1 except that in step (1), the molar ratio of amidine hydrochloride to ammonium carbonate is different as shown in table 2 below:
TABLE 2
| Amidine hydrochloride (mmol) | Ammonium carbonate (mmol) | Yield (%) |
| 0.3 | 0.81 | 37 |
| 0.3 | 1.38 | 35 |
| 0.3 | 1.92 | 74 |
| 0.3 | 2.46 | 38 |
As can be seen from Table 2, under the same reaction conditions, in the case of fixed molar amount of amidine hydrochloride, increasing the molar amount of ammonium carbonate is favorable for improving the reaction yield, especially at 0.3mmol of amidine hydrochloride and 1.92mmol of ammonium carbonate, the reaction yield is up to 74%. When the molar amount of ammonium carbonate is further increased, the reaction yield is rather lowered.
Example 6
Example 6 is essentially the same as example 1, except that in step (1) the molar ratio of amidine hydrochloride to water is different, as shown in table 3 below:
TABLE 3
| Amidine hydrochloride (mmol) | Water (mmol) | Yield (%) |
| 0.3 | 0 | 65 |
| 0.3 | 1.5 | 74 |
| 0.3 | 3 | 72 |
As can be seen from Table 3, under the same reaction conditions, the addition of water is advantageous for increasing the reaction yield with a fixed molar amount of amidine hydrochloride, especially the highest reaction yield with 0.3mmol of amidine hydrochloride and 1.5mmol of water. When the molar amount of water is further increased, the reaction yield is rather lowered.
Example 7
Example 7 is essentially the same as example 1, except that in step (1), the reaction solvent is different, as shown in table 4 below:
TABLE 4
| Reaction solvent | Yield (%) |
| DMA | 74 |
| DMSO | 52 |
| MeCN | 4 |
| DCE | trace |
| t BuOH | trace |
As can be seen from table 4, under the same reaction conditions, solvents were used, such as: acetonitrile (MeCN), 1, 2-Dichloroethane (DCE) tert-butanol (i) t BuOH), the yield is low; when dimethyl sulfoxide (DMSO) is used as a solvent, the reaction yield is 52 percent; the reaction yield was highest when N, N-Dimethylacetamide (DMA) was used as the solvent.
Example 8
Example 8 is essentially the same as example 1, except that in step (1), the temperature is different, as shown in table 5 below:
TABLE 5
| Temperature (. Degree.C.) | Yield (%) |
| 50 | 74 |
| 70 | 44 |
| 90 | tarce |
As can be seen from Table 5, the reaction yield was the highest at the reaction temperature of 50 ℃ under the same reaction conditions; increasing the reaction temperature results in a decrease in the reaction yield.
Example 9
Example 9 is essentially the same as example 1, except that in step (1), the reaction time is different, as shown in table 6 below:
TABLE 6
| Reaction time | Yield (%) |
| 6h | 53 |
| 12h | 62 |
| 24h | 74 |
As can be seen from Table 6, under the same reaction conditions, the increase of the reaction yield is facilitated by the extension of the reaction time; the reaction yield was 74% when calculated for 24h.
Example 10
Example 10 is essentially the same as example 1, except that in step (1), the amidine hydrochloride compound is different and the desired product is obtained as shown in table 7 below:
TABLE 7
Example 11
Example 11 is substantially the same as example 3, except that in step (1), the hydroxyl group-containing allylic fluoride compound is different, and the target product is obtained as shown in table 8 below:
TABLE 8
The invention provides a method for generating a series of beta-fluoroalkyl-beta-amino vinyl ketone compounds by carrying out defluorination reaction on amidine hydrochloride and hydroxyl-containing allyl fluoride compounds in N, N-dimethylacetamide under the action of ammonium carbonate and water under the condition of no metal; the method has the characteristics of mild reaction conditions, good functional group tolerance, simple post-treatment, green steps, low pollution, high economic benefit and the like.
It should be noted that the above-mentioned embodiments are only for illustrating the technical solutions of the present invention and not for limiting, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, which should be covered by the claims of the present invention.
Claims (10)
1. A method for producing a beta-fluoroalkyl-beta-aminovinyl ketone compound, characterized in that: comprises the steps of (a) preparing a mixture of a plurality of raw materials,
carrying out defluorination reaction on amidine hydrochloride shown in a formula I and allyl fluoride containing hydroxyl shown in a formula II in a solvent under the action of alkali to obtain a compound shown in a formula III;
wherein R is selected from one of phenyl, methoxy substituted phenyl, ethoxy substituted phenyl, methyl substituted phenyl, halogen substituted phenyl, nitro substituted phenyl, cyano substituted phenyl, trifluoromethyl substituted phenyl, thienyl, pyridyl and cyclopropyl;
R 1 、R 2 one selected from methyl, isobutyl, methoxy substituted benzyl, halogen substituted benzyl, cyclobutyl, cyclohexyl and indenyl;
R f selected from perfluoropropyl, perfluoropentyl, perfluoroheptyl, perfluorononyl.
2. The process for producing a β -fluoroalkyl- β -aminovinyl ketone compound according to claim 1, wherein: the molar ratio of the amidine hydrochloride to the hydroxyl-containing allyl fluoride is 1:1 to 2.
3. The process for producing a β -fluoroalkyl- β -aminovinyl ketone compound according to claim 1 or 2, wherein: the molar ratio of the amidine hydrochloride to the base is 1:2.7 to 8.2.
4. A process for producing a β -fluoroalkyl- β -aminovinyl ketone compound according to claim 3, wherein: the alkali is one or more of ammonium carbonate, ammonium chloride, ammonium acetate and cesium carbonate.
5. The process for producing a β -fluoroalkyl- β -aminovinyl ketone compound according to claim 4, wherein: the alkali is ammonium carbonate.
6. The process for producing a β -fluoroalkyl- β -aminovinyl ketone compound according to any one of claims 1,2, 4 and 5, wherein: the solvent comprises one of acetonitrile, dimethyl sulfoxide and N, N-dimethylacetamide.
7. The process for producing a β -fluoroalkyl- β -aminovinyl ketone compound according to claim 6, wherein: the defluorination reaction is carried out at the reaction temperature of 50-90 ℃ for 6-24 h.
8. The process for producing a β -fluoroalkyl- β -aminovinyl ketone compound according to claim 7, wherein: the defluorination reaction is carried out at the reaction temperature of 50 ℃.
9. The process for producing a β -fluoroalkyl- β -aminovinylketone compound according to any one of claims 1,2, 4,5, 7 and 8, wherein: also comprises adding water into the reaction system.
10. The process for producing a β -fluoroalkyl- β -aminovinyl ketone compound according to claim 9, wherein: the molar ratio of the amidine hydrochloride to the water is 1:0 to 10.
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| CN113024470A (en) * | 2021-03-17 | 2021-06-25 | 南京工业大学 | 4-perfluoroalkyl substituted pyrimidine compound and preparation method and application thereof |
| CN114853681A (en) * | 2022-05-27 | 2022-08-05 | 南京工业大学 | Preparation method of pyrimidine heterocyclic guanyl formate compound |
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| CN113024470A (en) * | 2021-03-17 | 2021-06-25 | 南京工业大学 | 4-perfluoroalkyl substituted pyrimidine compound and preparation method and application thereof |
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