WO2022156025A1 - 4-(2,2,2-三氯乙基)-β-内酰胺衍生物的合成方法 - Google Patents
4-(2,2,2-三氯乙基)-β-内酰胺衍生物的合成方法 Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 82
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 58
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 150000001879 copper Chemical class 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 239000007800 oxidant agent Substances 0.000 claims abstract description 10
- 230000001590 oxidative effect Effects 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 3
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical group CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- -1 halopropyl Chemical class 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 5
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical group Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 5
- 125000001797 benzyl group Chemical class [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
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003903 2-propenyl group Chemical class [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000004850 cyclobutylmethyl group Chemical class C1(CCC1)C* 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical class [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims 1
- 239000001273 butane Substances 0.000 claims 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims 1
- 125000005610 enamide group Chemical group 0.000 claims 1
- 150000002148 esters Chemical group 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 229960001701 chloroform Drugs 0.000 abstract description 29
- 238000000034 method Methods 0.000 abstract description 12
- 230000008569 process Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- 239000012043 crude product Substances 0.000 description 22
- 239000000203 mixture Substances 0.000 description 22
- 239000003208 petroleum Substances 0.000 description 22
- 238000010898 silica gel chromatography Methods 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 21
- 239000010949 copper Substances 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 21
- 150000003952 β-lactams Chemical class 0.000 description 9
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 8
- RBBJXENQWXGNST-UHFFFAOYSA-N N-quinolin-8-ylbut-3-enamide Chemical compound N1=CC=CC2=CC=CC(=C12)NC(CC=C)=O RBBJXENQWXGNST-UHFFFAOYSA-N 0.000 description 6
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000002994 raw material Substances 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- XTEOJPUYZWEXFI-UHFFFAOYSA-N butyl n-[3-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate Chemical compound S1C(CC(C)C)=CC(C=2C=CC(CN3C=NC=C3)=CC=2)=C1S(=O)(=O)NC(=O)OCCCC XTEOJPUYZWEXFI-UHFFFAOYSA-N 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 1
- VPMIAOSOTOODMY-KJAPKAAFSA-N (4r)-6-[(e)-2-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1/C=C/C=1C(C(C)C)=NC(C(C)(C)C)=CC=1C1=CC=C(F)C=C1 VPMIAOSOTOODMY-KJAPKAAFSA-N 0.000 description 1
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 1
- QBHCDUCXRVOUCN-UHFFFAOYSA-N 2-benzyl-N-quinolin-8-ylbut-3-enamide Chemical compound N1=CC=CC2=CC=CC(=C12)NC(C(C=C)CC1=CC=CC=C1)=O QBHCDUCXRVOUCN-UHFFFAOYSA-N 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- REDUQXCPUSNJOL-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O Chemical compound C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O REDUQXCPUSNJOL-UHFFFAOYSA-N 0.000 description 1
- RZTNANZSMJVWAR-UHFFFAOYSA-N C=CC(CCC(C=C1)=CC=C1F)C(NC1=C2N=CC=CC2=CC=C1)=O Chemical compound C=CC(CCC(C=C1)=CC=C1F)C(NC1=C2N=CC=CC2=CC=C1)=O RZTNANZSMJVWAR-UHFFFAOYSA-N 0.000 description 1
- QCIOLZTWFGDRKZ-UHFFFAOYSA-N CC(C=CCC(NC1=C2N=CC=CC2=CC=C1)=O)C1=CC=CC=C1 Chemical compound CC(C=CCC(NC1=C2N=CC=CC2=CC=C1)=O)C1=CC=CC=C1 QCIOLZTWFGDRKZ-UHFFFAOYSA-N 0.000 description 1
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 1
- QXCCLKZFWDNVFD-UHFFFAOYSA-N N-quinolin-8-ylhex-3-enamide Chemical compound N1=CC=CC2=CC=CC(=C12)NC(CC=CCC)=O QXCCLKZFWDNVFD-UHFFFAOYSA-N 0.000 description 1
- MDIILATYPIDCQV-UHFFFAOYSA-N N-quinolin-8-ylpent-3-enamide Chemical compound N1=CC=CC2=CC=CC(=C12)NC(CC=CC)=O MDIILATYPIDCQV-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- ADLCINRDGVAUKU-UHFFFAOYSA-N N1=CC=CC2=CC=CC(=C12)NC(C(C=C)C(C)C)=O Chemical compound N1=CC=CC2=CC=CC(=C12)NC(C(C=C)C(C)C)=O ADLCINRDGVAUKU-UHFFFAOYSA-N 0.000 description 1
- AQHUQAGJIBUBHG-UHFFFAOYSA-N N1=CC=CC2=CC=CC(=C12)NC(C(C=C)C)=O Chemical compound N1=CC=CC2=CC=CC(=C12)NC(C(C=C)C)=O AQHUQAGJIBUBHG-UHFFFAOYSA-N 0.000 description 1
- OHYGZNZPKLAJSE-UHFFFAOYSA-N N1=CC=CC2=CC=CC(=C12)NC(C(C=C)CC)=O Chemical compound N1=CC=CC2=CC=CC(=C12)NC(C(C=C)CC)=O OHYGZNZPKLAJSE-UHFFFAOYSA-N 0.000 description 1
- SSCVUFQUIVCJOH-UHFFFAOYSA-N N1=CC=CC2=CC=CC(=C12)NC(C(C=C)CCC1=CC=CC=C1)=O Chemical compound N1=CC=CC2=CC=CC(=C12)NC(C(C=C)CCC1=CC=CC=C1)=O SSCVUFQUIVCJOH-UHFFFAOYSA-N 0.000 description 1
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- KSCRVOKQPYZBHZ-IXPOFIJOSA-N benzyl n-[(2s)-1-[[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@H]1C(NCC1)=O)C(=O)C=1SC2=CC=CC=C2N=1)C(C)C)C(=O)OCC1=CC=CC=C1 KSCRVOKQPYZBHZ-IXPOFIJOSA-N 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 1
- BSXVKCJAIJZTAV-UHFFFAOYSA-L copper;methanesulfonate Chemical compound [Cu+2].CS([O-])(=O)=O.CS([O-])(=O)=O BSXVKCJAIJZTAV-UHFFFAOYSA-L 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention relates to the technical field of preparation of organic compounds, in particular to a method for synthesizing 4-(2,2,2-trichloroethyl)- ⁇ -lactam derivatives.
- ⁇ -Lactam is an important part of N heterocycle, and it is the core skeleton of many natural products and drug molecules, especially the specific drugs of some antibiotics. Therefore, the synthesis of ⁇ -lactam derivatives is of great value.
- the yield is low, expensive raw materials are used, the reaction conditions are harsh and the environment is unfriendly.
- the purpose is to provide a preparation method of 4-(2,2,2-trichloroethyl)- ⁇ -lactam derivatives, which has easy-to-obtain raw materials, high yield, mild reaction conditions, good universality and Green.
- 4-(2,2,2-trichloroethyl)- ⁇ -lactam derivatives can be synthesized with high efficiency by initiating the tandem ring formation reaction of trichloromethyl radicals.
- -Quinoline-3-butenamide derivatives and trichloromethane react at 100-120 °C under the catalysis of copper salts and oxidation by oxidants, and 4-(2,2,2-trichloroethane can be obtained in high yields) base)- ⁇ -lactam derivatives.
- a preparation method of 4-(2,2,2-trichloroethyl)- ⁇ -lactam derivatives comprising the following steps: substituted N-quinoline-3-butenamide derivatives of formula (1) Under the action of an oxidant and a copper salt catalyst, the reaction is carried out in chloroform at 100-120 °C, and after the reaction is complete, 4-(2,2,2-trichloroethyl)- ⁇ -endogen of formula (2) is obtained.
- amide derivatives
- R 1 is hydrogen, C1-C6 alkyl, phenyl or substituted phenyl;
- R 2 and R 3 are independently selected from hydrogen, C1-C6 alkyl, phenyl, substituted phenyl or C1-C6 unsaturated hydrocarbon group;
- the substituents on the substituted phenyl group are one or more of C1-C6 alkyl groups, halogen and ester groups.
- chloroform not only serves as the solvent required for the reaction, but also serves as the reactant.
- the reaction route of the above method is:
- the above method belongs to the addition and ring formation of double bond radicals promoted by trichloromethyl radicals, and the conditions are relatively mild and meet the requirements of green chemistry.
- C1-C6 alkyl includes one of substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched-chain alkyl, and substituted or unsubstituted cycloalkyl; wherein substituted straight-chain alkyl, substituted or unsubstituted Substituents on branched alkyl and substituted cycloalkyl are independently selected from alkyl, halogen.
- R 1 is hydrogen
- R 3 is hydrogen or methyl
- R 2 is hydrogen, unsubstituted C1-C6 straight-chain alkyl, ester-substituted C1-C6 alkyl, allyl, benzyl, phenethyl, cyclopropylmethyl, cyclobutylmethyl, halopropyl, p-tolylethyl or halophenethyl.
- R 2 is hydrogen
- R 3 is hydrogen
- R 1 is C1-C6 alkyl or benzyl.
- the oxidizing agent is di-tert-butyl peroxide (DTBP).
- the copper salt catalyst is cuprous bromide (CuBr), copper acetate (Cu(OAc) 2 ), cuprous chloride, tetraacetonitrile copper hexafluorophosphate (Cu(CH 3 CN) 4 PF 6 ), trifluoro One or more of copper methanesulfonate and copper bromide (CuBr 2 ).
- the copper salt catalyst is copper tetraacetonitrile hexafluorophosphate.
- the molar ratio of the substituted N-quinoline-3-butenamide derivative, chloroform, oxidant and copper salt catalyst is 1:8-12:3-8:0.05-0.2.
- the molar ratio of the substituted N-quinoline-3-butenamide derivative, chloroform, oxidant and copper salt catalyst is 1:10:6:0.1.
- the reaction temperature is 110°C.
- the present invention has at least the following advantages:
- the present invention provides a brand-new system, which realizes the synthesis of 4-(2,2,2-trichloroethyl)- ⁇ -lactam derivatives by free radical reaction.
- the present invention uses substituted N-quinoline-3-butenamide derivatives as starting materials, and the raw materials are easy to obtain and have many types; the types of products obtained by the method of the present invention are diverse, which can be used directly or in other further responses.
- the present invention has novel reaction, simple reaction operation and post-treatment process, high yield, and is suitable for large-scale production.
- N-(8-quinolinyl)-2-phenethyl-3-butenamide 1 g (0.063 g, 0.2 mmol), Cu(CH 3 CN) 4 PF 6 (0.008 g, 0.02 mmol) was dissolved in To 2 mL of chloroform, was added DTBP (0.176 g, 1.2 mmol). The mixture was heated to 110°C and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate 30:1) and purified to obtain compound 2g. The isolated yield was 61%.
- the present invention discloses a preparation method of 4-(2,2,2-trichloroethyl)-1-(8-quinolinyl)- ⁇ -lactam derivatives, which is characterized in that: replacing N -Quinoline-3-butenamide derivatives, di-tert-butyl peroxide and copper salts such as copper tetraacetonitrile hexafluorophosphate were dissolved in chloroform, reacted at 110 °C, and multiple 4 -(2,2,2-Trichloroethyl)- ⁇ -lactam derivatives.
Abstract
一种N-喹啉-4-(2,2,2-三氯乙基)-β-内酰胺衍生物的制备方法,包括:将N-喹啉-3-丁烯酰胺衍生物在氧化剂和铜盐催化剂的作用下,在三氯甲烷中于100~120℃下反应,反应完全后得到N-喹啉-4-(2,2,2-三氯乙基)-β-内酰胺衍生物。该方法收率高、反应条件较温和、反应操作和后处理过程简单,适合于规模化生产。
Description
本发明涉及一种有机化合物的制备技术领域,尤其涉及一种4-(2,2,2-三氯乙基)-β-内酰胺衍生物的合成方法。
β-内酰胺是N杂环中的一个重要组成部分,是很多天然产物和药物分子的核心骨架,尤其是一些抗生素的特效药。因此合成β-内酰胺衍生物具有重要的价值。
至今,β-内酰胺衍生物的合成方法主要有以下几种:
β-内酰胺衍生物的合成方法在J.Am.Chem.Soc,1982,104,3233有所披露,该方法通过氧化关环。J.Org.Chem.1995,60,1276上披露了一种还原法关环反应制备β-内酰胺衍生物。
利用C-H键活化和金属催化合成β-内酰胺的方法,分别在Angewandte Chemie,2013,52,13588、Angewandte Chemie 2014,53,3496和Chem.Eur.J,2014,20,9530上公开。
2019年,发明人所在团队在Chem.Common.2019,55,10523报道了自由基促进的加成成环反应,合成了β-内酰胺。该反应有一定的技术优势,然而仅限于苄基自由基促进的反应,该法不适用于合成4-(2,2,2-三氯乙基)-β-内酰胺衍生物。
总之,现有的合成4-(2,2,2-三氯乙基)-β-内酰胺衍生物的方法一般使用十分昂贵的原料,反应条件苛刻,对环境不友好。
发明内容
为了克服现有技术制备4-(2,2,2-三氯乙基)-β-内酰胺衍生物收率较低,使用昂贵原料,反应条件苛刻和对环境不友好的不足,本发明的目的是提供一种4-(2,2,2-三氯乙基)-β-内酰胺衍生物的制备方法,该方法原料易得、高收率、反应条件较温和、普适性好且绿色环保。
发明人通过深入细致的研究发现通过引发三氯甲基自由基串联成环反应,可以高效率合成4-(2,2,2-三氯乙基)-β-内酰胺衍生物,利用取代N-喹啉-3-丁烯酰胺衍生物和三氯甲烷在铜盐催化和氧化剂氧化下,在100-120℃下反应,可以高收率的得到4-(2,2,2-三氯乙基)-β-内酰胺衍生物。
具体地,本发明的技术方案如下:
一种4-(2,2,2-三氯乙基)-β-内酰胺衍生物的制备方法,包括以下步骤:将式(1)的取代N-喹啉-3-丁烯酰胺衍生物在氧化剂和铜盐催化剂的作用下,在三氯甲烷中于100~120℃下反应,反应完全后得到式(2)的4-(2,2,2-三氯乙基)-β-内酰胺衍生物;
其中,R
1为氢、C1~C6烷基、苯基或取代苯基;
R
2和R
3分别独立地选自氢、C1~C6烷基、苯基、取代苯基或C1~C6不饱和烃基;
取代苯基上的取代基为C1~C6烷基、卤素和酯基中的一种或几种。
本发明中,三氯甲烷既作为反应所需溶剂,又作为反应物。
以上方法的反应路线为:
以上方法属于三氯甲基自由基促进的双键自由基加成成环反应,条件较温和、符合绿色化学要求。
进一步地,C1~C6烷基包括取代或未取代的直链烷基、取代或未取代的支链烷基、取代或未取代的环烷基中的一种;其中取代直链烷基、取代支链烷基和取代环烷基上的取代基分别独立地选自烷基、卤素。
进一步地,R
1为氢,R
3为氢或甲基,R
2为氢、未取代的C1~C6直链烷基、酯基取代的C1~C6烷基、烯丙基、苯甲基、苯乙基、环丙基甲基、环丁基甲基、卤代丙基、对甲苯乙基或卤代苯乙基。
进一步地,R
2为氢,R
3为氢,R
1为C1~C6烷基或苯甲基。
进一步地,氧化剂为二叔丁基过氧化物(DTBP)。
进一步地,铜盐催化剂为溴化亚铜(CuBr)、醋酸铜(Cu(OAc)
2)、氯化亚铜、四乙腈六氟磷酸铜(Cu(CH
3CN)
4PF
6)、三氟甲磺酸铜和溴化铜(CuBr
2)中的一种或几种。优选地, 铜盐催化剂为四乙腈六氟磷酸铜。
进一步地,取代N-喹啉-3-丁烯酰胺衍生物、三氯甲烷、氧化剂和铜盐催化剂的摩尔比为1:8~12:3~8:0.05~0.2。
优选地,取代N-喹啉-3-丁烯酰胺衍生物、三氯甲烷、氧化剂和铜盐催化剂的摩尔比为1:10:6:0.1。
优选地,反应温度为110℃。
借由上述方案,本发明至少具有以下优点:
1、本发明提供了一个全新的体系,利用自由基反应实现了4-(2,2,2-三氯乙基)-β-内酰胺衍生物的合成。
2、本发明使用取代N-喹啉-3-丁烯酰胺衍生物为起始物,原料易得、种类很多;利用本发明的方法得到的产物类型多样,既可以直接使用,又可以用于其他进一步的反应。
3、本发明反应新颖、反应操作和后处理过程简单,产率很高,适合于规模生产。
上述说明仅是本发明技术方案的概述,为了能够更清楚了解本发明的技术手段,并可依照说明书的内容予以实施,以下以本发明的较佳实施例并配合详细说明如后。
下面结合实施例,对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明,但不用来限制本发明的范围。
实施例一:4-(2,2,2-三氯乙基)-1-(8-喹啉基)-β-内酰胺的合成
(1)称取N-(8-喹啉基)-3-丁烯酰胺1a(0.042g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2a。分离产率为92%。
(2)称取N-(8-喹啉基)-3-丁烯酰胺1a(0.042g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到100℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯= 30:1)提纯后得到化合物2a。分离产率为83%。
(3)称取N-(8-喹啉基)-3-丁烯酰胺1a(0.042g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到120℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2a。分离产率为41%。
(4)称取N-(8-喹啉基)-3-丁烯酰胺1a(0.042g,0.2mmol),CuBr
2(0.005g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2a。分离产率为62%。
(5)称取N-(8-喹啉基)-3-丁烯酰胺1a(0.042g,0.2mmol),Cu(OAc)
2(0.004g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2a。分离产率为45%。
(6)称取N-(8-喹啉基)-3-丁烯酰胺1a(0.042g,0.2mmol),CuBr(0.003g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2a。分离产率为50%。
2a:
1H NMR(400MHz,CDCl
3)δ8.84(dd,J=4.1,1.8Hz,1H),8.33(dd,J=7.5,1.4Hz,1H),8.15(dd,J=8.4,1.7Hz,1H),7.60(dd,J=8.2,1.3Hz,1H),7.55–7.50(m,1H),7.42(dd,J=8.3,4.1Hz,1H),5.70–5.62(m,1H),3.66(dd,J=14.3,1.6Hz,1H),3.57(dd,J=15.6,5.2Hz,1H),3.29(dd,J=15.6,2.6Hz,1H),2.91(dd,J=14.3,10.2Hz,1H).;
13C NMR(101MHz,CDCl
3)δ165.82,149.13,140.06,136.13,132.86,128.97,126.82,124.12,121.58,121.17,96.68,57.07,54.23,45.56;HRMS(ESI-TOF)Calcd for C
14H
12Cl
3N
2O[M+H]
+:329.0015,found:329.0013.
实施例二:3-甲基-4-(2,2,2-三氯乙基)-1-(8-喹啉基)-β-内酰胺的合成
称取N-(8-喹啉基)-2-甲基-3-丁烯酰胺1b(0.045g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g, 0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2b。分离产率为59%。
2b:
1H NMR(400MHz,CDCl
3)δ8.83(dd,J=4.1,1.8Hz,1H),8.33(dd,J=7.5,1.4Hz,1H),7.59(dd,J=8.2,1.4Hz,1H),7.55–7.50(m,1H),7.42(dd,J=8.4,4.1Hz,1H),5.28(dt,J=10.2,2.0Hz,1H),3.64(dd,J=14.3,1.8Hz,1H),3.47–3.40(m,1H),2.93(dd,J=14.3,10.2Hz,1H),1.57(d,J=7.3Hz,3H).
13C NMR(101MHz,CDCl
3)δ169.54,149.11,140.12,136.12,132.77,129.00,126.82,124.03,121.54,121.43,96.62,62.25,56.97,53.02,13.40;HRMS Calcd for C
15H
14Cl
3N
2O[M+H]
+:343.0172,Found:343.0169.
实施例三:3-乙基-4-(2,2,2-三氯乙基)-1-(8-喹啉基)-β-内酰胺的合成
称取N-(8-喹啉基)-2-乙基-3-丁烯酰胺1c(0.048g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2c。分离产率为61%。
2c:
1H NMR(400MHz,CDCl
3)δ8.84(dd,J=4.1,1.8Hz,1H),8.35(dd,J=7.5,1.4Hz,1H),8.14(dd,J=8.3,1.7Hz,1H),7.59(dd,J=8.2,1.3Hz,1H),7.52(t,J=7.8Hz,1H),7.42(dd,J=8.3,4.1Hz,1H),5.39(dt,J=10.1,2.0Hz,1H),3.63(dd,J=14.3,1.9Hz,1H),3.46–3.41(m,1H),2.94(dd,J=14.3,10.1Hz,1H),2.09–1.97(m,2H),1.19(t,J=7.5Hz,3H);
13C NMR(101MHz,CDCl
3)δ169.09,149.12,140.16,136.09,132.76,128.99,126.82,123.98,121.52,121.35,96.67,59.65,59.01,56.97,21.89,11.22;HRMS Calcd for C
16H
16Cl
3N
2O[M+H]
+:357.0328,Found:357.0321.
实施例四:3-异丙基-4-(2,2,2-三氯乙基)-1-(8-喹啉基)-β-内酰胺的合成
称取N-(8-喹啉基)-2-异丙基-3-丁烯酰胺1d(0.051g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2d。分离产率为50%。
2d:
1H NMR(400MHz,CDCl
3)δ8.84(dd,J=4.1,1.6Hz,1H),8.36(dd,J=7.5,1.2Hz,1H),8.12(d,J=8.2Hz,1H),7.58(d,J=7.8Hz,1H),7.51(t,J=7.8Hz,1H),7.40(dd,J=8.3,4.1Hz,1H),5.45(dt,J=9.8,2.0Hz,1H),3.59(dd,J=14.4,2.1Hz,1H),3.38(dd,J=5.6,2.0Hz,1H),2.93(dd,J=14.4,9.9Hz,1H),2.35–2.26(m,1H),1.21(dd,J=9.6,6.9Hz,6H).
13C NMR(101MHz,CDCl
3)δ168.40,149.14,140.24,136.06,132.65,128.96,126.80,123.99,121.50,121.37,96.63,63.75,58.41,57.03,28.22,21.52,18.91;HRMS Calcd for C
17H
18Cl
3N
2O[M+H]
+:371.0485,Found:371.0491.
实施例五:3-烯丙基-4-(2,2,2-三氯乙基)-1-(8-喹啉基)-β-内酰胺的合成
称取N-(8-喹啉基)-2-烯丙基-3-丁烯酰胺1e(0.050g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2e。分离产率为47%。
2e:
1H NMR(400MHz,CDCl
3)δ8.84(dd,J=4.1,1.8Hz,1H),8.34(dd,J=7.5,1.4Hz,1H),8.14(dd,J=8.4,1.8Hz,1H),7.60(dd,J=8.2,1.4Hz,1H),7.55–7.50(m,1H),7.42(dd,J=8.4,4.1Hz,1H),6.04–5.97(m,1H),5.42(dt,J=10.1,2.1Hz,1H),5.28–5.23(m,1H),5.16–5.12(m,1H),3.65(dd,J=14.3,1.9Hz,1H),3.56–3.51(m,1H),2.95(dd,J=14.3,10.1Hz,1H), 2.79–2.67(m,2H).
13C NMR(101MHz,CDCl
3)δ168.28,149.15,140.11,136.08,133.89,132.70,128.98,126.81,124.05,121.53,121.35,118.12,96.59,59.24,57.23,56.84,32.68(s),120.83(s),55.58(s),42.68(s),33.30(s),28.99(s);HRMS Calcd for C
17H
15Cl
3N
2ONa[M+H]
+:391.0148,Found:391.0148.
实施例六:3-苄基-4-(2,2,2-三氯乙基)-1-(8-喹啉基)-β-内酰胺的合成
称取N-(8-喹啉基)-2-苄基-3-丁烯酰胺1f(0.061g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2f。分离产率为70%。
2f:
1H NMR(400MHz,CDCl
3)δ8.79(dd,J=4.1,1.8Hz,1H),8.27(dd,J=7.5,1.3Hz,1H),8.14–8.09(m,1H),7.58(dd,J=8.2,1.3Hz,1H),7.50(t,J=7.8Hz,1H),7.42–7.35(m,3H),7.32–7.25(m,2H),7.22–7.17(m,1H),5.40(dt,J=10.0,2.0Hz,1H),3.74–3.67(m,1H),3.60(dd,J=14.4,1.9Hz,1H),3.37–3.24(m,2H),2.95(dd,J=14.4,10.1Hz,1H).
13C NMR(101MHz,CDCl
3)δ168.30,149.11,140.19,137.93,136.03,132.59,129.51,128.94,128.51,126.76,126.64,124.19,121.52,121.49,96.51,59.44,58.91,56.85,34.73;HRMS Calcd for C
21H
18Cl
3N
2O[M+H]
+:419.0485,Found:419.0485.
实施例七:3-苯乙基-4-(2,2,2-三氯乙基)-1-(8-喹啉基)-β-内酰胺的合成
称取N-(8-喹啉基)-2-苯乙基-3-丁烯酰胺1g(0.063g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2g。分离产率为61%。
2g:
1H NMR(400MHz,CDCl
3)δ8.82(dd,J=4.1,1.8Hz,1H),8.35(dd,J=7.5,1.4Hz,1H),8.14(dd,J=8.4,1.7Hz,1H),7.60(dd,J=8.2,1.4Hz,1H),7.56–7.50(m,1H),7.41(dd,J=8.3,4.1Hz,1H),7.28–7.24(m,4H),7.22–7.15(m,1H),5.39(dt,J=10.1,2.0Hz,1H),3.61(dd,J=14.3,1.9Hz,1H),3.50–3.42(m,1H),3.11–3.01(m,1H),2.94–2.84(m,2H),2.38–2.26(m,2H).
13C NMR(101MHz,CDCl
3)δ168.88,149.14,141.38,140.16,136.12,132.72,129.00,128.56,128.42,126.83,126.03,124.08,121.56,121.37,96.59,60.20,57.01,56.90,32.98,30.74;HRMS Calcd for C
22H
20Cl
3N
2O[M+H]
+:433.0641,Found:433.0646.
实施例八:3-甲基环丙烷-4-(2,2,2-三氯乙基)-1-(8-喹啉基)-β-内酰胺的合成
称取N-(8-喹啉基)-2-甲基环丙烷-3-丁烯酰胺1h(0.063g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2h。分离产率为50%。
2h:
1H NMR(400MHz,CDCl
3)δ8.84(dd,J=4.1,1.8Hz,1H),8.36(dd,J=7.5,1.4Hz,1H),8.14(dd,J=8.4,1.7Hz,1H),7.59(dd,J=8.2,1.4Hz,1H),7.53(t,J=7.8Hz,1H),7.42(dd,J=8.3,4.1Hz,1H),5.54(dt,J=10.1,2.0Hz,1H),3.64(dd,J=14.3,1.9Hz,1H),3.58–3.52(m,1H),2.94(dd,J=14.3,10.1Hz,1H),1.95–1.83(m,2H),1.08–0.98(m,1H),0.57–0.47(m,2H),0.23–0.12(m,2H).
13C NMR(101MHz,CDCl
3)δ169.14,149.11,140.17,136.08,132.80,128.99,126.83,123.98,121.52,121.34,96.72,59.62,58.08,57.04,33.62,8.42,5.25,4.65;HRMS Calcd for C
18H
18Cl
3N
2O[M+H
+]:383.0485,Found:383.0481.
实施例九:3-甲基环丁烷-4-(2,2,2-三氯乙基)-1-(8-喹啉基)-β-内酰胺的合成
称取N-(8-喹啉基)-2-甲基环丁烷-3-丁烯酰胺1i(0.056g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2i。分离产率为50%。
2i:
1H NMR(400MHz,CDCl
3)δ8.83(dd,J=4.1,1.8Hz,1H),8.34(dd,J=7.5,1.4Hz,1H),8.14(dd,J=8.4,1.7Hz,1H),7.59(dd,J=8.2,1.3Hz,1H),7.52(t,J=7.8Hz,1H),7.41(dd,J=8.3,4.1Hz,1H),5.37(dt,J=10.1,2.0Hz,1H),3.60(dd,J=14.3,1.9Hz,1H),3.40–3.34(m,1H),2.90(dd,J=14.3,10.1Hz,1H),2.75–2.65(m,1H),2.20–2.12(m,2H),2.09(t,J=7.2Hz,2H),1.86–1.67(m,4H)..
13C NMR(101MHz,CDCl
3)δ169.18,149.07,140.12,136.07,132.77,128.96,126.81,123.93,121.50,121.29,96.70,59.97,57.06,56.33,35.95,33.52,29.02,28.35,18.44;HRMS Calcd for C
19H
20Cl
3N
2O[M+H]
+:397.0641,Found:397.0638.
实施例十:2-(2-氧代-1-(8-喹啉基)-4-(2,2,2-三氯乙基)氮杂环丁烷基)乙酸乙酯的合成
称取3-(8-喹啉胺羰基)-4-戊烯酸乙酯1j(0.060g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2j。分离产率为62%。
2j:
1H NMR(400MHz,CDCl
3)δ8.83(dd,J=4.1,1.8Hz,1H),8.30(dd,J=7.5,1.4Hz,1H),8.14(dd,J=8.4,1.7Hz,1H),7.60(dd,J=8.2,1.3Hz,1H),7.52(t,J=7.8Hz,1H),7.41(dd,J=8.3,4.1Hz,1H),5.51(dt,J=9.9,2.2Hz,1H),4.19–4.12(m,2H),3.78–3.73(m,1H),3.69(dd,J=14.4,2.0Hz,1H),3.04–2.93(m,3H),1.20(t,J=7.1Hz,3H).
13C NMR(101MHz,CDCl
3)δ170.62,167.09,149.20,140.21,136.13,132.53,128.98,126.79,124.28,121.63,121.57,96.40,61.01,59.83,57.03,53.51,32.85,14.08;HRMS Calcd for C
18H
17Cl
3N
2O
3Na[M+Na]
+:437.0202,Found:437.0201.
实施例十一:3-(1-氯丙基)-4-(2,2,2-三氯乙基)-1-(8-喹啉基)-β-内酰胺的合成
称取N-(8-喹啉基)-2-(1-氯丙烷)-3-丁烯酰胺1k(0.058g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2k。分离产率为48%。
2k:
1H NMR(400MHz,CDCl
3)δ8.84(dd,J=4.1,1.7Hz,1H),8.32(dd,J=7.5,1.2Hz,1H),8.15(dd,J=8.4,1.7Hz,1H),7.61(dd,J=8.2,1.2Hz,1H),7.53(t,J=7.9Hz,1H),5.38(dt, J=10.1,2.0Hz,1H),3.66–3.59(m,3H),3.50–3.44(m,1H),2.94(dd,J=14.4,10.1Hz,1H),2.27–2.16(m,2H),2.12–2.00(m,2H).
13C NMR(101MHz,CDCl
3)δ168.50,149.21,140.16,136.14,132.54,128.99,126.79,124.23,121.60,121.46,96.52,60.22,56.89,56.87,44.75,29.71,26.36;HRMS Calcd for C
17H
17Cl
4N
2O[M+H]
+:321.1403,Found:405.0087.
实施例十二:3,3’-二甲基-4-(2,2,2-三氯乙基)-1-(8-喹啉基)-β-内酰胺的合成
称取N-(8-喹啉基)-2,2’-二甲基-3-丁烯酰胺1l(0.048g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2l。分离产率为43%。
2l:
1H NMR(400MHz,CDCl
3)δ8.84(dd,J=4.2,1.8Hz,1H),8.13(dd,J=8.3,1.7Hz,1H),8.11(dd,J=7.5,1.3Hz,1H),7.65(dd,J=8.2,1.3Hz,1H),7.55–7.50(m,1H),7.42(dd,J=8.3,4.2Hz,1H),5.32(dd,J=9.4,1.5Hz,1H),3.28(dd,J=15.1,1.5Hz,1H),3.15(dd,J=15.1,9.4Hz,1H),1.59(s,3H),1.52(s,3H).
13C NMR(101MHz,CDCl
3)δ172.94,149.41,141.43,136.02,132.17,129.03,126.61,125.05,123.52,121.60,96.82,65.61,54.19,52.55,22.11,18.76;HRMS Calcd for C
16H
15Cl
3N
2ONa[M+Na]
+:379.0148,Found:379.0149.
实施例十三:3-对甲苯乙基-4-(2,2,2-三氯乙基)-1-(8-喹啉基)β-内酰胺的合成
称取N-(8-喹啉基)-2-对甲苯乙基-3-丁烯酰胺1m(0.063g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层 析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2m。分离产率为52%。
2m:
1H NMR(400MHz,CDCl
3)δ8.80(dd,J=4.1,1.8Hz,1H),8.28(dd,J=7.5,1.3Hz,1H),8.11(dd,J=8.3,1.7Hz,1H),7.58(dd,J=8.2,1.3Hz,1H),7.52–7.48(m,1H),7.39(dd,J=8.3,4.1Hz,1H),7.25(d,J=7.6Hz,2H),7.09(d,J=7.8Hz,2H),5.39(dt,J=10.0,2.0Hz,1H),3.71–3.65(m,1H),3.61(dd,J=14.4,1.9Hz,1H),3.33–3.20(m,2H),2.94(dd,J=14.4,10.1Hz,1H),2.28(s,3H).
13C NMR(101MHz,CDCl
3)δ168.41,149.09,140.18,136.06,136.02,134.81,132.65,129.34,129.18,128.94,126.76,124.12,121.50,121.46,96.54,59.48,59.04,56.88,34.29,21.07;HRMS Calcd for C
22H
19Cl
3N
2ONa[M+Na]
+:455.0461,Found:455.0461.
实施例十四:3-对氟苯乙基-4-(2,2,2-三氯乙基)-1-(8-喹啉基)β-内酰胺的合成
称取N-(8-喹啉基)-2-对氟苯乙基-3-丁烯酰胺1n(0.064g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2n。分离产率为61%。
2n:
1H NMR(400MHz,CDCl
3)δ8.78(dd,J=4.1,1.7Hz,1H),8.26(dd,J=7.5,1.2Hz,1H),8.12(dd,J=8.3,1.7Hz,1H),7.59(dd,J=8.1,1.1Hz,1H),7.50(t,J=7.9Hz,1H),7.40(dd,J=8.3,4.1Hz,1H),7.34–7.30(m,2H),7.00–6.93(m,2H),5.38(dt,J=10.1,2.0Hz,1H),3.70–3.65(m,1H),3.59(dd,J=14.4,1.9Hz,1H),3.32(dd,J=14.3,5.0Hz,1H),3.23(dd,J=14.3,7.6Hz,1H),2.95(dd,J=14.4,10.2Hz,1H).
13C NMR(101MHz,CDCl
3)δ168.08,161.77(d,J=244.3Hz),149.14,140.17,136.05,133.52,133.49,132.42,131.05,130.97,128.95,126.73,124.28,121.55,121.50,115.40,115.19,96.52,59.16,58.81,56.74,33.73.
19F NMR(377MHz,CDCl
3)δ-116.53(s);HRMS Calcd for C
21H
17Cl
3FN
2O[M+H]
+:437.0390,Found:437.0388.
实施例十五:1-(8-喹啉基)-4-(2-(1,1,1-三氯丙基))氮杂环丁烷-2酮的合成
称取N-(8-喹啉基)-3-戊烯酰胺1o(0.045g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2o。分离产率为41%。
2o:
1H NMR(400MHz,CDCl
3)δ8.89(dd,J=4.2,1.7Hz,1H),8.15(dd,J=8.3,1.7Hz,1H),7.89(dd,J=7.4,1.3Hz,1H),7.68(dd,J=8.2,1.2Hz,1H),7.59–7.50(m,1H),7.43(dd,J=8.3,4.2Hz,1H),5.80(ddd,J=6.7,5.6,2.6Hz,1H),3.64(dd,J=15.5,5.5Hz,1H),3.27(dd,J=15.5,2.6Hz,1H),3.08(p,J=6.8Hz,1H),1.22(d,J=6.8Hz,3H).
13C NMR(101MHz,CDCl
3)δ166.29(s),148.92(s),140.72(s),140.58(s),137.37(s),136.09(s),133.51(s),130.38(s),128.99(s),126.73(s),124.08(s),121.62(s),121.37(s),91.01(s),55.89(s),43.04(s),34.93(s),31.09(s);HRMS Calcd for C
15H
14Cl
3N
2O[M+H]
+:343.0172,found:343.0168.
实施例十六:1-(8-喹啉基)-4-(2-(1,1,1-三氯丁基))氮杂环丁烷-2酮的合成
称取N-(8-喹啉基)-3-己烯酰胺1p(0.048g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2p。分离产率为33%。
2p:
1H NMR(400MHz,CDCl
3)δ8.85(dd,J=4.2,1.7Hz,1H),8.16(dd,J=8.3,1.7Hz,1H),8.01(dd,J=7.5,1.3Hz,1H),7.66(dd,J=8.2,1.2Hz,1H),7.57–7.52(m,1H),7.43(dd,J=8.3,4.2Hz,1H),5.83(dd,J=8.6,4.8Hz,1H),3.55–3.50(m,2H),2.94–2.88(m,1H),1.68–1.53(m,2H),1.13(t,J=7.5Hz,3H).
13C NMR(101MHz,CDCl
3)δ166.62,149.19,141.95,136.24,133.22,129.10,126.65,125.24,123.97,121.51,102.53,62.31,57.22,42.94,24.11,14.02; HRMS Calcd for C
16H
16Cl
3N
2O[M+H]
+:357.0328,found:357.0320.
实施例十七:1-(8-喹啉基)-4-(1,1,1-三氯-3-苯基-2-丙基)氮杂环丁烷-2酮的合成
称取N-(8-喹啉基)-5-苯基-3-己烯酰胺1q(0.048g,0.2mmol),Cu(CH
3CN)
4PF
6(0.008g,0.02mmol)溶于2mL三氯甲烷中,加入DTBP(0.176g,1.2mmol)。混合物加热到110℃反应,TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯=30:1)提纯后得到化合物2q。分离产率为21%。
2q:
1H NMR(400MHz,CDCl
3)δ8.18(dd,J=4.2,1.8Hz,1H),8.08(dd,J=8.3,1.7Hz,1H),7.89(dd,J=7.5,1.3Hz,1H),7.58(dd,J=8.2,1.3Hz,1H),7.49–7.42(m,1H),7.37–7.27(m,4H),7.24–7.19(m,2H),5.83(dt,J=6.4,3.3Hz,1H),3.61–3.53(m,2H),3.49–3.38(m,2H),2.84(dd,J=14.7,9.2Hz,1H).
13C NMR(101MHz,CDCl
3)δ166.04,148.90,141.45,138.55,135.98,133.23,128.98,128.84,128.71,126.77,126.59,124.76,123.33,121.23,102.07,60.87,56.80,41.27,36.48;HRMS Calcd for C
21H
18Cl
3N
2O[M+H]
+:393.1191,Found:393.1198.
总之,本发明公开了一种4-(2,2,2-三氯乙基)-1-(8-喹啉基)-β-内酰胺衍生物的制备方法,其特征在于:将取代N-喹啉-3-丁烯酰胺衍生物、二叔丁基过氧化物和四乙腈六氟磷酸铜等铜盐溶于三氯甲烷中,于110℃反应,高收率的制得多个4-(2,2,2-三氯乙基)-β-内酰胺衍生物。
以上仅是本发明的优选实施方式,并不用于限制本发明,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明技术原理的前提下,还可以做出若干改进和变型,这些改进和变型也应视为本发明的保护范围。
Claims (9)
- 根据权利要求1所述的制备方法,其特征在于:所述C1~C6烷基包括取代或未取代的直链烷基、取代或未取代的支链烷基、取代或未取代的环烷基中的一种;其中取代直链烷基、取代支链烷基和取代环烷基上的取代基分别独立地选自烷基、卤素和酯基中的一种或几种。
- 根据权利要求1所述的制备方法,其特征在于:R 1为氢,R 3为氢或甲基,R 2为氢、未取代的C1~C6直链烷基、酯基取代的C1~C6烷基、烯丙基、苯甲基、苯乙基、环丙基甲基、环丁基甲基、卤代丙基、对甲苯乙基或卤代苯乙基。
- 根据权利要求1所述的制备方法,其特征在于:R 2为氢,R 3为氢,R 1为C1~C6烷基或苯甲基。
- 根据权利要求1所述的制备方法,其特征在于:所述氧化剂为二叔丁基过氧化物。
- 根据权利要求1所述的制备方法,其特征在于:所述铜盐催化剂为溴化亚铜、醋酸铜、氯化亚铜、四乙腈六氟磷酸铜、三氟甲磺酸铜和溴化铜中的一种或几种。
- 根据权利要求1所述的制备方法,其特征在于:所述取代N-喹啉-3-丁烯酰胺衍生物、三氯甲烷、氧化剂和铜盐催化剂的摩尔比为1:8~12:3~8:0.05~0.2。
- 根据权利要求1所述的制备方法,其特征在于:所述取代N-喹啉-3-丁烯酰胺衍生物、三氯甲烷、氧化剂和铜盐催化剂的摩尔比为1:10:6:0.1。
- 根据权利要求1所述的制备方法,其特征在于:反应温度为110℃。
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