CN109293569B - Method for preparing formamide derivative through amine transfer reaction without participation of catalyst - Google Patents
Method for preparing formamide derivative through amine transfer reaction without participation of catalyst Download PDFInfo
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- CN109293569B CN109293569B CN201811327786.2A CN201811327786A CN109293569B CN 109293569 B CN109293569 B CN 109293569B CN 201811327786 A CN201811327786 A CN 201811327786A CN 109293569 B CN109293569 B CN 109293569B
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- 150000003948 formamides Chemical class 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 16
- 239000003054 catalyst Substances 0.000 title claims abstract description 11
- 150000001412 amines Chemical class 0.000 title claims description 21
- 238000006276 transfer reaction Methods 0.000 title claims description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 97
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000005580 one pot reaction Methods 0.000 claims abstract description 6
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 20
- YYTAYINRPUJPNH-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroisoquinoline Chemical compound C1NCCC2=CC(OC)=CC=C21 YYTAYINRPUJPNH-UHFFFAOYSA-N 0.000 claims description 8
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 8
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 8
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 7
- 239000012298 atmosphere Substances 0.000 claims description 7
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 claims description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 6
- 229960002464 fluoxetine Drugs 0.000 claims description 5
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 claims description 4
- AIJFPNKGGAPZFJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)-n-methylmethanamine Chemical compound CNCC1=CC=C(OC)C=C1 AIJFPNKGGAPZFJ-UHFFFAOYSA-N 0.000 claims description 4
- LYUQWQRTDLVQGA-UHFFFAOYSA-N 3-phenylpropylamine Chemical compound NCCCC1=CC=CC=C1 LYUQWQRTDLVQGA-UHFFFAOYSA-N 0.000 claims description 4
- UTBULQCHEUWJNV-UHFFFAOYSA-N 4-phenylpiperidine Chemical compound C1CNCCC1C1=CC=CC=C1 UTBULQCHEUWJNV-UHFFFAOYSA-N 0.000 claims description 4
- OYODEQFZAJVROF-UHFFFAOYSA-N 7-bromo-1,2,3,4-tetrahydroisoquinoline Chemical compound C1CNCC2=CC(Br)=CC=C21 OYODEQFZAJVROF-UHFFFAOYSA-N 0.000 claims description 4
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 4
- -1 dodecyl primary amine Chemical class 0.000 claims description 4
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 claims description 4
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 claims description 4
- SASNBVQSOZSTPD-UHFFFAOYSA-N n-methylphenethylamine Chemical compound CNCCC1=CC=CC=C1 SASNBVQSOZSTPD-UHFFFAOYSA-N 0.000 claims description 4
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 3
- MQRIUFVBEVFILS-UHFFFAOYSA-N n-methyl-1-naphthalen-1-ylmethanamine Chemical compound C1=CC=C2C(CNC)=CC=CC2=C1 MQRIUFVBEVFILS-UHFFFAOYSA-N 0.000 claims description 2
- 239000012300 argon atmosphere Substances 0.000 claims 1
- 239000007789 gas Substances 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 43
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 150000003511 tertiary amides Chemical class 0.000 abstract description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 abstract description 2
- 231100000086 high toxicity Toxicity 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 238000005891 transamination reaction Methods 0.000 abstract description 2
- 230000009257 reactivity Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 117
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 76
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- 239000000047 product Substances 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 20
- 239000012043 crude product Substances 0.000 description 20
- 239000003480 eluent Substances 0.000 description 20
- 239000000706 filtrate Substances 0.000 description 20
- 239000003208 petroleum Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 238000001816 cooling Methods 0.000 description 19
- 239000000284 extract Substances 0.000 description 19
- 239000011261 inert gas Substances 0.000 description 19
- 238000003756 stirring Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000022244 formylation Effects 0.000 description 3
- 238000006170 formylation reaction Methods 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- YGKOJGIYEHULCD-UHFFFAOYSA-N 1,3-dihydroisoindole-2-carbaldehyde Chemical compound C1=CC=C2CN(C=O)CC2=C1 YGKOJGIYEHULCD-UHFFFAOYSA-N 0.000 description 1
- ZEMNVPLWDUWKEG-UHFFFAOYSA-N 3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound C1=CC=C2CN(C=O)CCC2=C1 ZEMNVPLWDUWKEG-UHFFFAOYSA-N 0.000 description 1
- LOONFRKFJPYULD-UHFFFAOYSA-N 4-(dimethylamino)-3-methylbenzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1C LOONFRKFJPYULD-UHFFFAOYSA-N 0.000 description 1
- ZJQOHRIHVHFULX-UHFFFAOYSA-N 4-phenylpiperazine-1-carbaldehyde Chemical compound C1CN(C=O)CCN1C1=CC=CC=C1 ZJQOHRIHVHFULX-UHFFFAOYSA-N 0.000 description 1
- SLKIUHCTAYVKKN-UHFFFAOYSA-N 4-phenylpiperidine-1-carbaldehyde Chemical compound C1CN(C=O)CCC1C1=CC=CC=C1 SLKIUHCTAYVKKN-UHFFFAOYSA-N 0.000 description 1
- KAICOAHKBXXZQA-UHFFFAOYSA-N 6-methoxy-3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound C1N(C=O)CCC2=CC(OC)=CC=C21 KAICOAHKBXXZQA-UHFFFAOYSA-N 0.000 description 1
- NKIIXSDFCKCERN-UHFFFAOYSA-N 7-bromo-3,4-dihydro-1h-isoquinoline-2-carbaldehyde Chemical compound C1CN(C=O)CC2=CC(Br)=CC=C21 NKIIXSDFCKCERN-UHFFFAOYSA-N 0.000 description 1
- 229910052684 Cerium Inorganic materials 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000028689 Eurylophella doris Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- IIBOGKHTXBPGEI-UHFFFAOYSA-N N-benzylformamide Chemical compound O=CNCC1=CC=CC=C1 IIBOGKHTXBPGEI-UHFFFAOYSA-N 0.000 description 1
- 241000727427 Nirmala Species 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 244000122221 Xanthosoma violaceum Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229920001002 functional polymer Polymers 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- NOOOMJZHMKSKBF-UHFFFAOYSA-N n-(2-phenylethyl)formamide Chemical compound O=CNCCC1=CC=CC=C1 NOOOMJZHMKSKBF-UHFFFAOYSA-N 0.000 description 1
- DTMJCJINCCWTTG-UHFFFAOYSA-N n-(3-phenylpropyl)formamide Chemical compound O=CNCCCC1=CC=CC=C1 DTMJCJINCCWTTG-UHFFFAOYSA-N 0.000 description 1
- WUZNVFUYFDVUIC-UHFFFAOYSA-N n-[2-(3,4-dimethoxyphenyl)ethyl]formamide Chemical compound COC1=CC=C(CCNC=O)C=C1OC WUZNVFUYFDVUIC-UHFFFAOYSA-N 0.000 description 1
- AKEYUWUEAXIBTF-UHFFFAOYSA-N n-methylnaphthalen-1-amine Chemical compound C1=CC=C2C(NC)=CC=CC2=C1 AKEYUWUEAXIBTF-UHFFFAOYSA-N 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/03—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to hydrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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Abstract
The invention discloses a method for synthesizing formamide derivatives by the transamination reaction of catalyst-free solvent-free tertiary amide with low reactivity and aliphatic amine. The method directly uses N, N-Dimethylformamide (DMF) as a formyl group source to obtain the formamide derivative with high yield. The method has the advantages of cheap and easily obtained raw materials and acylating reagent, high reaction yield, one-step reaction, low cost, high reaction selectivity, simple operation and the like. The defects of high toxicity of reaction reagents, need of using different types of catalysts, higher cost of the synthesis method, more reaction steps, more byproducts and the like in the prior art are overcome.
Description
Technical Field
The invention relates to a method for preparing formamide derivatives through a catalyst-free and solvent-free amine transfer reaction of tertiary amide and fatty amine, belonging to the field of medical intermediate synthesis and fine organic synthesis.
Technical Field
Formamide derivatives are one of important organic compounds, and are widely present in bioactive molecules (such as the following molecular structural formula), organic synthetic intermediates and functional polymer materials [ a.r.kiniss, nat.commun.2017,8,14865; d.j.c. Constable, Green chem.2007,9,411; v.r. pattabiiraman1, j.w. bode, Nature 2011,480,471; C. W.Cheung, J. -A.Ma, X.Hu, J.Am.chem.Soc.2018,140,6789 ]. Various metals and protonic acids have been used as catalysts for the synthesis of formamide derivatives, such as palladium, ruthenium, gold, indium, cerium, copper, supported sulfuric acid, ionic liquids, etc. [ d.w. Gu, x.x.guo, Tetrahedron 2015,71, 9117; m.nirmala, g.prakash, p.viswanathamurthi, j.g. Malecki, j.mol.catal.a: chem.2015,403, 15; n.shah, e.grave, d.v.jawale, e.doris, n.n.i.namboothiri, ChemCatChem 2014,6, 2201; J. king, d.o.jang, Synlett 2010,2010,1231; s, m.sajadi, m.maham, a.rezaei, lett.org.chem.2014,11, 49; h.q.liu, j.liu, y.h.zhang, c.d.shao, j.x.yu, chi.chem.lett.2015, 26, 11; s.rasheed, d.n.rao, a.s.reddy, r.shankar, p.das, RSC adv.2015,5,10567; chen, r.fu, w.chai, h.zheng, l.sun, q.lu, r.yuan, Tetrahedron 2014,70, 2237. However, these methods have problems such as the use of a toxic formylation reagent, the use of a different type of catalyst, and the use of a large amount of by-products. Therefore, the development of a new method for synthesizing the formamide derivative, which has the advantages of simple and easily-obtained raw materials, simple operation and low cost, has important theoretical significance and application value.
Disclosure of Invention
Aiming at the defects of the existing method for synthesizing formamide derivatives, such as the use of toxic formylation reagents, the need of using different types of catalysts, more byproducts and the like, the invention aims to provide a method for preparing formamide derivatives by non-catalytic and solvent-free transamination reaction, which directly uses tertiary amide with low reaction activity and fatty amine to prepare formamide derivatives. The method directly uses cheap N, N-Dimethylformamide (DMF) as a formyl group source, and realizes the amine transfer reaction of various primary amines and secondary amines under the conditions of no catalyst and no solvent, so the method has good application prospect in the field of synthesis and application of formamide derivatives.
In order to achieve the technical purpose, the invention provides a method for preparing formamide derivatives by a catalyst-free and solvent-free amine transfer reaction, which comprises the following steps: under the protective atmosphere, fatty amine in a formula 1 and DMF react in one pot to obtain formamide derivatives in a formula 2;
wherein,
r1 and R2 are independently selected from hydrogen or other substituents.
In a preferred embodiment, the fatty amine of formula 1 is 1,2,3, 4-tetrahydroisoquinoline, 6-methoxy-1, 2,3, 4-tetrahydroisoquinoline, 7-bromo-1, 2,3, 4-tetrahydroisoquinoline, 4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride, isoindoline, N-phenylpiperazine, 4-phenylpiperidine, N-methyl-N- (4-trifluoromethyl) benzylamine, N-methyl-4-methoxybenzylamine, N-methylbenzylamine, N-methyl-1-methylamine, fluoxetine, benzylamine, 2-phenylethylamine, 3-phenyl-1-propylamine, 3, 4-dimethoxyphenylethylamine, a salt thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, Dodecyl primary amine.
In a preferable scheme, under the protective atmosphere, the aliphatic amine shown in the formula 1 and DMF react at 130-150 ℃ in one step under the condition of no catalyst and no solvent to obtain the formamide derivative shown in the formula 2. The substituted amine is 0.5-1.0 mmol, DMF is 1.0-2.5 mmol, and the 1,2,3, 4-tetrahydroisoquinoline: the molar ratio of DMF is 1: (1-5). By controlling the reaction temperature and the molar ratio of the reactants within an appropriate range, a formamide derivative is produced.
In a further preferred embodiment, the aliphatic amine suitable for the preparation of the carboxamide derivative is 1,2,3, 4-tetrahydroisoquinoline, 6-methoxy-1, 2,3, 4-tetrahydroisoquinoline, 7-bromo-1, 2,3, 4-tetrahydroisoquinoline, 4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride, isoindoline, N-phenylpiperazine, 4-phenylpiperidine, N-methyl-N- (4-trifluoromethyl) benzylamine, N-methyl-4-methoxybenzylamine, N-methylbenzylamine, N-methyl-1-naphthylmethylamine, fluoxetine, benzylamine, 2-phenylethylamine, 3-phenyl-1-propylamine, 3, 4-dimethoxyphenethylamine and dodecyl primary amine. The fatty amines are converted into the corresponding formamide derivatives by formylation, such as N-formyl-1, 2,3, 4-tetrahydroisoquinoline, N-formyl-6-methoxy-1, 2,3, 4-tetrahydroisoquinoline, N-formyl-7-bromo-1, 2,3, 4-tetrahydroisoquinoline, N-formyl-4, 5,6, 7-tetrahydrothieno [3,2-c ] pyridine hydrochloride, N-formyl isoindoline, N-formyl-N ' -phenylpiperazine, N-formyl-4-phenylpiperidine, N-formyl-N ' -methyl-4-methoxybenzylamine, N-formyl-N ' -methylbenzylamine, N-formyl-N '-methylphenethylamine, N-formyl-N' -methyl-1-naphthylamine, N-formyl fluoxetine, N-formyl benzylamine, N-formyl-2-phenylethylamine, N-formyl-3-phenyl-1-propylamine, N-formyl dodecyl primary amine and N-formyl-3, 4-dimethoxyphenylethylamine.
In a more preferable scheme, the aliphatic amine in the formula 1 reacts with DMF at 150 ℃ in one pot under a protective atmosphere to obtain the formamide derivative in the formula 2. 1.0mmol of fatty amine, 2.5mmol of DMF, and the molar ratio of the fatty amine to the DMF is 1:2.5, the reaction time is 24 h.
The reaction equation in the synthesis of the formamide derivative of the invention is as follows.
Based on a large number of experimental summaries and with reference to previous literature reports, the present invention proposes the following rational reaction mechanism. The substituted amine and DMF are used as raw materials for specific description. Firstly, hydrogen in amine and a carbonyl group of DMF form a hydrogen bond and activate the carbonyl group to obtain (i), then lone pair electrons on nitrogen attack the carbonyl group of (i) to obtain an intermediate (ii), and then the intermediate (ii) is cracked again to obtain a product, fatty amine and ammonia gas. The aliphatic amine was then reacted with DMF until complete consumption and the reaction was terminated.
According to the technical scheme, the aliphatic amine is dissolved in DMF, the solution is placed into an oil bath kettle at a set temperature under the protection of argon, the reaction is carried out under the condition of sealing by magnetic stirring, after the reaction is carried out for a set time, a reaction tube is cooled, then 15mL of water is added for dilution, and extraction is carried out for 3 times by ethyl acetate, wherein each time is 15 mL. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (0-1: 3) as an eluent to obtain a pure product.
Weighing raw materials according to the aromatic amine of 0.5-1.0 mmol (based on the aromatic amine). Dissolving the substances in 2.5-5.0 mmol of DMF, and stirring and reacting for 24-96 hours at 150 ℃ under the protection of inert gas. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (0-1: 3) as an eluent to obtain a pure product.
Compared with the prior art, the technical scheme of the invention has the following advantages and effects:
the technical scheme of the invention realizes the amine transfer reaction of aliphatic amine and DMF for the first time under the condition of no catalyst and no solvent, and the formamide derivative with high yield is obtained. The method has the advantages of cheap and easily obtained raw materials and acylating reagent, high reaction yield, one-step reaction, low cost, high reaction selectivity, simple operation and the like. The defects of high toxicity of reaction reagents, need of using different types of catalysts, higher cost of the synthesis method, more reaction steps, more byproducts and the like in the prior art are overcome.
Drawings
FIG. 1 shows the product obtained in example 11H NMR chart;
FIG. 2 shows the product obtained in example 113C NMR chart;
FIG. 3 shows the product obtained in example 111H NMR chart;
FIG. 4 shows thatExample 11 preparation of the product13C NMR chart.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples and the accompanying drawings. The procedures, conditions, reagents, test methods and the like for carrying out the present invention are general and common general knowledge in the art, and the present invention is not particularly limited, except for those specifically mentioned below.
Example 1
1,2,3, 4-tetrahydroisoquinoline (128. mu.L, 1.0mmol) and a stirring pellet were put into a reaction tube, and after replacing the inert gas, DMF (193. mu.L, 2.5mmol) was added, and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 24 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow oil, 74% yield.1H NMR(400 MHz,CDCl3)δ8.25(minor rotamer,s,0.36H),8.19(major rotamer,s,0.64H),7.22–7.08(m,4H), 4.68(major rotamer,s,1.24H),4.54(minor rotamer,s,0.75H),3.78(minor rotamer,t,J＝6.2Hz, 0.74H),3.64(major rotamer,t,J＝5.8Hz,1.27H),2.92–2.85(m,2H)；13C NMR(100MHz, CDCl3)δ161.6(major rotamer),161.1(minor rotamer),134.3(minor rotamer),133.4(major rotamer),132.1(minor rotamer),131.7(major rotamer),129.1(minor rotamer),128.8(major rotamer),127.0,126.6–126.4(m),125.8,47.2(minor rotamer),43.1(major rotamer),42.2(major rotamer),37.9(minor rotamer),29.6(major rotamer),27.8(minor rotamer)；IR(neat)3151,3025, 2931,2862,1672,1584,1498,1439,1400,1343,1318,1282,1228,1197,1164,1109,1049,930, 882,814,751,710,675,606,477cm-1；HRMS(ESI):m/z[M+Na]+calcd for C10H11NNaO 184.0733,found 184.0733.
Example 2
Placing 6-methoxy-1, 2,3, 4-tetrahydroisoquinoline (81.6mg,0.5mmol) and a stirrerAfter the inert gas had been replaced, DMF (193. mu.L, 2.5mmol) was added to the reaction tube, and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 96 hours; after cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow solid, m.p. 63-64 deg.C, 74% yield.1H NMR(400MHz,CDCl3)δ8.22(minor rotamer,s,0.40H),8.17(major rotamer,s, 0.60H),7.04–6.99(m,1H),6.78–6.74(m,1H),6.65(d,J＝10.0Hz,1H),4.60(major rotamer,s, 1.24H),4.47(minor rotamer,s,0.77H),3.77–3.73(m,3.76H),3.61(major rotamer,t,J＝5.8Hz, 1.24H),2.87–2.81(m,2H)；13C NMR(100MHz,CDCl3)δ161.5(major rotamer),161.1(minor rotamer),158.4(minor rotamer),158.1(major rotamer),135.6(minor rotamer),134.7(major rotamer),127.6(major rotamer),126.8(minor rotamer),124.3(minor rotamer),123.7(major rotamer),113.6(minor rotamer),113.5(major rotamer),112.9(major rotamer),112.7(minor rotamer),55.2(s),46.8(minor rotamer),43.1(major rotamer),41.7(major rotamer),37.8(minor rotamrer),29.9(major rotamer),28.2(minor rotamer)；IR(neat)3140,1672,1612,1508,1402, 1312,1277,1262,1241,1119,1036,529cm-1；HRMS(ESI):m/z[M+HCO2H-H]－calcd for C12H14NO4236.0917,found 236.0921.
Example 3
7-bromo-1, 2,3, 4-tetrahydroisoquinoline (212.1mg,1.0mmol) and a stirrer were placed in a reaction tube, and after the inert gas was replaced, DMF (386. mu.L, 5.0mmol) was added, and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 24 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. A yellow solid, which is a solid,melting point 58-60 ℃ and yield 93%.1H NMR(400MHz,CDCl3)δ8.24(minor rotamer,s,0.37H),8.19(major rotamer,s, 0.63H),7.34–7.26(m,2H),7.02(t,J＝8.8Hz,1H),4.66(major rotamer,s,1.31H),4.52(minor rotamer,s,0.72H),3.78(minor rotamer,t,J＝6.2Hz,0.72H),3.65(major rotamer,t,J＝5.8Hz, 1.32H),2.86(major rotamer,t,J＝5.8Hz,1.28H),2.82(minor rotamer,t,J＝6.0Hz,0.80H)；13C NMR(100MHz,CDCl3)δ161.6(major rotamer),161.0(minor rotamer),134.2(minor rotamer), 133.8(major rotamer),133.3(minor rotamer),132.4(major rotamer),130.8(minor rotamer), 130.5(major rotamer),130.1(minor rotamer),129.7(major rotamer),129.4(major rotamer), 128.7(minor rotamer),120.2(major rotamer),119.9(minor rotamer),46.8(minor rotamer),42.9 (major rotamer),41.8(major rotamer),37.7(minor rotamer),29.2(major rotamer),27.4(minor rotamer)；IR(neat)3140,1672,1402,1191,1157,1116,1075,1051,932,829,531cm-1；HRMS (ESI):m/z[M+NH4]+calcd for C10H14BrN2 257.0284,found 257.0275.
Example 4
4,5,6, 7-tetrahydrothiophene [3,2-c ]]Pyridine hydrochloride (139.2mg,1.0mmol) and a stirring bar were placed in a reaction tube, after inert gas was replaced, DMF (386. mu.L, 5.0mmol) was added, and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 96 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow oily liquid, 89% yield.1H NMR(400MHz,CDCl3)δ8.24(minor rotamer,s,0.38H),8.20(major rotamer,s, 0.62H),7.17–7.15(m,1H),6.80(t,J＝4.4Hz,1H),4.60(major rotamer,s,1.28H),4.47(minor rotamer,s,0.74H),3.86(minor rotamer,t,J＝5.8Hz,0.74H),3.69(major rotamer,t,J＝5.8Hz, 1.28H),2.93(major rotamer,t,J＝5.8Hz,1.26H),2.88(minor rotamer,t,J＝5.8Hz,0.75H)；13C NMR(100MHz,CDCl3)δ161.7(major rotamer),161.4(minor rotamer),133.8(minor rotamer), 132.1(major rotamer),130.8(major rotamer),130.7(minor rotamer),125.0(major rotamer), 124.3(minor rotamer),123.8(s),45.7(minor rotamer),43.7(major rotamer),40.6(major rotamer),37.9(minor rotamer),25.8(major rotamer),24.4(minor rotamer)；IR(neat)3129,1705, 1670,1433,1402,1314,1176,1043,1018,824,706,593,567cm-1；HRMS(ESI):m/z[M+NH4]+ calcd for C8H13N2SO 185.0743,found 185.0735.
Example 5
Isoindoline (58. mu.L, 0.5mmol) and a stir-particle were placed in a reaction tube, inert gas was replaced, DMF (193. mu.L, 2.5mmol) was added, and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 96 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Black oily liquid, yield 80%.1H NMR(400MHz, CDCl3)δ8.42(s,1H),7.31–7.27(m,4H),4.89(s,2H),4.76(s,2H)；13C NMR(100MHz,CDCl3) δ161.5(s),135.9(s),135.2(s),128.0(s),127.7(s),123.2(s),122.8(s),51.4(s),49.8(s)；IR(neat) 3140,1668,1465,1402,1159,1092,747,608,531,416cm-1；HRMS(ESI):m/z[M+Cl]－calcd for C9H9ClNO 182.0367,found 182.0368.
Example 6
N-phenylpiperazine (161. mu.L, 1.0mmol) and a stir-bar were placed in a reaction tube, the inert gas was replaced, DMF (386. mu.L, 5.0mmol) was added, and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 96 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: petroleum ether 1:3 (containing 1% triethylamine)And carrying out column chromatography on the crude product as an eluent to obtain a pure product. Yellow solid, mp 86-87 deg.C, 80% yield.1H NMR(400MHz,CDCl3)δ8.08(s,1H),7.30–7.27(m,2H),6.94–6.90(m,3H),3.69(t,J＝5.2Hz, 2H),3.51(t,J＝5.0Hz,2H),3.15(dt,J＝15.2,5.2Hz,4H)；13C NMR(100MHz,CDCl3)δ160.6 (s),150.8(s),129.1(s),120.7(s),116.9(s),50.3(s),49.2(s),45.4(s),39.8(s)；IR(neat)3131, 1664,1402,1152,1115,529cm-1；HRMS(ESI):m/z[M+K]+calcd for C11H14N2KO 229.0738, found 229.0742.
Example 7
4-phenylpiperidine (80.7mg,1.0mmol) and a stirring pellet were put into a reaction tube, and after replacing the inert gas, DMF (193. mu.L, 2.5mmol) was added to seal the reaction tube. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 48 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow solid, mp 98-99 deg.C, 91% yield.1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.31(t,J＝7.4Hz,2H),7.24–7.18(m,3H),4.56(d,J＝ 13.6Hz,1H),3.73(d,J＝13.2Hz,1H),3.19(td,J＝12.9,2.6Hz,1H),2.81–2.67(m,2H),1.92(t, J＝15.8Hz,2H),1.67–1.54(m,2H)；13C NMR(100MHz,CDCl3)δ160.8(s),144.8(s),128.5 (s),126.6(s),126.5(s),46.4(s),42.8(s),40.1(s),33.8(s),32.3(s)；IR(neat)3140,1675,1653, 1402,1170,1064,759,699,529cm-1；HRMS(ESI):m/z[M+Na]+calcd for C12H15NNaO 212.1046,found 212.1048.
Example 8
N-methyl-N- (4-trifluoromethyl) benzylamine (85. mu.L, 0.5mmol), and one stir-bar were placed in the reaction tube, after inert gas was replaced, DMF (193. mu.L, 2.5mmol) was added, and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 96 hours. After cooling to room temperature, diluted with 15mL of water,and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow oil, yield 70%.1H NMR (400MHz,CDCl3)δ8.31(minor rotamer,s,0.48H),8.19(major rotamer,s,0.52H),7.63(dd,J＝ 18.2,8.2Hz,2.0H),7.36(dd,J＝12.6,8.2Hz,2H),4.59(major rotamer,s,1.07H),4.48(minor rotamer,s,0.96H),2.89(major rotamer,s,1.64H),2.80(minor rotamer,s,1.42H)；13C NMR(100 MHz,CDCl3)δ162.9(minor rotamer),162.8(major rotamer),140.2(major rotamer),140.0 (minor rotamer),130.3(major rotamer,dd,J＝51.2,32.3Hz),128.5(major rotamer),127.7 (minor rotamer),126.0(minor rotamer,q,J＝3.7Hz),125.8(major rotamer,q,J＝3.7Hz),125.5 (major rotamer),125.3(minor rotamer),122.8(major rotamer),122.6(minor rotamer),53.1 (minor rotamer),47.5(major rotamer),34.3(major rotamer),29.7(minor rotamer)；19F NMR(377 MHz,CDCl3)δ-62.53(major rotamer,s),-62.58(minor rotamer,s)；IR(neat)3140,2361,2343, 1675,1621,1402,1327,1165,1113,1068,1019,848,818,527cm-1；HRMS(ESI):m/z [M+NH4]+calcd for C10H12FN2O 235.1053,found 235.1067.
Example 9
N- (4-methoxybenzyl) -N-methylamine (78. mu.L, 0.5mmol), and a stirring pellet were placed in a reaction tube, and after inert gas was replaced, DMF (193. mu.L, 2.5mmol) was added, and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 96 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Yellow oil, yield 99%.1H NMR (400MHz,CDCl3)δ8.22(major rotamer,s,0.58H),8.08(minor rotamer,s,0.42H),7.14(minor rotamer,d,J＝8.4Hz,0.86H),7.08(major rotamer,d,J＝8.4Hz,1.15H),6.86–6.81(m,2H), 4.41(minor rotamer,s,0.86H),4.28(major rotamer,s,1.20H),3.76(major rotamer,s,1.78H), 3.75(minor rotamer,s,1.23H),2.78(minor rotamer,s,1.30H),2.71(major rotamer,s,1.75H)；13C NMR(100MHz,CDCl3)δ162.5(major rotamer),162.4(minor rotamer),159.3(major rotamer), 159.0(minor rotamer),130.3,129.5(minor rotamer),128.7(major rotamer),128.0(minor rotamer),127.5(major rotamer),114.1(major rotamer),113.9(minor rotamer),113.5,55.2(major rotamer,d,J＝4.4Hz),52.8(minor rotamer),47.0(major rotamer),44.7(minor rotamer),33.8 (minor rotamer),29.1(major rotamer)；IR(neat)3140,1671,1612,1515,1402,1303,1249,1176, 1079,1032,846,814,559,522cm-1；HRMS(ESI):m/z[M+NH4]+calcd for C10H17N2O2197.1285,found 197.1304.
Example 10
N-methylbenzylamine (130. mu.L, 1.0mmol) and a stirring pellet were placed in a reaction tube, and after replacing the inert gas, DMF (386. mu.L, 5.0mmol) was added, and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 96 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow oily liquid, yield 80%.1H NMR(400 MHz,CDCl3)δ8.29(major rotamer,s,0.57H),8.17(minor rotamer,s,0.43H),7.40–7.20(m,5H), 4.53(minor rotamer,s,0.84H),4.40(major rotamer,s,1.16H),2.85(minor rotamer,s,1.30H), 2.79(major rotamer,s,1.75H)；13C NMR(100MHz,CDCl3)δ162.8(major rotamer),162.6 (minor rotamer),135.9(minor rotamer),135.6(major rotamer),128.9(major rotamer),128.7 (minor rotamer),128.2(major rotamer),128.1(minor rotamer),127.6(minor rotamer),127.4 (major rotamer),53.5(major rotamer),47.7(minor rotamer),34.1(minor rotamer),29.4(major rotamer)；IR(neat)3122,1664,1402,1379,1140,1066,1081,705,529cm-1；HRMS(ESI):m/z [M+CH3CO2H-H]-calcd for C11H14NO3 208.0968,found 208.0971.
Example 11
N-methylphenethylamine (75. mu.L, 0.5mmol) and a stirring bar were placed in a reaction tube, after replacing inert gas, DMF (193. mu.L, 2.5mmol) was added, and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 96 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow oily liquid, yield 99%.1H NMR(400 MHz,CDCl3)δ8.02(minor rotamer,s,0.37H),7.80(major rotamer,s,0.63H),7.33–7.22(m,4H), 7.14(d,J＝7.2Hz,1H),3.56(minor rotamer,t,J＝7.6Hz,0.79H),3.47(major rotamer,t,J＝7.0 Hz 1.25H),2.90–2.82(m,5H)；13C NMR(100MHz,CDCl3)δ162.6(major rotamer),162.4 (minor rotamer),138.5(minor rotamer),137.6(major rotamer),128.7(major rotamer),128.7 (minor rotamer),128.6(major rotamer),128.5(minor rotamer),126.7(major rotamer),126.4 (minor rotamer),51.2(major rotamer),45.9(minor rotamer),35.0(minor rotamer),34.7(major rotamer),33.1(minor rotamer),29.7(minor rotamrer)；IR(neat)3140,1666,1402,1152,529cm-1； HRMS(ESI):m/z[M+H]+calcd for C10H13NO 164.1070,found 164.1071.
Example 12
N-methyl-1-naphthylamine (167. mu.L, 1.0mmol) and a stirrer were placed in a reaction tube, after inert gas was replaced, DMF (386. mu.L, 5.0mmol) was added, and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 96 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. Mixing the extractive solutions, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and adding ethyl acetateEster: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Yellow oily liquid, yield 86%.1H NMR(400 MHz,CDCl3)δ8.38(minor rotamer,s,0.4H),8.18(major rotamer,s,0.61H),8.10(d,J＝8.0Hz, 0.61H),7.91–7.82(m,2.46H),7.55–7.30(m,4H),4.98(major rotamer,s,1.20H),4.87(minor rotamer,s,0.77H),2.85(minor rotamer,s,1.20H),2.74(major rotamer,s,1.78H)；13C NMR(100 MHz,CDCl3)δ163.3(minor rotamer),162.4(major rotamer),133.9,131.6,131.3(major rotamer),131.3(minor rotamer),131.1(minor rotamer),131.0(major rotamer),129.2(minor rotamer),129.0(major rotamer),128.9(minor rotamer),128.7(major rotamer),127.8(minor rotamer),126.8(minor rotamer),126.2(major rotamer),125.6(minor rotamer),125.2(minor rotamer),123.9(major rotamer),122.4(minor rotamer),51.1(minor rotamer),45.9(major rotamer),34.1(major rotamer),30.1(minor rotamer)；IR(neat)3140,1672,1510,1402,1258, 1161,1081,803,779,529cm-1；HRMS(ESI):m/z[M+H]+calcd for C13H14NO 200.1070,found 200.1069.
Example 13
Fluoxetine (154.7mg,0.5mmol) and a stir-particle were placed in a reaction tube, after inert gas had been replaced, DMF (193. mu.L, 2.5mmol) was added and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 96 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Yellow oily liquid, yield 76%.1H NMR(400MHz, CDCl3)δ8.02(minor rotamer,s,0.41H),7.99(major rotamer,s,0.59H),7.43(d,J＝8.8Hz,2H), 7.37–7.27(m,5H),6.90–6.86(m,2H),5.20(minor rotamer,dd,J＝8.8,4.4Hz,0.42H),5.14 (major rotamer,dd,J＝8.8,4.0Hz,0.61H),3.59–3.52(major rotamer,m,1.42H),3.42–3.35 (minor rotamer,m,0.62H),2.94(minor rotamer,s,1.21H),2.90(major rotamer,s,1.84H),2.27– 2.17(m,1.06H),2.15–2.04(m,1.15H)；13C NMR(100MHz,CDCl3)δ162.7(major rotamer), 162.6(minor rotamer),160.1(minor rotamer),159.8(major rotamer),140.4(minor rotamer), 139.8(major rotamer),129.0(major rotamer),128.8(minor rotamer),128.2(major rotamer), 128.0(minor rotamer),126.9–126.7(m),125.6(minor rotamer),125.5(major rotamer),123.3– 122.7(m),115.7(minor rotamer),115.6(major rotamer),78.1(minor rotamer),76.9(major rotamer),45.9(major rotamer),41.5(minor rotamer),36.9(major rotamer),35.8(minor rotamer), 34.8(minor rotamer),29.5(major rotamer)；19F NMR(377MHz,CDCl3)δ-61.52(minor rotamer, s)；-61.59(major rotamer,s)；IR(neat)3140,1675,1616,1519,1329,1251,1161,1113,1068,837, 703,527cm-1；HRMS(ESI):m/z[M+Na]+calcd for C18H18F3NNaO2360.1182,found 360.1178.
Example 14
Benzylamine (110. mu.L, 1.0mmol) and a stirrer were placed in a reaction tube, the inert gas was replaced, DMF (386. mu.L, 5.0mmol) was added, and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 96 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow solid, m.p. 54-58 deg.C, 75% yield.1H NMR(400 MHz,CDCl3)δ8.25(major rotamer,s,0.87H),8.16(minor rotamer,d,J＝12Hz,0.13H),7.35– 7.27(m,5H),6.08(br s,1H),4.48(major rotamer,d,J＝6.0Hz,1.73H),4.41(minor rotamer,d,J ＝6.4Hz,0.34H)；13C NMR(100MHz,CDCl3)δ164.7(minor rotamer),161.0(major rotamer), 137.5(major rotamer),137.4(minor rotamer),128.9(minor rotamer),128.7(major rotamer), 127.9(minor rotamer),127.7(major rotamer),127.6(major rotamer),126.9(minor rotamer),45.6 (minor rotamer),42.1(major rotamer)；IR(neat)3140,1666,1402,699,526cm-1；HRMS(ESI): m/z[M+H]+calcd for C8H10NO 136.0757,found 136.0747.
Example 15
2-phenethylamine (128.5. mu.L, 1.0mmol) and a stirrer were placed in a reaction tube, after inert gas was replaced, DMF (386. mu.L, 5.0mmol) was added, and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 48 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Yellow oily liquid, yield 86%.1H NMR(400 MHz,CDCl3)δ8.10(major rotamer,s,0.84H),7.89(minor rotamer,d,J＝12Hz,0.16H),7.32– 7.20(m,5H),5.83(br s,1H),3.59–3.46(m,2H),2.86–2.82(m,2H)；13C NMR(100MHz,CDCl3) δ164.5(minor rotamer),161.2(major rotamer),138.4(major rotamer),137.5(minor rotamer), 128.8–128.6(m),126.8(minor rotamer),126.6(major rotamer),43.1(minor rotamer),39.1(major rotamer),37.6(minor rotamer),35.4(major rotamer)；IR(neat)3140,1670,1402,1154,689,527 cm-1；HRMS(ESI):m/z[M+Na]+calcd for C9H11NNaO 172.0733,found 172.0741.
Example 16
3-phenyl-1-propylamine (153. mu.L, 1.0mmol) and a stirring bar were placed in a reaction tube, and after replacing the inert gas, DMF (386. mu.L, 5.0mmol) was added, and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 48 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Yellow oily liquid, yield 99%.1H NMR(400 MHz,CDCl3)δ8.13(major rotamer,s,0.82H),7.99(minor rotamer,d,J＝12Hz,0.18H),7.32– 7.17(m,5H),6.04(br s,1H),3.31(major rotamer,q,J＝6.8Hz,1.64H),3.20(minor rotamer,q,J ＝6.8Hz,0.36H),2.68–2.64(m,2H),1.89–1.82(m,2H)；13C NMR(100MHz,CDCl3)δ164.8 (minor rotamer),161.3(major rotamer),141.1(major rotamer),140.5(minor rotamer),128.5 (minor rotamer),128.4(major rotamer),128.3(major rotamer),126.2(minor rotamer),126.0 (major rotamer),41.0(minor rotamer),37.7(major rotamer),33.0(major rotamer),32.4(minor rotamer),32.4(minor rotamer),31.0(major rotamer)；IR(neat)3122,1666,1402,1154,1113,749, 701,529cm-1；HRMS(ESI):m/z[M+Na]+calcd for C10H13NNaO 186.0889,found 186.0897.
Example 17
3, 4-Dimethoxyphenethylamine (173. mu.L, 1.0mmol) and a stirrer were placed in a reaction tube, the inert gas was replaced, DMF (386. mu.L, 5.0mmol) was added, and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 48 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Yellow oily liquid, yield 86%.1H NMR (400MHz,CDCl3)δ8.09(major rotamer,s,0.85H),7.87(minor rotamer,d,J＝12Hz,0.15H), 6.79–6.65(m,3H),5.93(br s,1H),3.83(major rotamer,s,3.73H),3.82(minor rotamer,s,2.25H), 3.51(major rotamer,q,J＝6.4Hz,1.64H),3.41(minor rotamer,q,J＝6.4Hz,0.36H),2.77–2.71 (m,2H)；13C NMR(100MHz,CDCl3)δ164.5(minor rotamer),161.2(major rotamer),148.9 (minor rotamer),148.8(major rotamer),147.7(minor rotamer),147.5(major rotamer),130.8 (major rotamer),130.0(minor rotamer),120.8(minor rotamer),120.5(major rotamer),111.8 (minor rotamer),111.7(major rotamer),111.3(minor rotamer),111.2(major rotamer),55.9(major rotamer),55.7(minor rotamer),43.2(minor rotamer),39.2(major rotamer),37.2(minor rotamer), 34.9(major rotamer)；IR(neat)3140,3006,2941,2838,1668,1610,1593,1519,1467,1400, 1265,1238,1195,1159,1142,1029,937,859,811,810,766,632cm-1；HRMS(ESI):m/z [M+H]+calcd for C10H16NO3 210.1125,found 210.1122.
Example 18
The dodecylprimary amine (237.5. mu.L, 1.0mmol) and a stirring bar were placed in a reaction tube, after inert gas was replaced, DMF (386. mu.L, 5.0mmol) was added, and the reaction tube was sealed. The reaction tube was placed in a 150 ℃ oil bath reaction vessel and stirred for 48 hours. After cooling to room temperature, it was diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Grey solid, m.p. 33-35 ℃, 73% yield.1H NMR(400MHz,CDCl3)δ8.15(major rotamer,s,0.82H),8.03(minor rotamer,d,J＝12Hz, 0.18H),5.63(br s,1H),3.28(major rotamer,q,J＝6.8Hz,1.66H),3.20(minor rotamer,q,J＝6.8 Hz,0.44H),1.53–1.48(m,2H),1.29–1.24(m,18H),0.87(t,J＝6.8Hz,3H)；13C NMR(100MHz, CDCl3)δ164.7(minor rotamer),161.0(major rotamer),41.8(minor rotamer),38.2(major rotamer),31.9(major rotamer),31.2(minor rotamer),29.6–29.1(m),26.8(major rotamer),26.3 (minor rotamer),22.6,14.1；IR(neat)3122,1670,1401,1150,1113,529cm-1；HRMS(ESI):m/z [M+K]+calcd for C13H27NKO 252.1724,found 252.1724.
1-8 of control test group:
adding 1,2,3, 4-tetrahydroisoquinoline and DMF into a 25mL reaction vessel, introducing nitrogen for protection, heating for reaction, and taking nitroethane as an internal standard1H NMR quantitative analysis. The specific reaction conditions of each control test group are shown in Table 1.
As can be seen from the above table, the reaction temperature of 1,2,3, 4-tetrahydroisoquinoline and DMF was above 130 ℃. The optimum temperature is 150 ℃.
As can be seen from the above table, for 1,2,3, 4-four hydrogen isoquinoline reaction in 3 ~ 24 hours can be smoothly carried out. Moderate yields were obtained with a reaction time of 12 hours. The optimum reaction time is 24 hours.
It can also be seen from the above table that the choice of atmosphere also affects the yield of the reaction, and that good yields can be obtained with an air atmosphere. The most preferred atmosphere is argon.
From the above table, it can also be seen that the mole ratio of 1,2,3, 4-tetrahydroisoquinoline to DMF has a direct effect when the molar ratio of 1,2,3, 4-tetrahydroisoquinoline: DMF 1:1 (based on 1,2,3, 4-tetrahydroisoquinoline) gave low yields. When the molar ratio of the two is 1:5, the yield is improved. When the 1,2,3, 4-four hydrogen isoquinoline dosage is 1.0mmol, two molar ratio is 1:2.5, the best yield.
Claims (1)
1. A method for preparing formamide derivatives through amine transfer reaction without participation of a catalyst is characterized in that: under the atmosphere of argon gas, the reaction kettle is,
reacting fatty amine shown in a formula 1 with DMF in one pot to obtain formamide derivatives shown in a formula 2;
the fatty amine of the formula 1 is 1,2,3, 4-tetrahydroisoquinoline, 6-methoxy-1, 2,3, 4-tetrahydroisoquinoline, 7-bromo-1, 2,3, 4-tetrahydroisoquinoline, 4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride, isoindoline, N-phenylpiperazine, 4-phenylpiperidine, N-methyl-N- (4-trifluoromethyl) benzylamine, N-methyl-4-methoxybenzylamine, n-methylbenzylamine, N-methylphenethylamine, N-methyl-1-naphthylmethylamine, fluoxetine, benzylamine, 2-phenylethylamine, 3-phenyl-1-propylamine, 3, 4-dimethoxyphenylethylamine and dodecyl primary amine;
the reaction is carried out in an argon atmosphere, and the aliphatic amine shown in the formula 1 and DMF react at 150 ℃ in one pot to obtain the formamide derivative shown in the formula 2; the aliphatic amine is 0.5-1.0 mmol, the DMF is 2.5-5.0 mmol, and the reaction time is 24-96 h.
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