ITMI20110340A1 - PROCEDURE FOR THE PREPARATION OF SECONDARY AMIDIS AND LACTAMI - Google Patents
PROCEDURE FOR THE PREPARATION OF SECONDARY AMIDIS AND LACTAMI Download PDFInfo
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- ITMI20110340A1 ITMI20110340A1 IT000340A ITMI20110340A ITMI20110340A1 IT MI20110340 A1 ITMI20110340 A1 IT MI20110340A1 IT 000340 A IT000340 A IT 000340A IT MI20110340 A ITMI20110340 A IT MI20110340A IT MI20110340 A1 ITMI20110340 A1 IT MI20110340A1
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- Prior art date
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- 238000000034 method Methods 0.000 title claims description 33
- 238000002360 preparation method Methods 0.000 title claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 238000006237 Beckmann rearrangement reaction Methods 0.000 claims description 15
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 150000003951 lactams Chemical group 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical compound OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 claims description 7
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 230000003197 catalytic effect Effects 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012190 activator Substances 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 2
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 claims description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 239000012454 non-polar solvent Substances 0.000 claims description 2
- 150000007530 organic bases Chemical group 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 1
- 150000002923 oximes Chemical class 0.000 description 10
- 230000008707 rearrangement Effects 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- VEZUQRBDRNJBJY-UHFFFAOYSA-N cyclohexanone oxime Chemical compound ON=C1CCCCC1 VEZUQRBDRNJBJY-UHFFFAOYSA-N 0.000 description 8
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- -1 arylsulfonyl ester Chemical class 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- JHNRZXQVBKRYKN-VQHVLOKHSA-N (ne)-n-(1-phenylethylidene)hydroxylamine Chemical compound O\N=C(/C)C1=CC=CC=C1 JHNRZXQVBKRYKN-VQHVLOKHSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 description 3
- LZKGFGLOQNSMBS-UHFFFAOYSA-N 4,5,6-trichlorotriazine Chemical compound ClC1=NN=NC(Cl)=C1Cl LZKGFGLOQNSMBS-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HAUGRYOERYOXHX-UHFFFAOYSA-N Alloxazine Chemical compound C1=CC=C2N=C(C(=O)NC(=O)N3)C3=NC2=C1 HAUGRYOERYOXHX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229960001413 acetanilide Drugs 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 125000002015 acyclic group Chemical group 0.000 description 2
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000006362 organocatalysis Methods 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 150000003334 secondary amides Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 230000001131 transforming effect Effects 0.000 description 2
- HFFLGKNGCAIQMO-UHFFFAOYSA-N trichloroacetaldehyde Chemical compound ClC(Cl)(Cl)C=O HFFLGKNGCAIQMO-UHFFFAOYSA-N 0.000 description 2
- 239000012808 vapor phase Substances 0.000 description 2
- 239000003021 water soluble solvent Substances 0.000 description 2
- HUCQPHINKBNKRU-UHFFFAOYSA-N (4-methylphenyl)phosphane Chemical compound CC1=CC=C(P)C=C1 HUCQPHINKBNKRU-UHFFFAOYSA-N 0.000 description 1
- 125000006732 (C1-C15) alkyl group Chemical group 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 1
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 1
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- PVJZBZSCGJAWNG-UHFFFAOYSA-N 2,4,6-trimethylbenzenesulfonyl chloride Chemical compound CC1=CC(C)=C(S(Cl)(=O)=O)C(C)=C1 PVJZBZSCGJAWNG-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- PQJUJGAVDBINPI-UHFFFAOYSA-N 9H-thioxanthene Chemical compound C1=CC=C2CC3=CC=CC=C3SC2=C1 PQJUJGAVDBINPI-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 229920002292 Nylon 6 Polymers 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 239000001166 ammonium sulphate Substances 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 150000003931 anilides Chemical class 0.000 description 1
- HIGZEFHDFAMPND-UHFFFAOYSA-N azepan-2-one;sulfuric acid Chemical compound OS(O)(=O)=O.O=C1CCCCCN1 HIGZEFHDFAMPND-UHFFFAOYSA-N 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 150000002730 mercury Chemical class 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 1
- NGTGENGUUCHSLQ-UHFFFAOYSA-N n-heptan-2-ylidenehydroxylamine Chemical compound CCCCCC(C)=NO NGTGENGUUCHSLQ-UHFFFAOYSA-N 0.000 description 1
- VLVVDHDKRHWUSQ-UHFFFAOYSA-N n-heptan-4-ylidenehydroxylamine Chemical compound CCCC(=NO)CCC VLVVDHDKRHWUSQ-UHFFFAOYSA-N 0.000 description 1
- TUDFZSGUEDLTJC-UHFFFAOYSA-N n-propylbutanamide Chemical compound CCCNC(=O)CCC TUDFZSGUEDLTJC-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D223/08—Oxygen atoms
- C07D223/10—Oxygen atoms attached in position 2
Description
Descrizione del brevetto per invenzione industriale avente per titolo M/mc “PROCEDIMENTO PER LA PREPARAZIONE DI AMMIDI SECONDARIE E LATTAMI” Description of the patent for industrial invention having the title M / mc "PROCEDURE FOR THE PREPARATION OF SECONDARY STARCHES AND LACTAMES"
CAMPO DELL’INVENZIONE FIELD OF THE INVENTION
La presente invenzione riguarda un nuovo procedimento per la preparazione di ammidi secondarie e lattami di interesse industriale. STATO DELLA TECNICA The present invention relates to a new process for the preparation of secondary amides and lactams of industrial interest. STATE OF THE TECHNIQUE
Il riarrangiamento di Beckmann è una delle reazioni organiche più potenti e diffuse sia in ambito accademico che a livello industriale per effettuare la trasformazione acido catalizzata di chetossime 1 in ammidi 2 (Schema 1). La reazione prende il nome dal chimico tedesco Ernst Otto Beckmann che la pubblicò già nel 1886 impiegando PC15come attivatore più che stechiometrico della reazione. Beckmann rearrangement is one of the most powerful and widespread organic reactions both in academia and industry to effect the acid-catalyzed transformation of ketoxime 1 into amides 2 (Scheme 1). The reaction takes its name from the German chemist Ernst Otto Beckmann who published it as early as 1886 using PC15 as a rather than stoichiometric activator of the reaction.
Il riarrangiamento di Beckmann ha una notevole importanza industriale poiché è alla base della preparazione del Nylon-6. Per riarrangiamento di Beckmann catalizzato da acido solforico della cicloesanone ossima 3 infatti nel 2005 sono stati preparati ben quattro milioni di tonnellate di ε-caprolattame solfato, che viene prima sbloccato a caprolattame 4 per aggiunta di ammoniaca (Schema 2) e poi convertito in Nylon. The Beckmann rearrangement is of considerable industrial importance since it is the basis of the preparation of Nylon-6. By Beckmann rearrangement catalyzed by sulfuric acid of cyclohexanone oxime 3, in fact in 2005 four million tons of ε-caprolactam sulphate were prepared, which is first unblocked to caprolactam 4 by adding ammonia (Scheme 2) and then converted into Nylon.
La reazione procede normalmente in condizioni piuttosto drastiche a causa delle alte concentrazioni di acido impiegato e di alte temperature di reazione, necessarie a promuovere il riarrangiamento. Per questa ragione purtroppo per ogni tonnellata di caprolattame 4 preparato si ha la formazione di 1.7 tonnellate di ammonio solfato come sottoprodotto. The reaction normally proceeds under rather drastic conditions due to the high concentrations of acid used and the high reaction temperatures, necessary to promote the rearrangement. For this reason, unfortunately, for each ton of caprolactam 4 prepared there is the formation of 1.7 tons of ammonium sulphate as a by-product.
Altri acidi, oltre airH2S04, impiegati per effettuare la trasformazione di chetossime ad ammidi sono ad esempio l’acido formico, l’acido metansolfonico, o la miscela di HC1-AC0H-AC20 nota come miscela di Beckmann, l’acido polifosforico e l’acido ossalico. Other acids, besides airH2S04, used to effect the transformation of ketoxime to amides are, for example, formic acid, methanesulfonic acid, or the mixture of HC1-AC0H-AC20 known as Beckmann's mixture, polyphosphoric acid and oxalic acid.
Non solo le chetossime si sottopongono a riarrangiamento di Beckmann ma anche diversi derivati delle ossime ottenuti per trattamento delle ossime con un opportuno reagente. Questi intermedi possono dare riarrangiamento per prolungato riscaldamento o se opportunamente attivati. Not only the ketoximes undergo Beckmann rearrangement but also various derivatives of the oximes obtained by treating the oximes with a suitable reagent. These intermediates can give rearrangement due to prolonged heating or if suitably activated.
L’esempio più classico di queste trasformazioni prevede la preparazione, a partire da una chetossima, del corrispondente alchil o arilsolfonil estere 5, che per riscaldamento e idrolisi porta alla desiderata ammide 2 (Schema 3). La preparazione di questi solfonilesteri delle ossime è stata ottenuta impiegando i più svariati solfonil cloruri come ad esempio l’SOCl2, il cloruro di tosile, l’acido clorosolfonico, il mesitilene solfonilcloruro solo per citarne alcuni. The most classic example of these transformations involves the preparation, starting from a kethoxime, of the corresponding alkyl or arylsulfonyl ester 5, which by heating and hydrolysis leads to the desired amide 2 (Scheme 3). The preparation of these oximes sulfonylesters was obtained using the most varied sulfonyl chlorides such as SOCl2, tosyl chloride, chlorosulfonic acid, mesitylene sulfonyl chloride just to name a few.
Tra i reagenti in grado di trasformare l’ossidrile dell’ossima di partenza in miglior gruppo uscente, diversi sia da quelli appena citati per preparare i solfonile steri, sia dal classico PC15, sono stati anche impiegati eleganti sistemi come la miscela triclorotriazina/DMF, la PPh3/N-clorosuccinimmide, ed il cloralio. Among the reagents capable of transforming the hydroxyl of the starting oxime into the best leaving group, other than those just mentioned to prepare the sulfonyl sters, and the classic PC15, elegant systems such as the trichlorotriazine / DMF mixture were also used, PPh3 / N-chlorosuccinimide, and chloral.
Tutti i reagenti fin qui elencati in grado di promuovere il riarrangiamento di Beckmann sono stati impiegati in quantità stechiometrica e quasi sempre in fase liquida. Tuttavia il riarrangiamento di Beckmann è stato sviluppato anche in acqua supercritica, nei liquidi ionici ed in fase vapore. All the reagents listed up to now capable of promoting Beckmann rearrangement have been used in stoichiometric quantities and almost always in the liquid phase. However, the Beckmann rearrangement has also been developed in supercritical water, ionic liquids and the vapor phase.
Quest’ultima metodologia ha trovato applicazione anche in campo industriale, infatti, nel 2003 la Sumitomo Chemical ha industrializzato un processo di produzione del caprolattame 4, evitando la formazione dei solfati come sottoprodotto, promuovendo il riarrangiamento di Beckmann con una metodica messa a punto in Enichem che prevede la reazione in fase vapore ad alta temperatura catalizzata da zeoliti e descritta in EP 564040. This last methodology has also found application in the industrial field, in fact, in 2003 Sumitomo Chemical industrialized a production process of caprolactam 4, avoiding the formation of sulphates as a by-product, promoting the Beckmann rearrangement with a method developed in Enichem which involves the high temperature vapor phase reaction catalyzed by zeolites and described in EP 564040.
Sebbene sia sinteticamente utilissimo, il riarrangiamento di Beckmann condotto in condizioni classiche, ad alte temperature o in ambiente fortemente acido, soffre del limite di applicabilità della metodologia a substrati più delicati o variamente funzionalizzati, così come alla sintesi di sostanze organiche naturali o complessi principi attivi farmaceutici. Un enorme sforzo è stato compiuto comunque neH’ultimo decennio al fine di trovare metodi blandi e soprattutto catalizzati per promuovere il riarrangiamento di Beckmann. Although synthetically very useful, the Beckmann rearrangement carried out in classical conditions, at high temperatures or in a strongly acid environment, suffers from the limit of applicability of the methodology to more delicate or variously functionalized substrates, as well as to the synthesis of natural organic substances or complex active ingredients pharmaceuticals. However, a huge effort has been made in the last decade in order to find bland and above all catalyzed methods to promote Beckmann's rearrangement.
Ampio spazio in questa direzione è stato dato ai catalizzatori metallici, sia di transizione che dei gruppi principali. I triflati di metalli pesanti come Ga(OTf)3, Yb(OTf)3, o In(OTf)3, solo per citarne alcuni, sono risultati attivi in acetonitrile nel promuovere il riarrangiamento di Beckmann sebbene la quantità necessaria di catalizzatore sia ancora elevata e in nessun caso la reazione proceda senza riscaldamento. Ample space in this direction has been given to metal catalysts, both transition and main group. Heavy metal triflates such as Ga (OTf) 3, Yb (OTf) 3, or In (OTf) 3, just to name a few, have been found to be active in acetonitrile in promoting Beckmann rearrangement although the required amount of catalyst is still high. and in no case does the reaction proceed without heating.
Un altro catalizzatore piuttosto efficiente ma estremamente costoso è risultato un catalizzatore a base di Rh generato in situ impiegando il [RhCl(cod)]2in presenza di acido triflico e paratolilfosfina come leganti. Sebbene il metodo risulti piuttosto elegante ed efficiente nel catalizzare il riarrangiamento di chetossime acicliche nelle corrispondenti ammidi, il metodo fallisce tuttavia nel trasformare le chetossime cicliche nei corrispondenti lattami. Another rather efficient but extremely expensive catalyst was an in situ generated Rh-based catalyst using [RhCl (cod)] 2 in the presence of triflic acid and paratolylphosphine as ligands. Although the method is quite elegant and efficient in catalyzing the rearrangement of acyclic ketoximes into the corresponding amides, the method nevertheless fails in transforming the cyclic ketoximes into the corresponding lactams.
E noto che anche solo 12 moli % di HgCl2in acetonitrile a riflusso sono in grado di promuovere il riarrangiamento di Beckmann. In questo caso la reazione procede in condizioni neutre e fornisce in rese del 48-98% le ammidi di chetossime sia cicliche che acicliche. E’ evidente però che il grande limite di questo metodo è l’impiego di un sale di un metallo altamente tossico come il mercurio. It is known that even 12 mol% of HgCl2 in reflux acetonitrile are able to promote Beckmann rearrangement. In this case, the reaction proceeds under neutral conditions and provides both cyclic and acyclic ketoxime amides in yields of 48-98%. It is evident, however, that the great limitation of this method is the use of a salt of a highly toxic metal such as mercury.
Le ricerche di Chandrasekhar e Gopalaiah (acido ossalico e cloralio), ma soprattutto di Giacomelli (triclorotriazina) sull’impiego di piccole molecole organiche in grado di promuovere la reazione hanno portato Γ attenzione dei ricercatori verso la possibilità di mettere a punto un metodo del tutto organocatalitico in fase liquida per effettuare il riarrangiamento di Beckmann. The researches of Chandrasekhar and Gopalaiah (oxalic acid and chloral), but above all of Giacomelli (trichlorotriazine) on the use of small organic molecules capable of promoting the reaction have brought Γ the researchers' attention to the possibility of developing a completely liquid phase organocatalytic to perform the Beckmann rearrangement.
Ed infatti nel 2005, in un lavoro di Ishihara e collaboratori: /. Am. Chem. Soc. 2005, 127, 11240-11241, è stato riportato il primo metodo organocatalitico per effettuare la reazione che prevede Eimpiego della triclorotriazina in quantità catalitiche (cloruro di cianurile, 5 mol%) in acetonitrile a riflusso. And in fact in 2005, in a work by Ishihara and collaborators: /. Am. Chem. Soc. 2005, 127, 11240-11241, the first organocatalytic method was reported to carry out the reaction which involves the use of trichlorotriazine in catalytic quantities (cyanuryl chloride, 5 mol%) in reflux acetonitrile.
Da quanto sopra riportato appare evidente il lungo cammino effettuato fino ad oggi ed i grandi miglioramenti ottenuti nel rendere il riarrangiamento di Beckmann semplicemente praticabile su scala industriale. In particolare, su molecole complesse, utili nel campo della chimica farmaceutica e nella produzione di principi attivi farmaceutici, senza l’impiego di reagenti costosi, tossici (cloruro di cianurile, sali di mercurio ecc.) e in condizioni blande di reazione. Tuttavia esiste ancora la necessità di disporre di un metodo universale che funzioni in maniera stechiometrica o catalitica secondo le necessità, che possa essere effettuato in condizioni blande di reazione e non faccia uso di reagenti tossici o porti alla formazione di elevate quantità di sottoprodotti. From what has been reported above it is evident the long progress made to date and the great improvements obtained in making the Beckmann rearrangement simply practicable on an industrial scale. In particular, on complex molecules, useful in the field of pharmaceutical chemistry and in the production of active pharmaceutical ingredients, without the use of expensive, toxic reagents (cyanuryl chloride, mercury salts, etc.) and in mild reaction conditions. However, there is still a need for a universal method that works in a stoichiometric or catalytic manner as required, which can be carried out under mild reaction conditions and does not use toxic reagents or lead to the formation of large quantities of by-products.
SOMMARIO DELL’INVENZIONE SUMMARY OF THE INVENTION
E stato sorprendentemente trovato che è possibile preparare in maniera altamente selettiva, alte rese ed efficienza ammidi secondarie e lattami mediante la reazione di riarrangiamento di Beckmann, impiegando come attivante il tricloroacetonitrile. It has surprisingly been found that it is possible to prepare secondary amides and lactams in a highly selective, high yield and efficiency manner by means of the Beckmann rearrangement reaction, using trichloroacetonitrile as activator.
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Oggetto della presente invenzione è un procedimento per la preparazione di un composto di formula (I) The object of the present invention is a process for the preparation of a compound of formula (I)
dove ciascuno di A e B, uguale o diverso, è un radicale idrocarburico saturo, insaturo o parzialmente insaturo, opzionalmente sostituito, o un gruppo arile o eteroarile opzionalmente sostituito; oppure A e B, presi insieme, completano un anello lattamico, dove uno o più gruppi -CH2- di tale anello possono essere rimpiazzati da altrettanti gruppi -O-, -S- oppure -NZ- dove Z è CÌ-CÈalchile, arile o eteroarile; e dove detto anello lattamico può essere condensato con uno o più gruppi arile o eteroarile; comprendente la reazione di riarrangiamento di Beckmann di un composto di formula (II) wherein each of A and B, equal or different, is an optionally substituted saturated, unsaturated or partially unsaturated hydrocarbon radical, or an optionally substituted aryl or heteroaryl group; or A and B, taken together, complete a lactam ring, where one or more -CH2- groups of this ring can be replaced by as many -O-, -S- or -NZ- groups where Z is C1-CÈalkyl, aryl or heteroaryl; and where said lactam ring can be condensed with one or more aryl or heteroaryl groups; comprising the Beckmann rearrangement reaction of a compound of formula (II)
dove ciascuno di A e B, uguale o diverso, è un radicale idrocarburico saturo, insaturo o parzialmente insaturo, opzionalmente sostituito, o un gruppo arile o eteroarile opzionalmente sostituito; oppure A e B, presi insieme, completano un anello cicloalchilico, dove uno o più gruppi -CH2- di tale anello possono essere rimpiazzati da altrettanti gruppi -O-, -S- oppure -NZ- dove Z è Ci-C6alchile, arile o eteroarile; e dove detto anello cicloalchilico può essere condensato con uno o più gruppi arile o eteroarile; impiegando il tricloroacetonitrile come attivante, in presenza di un acido. wherein each of A and B, equal or different, is an optionally substituted saturated, unsaturated or partially unsaturated hydrocarbon radical, or an optionally substituted aryl or heteroaryl group; or A and B, taken together, complete a cycloalkyl ring, where one or more -CH2- groups of this ring can be replaced by as many -O-, -S- or -NZ- groups where Z is C6-C6alkyl, aryl or heteroaryl; and where said cycloalkyl ring can be condensed with one or more aryl or heteroaryl groups; using trichloroacetonitrile as activator, in the presence of an acid.
Preferibilmente ciascuno di A e B, uguale o diverso, è Ci-C15alchile, C2-C15alchenile; C2-C15alchimie, arile o eteroarile; oppure A e B, presi insieme, completano, rispettivamente, un anello C5-C8cicloalchilico o C5-C8lattamico, dove uno o più gruppi -CH2- possono essere rimpiazzati da altrettanti gruppi -O-, -S- oppure -NZ- dove Z è Ci-C6alchile, arile o eteroarile; e dove detto anello cicloalchilico o lattamico può essere condensato con uno o più gruppi arile o eteroarile. Preferably each of A and B, the same or different, is C1-C15alkyl, C2-C15alkenyl; C2-C15alchemies, aryl or heteroaryl; or A and B, taken together, complete, respectively, a C5-C8cycloalkyl or C5-C8lactam ring, where one or more -CH2- groups can be replaced by as many -O-, -S- or -NZ- groups where Z is C 1 -C6alkyl, aryl or heteroaryl; and where said cycloalkyl or lactam ring can be condensed with one or more aryl or heteroaryl groups.
Un gruppo Ci-C15alchile, che può essere lineare o ramificato, è ad esempio un gruppo Ci-C6alchile, preferibilmente Ci-C4alchile, e opzionalmente sostituto da uno o più, tipicamente da 1 a 4, sostituenti scelti indipendentemente tra alogeno, ad esempio fluoro, cloro o bromo; -CF3, nitro, ciano; -OH, -SH, -NRÌR2, dove ciascuno di Ri e R2, indipendentemente, è Ci-C6alchile, preferibilmente Ci-C4alchile; -OR1;-SR1;oppure -COORÌdove Ri è come prima definito. A C1-C15alkyl group, which can be linear or branched, is for example a C1-C6alkyl group, preferably C1-C4alkyl, and optionally substituted by one or more, typically from 1 to 4, substituents independently selected from halogen, for example fluorine , chlorine or bromine; -CF3, nitro, cyan; -OH, -SH, -NR1R2, where each of R1 and R2, independently, is C1-C6alkyl, preferably C1-C4alkyl; -OR1; -SR1; or -COORÌ where Ri is defined as above.
Un gruppo C2-C15alchenile che può essere lineare o ramificato, è ad esempio un gruppo C2-C6alchenile, preferibilmente C2-C4alchenile, e opzionalmente sostituto da uno o più, tipicamente da 1 a 4, sostituenti scelti indipendentemente tra alogeno, ad esempio fluoro, cloro o bromo; -CF3, nitro, ciano; -OH, -SH, -NRÌR2, dove ciascuno di R3e R2, indipendentemente, è CÌ-CÈalchile, preferibilmente Ci-C4alchile; -OR1;-SR1;oppure -COORÌdove Ri è come prima definito. A C2-C15alkenyl group which can be linear or branched, is for example a C2-C6alkenyl group, preferably C2-C4alkenyl, and optionally substituted by one or more, typically from 1 to 4, independently selected substituents from halogen, for example fluorine, chlorine or bromine; -CF3, nitro, cyan; -OH, -SH, -NR1R2, where each of R3 and R2, independently, is C1-C6alkyl, preferably C1-C4alkyl; -OR1; -SR1; or -COORÌ where Ri is defined as above.
Un gruppo C2-C15alchimie che può essere lineare o ramificato, è ad esempio un gruppo C2-C6alchimie, preferibilmente C2-C4alchimie, e opzionalmente sostituto da uno o più, tipicamente da 1 a 4, sostituenti scelti indipendentemente tra alogeno, ad esempio fluoro, cloro o bromo; -CF3, nitro, ciano; -OH, -SH, -NRÌR^ dove ciascuno di Ri e R2, indipendentemente, è Ci-C6alchile, preferibilmente Ci-C4alchile; -OR1;-SR1;oppure -COORÌdove Ri è come prima definito. A C2-C15alchemy group which can be linear or branched, is for example a C2-C6alchemy group, preferably C2-C4alchemies, and optionally substituted by one or more, typically 1 to 4, independently selected substituents from halogen, for example fluorine, chlorine or bromine; -CF3, nitro, cyan; -OH, -SH, -NRÌR ^ wherein each of R1 and R2, independently, is C1-C6alkyl, preferably C1-C4alkyl; -OR1; -SR1; or -COORÌ where Ri is defined as above.
Un gruppo arile è ad esempio fenile o naftile, opzionalmente sostituto da uno o più, tipicamente da 1 a 4, sostituenti scelti indipendentemente tra alogeno, ad esempio fluoro, cloro o bromo; -CF3, nitro, ciano; -OH, -SH, -NRÌR^ dove ciascuno di Ri e R2, indipendentemente, è Ci-C6alchile, preferibilmente Ci-C4alchile; -OR1;-SR1;oppure -COORÌdove Ri è come prima definito. An aryl group is for example phenyl or naphthyl, optionally substituted by one or more, typically 1 to 4, substituents independently selected from halogen, for example fluorine, chlorine or bromine; -CF3, nitro, cyan; -OH, -SH, -NRÌR ^ wherein each of R1 and R2, independently, is C1-C6alkyl, preferably C1-C4alkyl; -OR1; -SR1; or -COORÌ where Ri is defined as above.
Un gruppo eteroarile è ad esempio un eterociclo mono o biciclico contenente da 1 a 4 eteroatomi scelti tra O, S e N, insaturo o parzialmente insaturo, opzionalmente sostituto da uno o più, tipicamente da 1 a 4, sostituenti scelti indipendentemente tra alogeno, ad esempio fluoro, cloro o bromo; -CF3, nitro, ciano; -OH, -SH, -NRÌR^ dove ciascuno di R3e R2, indipendentemente, è Ci-C6alchile, preferibilmente Ci-C4alchile; -OR1;-SR1;oppure -COORÌdove Ri è come prima definito. A heteroaryl group is for example a mono or bicyclic heterocycle containing from 1 to 4 heteroatoms selected from O, S and N, unsaturated or partially unsaturated, optionally substituted by one or more, typically from 1 to 4, substituents independently selected from halogen, for example for example fluorine, chlorine or bromine; -CF3, nitro, cyan; -OH, -SH, -NRÌR ^ wherein each of R3 and R2, independently, is C1-C6alkyl, preferably C1-C4alkyl; -OR1; -SR1; or -COORÌ where Ri is defined as above.
Preferibilmente detto eterociclo può essere scelto ad esempio tra piridina, imidazolo, tiazolo, furano, tiofene, indolo, chinossalina, chinazolina, ftalazina, pirrolo, chinolina, isochinolina, benzofurano, benzotiofene, pirazolo, imidazolo, ossazolo, isossazolo, tiazolo, indazolo, benzimidazolo, piridazina, pirimidina, 1,5-naftidrina, 1,2,3 -triazolo, 1,2,4-triazolo, 1.2.3.4-tetrazolo, 1,3,4-ossadiazolo, 1,2,4-ossadiazolo, l,2,5,tiadiazolo, 1.3.4-tiadiazolo, 1,2,3 -triazina, 1,2,4-triazina, 1,3,5-triazina, 1,2-benzisossazolo, 1,3-benzossazolo, 1,3-benzotiazolo, purina, pteridina, allossazina, acridina, xantene e tioxantene. Preferably, said heterocycle can be selected for example from pyridine, imidazole, thiazole, furan, thiophene, indole, quinoxaline, quinazoline, phthalazine, pyrrole, quinoline, isoquinoline, benzofuran, benzothiophene, pyrazole, imidazole, oxazole, isoxazole, benzimazole, thiazole , pyridazine, pyrimidine, 1,5-naphthrin, 1,2,3-triazole, 1,2,4-triazole, 1.2.3.4-tetrazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, l , 2,5, thiadiazole, 1.3.4-thiadiazole, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2-benzisoxazole, 1,3-benzoxazole, 1 , 3-benzothiazole, purine, pteridine, alloxazine, acridine, xanthene and thioxanthene.
Z come Ci-C6alchile è preferibilmente CrC4alchile. Z come arile è preferibilmente fenile o naftile, in particolare fenile. Z come eteroarile è ad esempio un eterociclo mono o biciclico come sopra definito. Z as C 1 -C6alkyl is preferably CrC4alkyl. Z as aryl is preferably phenyl or naphthyl, in particular phenyl. Z as heteroaryl is for example a mono or bicyclic heterocycle as defined above.
Un acido può essere ad esempio un acido forte o debole, organico o inorganico. Un acido organico può essere ad esempio un acido carbossilico o solfonico, preferibilmente l’acido trifluoroacetico o metansolfonico. Un acido inorganico può essere ad esempio l’acido cloridrico, preferibilmente gassoso. An acid can be for example a strong or weak, organic or inorganic acid. An organic acid can be, for example, a carboxylic or sulphonic acid, preferably trifluoroacetic or methanesulfonic acid. An inorganic acid can be, for example, hydrochloric acid, preferably gaseous.
Opzionalmente la reazione può essere condotta in presenza di un solvente, che può essere ad esempio, un solvente polare aprotico, tipicamente un’ammide, ad esempio dimetilformammide, dimetilacetammide, oppure N-metilpirrolidone, acetonitrile, dimetilsolfossido, preferibilmente dimetilacetammide; un etere, ad esempio tetraidrofurano o diossano; un solvente clorurato, ad esempio, diclorometano (DCM), dicloroetano, cloroformio o clorobenzene; un estere, ad esempio acetato di etile o di metile; un solvente apolare tipicamente toluene; o una miscela di due o più, preferibilmente di due o tre, di detti solventi. Lo stesso tricloroacetonitrile può essere impiegato come reagente e solvente della reazione. Optionally, the reaction can be carried out in the presence of a solvent, which can be, for example, an aprotic polar solvent, typically an amide, for example dimethylformamide, dimethylacetamide, or N-methylpyrrolidone, acetonitrile, dimethylsulfoxide, preferably dimethylacetamide; an ether, for example tetrahydrofuran or dioxane; a chlorinated solvent, for example, dichloromethane (DCM), dichloroethane, chloroform or chlorobenzene; an ester, for example ethyl or methyl acetate; a non-polar solvent typically toluene; or a mixture of two or more, preferably two or three, of said solvents. The same trichloroacetonitrile can be used as reagent and solvent of the reaction.
In accordo ad un aspetto dell’ invenzione la reazione può essere condotta in due passaggi sintetici, comprendenti la conversione di un composto di formula (II), come sopra definito, per trattamento con tricloroacetonitrile, in un tricloroacetimmidato intermedio di formula (III) According to an aspect of the invention, the reaction can be carried out in two synthetic steps, including the conversion of a compound of formula (II), as defined above, by treatment with trichloroacetonitrile, into an intermediate trichloroacetimidate of formula (III)
dove A e B sono come sopra definiti in un composto di formula (II), il successivo trattamento con una quantità stechiometrica di acido ed idrolisi, ad ottenere un composto di formula (I), come sopra definito. where A and B are as above defined in a compound of formula (II), the subsequent treatment with a stoichiometric quantity of acid and hydrolysis, to obtain a compound of formula (I), as defined above.
La reazione può essere così schematizzata The reaction can be summarized as follows
La conversione di un composto di formula (II) in un composto di formula (III) può essere condotta eventualmente in presenza di un solvente ed, opzionalmente, di un catalizzatore basico. The conversion of a compound of formula (II) into a compound of formula (III) can optionally be carried out in the presence of a solvent and, optionally, of a basic catalyst.
Un composto di formula (III) può essere isolato o non isolato. A compound of formula (III) can be isolated or non-isolated.
Il solvente può essere uno di quelli sopra riportati o una loro miscela oppure il tricloroacetonitrile stesso. The solvent can be one of the above or a mixture thereof or the trichloroacetonitrile itself.
Un catalizzatore basico può essere ad esempio una base organica, quale un’ammina terziaria, ad esempio l,8-diazabiciclo[5.4.0]undec-7-ene (DBU), l,5-diazabiciclo[4.3.0]non-5-ene (DBN), l,4-diazabiciclo[2.2.2]ottano (DABCO), diisopropiletilammina; oppure imidazolo, oppure trifenilfosfina; oppure una base inorganica quale, ad esempio, sodio idruro; tert-butossido di sodio o potassio; oppure carbonato di potassio o di cesio. A basic catalyst can be for example an organic base, such as a tertiary amine, for example 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non- 5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), diisopropylethylamine; or imidazole, or triphenylphosphine; or an inorganic base such as, for example, sodium hydride; tert-butoxide of sodium or potassium; or potassium or cesium carbonate.
La reazione può essere condotta ad una temperatura compresa tra circa 0° e circa 100°C, preferibilmente tra circa 20°C e circa 30°C. The reaction can be carried out at a temperature comprised between about 0 ° and about 100 ° C, preferably between about 20 ° C and about 30 ° C.
Un acido è ad esempio uno degli acidi sono riportati. An acid is for example one of the acids are reported.
La reazione può essere effettuata in un solvente, come prima definito, e alla temperatura precedentemente descritta. La successiva idrolisi della miscela di fine reazione può essere effettuata per aggiunta di acqua o di una soluzione acquosa di un solvente solubile con l’acqua, ad esempio acetonitrile. The reaction can be carried out in a solvent, as defined above, and at the temperature described above. The subsequent hydrolysis of the end-of-reaction mixture can be carried out by adding water or an aqueous solution of a water-soluble solvent, for example acetonitrile.
Un composto di formula (I) può essere quindi isolato e purificato mediante le tecniche ben note alla persona esperta dell’ arte. In molti casi il composto di formula (I) così ottenuto cristallizza direttamente dall’ambiente di reazione. A compound of formula (I) can then be isolated and purified by techniques well known to the person skilled in the art. In many cases the compound of formula (I) thus obtained crystallizes directly from the reaction environment.
In accordo ad un ulteriore aspetto dell’invenzione, la conversione di un composto di formula (II), come sopra definito, in un composto di formula (I), come sopra definito, può essere ottenuta in un unico passaggio impiegando quantità catalitiche di tricloroacetonitrile e di acido, e, opzionalmente, in presenza di un solvente. According to a further aspect of the invention, the conversion of a compound of formula (II), as defined above, into a compound of formula (I), as defined above, can be obtained in a single step using catalytic quantities of trichloroacetonitrile and acid, and optionally in the presence of a solvent.
Il tricloroacetonitrile e l’acido come prima definito possono essere impiegati in quantità comprese tra circa lo 1% e circa il 20% molare rispetto alla chetossima di formula (II), preferibilmente tra circa il 5% e circa il 10% molare. Trichloroacetonitrile and the acid as defined above can be used in quantities ranging from about 1% to about 20% by mol with respect to the ketoxime of formula (II), preferably between about 5% and about 10% by mol.
La reazione può essere condotta in presenza di un solvente come prima definito, preferibilmente in acetonitrile. L’acido impiegato può essere un acido come prima definito, preferibilmente l’acido metansolfonico o trifluoroacetico. The reaction can be carried out in the presence of a solvent as defined above, preferably in acetonitrile. The acid used can be an acid as defined above, preferably methanesulfonic or trifluoroacetic acid.
La reazione può essere condotta ad una temperatura compresa tra circa 0°C e circa 100°C, preferibilmente tra circa 70°C e circa 90°C. L’idrolisi della miscela di fine reazione può essere effettuata per aggiunta di acqua o di una soluzione acquosa di un solvente solubile con l’acqua, ad esempio aceto nitrile. The reaction can be carried out at a temperature between about 0 ° C and about 100 ° C, preferably between about 70 ° C and about 90 ° C. The hydrolysis of the end-of-reaction mixture can be carried out by adding water or an aqueous solution of a water-soluble solvent, for example nitrile vinegar.
Un composto di formula (I) può essere isolato e, se desiderato, purificato mediante le tecniche ben note alla persona esperta dell’ arte. In molti casi il composto di formula (I) così ottenuto cristallizza direttamente dall’ambiente di reazione. A compound of formula (I) can be isolated and, if desired, purified by techniques well known to the person skilled in the art. In many cases the compound of formula (I) thus obtained crystallizes directly from the reaction environment.
Un composto di formula (II) è commercialmente disponibile o può essere preparato a partire dal corrispondente chetone commercialmente disponibile con metodiche ben note alla persona esperta dell’arte. Ad esempio trattando un chetone con idrossilammina, impiegata come base libera in soluzione acquosa o come sale cloridrato, in una miscela solvente idroalcolica. A compound of formula (II) is commercially available or can be prepared starting from the corresponding commercially available ketone with methods well known to the person skilled in the art. For example by treating a ketone with hydroxylamine, used as a free base in aqueous solution or as a hydrochloride salt, in a hydroalcoholic solvent mixture.
I seguenti esempi illustrano l’invenzione. The following examples illustrate the invention.
Procedura generale in due passaggi General two-step procedure
In un pallone munito di termometro, agitazione magnetica ed in atmosfera inerte, si discioglie la chetossima di formula (II) in 5 volumi di tricloroacetonitrile. In a flask equipped with a thermometer, magnetic stirring and in an inert atmosphere, the ketoxime of formula (II) is dissolved in 5 volumes of trichloroacetonitrile.
La reazione viene mantenuta in agitazione a 20-25 °C per il tempo necessario al completamento della reazione. La conversione del prodotto di partenza può essere verificata tramite TLC o<1>H-NMR. Nei casi in cui la reazione sia risultata troppo lenta, sono stati aggiunti 5 volumi di toluene e da 0,05 fino a 0,50 equivalenti di DBU. The reaction is kept under stirring at 20-25 ° C for the time necessary to complete the reaction. The conversion of the starting product can be verified by TLC or <1> H-NMR. In cases where the reaction was too slow, 5 volumes of toluene and 0.05 to 0.50 equivalent of DBU were added.
Al termine della reazione, la massa viene concentrata a residuo distillando a pressione ridotta. Il residuo è stato diluito con 5 volumi di diclorometano e portato alla temperatura di -5/0°C. Alla soluzione sono stati aggiunti 1,05 equivalenti di acido trifluoroacetico, mantenendo la temperatura al di sotto dei 10°C. Nei casi in cui ci sia stata la necessità di promuovere l’addizione dell’ossima al tricloroacetonitrile con l’ausilio della DBU, l’acido trifluoroacetico è stato aggiunto nella quantità corrispondente da 1,10 a 1,55 equivalenti. At the end of the reaction, the mass is concentrated to residue by distilling under reduced pressure. The residue was diluted with 5 volumes of dichloromethane and brought to the temperature of -5 / 0 ° C. 1.05 equivalents of trifluoroacetic acid were added to the solution, keeping the temperature below 10 ° C. In cases where there was a need to promote the addition of oxime to trichloroacetonitrile with the help of DBU, trifluoroacetic acid was added in the corresponding amount from 1.10 to 1.55 equivalents.
Terminata raggiunta di acido, la miscela di reazione viene lasciata rinvenire a temperatura ambiente e mantenuta in agitazione per il tempo necessario al completamento della reazione. Una volta terminata la reazione, si concentra la soluzione a pressione ridotta e la si tratta con una miscela composta da acqua e acetonitrile. Si distilla nuovamente a pressione ridotta fino ad ottenere un residuo; i prodotti sono stati purificati tramite cromatografia flash o per cristallizzazione. When the acid has been reached, the reaction mixture is left to reach room temperature and kept under stirring for the time necessary to complete the reaction. Once the reaction is over, the solution is concentrated under reduced pressure and treated with a mixture of water and acetonitrile. It is distilled again under reduced pressure until a residue is obtained; the products were purified by flash chromatography or by crystallization.
Esempio 1: Riarrangiamento dell’a-tetralone ossima Example 1: Rearrangement of the a-tetralone oxime
L’ossima è trattata secondo la procedura generale. Sono messi a reagire 1,00 g di α-tetralone ossima ottenendo dopo 7 ore a temperatura ambiente il tricloroacetimmidato corrispondente. Il grezzo di reazione costituito dal residuo ottenuto per distillazione a pressione ridotta, una volta ripreso con diclorometano, è attivato con 0,74 g di acido trifluoroacetico. Il residuo di reazione, dopo trattamento con la soluzione di acqua e acetonitrile, è purificato per cromatografia, ottenendo 580 mg di lattarne con una resa del 58% Oxime is treated according to the general procedure. 1.00 g of α-tetralone oxime are reacted, obtaining the corresponding trichloroacetimidate after 7 hours at room temperature. The raw reaction consisting of the residue obtained by distillation at reduced pressure, once taken up with dichloromethane, is activated with 0.74 g of trifluoroacetic acid. The reaction residue, after treatment with the solution of water and acetonitrile, is purified by chromatography, obtaining 580 mg of lactam with a yield of 58%
(4C, Ar-CH), 134.2 e 138.1 (2C, Ar-C); 176.0 (C, C=0). (4C, Ar-CH), 134.2 and 138.1 (2C, Ar-C); 176.0 (C, C = 0).
Esempio 2: Riarrangiamento del eptan-4-one ossima (II), A=B=npropile Example 2: Rearrangement of the heptan-4-one oxime (II), A = B = npropyl
L’ossima di formula (II) è trattata secondo la procedura generale. Sono messi a reagire 500 mg di eptanone ossima ottenendo dopo 6 ore a temperatura ambiente il tricloroacetimmidato corrispondente. Il grezzo di reazione costituito dal residuo ottenuto per distillazione a pressione ridotta, una volta ripreso con diclorometano, è attivato con 0,46 g di acido trifluoroacetico. Il residuo di reazione, dopo trattamento con la soluzione di acqua e acetonitrile, è iniettato in gascromatografo. Sono stati titolati 325 mg di N-propilbutirrammide per una resa di reazione del 65%. The oxime of formula (II) is treated according to the general procedure. 500 mg of heptanone oxime are reacted, obtaining the corresponding trichloroacetimidate after 6 hours at room temperature. The raw reaction product consisting of the residue obtained by distillation at reduced pressure, once taken up with dichloromethane, is activated with 0.46 g of trifluoroacetic acid. The reaction residue, after treatment with the water and acetonitrile solution, is injected into a gas chromatograph. 325 mg of N-propylbutyramide were titrated for a reaction yield of 65%.
Esempio 3: Riarrangiamento del cicloesanone ossima Example 3: Rearrangement of the cyclohexanone oxime
La cicloesanone ossima è trattata secondo la procedura generale. Sono messi a reagire 500 mg di cicloesanone ossima ottenendo dopo 6 ore a temperatura ambiente il tricloroacetimmidato corrispondente. Il grezzo di reazione costituito dal residuo ottenuto per distillazione a pressione ridotta, una volta ripreso con diclorometano, è attivato con 0,53 g di acido trifluoroacetico. Il residuo di reazione, dopo trattamento con la soluzione di Cyclohexanone oxime is treated according to the general procedure. 500 mg of cyclohexanone oxime are reacted, obtaining the corresponding trichloroacetimidate after 6 hours at room temperature. The raw reaction product consisting of the residue obtained by distillation at reduced pressure, once taken up with dichloromethane, is activated with 0.53 g of trifluoroacetic acid. The reaction residue, after treatment with the solution of
acqua e acetonitrile, è stato iniettato in gascromatografo. Sono titolati 435 mg di caprolattame per una resa di reazione del 87%. water and acetonitrile, was injected into the gas chromatograph. 435 mg of caprolactam are titrated for a reaction yield of 87%.
Esempio 4: Riarrangiamento di (E)-acetofenone ossima, A = fenile, B = metile Example 4: Rearrangement of (E) -acetophenone oxime, A = phenyl, B = methyl
L’ossima è trattata in accordo alla procedura generale. Sono messi a reagire 1,00 g di acetofenone ossima ottenendo dopo 4 ore a temperatura ambiente il tricloroacetimmidato corrispondente. Il grezzo di reazione costituito dal residuo ottenuto per distillazione a pressione ridotta, una volta ripreso con diclorometano, è attivato con 0,89 g di acido trifluoroacetico. Il residuo di reazione, dopo trattamento con la soluzione di acqua e acetonitrile, è iniettato in HPLC. Sono titolati 821 mg di acetanilide con una resa di reazione del 82%. Oxime is treated in accordance with the general procedure. 1.00 g of acetophenone oxime are reacted, obtaining the corresponding trichloroacetimidate after 4 hours at room temperature. The raw reaction product consisting of the residue obtained by distillation at reduced pressure, once taken up with dichloromethane, is activated with 0.89 g of trifluoroacetic acid. The reaction residue, after treatment with the water and acetonitrile solution, is injected into HPLC. 821 mg of acetanilide are titrated with a reaction yield of 82%.
1H NMR (CDC13): δ 2.16 (s, 3H, C//3), 7.11 (t, H, / = 7.5 Hz, Ar-H), 7.27 (m, 2H, Ar-H), 7.42 (d, H, / = 7.5 Hz, Ar-H), 7.80 (s, H, N//). 1H NMR (CDC13): δ 2.16 (s, 3H, C // 3), 7.11 (t, H, / = 7.5 Hz, Ar-H), 7.27 (m, 2H, Ar-H), 7.42 (d, H, / = 7.5 Hz, Ar-H), 7.80 (s, H, N //).
Esempio 5: Riarrangiamento di (E)-2-acetonaftone ossima Example 5: Rearrangement of (E) -2-acetonaphthone oxime
L’ossima è trattata in accordo alla procedura generale. Sono messi a reagire 1,00 g di (E)-2-acetonaftone ossima ottenendo dopo 3 ore a temperatura ambiente il tricloroacetimmidato corrispondente. Il grezzo di reazione costituito dal residuo ottenuto per distillazione a pressione ridotta, una volta ripreso con diclorometano, è attivato con 0,65 g di acido trifluoroacetico. Il residuo di reazione, dopo trattamento con la soluzione di acqua e acetonitrile, è purificato per cromatografia ottenendo 837 mg di ammide per una resa del 84%. Oxime is treated in accordance with the general procedure. 1.00 g of (E) -2-acetonaphthone oxime are reacted, obtaining the corresponding trichloroacetimidate after 3 hours at room temperature. The raw reaction product consisting of the residue obtained by distillation at reduced pressure, once taken up with dichloromethane, is activated with 0.65 g of trifluoroacetic acid. The reaction residue, after treatment with the solution of water and acetonitrile, is purified by chromatography obtaining 837 mg of amide for a yield of 84%.
1H-NMR (CDC13); δ 2.22 (s, 3H, CH3), 7.45 (m, 3H, Ar-H), 7.77 (d, 3H, /= 8.4 Hz, Ar-H), 7.92 (s, H, NH), 8.17 (s, H, Ar-H). 1H-NMR (CDC13); δ 2.22 (s, 3H, CH3), 7.45 (m, 3H, Ar-H), 7.77 (d, 3H, / = 8.4 Hz, Ar-H), 7.92 (s, H, NH), 8.17 (s, H, Ar-H).
Esempio 6: Riarrangiamento di (E)-acetofenone ossima, A = fenile, B = metile in maniera catalitica Example 6: Rearrangement of (E) -acetophenone oxime, A = phenyl, B = methyl in a catalytic manner
In un pallone da 100 mi si caricano in atmosfera inerte, 1,50 g di (E)-acetofenone ossima [11,1 mmol], 7,5 mi di acetonitrile, 79,0 mg di tricloroacetonitrile [0,55 mmol] e 53,3 mg di acido metansolfonico [0,55 mmol]. Si scalda la miscela di reazione alla temperatura di riflusso e si segue la conversione dell’ossima di partenza tramite<1>H-NMR. La reazione risulta completa dopo 1 ora, viene quindi concentrata a residuo distillando il solvente a pressione ridotta. La acetanilide viene ottenuta cristallizzando il residuo di reazione da una miscela di acetone/acqua 1:1. Si ottengono, dopo essiccamento 1,20 g [8,88 mmol] di anilide con una resa dell’80%. In an inert atmosphere, 1.50 g of (E) -acetophenone oxime [11.1 mmol], 7.5 ml of acetonitrile, 79.0 mg of trichloroacetonitrile [0.55 mmol] and 53.3 mg of methanesulfonic acid [0.55 mmol]. The reaction mixture is heated to the reflux temperature and the conversion of the starting oxime is followed via <1> H-NMR. The reaction is complete after 1 hour, it is then concentrated to a residue by distilling the solvent at reduced pressure. Acetanilide is obtained by crystallizing the reaction residue from a 1: 1 acetone / water mixture. After drying 1.20 g [8.88 mmol] of anilide are obtained with a yield of 80%.
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| IT000340A ITMI20110340A1 (en) | 2011-03-04 | 2011-03-04 | PROCEDURE FOR THE PREPARATION OF SECONDARY AMIDIS AND LACTAMI |
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| Country | Link |
|---|---|
| IT (1) | ITMI20110340A1 (en) |
-
2011
- 2011-03-04 IT IT000340A patent/ITMI20110340A1/en unknown
Non-Patent Citations (4)
| Title |
|---|
| BOEV, V. I.; DOMBROVSKII, A. V., ZHURNAL ORGANICHESKOI KHIMII, vol. 13, no. 5, 1977, pages 1124 - 1126, XP009150107 * |
| DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; "Use of trichloroacetonitrile as a catalyst of the Beckmann rearrangement", XP002649057, Database accession no. 1977:534375 * |
| MASAHARU HASHIMOTO ET AL: "Beckmann Rearrangement of Ketoximes to Lactams by Triphosphazene Catalyst +", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 73, no. 7, 4 April 2008 (2008-04-04), pages 2894 - 2897, XP055002394, ISSN: 0022-3263, DOI: 10.1021/jo702277g * |
| PI H J ET AL: "Unexpected results from the re-investigation of the Beckmann rearrangement of ketoximes into amides by using TsCl", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 65, no. 37, 12 September 2009 (2009-09-12), pages 7790 - 7793, XP026448283, ISSN: 0040-4020, [retrieved on 20090722], DOI: DOI:10.1016/J.TET.2009.07.036 * |
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