CN106831445B - A kind of preparation method of indenyl amine compounds - Google Patents
A kind of preparation method of indenyl amine compounds Download PDFInfo
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- CN106831445B CN106831445B CN201611029193.9A CN201611029193A CN106831445B CN 106831445 B CN106831445 B CN 106831445B CN 201611029193 A CN201611029193 A CN 201611029193A CN 106831445 B CN106831445 B CN 106831445B
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- -1 indenyl amine compounds Chemical class 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 10
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 8
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims abstract description 7
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims abstract description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 7
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 7
- 229940125773 compound 10 Drugs 0.000 claims abstract description 7
- 229940125797 compound 12 Drugs 0.000 claims abstract description 7
- 229940125782 compound 2 Drugs 0.000 claims abstract description 7
- 229940126214 compound 3 Drugs 0.000 claims abstract description 7
- 229940125898 compound 5 Drugs 0.000 claims abstract description 7
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims abstract description 7
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N 1,2-diethylbenzene Chemical compound CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000007858 starting material Substances 0.000 claims abstract description 6
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 5
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims abstract description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 4
- 230000031709 bromination Effects 0.000 claims abstract description 4
- 238000005893 bromination reaction Methods 0.000 claims abstract description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 4
- 229910015900 BF3 Inorganic materials 0.000 claims abstract description 3
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 230000009471 action Effects 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- UBHZUDXTHNMNLD-UHFFFAOYSA-N dimethylsilane Chemical compound C[SiH2]C UBHZUDXTHNMNLD-UHFFFAOYSA-N 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract 5
- 230000003197 catalytic effect Effects 0.000 abstract 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 abstract 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 abstract 1
- 230000001476 alcoholic effect Effects 0.000 abstract 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 150000003053 piperidines Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 19
- 239000007787 solid Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000001514 detection method Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- ZOVIYWYFBOQKIA-UHFFFAOYSA-N 5,6-diethyl-2,3-dihydro-1h-inden-2-amine;hydrochloride Chemical compound Cl.C1=C(CC)C(CC)=CC2=C1CC(N)C2 ZOVIYWYFBOQKIA-UHFFFAOYSA-N 0.000 description 2
- 241000588832 Bordetella pertussis Species 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- QZZUEBNBZAPZLX-QFIPXVFZSA-N indacaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)CNC1CC(C=C(C(=C2)CC)CC)=C2C1 QZZUEBNBZAPZLX-QFIPXVFZSA-N 0.000 description 2
- 229960004078 indacaterol Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229940066827 pertussis vaccine Drugs 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000000588 effect on asthma Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 208000017561 flaccidity Diseases 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/12—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the ring of aromatic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/08—Hydroxylamino compounds or their ethers or esters
- C07C239/14—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/36—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by hydrogenation of carbon-to-carbon unsaturated bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of preparation method of indenyl amine compounds, which, for starting material, generates compound 2 by the catalytic bromination of Fe and I2 with 1,2- diethylbenzene；By generating compound 3 with DMF in the case where butyl lithium is acted on；It is reacted under piperidines effect with malonic acid and generates compound 4；Compound 5 is reduced under Raney's nickel effect；Compound 6 is generated by the catalytic bromination of Fe and I2；Friedel-crafts acylation, which is carried out, under AlCl3 effect generates compound 7；It is reacted with nitrous acid straight butyl and generates compound 8；Compound 9 is generated under Pd/C catalysis；It is reacted with trifluoroacetic acid and generates compound 10；It is reacted with sodium borohydride and is reduced into alcoholic compound 11；Hydroxyl, which is taken off, under dimethylsilane and boron trifluoride effect generates compound 12；Trifluoroacetyl group, which is taken off, under potassium carbonate effect generates target compound 13.
Description
Technical Field
The invention relates to the field of compound production, in particular to a preparation method of an indenyl amine compound.
Background
5,6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride in the indenylamine compound is an indacaterol intermediate, the English name is 5,6-diethyl-2, 3-dihydro-1H-inden-2-aminohydrochlorid, CAS 312753-53-0, the molecular formula is C13H19N.HCl, the molecular weight is 225.76, the density is 0.00285mmHg at 25 ℃, the purity is more than 99 percent of white solid, the melting point is more than 250 ℃, the intermediate is a new drug of COPD indacaterol for chronic obstructive pulmonary disease.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of indenyl amine compound.
In order to solve the technical problems, the technical scheme of the invention is as follows:
an indenylamine compound, 4, 5-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride, which has a structural formula shown in (I),
preferably, the NMR data of the indenyl amine compound, 4, 5-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride, are 1.158 to 1.059(m, 6H), 2.617 to 2.503(m,4H),2.980 to 2.926(dd,2H),3.266 to 3.193(m,2H),3.972 to 3.960(b,1H),7.021(s,2H),8.382(b, 3H).
The preparation method of the indenyl amine compound takes 1, 2-diethylbenzene as a starting material, and obtains a target compound through 12 steps of reactions, and comprises the following specific steps:
(1) compound 1 is catalyzed by bromination of Fe and I2 to produce compound 2;
(2) compound 2 is reacted with DMF under the action of butyl lithium to generate compound 3;
(3) reacting the compound 3 with malonic acid under the action of piperidine to generate a compound 4;
(4) reducing the compound 4 into a compound 5 under the action of Raney nickel;
(5) compound 5 is catalytically brominated by Fe and I2 to produce compound 6;
(6) carrying out Friedel-crafts acylation reaction on the compound 6 under the action of AlCl3 to generate a compound 7;
(7) reacting the compound 7 with n-butyl nitrite to generate a compound 8;
(8) the compound 8 is catalyzed by Pd/C to generate a compound 9;
(9) reacting the compound 9 with trifluoroacetic acid to generate a compound 10;
(10) the compound 10 reacts with sodium borohydride and is reduced into an alcohol compound 11;
(11) removing hydroxyl from the compound 11 under the action of dimethylsilane and boron trifluoride to generate a compound 12;
(12) removing trifluoroacetyl from the compound 12 under the action of potassium carbonate to generate a target compound 13; wherein,
the specific reaction equation of the above-mentioned preparation method of the indenyl amine compound is as follows:
the invention has the beneficial effects that:
the indenyl amine compound 4, 5-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride has application value in the aspect of preventing and treating respiratory diseases; the preparation method has the advantages of cheap and easily-obtained raw materials and simple synthesis method, is a brand new method for synthesizing the indenyl amine compound, and is suitable for the requirement of large-scale industrial production.
Drawings
FIG. 1 is a HNMR spectrum of 4, 5-diethyl-2, 3-dihydro-1H-inden-2-amine hydrochloride. The hydrogen spectrum data are as follows: 1.158-1.059(m, 6H), 2.617-2.503(m,4H),2.980-2.926(dd,2H),3.266-3.193(m,2H),3.972-3.960(b,1H),7.021(s,2H),8.382(b, 3H).
Detailed Description
In order to make those skilled in the art better understand the technical solution of the present invention, the following detailed description will be given with reference to specific embodiments.
Example 1
The preparation method of the 4, 5-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride comprises the following specific steps:
(1) compound 1 was charged into a 5L three-necked flask, and 2.3g Fe and 0.1g I were added2126.3g Br were slowly added dropwise with stirring at 0 deg.C2The mixture was stirred at room temperature overnight. Detecting the reaction solution, confirming reaction completion by crude nuclear magnetic resonance (HNMR), adding appropriate amount of water into the system, extracting with ethyl acetate for 2 times, washing the organic phase with saturated sodium bisulfite aqueous solution and saturated sodium chloride aqueous solution twice, respectively, and adding anhydrous Na2SO4Drying and concentration gave 173g of a yellowish brown oily liquid (Compound 2). The yield thereof was found to be 90%.
(2) 360ml of n-BuLi was slowly added dropwise to a solution of 2173g of Compound 2 in 1L of THF at-80 ℃ and, after completion of the addition, stirred for 30min, DMF was added dropwise at-80 ℃ and, after completion of the addition, gradually returned to room temperature. Dot-panel detection (PE: EA: 30:1, R)fA value equal to about 0.5). Adding appropriate amount of saturated ammonium chloride aqueous solution into the reaction solution, adding methyl tert-butyl ether, separating, extracting the water phase with methyl tert-butyl ether for several times until the water phase has no ultraviolet point, combining the organic phases, washing with saturated salt for three times, drying, spin drying to obtain 150g yellow solidBody (compound 3). Yield 114% (crude).
(3) 165.4g malonic acid, 450ml piperidine were added in succession to 150g compound 3 in pyridine solution, heated under reflux overnight, spotted and tested (PE: EA: 3:1, one drop glacial acetic acid, RfValue about 0.5) after the reaction is finished, directly distilling and concentrating the reaction liquid under reduced pressure. And adding a 2M hydrochloric acid solution into the concentrated solution to separate out a large amount of yellow solid, adjusting the pH value to be less than 1, adding enough DCM to dissolve and separate the solid, extracting the water phase by DCM for several times until the water phase does not contain the target product, combining the organic phases, drying, spinning, mixing the sample, separating by a column (when the PE: DCM is 10:1, impurities come out, when the PE: DCM is 5:1, the raw material comes out, when the PE: DCM is 3:1, the product comes out, washing the product by pure DCM with 10mL of anhydrous formic acid added into each liter) to obtain 138.8g of yellow solid (compound 4) in total, wherein the yield is 70%.
(4) 26.5g of Raney nickel are taken out under argon protection, washed three times with 2.5L of methanol, 138.8g of compound 4 are added, hydrogen is introduced and stirring is carried out overnight at room temperature. The next day the crude product was taken for nmr detection, after reaction was complete, filtered and the filtrate was spin dried to give 135g of solid (compound 5) in 100% yield.
(5) 2.2g Fe, 0.1g I2 were added to 135g of Compound 5 in Dichloromethane (DCM) and 125.6g Br were added under ice water2Stirred at room temperature overnight. The next day plate detection (PE: EA ═ 5:1 with a drop of glacial acetic acid, RfValue equal to about 0.4), the reaction is complete, ice is added and a saturated aqueous solution of sodium bisulfite is added, the phases are separated, the aqueous phase is extracted twice with DCM, the organic phases are combined, dried, spun dry, sample-mixed, column-separated (PE: EA 50:1 → 30:1 → 10:1 → 5:1), and finally 140g of oily liquid (compound 6) was obtained in a total yield of 75%.
(6) 280ml of thionyl chloride were added to 140g of compound 6, heated to reflux and the reaction detected on a dot plate after one hour (PE: EA: 3:1, R)fValue about 0.4), after the reaction of the raw materials is finished, the reaction solution is concentrated, 1.2L DCM is added under ice bath, 72g of aluminum trichloride is added under 0 ℃, and then the reaction is carried out gradually while stirringGradually rising to room temperature. Detection reaction (PE: EA: 20:1, R)fApproximately equal to 0.6), and after the reaction is completed, the reaction solution is started to be treated. The reaction solution was poured into a solution of hydrochloric acid with ice, extracted twice with DCM, the organic phases were combined, dried, spin dried, stirred with silica gel, and separated by column (the product could be washed off directly with petroleum ether, and then washed off all the product with increasing polarity step by step) to give 106g of yellow solid (compound 7) in 80% yield.
(7) 21g n-BuONO, 19ml of concentrated hydrochloric acid, were added to a solution of 50g of Compound 7 in 800ml of MeOH under argon. Heating and stirring at the external temperature of 5 ℃. After four hours, spot plate detection (PE: EA 20:1, raw material R)fApproximately equal to 0.6), the starting materials were substantially reacted and filtered to obtain a total of 26g of a white solid (Compound 8). The yield thereof was found to be 47%.
(8) 10g of palladium on carbon and 26g of Compound 8 were put in a reaction flask containing 1L of methanol, 100ml of concentrated hydrochloric acid was added, and after replacing the air with a hydrogen balloon three times, the mixture was stirred at room temperature overnight. And (3) sending the crude product to nuclear magnetic detection, and directly spin-drying the reaction solution after the reaction is finished to obtain 26g of white solid (compound 9). The yield thereof was found to be 100%.
(9) 36.8g of TEA, 36.7g of trifluoroacetic acid (TFAA) were added slowly, in succession, dropwise to 21g of Compound 9 in a solvent of 1LTHF under argon Ar, the temperature being controlled at-10 ℃ and the mixture was stirred overnight at room temperature. The next day of plate detection (PE: EA: 5:1, rf value about 0.6), after completion of the reaction, 200mL of water and 200mL of EA were added to the reaction mixture, and the mixture was separated. The aqueous phase is then extracted three times with EA, the organic phases are combined, dried, stirred and separated by column separation (PE/THF system 10:1 product off) to give 26g of a pale yellow solid (compound 10). The yield thereof was found to be 99%.
(10) 4.3g of sodium borohydride were added to a solution of 25g of Compound 10 in 500ml of ethanol and stirred at room temperature. After one hour, dot plate detection (color development with phosphomolybdic acid, PE: EA: 5:1, R)fValue about 0.3), the starting material has not reacted completely, 1.1g of sodium borohydride are added and stirring is continued at room temperature. After half an hour, the reaction was completed by spotting and detection. Adding 200mL of water and 3000mL of LEA into the reaction solution, separating, extracting the aqueous phase with 100mL of EA twice, combining the organic phases, and dryingSpin-dry, column isolate (PE: EA ═ 20:1 impurities, 10:1 product) to give 10g of a white solid (compound 11). The yield thereof was found to be 39.5%.
(11) 8ml of triethylsilane and 6.5ml of boron trifluoride diethyl etherate were added to a solution of 8.2g of Compound 11 in 1, 2-dichloroethane, respectively, and the mixture was refluxed at 80 ℃ and stirred with heating. After one hour, dot plate detection (phosphomolybdic acid color development, PE: EA: 5:1, R)fValue about 0.9), the starting material was reacted, and 100mL of water and 100mL of methylene chloride were added to the reaction mixture. The phases were separated and the aqueous phase was extracted twice with 50mL dichloromethane, the organic phases combined, dried, spun and column separated (petroleum ether washes away impurities and 80:1 washes out product) to give 4.5g white solid (Compound 12) in 58% yield.
(12) 4.5g of Compound 12 and 4.2g of potassium carbonate were added to a mixed solution of 100ml of methanol and 50ml of water, respectively, heated to 85 ℃ and stirred. After half an hour, dot panel detection (PE: EA: 10:1, R)fThe value is equal to about 0.7), and the hydrolysis reaction of the raw materials is finished. To the reaction solution were added 50mL of Ethyl Acetate (EA) and 50mL of water, followed by liquid separation, drying of the organic phase, and concentration to obtain a product. And continuously adding a small amount of methyl tert-butyl ether to dissolve, adding 2mL of concentrated hydrochloric acid to separate out a large amount of solid, adding 50mL of n-hexane, and washing the solid. The solid was filtered off and dried under reduced pressure to give the desired product compound 13 in a total of 3.1g, yield 86.9%. As shown in FIG. 1, HNMR spectrum (CDCl) of 4, 5-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride3) The hydrogen spectrum data is as follows: 1.158-1.059(m, 6H), 2.617-2.503(m,4H),2.980-2.926(dd,2H),3.266-3.193(m,2H),3.972-3.960(b,1H),7.021(s,2H),8.382(b, 3H).
The specific reaction equation is as follows:
application test example
Male SD rats, aged 4-6 weeks for months, weighing 130-.
The first group, asthma group, was prepared by intraperitoneal injection of 1ml antigen solution (containing 100mg egg protein, inactivated Bordetella pertussis vaccine 5 x 10) into each rat9And 100mg of aluminum hydroxide dry powder) sensitization;
the second group, asthma treatment group, was a group in which each rat was gavaged with 1.2. mu.g/kg of the compound obtained in example 1, 1 time every 12 hours, and three days later, each rat was intraperitoneally injected with 1ml of antigen solution (containing 100mg of egg protein, inactivated Bordetella pertussis vaccine 5. about.10)9And 100mg of aluminum hydroxide dry powder).
The results showed that the first group, asthma-group antigen challenge, immediately exhibited shortness of breath, flaccidity of limbs, sluggish movement or pronation, while the second group, asthma-treated group showed no significant response. The compound of the invention has certain inhibition effect on asthma.
The above detailed description of the process for the preparation of an indenyl amine compound with reference to specific embodiments is illustrative and not restrictive, and several examples are set forth within the limits of the invention, and therefore variations and modifications may be made without departing from the general inventive concept within the scope of the present invention.
Claims (1)
1. A process for the preparation of an indenylamine compound which is 4, 5-diethyl-2, 3-dihydro-1H-inden-2-amine hydrochloride, characterized in that: 1, 2-diethylbenzene is used as a starting material, and a target compound is obtained through 12 steps of reaction, and the method comprises the following specific steps:
(1) compound 1 is catalyzed by bromination of Fe and I2 to produce compound 2;
(2) compound 2 is reacted with DMF under the action of butyl lithium to generate compound 3;
(3) reacting the compound 3 with malonic acid under the action of piperidine to generate a compound 4;
(4) reducing the compound 4 into a compound 5 under the action of Raney nickel;
(5) compound 5 is catalytically brominated by Fe and I2 to produce compound 6;
(6) carrying out Friedel-crafts acylation reaction on the compound 6 under the action of AlCl3 to generate a compound 7;
(7) reacting the compound 7 with n-butyl nitrite to generate a compound 8;
(8) the compound 8 is catalyzed by Pd/C to generate a compound 9;
(9) reacting the compound 9 with trifluoroacetic acid to generate a compound 10;
(10) the compound 10 reacts with sodium borohydride and is reduced into an alcohol compound 11;
(11) removing hydroxyl from the compound 11 under the action of triethylsilane and boron trifluoride to generate a compound 12;
(12) removing trifluoroacetyl from the compound 12 under the action of potassium carbonate to generate a target compound 13; wherein,
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