CN102336738A - Synthesis method of 2-thiopheneethamine - Google Patents
Synthesis method of 2-thiopheneethamine Download PDFInfo
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- CN102336738A CN102336738A CN201110357618XA CN201110357618A CN102336738A CN 102336738 A CN102336738 A CN 102336738A CN 201110357618X A CN201110357618X A CN 201110357618XA CN 201110357618 A CN201110357618 A CN 201110357618A CN 102336738 A CN102336738 A CN 102336738A
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- thiophene
- compound method
- ethyl amine
- acid ester
- ion
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- 238000001308 synthesis method Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 37
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 238000007259 addition reaction Methods 0.000 claims abstract description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 62
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- 229930192474 thiophene Natural products 0.000 claims description 25
- HVLUYXIJZLDNIS-UHFFFAOYSA-N 2-thiophen-2-ylethanamine Chemical compound NCCC1=CC=CS1 HVLUYXIJZLDNIS-UHFFFAOYSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 17
- -1 metals ion Chemical class 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 8
- 239000011707 mineral Substances 0.000 claims description 8
- 235000010755 mineral Nutrition 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 239000007818 Grignard reagent Substances 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 150000002500 ions Chemical class 0.000 claims description 6
- 229910001416 lithium ion Inorganic materials 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000000638 solvent extraction Methods 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 2
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 claims description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 150000005840 aryl radicals Chemical class 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- OPHUWKNKFYBPDR-UHFFFAOYSA-N copper lithium Chemical compound [Li].[Cu] OPHUWKNKFYBPDR-UHFFFAOYSA-N 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- GCICAPWZNUIIDV-UHFFFAOYSA-N lithium magnesium Chemical compound [Li].[Mg] GCICAPWZNUIIDV-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 230000004044 response Effects 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229910001415 sodium ion Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000003440 toxic substance Substances 0.000 abstract description 2
- 229910019142 PO4 Inorganic materials 0.000 abstract 2
- 239000010452 phosphate Substances 0.000 abstract 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 239000003638 chemical reducing agent Substances 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 231100000614 poison Toxicity 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 5
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical compound BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- VODRWDBLLGYRJT-UHFFFAOYSA-N propan-2-yl 2-chloroacetate Chemical compound CC(C)OC(=O)CCl VODRWDBLLGYRJT-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- ONRREFWJTRBDRA-UHFFFAOYSA-N 2-chloroethanamine;hydron;chloride Chemical compound [Cl-].[NH3+]CCCl ONRREFWJTRBDRA-UHFFFAOYSA-N 0.000 description 3
- CLSHQIDDCJTHAJ-UHFFFAOYSA-N 2-thienylacetonitrile Chemical compound N#CCC1=CC=CS1 CLSHQIDDCJTHAJ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 3
- UCQFCFPECQILOL-UHFFFAOYSA-N diethyl hydrogen phosphate Chemical compound CCOP(O)(=O)OCC UCQFCFPECQILOL-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 3
- FZENGILVLUJGJX-NSCUHMNNSA-N (E)-acetaldehyde oxime Chemical compound C\C=N\O FZENGILVLUJGJX-NSCUHMNNSA-N 0.000 description 2
- 238000004679 31P NMR spectroscopy Methods 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 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 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 229910019213 POCl3 Inorganic materials 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 231100000004 severe toxicity Toxicity 0.000 description 2
- 238000004904 shortening Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- FUOHKPSBGLXIRL-UHFFFAOYSA-N 2-(chloromethyl)thiophene Chemical compound ClCC1=CC=CS1 FUOHKPSBGLXIRL-UHFFFAOYSA-N 0.000 description 1
- JTGKLBDOZYMAEA-UHFFFAOYSA-N 2-thiophen-2-ylacetaldehyde Chemical compound O=CCC1=CC=CS1 JTGKLBDOZYMAEA-UHFFFAOYSA-N 0.000 description 1
- VMJOFTHFJMLIKL-UHFFFAOYSA-N 2-thiophen-2-ylethanol Chemical compound OCCC1=CC=CS1 VMJOFTHFJMLIKL-UHFFFAOYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- VUCIUWIFGVLMKK-UHFFFAOYSA-N ClC1=NC=CC=C1.S1C=CC=C1.Cl Chemical compound ClC1=NC=CC=C1.S1C=CC=C1.Cl VUCIUWIFGVLMKK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 238000003476 Darzens condensation reaction Methods 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 238000005856 Pictet-Gams synthesis reaction Methods 0.000 description 1
- NJHPWOQALXDSNZ-UHFFFAOYSA-N [Mg].[Br] Chemical compound [Mg].[Br] NJHPWOQALXDSNZ-UHFFFAOYSA-N 0.000 description 1
- CZCZJRIRZDAEEE-UHFFFAOYSA-N [N+](=O)([O-])C=1SC=CC1.C=C Chemical compound [N+](=O)([O-])C=1SC=CC1.C=C CZCZJRIRZDAEEE-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- AJSHDAOMUKXVDC-UHFFFAOYSA-N butan-1-amine;sulfuric acid Chemical compound CCCC[NH3+].OS([O-])(=O)=O AJSHDAOMUKXVDC-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000001465 metallisation Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 150000003463 sulfur Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a novel preparation method of 2-thiopheneethamine, which comprises the following steps: carrying out addition reaction on 2- activated thiophene and N-(phosphate)-aziridine which serve as initial raw materials to generate N-(phosphate)-2-thiopheneethamine, and further hydrolyzing to generate the 2-thiopheneethamine. The invention greatly lowers the production cost, has the advantages of mild reaction conditions, simple technique and small pollution, and is beneficial to implementing industrial production; and invention does not need to use any reducer, thereby avoiding using expensive or extremely toxic substances and greatly reducing the environmental pollution.
Description
Technical field
The present invention relates to the preparation method of 2 thiophene ethyl amine, belong to medicine and chemical technology field.
Background technology
2 thiophene ethyl amine is the midbody of biologically active drugs such as hypolipidemic, anticoagulant, cardiovascular vasodilator, 5-lipoxidase inhibitor and multiple antimicrobial drug, is mainly used in the important drugs hydrochloric acid thiophene chloropyridine and the bisulfate clopidogrel of synthetic cardiovascular and cerebrovascular diseases.Along with the downstream medicine is continually developed, 2 thiophene ethyl amine becomes the fine-chemical intermediate that receives much concern.
At present, the industriallization of known 2 thiophene ethyl amine or four routes that mainly contain: Nitromethane 99Min. method, isopropyl chloracetate method, 2 thiophene acetonitrile method and epoxyethane method with industrial applications prospect.The Nitromethane 99Min. method is the method that two step reductase 12-nitrothiophenes prepare 2-thiophene ethane; In the presence of POCl3, obtaining 2 thiophene carboxaldehyde by thiophene and DMF, prepare 2-nitrothiophene ethene by 2 thiophene carboxaldehyde and nitro methyl hydride again, is 2 thiophene ethyl amine (the surplus Jin Tao of Wang Haitang etc. with various reductive agent reductase 12s-(nitro) thiofuran ethylene at last; Synthesizing of 2-thiophene ethamine; Wuhan Institute of Chemical Technology's journal, 2002,24 (3): 14-16).The used reductive agent of this method exist toxicity big, volatile or cost an arm and a leg, shortcoming such as consumption is big, and technology is tediously long, long reaction time.The isopropyl chloracetate method is to react in the presence of POCl3 with DMF and thiophene to obtain 2 thiophene carboxaldehyde; Mono Chloro Acetic Acid and Virahol esterification obtain isopropyl chloracetate; The Darzens reaction takes place and obtains 2-thiophene acetaldehyde in 2 thiophene carboxaldehyde and isopropyl chloracetate, obtains 2-thiophene ethylidenehydroxylamine with the oxammonium hydrochloride reaction again, and the reduction of 2-thiophene ethylidenehydroxylamine obtains 2 thiophene ethyl amine (fine chemistry industry; 2001,1 (1): 53-55; Xu's precious wealth king large bell etc., 2-thiophene ethamine synthetic).This method reaction conditions is relatively harsher, reductive agent and catalyzer expensive, and yield is compared low with article one route, be not suitable for suitability for industrialized production.The 2 thiophene acetonitrile method is to be raw material Synthetic 2 one chloromethyl thiophene with the thiophene, reacts with nacn then to obtain 2 thiophene acetonitrile, restores preparation 2 thiophene ethyl amine (Werner Herz; Lin Tsai; Sulfur Analogs of Isoquinolines. IV. The Pictet-Gams Reaction and Attempts to Prepare Analogs of Papaverine, Journal of the American Chemical Society, 77; 3529-33,1955;
)。This method need be used the nacn of severe toxicity, and environmental pollution is bigger, and the reductive agent consumption is big, and cost is high.In addition, to disclose a kind of be the method for raw material through shortening Synthetic 2-thiophene ethamine with the 2 thiophene carboxaldehyde to Chinese patent CN1341598 A.Yet this method shortening catalyst system therefor costs an arm and a leg, and can not reuse, and having limited its industriallization should.Chinese patent CN101885720 A discloses a kind of epoxyethane method and has prepared 2 thiophene ethyl amine; With the thiophene is raw material; Prepare midbody 2-bromothiophene earlier; Generate 2-thiophene magnesium bromine grignard reagent with magnesium chips again, generate the 2-thiophene ethanol with the oxyethane effect again, separate through over-churning, ammonia then and make 2 thiophene ethyl amine.This method need use the oxyethane of severe toxicity very huge to the harm of workers ' health and environment, and the risk of accident is also very high, and oxyethane use cost on industrial production is very high.In addition, like one Chinese patent application CN102093333A, CN102020631A; CN101885770A and U.S. Pat 4458086; US4970325 etc. have route longer, and are not easy to operate, and some also has the use of violent in toxicity; And shortcoming such as yield is low, these have all limited the application in the big production of industry.
Summary of the invention
The problem that the present invention solved is not enough to prior art, provides a kind of technology simple, with low cost, and operational safety is applicable to the preparation method of suitability for industrialized production 2 thiophene ethyl amine.
The present invention is a raw material with 2-activatory thiophene and N-(SULPHOSUCCINIC ACID ESTER)-Soluol XC 100, first preparation intermediate N (SULPHOSUCCINIC ACID ESTER)-2 thiophene ethyl amine, again through after the hydrolysis alkalization, extract the product 2 thiophene ethyl amine.
Concrete technical scheme of the present invention is following:
A kind of compound method of 2 thiophene ethyl amine is characterized in, its step is following:
(1) preparation of N-(SULPHOSUCCINIC ACID ESTER)-2 thiophene ethyl amine: 2-activatory thiophene and N-(SULPHOSUCCINIC ACID ESTER)-Soluol XC 100 are carried out addition reaction in anhydrous non-protonic solvent; After question response finishes; Add the water termination reaction; Use organic solvent extraction, dry concentrate N-(SULPHOSUCCINIC ACID ESTER)-2 thiophene ethyl amine.
(2) finished product preparation: with N-(SULPHOSUCCINIC ACID ESTER)-2 thiophene ethyl amine through hydrolysis, after the alkalization, extract the product 2 thiophene ethyl amine.
A kind of reaction equation of the compound method of above-described 2 thiophene ethyl amine is following:
or
In the step (1), described 2-activatory thiophene, its chemical structural formula is following:
Wherein, M is the salt of metals ion or metals ion, any one in preferably magnesium bromine grignard reagent, magnesium cl ions, lithium ion, sodium ion, aluminum ion, zine ion, zinc cl ions, cupric ion, magnesium lithium ion, the copper lithium ion etc.
Described N-(SULPHOSUCCINIC ACID ESTER)-Soluol XC 100, its chemical structural formula is following:
R wherein
1, R
2Be any of alkyl or aryl radical; Ar
1, Ar
2Be any of aromatic base, preferred R
1, R
2Be methyl, ethyl, n-propyl, sec.-propyl, cyclohexyl, any one in the benzyl; Ar
1, Ar
2Be phenyl, any in the pyridyl.
The mol ratio of the 2-activatory thiophene described in the step (1) and N-(SULPHOSUCCINIC ACID ESTER)-Soluol XC 100 is 0.5-5:1, further preferred 1-3:1; In the step (2), the mol ratio of N-(SULPHOSUCCINIC ACID ESTER)-2 thiophene ethyl amine and acid or alkali is 1:3-50, further preferred 1:4-10.
In the step (1), 2-activatory thiophene and N-(SULPHOSUCCINIC ACID ESTER)-Soluol XC 100 can add with random order on demand.
In the step (1), the TR of addition reaction is-50-100 ℃, and further preferred-30-60 ℃.
In the step (1), described anhydrous non-protonic solvent is one or more combination such as toluene, ether, THF, the mixed solvent of further preferred toluene and THF, and solvent ratios is 1:1-5.
In the step (1), described organic solvent is one or more combination such as toluene, methylene dichloride, ether, ETHYLE ACETATE.
In the step (2), hydrolysis reaction carries out under acidity or alkaline condition, and said acidic conditions is for to carry out in the aqueous solution that contains organic acid, organic bases, mineral acid or mineral alkali; Wherein organic acid or mineral acid are selected from toluene sulfonic acide; Hydrochloric acid, any one or a few combination such as sulfuric acid, organic bases or mineral alkali are selected from triethylamine; Sodium hydroxide, one or more combination such as salt of wormwood.
In the step (2), the TR of hydrolysis reaction is 0-150 ℃, further preferred 60-100 ℃.
In the step (2), during alkalization, pH value of aqueous solution is transferred to greater than 7, further be preferably more than 12.
Wherein, raw material N-(the SULPHOSUCCINIC ACID ESTER)-Soluol XC 100 of the present invention's employing can be the example preparation through following steps.
Terepthaloyl moietie amine and sulfur oxychloride generated in reaction in the presence of the concentrated hydrochloric acid or under the logical HCl gas condition obtain chloroethylamine hydrochloride, with chloroethylamine hydrochloride further with mixing solutions reaction generation N-(the diethyl phosphoric acid)-chlorethamin of diethyl chloro-phosphate and triethylamine.The cyclization under alkaline condition of gained N-(diethyl phosphoric acid)-chlorethamin generates N-(diethyl phosphoric acid)-Soluol XC 100.
When the present invention adopts raw material 2-activatory thiophene for 2-thiophene metallization reagent, can be through following example preparation.
The preparation of grignard reagent: thiophene and bromide reagent reaction generate the 2-bromothiophene, with the magnesium chips reaction, generate grignard reagent again, directly are used for step reaction down.
The preparation of lithium reagent: thiophene is added the n-butyllithium, stir, generate 2-thiophene lithium, directly be used for step reaction down.
The preparation of sodium reagent: sodium Metal 99.5 in reflux in toluene, is cooled to room temperature, joins then in the thiophene, generate 2-thiophene sodium, directly be used for step reaction down.
Compared with prior art, the present invention has the following advantages:
(1) is raw material with thiophene cheap and easy to get, makes product, greatly reduce production cost through addition, hydrolysis two-step reaction;
(2) need not to use reductive agent, avoided the use of costliness or highly toxic substance, significantly reduced pollution, protected operator's health, increased the security of producing environment;
(3) reaction conditions is gentle, and technology is simple, pollutes for a short time, helps realizing suitability for industrialized production.
Embodiment
Below through embodiment concrete process step of the present invention is described, but not limited by embodiment.
Employed in the present invention term except as otherwise noted, generally has the implication of those of ordinary skills' common sense.
Below in conjunction with specific embodiment and comparable data the present invention is described in further detail.Should be understood that these embodiment just in order to demonstrate the invention, but not limit scope of the present invention by any way.
In following examples, various processes and the method do not described in detail are ordinary methods as known in the art.
Embodiment 1The preparation of N-(diethyl phosphoric acid)-Soluol XC 100
(1) 2-chloroethyl amine hydrochloride 23.2g (0.2mol) is suspended in the 200ml methylene dichloride, is cooled to 0 ° below the C;
(2) with the mixing solutions of diethyl chloro-phosphate 34.5g (0.2mol) and triethylamine 40.4g (0.4mol), fully stir, be cooled to below 0 ℃, join then in the mixing solutions of (1);
(3) continue down to stir 1 hour at 0 ℃;
(4) filter, filter cake is used toluene wash;
(5) filtrating is with the washing of 30ml frozen water, and anhydrous sodium sulfate drying concentrates dried N-(2-chloroethyl) diethyl phosphoric acid 34, the 5g (yield 80%) of obtaining.
31PNMR（δ=8.52）
(6) toluene 100ml, N-(2-chloroethyl) diethyl phosphoric acid 10.8g (50mmol), sodium hydroxide powder 2g, potassium carbonate powder 10g, 4-butyl ammonium hydrogen sulfate 0.2g (0.5mmol), violent stirring is 4 hours under the room temperature;
(7) filter, filter cake is used the 50ml toluene wash;
(8) filtrating concentrates, and underpressure distillation obtains colorless oil N-(diethyl phosphoric acid)-Soluol XC 100 7.2g (yield 80%).Boiling point: 118 ° of C/1.6KPa; n
D 201.4343; IR: ν=2990,1280,1245,1165,1100,1032,945,820,800,770,673 cm
-1 1HNMR (CDCl
3): δ=1.34 (t, 6H,
J=7.0Hz), 2.14 (d, 4H,
J=15.4Hz), 4.18 (qt, 4H,
J HH =
3 J PH =7.0Hz);
31PNMR (δ=15.4); MS:m/z (%)=180 (M
++ 1,62), 135 (100).
Embodiment 2The preparation of 2-thiophene grignard reagent
(1) preparation of 2-bromothiophene: organic solvent exists down, in thiophene, drips bromizating agent, and control reaction temperature is-10 ~ 10 ℃, drips the back insulation reaction 2-6 hour, layering, and precipitation, decompression steaming shop is collected 45-47 ℃/1.73Kpa cut and is got product again; Described organic solvent is selected from glacial acetic acid, tetracol phenixin, two oxidative ethanes, toluene or acetonitrile; Described bromizating agent is one or more in N-succinimide, pyridine hydrobromide salt, bromine or the Hydrogen bromide; The mol ratio of material is: thiophene: bromizating agent=1: 2-3.0;
(2) preparation of 2-thiophene magnesium bromine: get 2-bromothiophene and magnesium chips the grignard reaction preparation takes place in anhydrous solvent.
Embodiment 3The preparation of 2-lithium thiophene
(1) under the room temperature, 228mg (27mmol) thiophene is joined in the 3ml ether;
(2) then in 2 minutes, add 1.1ml (2.7mmol) butyllithium (cyclohexane solution of 2.5M) immediately;
(3) continue stirring under the room temperature and obtained 2-lithium thiophene in 30 minutes.
Embodiment 4The preparation of 2-sodium thiophene
Thiophene is cooled to 0 ℃, adds 1 normal sodium Metal 99.5, stir and obtained 2-sodium thiophene in 30 minutes.
Embodiment 5The preparation of N-(SULPHOSUCCINIC ACID ESTER)-2 thiophene ethyl amine
(1) (N-(SULPHOSUCCINIC ACID ESTER)-Soluol XC 100) is dissolved in the anhydrous non-protonic solvent, selects for use condition as shown in table 1 to prepare, be cooled to TR-50 ~ 100 ℃;
(2) control drips 2-activatory thiophene in (1), maintains the temperature at-50 ~ 100 ℃; Being stirred to reaction finishes;
(3) add the water termination reaction;
(4) water is used organic solvent extraction, anhydrous sodium sulfate drying, concentrate bullion N-(SULPHOSUCCINIC ACID ESTER)-2 thiophene ethyl amine.
Wherein the collection of illustrative plates of N-(diethyl phosphoric acid)-2 thiophene ethyl amine is following: IR (film) 3400 cm
-1, 1520 cm
-1, 1275cm
-1, 1210cm
-1 1HNMR (CDCl
3): 1.31 (t, 6H), 2.97-3.08 (m, 5H), 4.02 (dq, 4H), 6.76 (m, 1H), 6.91 (m, 1H), 7.12 (m, 1H).
Table 1 reaction conditions
Embodiment 6The preparation of 2 thiophene ethyl amine
(1) with N-(SULPHOSUCCINIC ACID ESTER)-2 thiophene ethyl amine, be suspended in the hydrating solution, select for use condition as shown in table 2 to react, heat tracing to reaction finishes, and reduces to room temperature;
(2) extract with organic solvent dichloromethane;
(3) water is transferred pH value with NaOH solution>7;
(4) use dichloromethane extraction, merge organic phase, drying, concentrate 2 thiophene ethyl amine.(yield 80%,
1HNMR (CDCl
3): 1.32 (s, 2H), 2.94-3.00 (m, 4H), 6.83 (m, 1 H), 6.95 (m, 1H), 7.12 (m, 1H).
Table 2 reaction conditions
Claims (14)
1. the compound method of a 2 thiophene ethyl amine is characterized in that comprising the steps:
(1) preparation of N-(SULPHOSUCCINIC ACID ESTER)-2 thiophene ethyl amine: 2-activatory thiophene and N-(SULPHOSUCCINIC ACID ESTER)-Soluol XC 100 are carried out addition reaction in anhydrous non-protonic solvent; After question response finishes; Add the water termination reaction; Use organic solvent extraction, dry concentrating obtains N-(SULPHOSUCCINIC ACID ESTER)-2 thiophene ethyl amine;
(2) preparation of 2 thiophene ethyl amine: with N-(SULPHOSUCCINIC ACID ESTER)-2 thiophene ethyl amine through hydrolysis, after the alkalization, extract the product 2 thiophene ethyl amine.
2. compound method according to claim 1 is characterized in that: in the step (1), and described 2-activatory thiophene, its chemical structural formula is following:
Wherein, M is the salt of metals ion or metals ion;
Described N-(SULPHOSUCCINIC ACID ESTER)-Soluol XC 100, its chemical structural formula is following:
R wherein
1, R
2Be any of alkyl or aryl radical; Ar
1, Ar
2Be any of aromatic base.
3. compound method as claimed in claim 2 is characterized in that said M is any one in magnesium bromine grignard reagent, magnesium cl ions, lithium ion, sodium ion, aluminum ion, zine ion, zinc cl ions, cupric ion, magnesium lithium ion, the copper lithium ion; Said R
1, R
2Be methyl, ethyl, n-propyl, sec.-propyl, cyclohexyl, any one in the benzyl; Said Ar
1, Ar
2Be phenyl, any in the pyridyl.
4. compound method according to claim 1 is characterized in that: the mol ratio of the 2-activatory thiophene described in the step (1) and N-(SULPHOSUCCINIC ACID ESTER)-Soluol XC 100 is 0.5-5:1; In the step (2), the mol ratio of N-(SULPHOSUCCINIC ACID ESTER)-2 thiophene ethyl amine and acid or alkali is 1:3-50.
5. compound method according to claim 4 is characterized in that: the mol ratio of the 2-activatory thiophene described in the step (1) and N-(SULPHOSUCCINIC ACID ESTER)-Soluol XC 100 is 1-3:1; In the step (2), the mol ratio of N-(SULPHOSUCCINIC ACID ESTER)-2 thiophene ethyl amine and acid or alkali is 1:4-10.
6. compound method according to claim 1 is characterized in that: in the step (1), the TR of addition reaction is-50-100 ° C.
7. compound method according to claim 6 is characterized in that: in the step (1), the TR of addition reaction is-30-60 ° C.
8. compound method according to claim 1 is characterized in that: in the step (1), described anhydrous non-protonic solvent is one or more the combination of toluene, ether, THF.
9. compound method according to claim 1 is characterized in that: in the step (1), described anhydrous non-protonic solvent is the mixed solvent of toluene and THF, and solvent ratios is 1:1-5.
10. compound method according to claim 1 is characterized in that: in the step (1), described organic solvent is one or more the combination of toluene, methylene dichloride, ether, ETHYLE ACETATE.
11. compound method according to claim 1 is characterized in that: in the step (2), hydrolysis reaction carries out under acidity or alkaline condition; Said acidic conditions is for to carry out in the aqueous solution that contains organic acid, organic bases, mineral acid or mineral alkali, and wherein organic acid or mineral acid are selected from toluene sulfonic acide, hydrochloric acid; Any one or a few combination such as sulfuric acid; Organic bases or mineral alkali are selected from triethylamine, sodium hydroxide, one or more combination of salt of wormwood.
12. compound method according to claim 1 is characterized in that: in the step (2), the TR of hydrolysis reaction is 0-150 oC.
13. compound method according to claim 12 is characterized in that: in the step (2), the TR of hydrolysis reaction is 60-100 oC.
14. compound method according to claim 1 is characterized in that: in the step (2), during alkalization, pH value of aqueous solution is transferred to greater than 7.
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| CN112341428A (en) * | 2020-11-04 | 2021-02-09 | 菏泽鸿特药业有限公司 | Production method of thiophene-2-ethylamine |
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| ROLF FIKENTSCHER, ET AL.: "Synthese von 2-(2-Aminoethyl)thiophen über aktivierte Arylsulfonylaziridine", 《LIEBIGS ANN. CHEM.》 * |
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| CN105294645A (en) * | 2014-05-30 | 2016-02-03 | 重庆安格龙翔医药科技有限公司 | Method for preparing 2-thiopheneethamine |
| CN112341428A (en) * | 2020-11-04 | 2021-02-09 | 菏泽鸿特药业有限公司 | Production method of thiophene-2-ethylamine |
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