CN103772081A - Protected amino ketone compound and preparation method thereof - Google Patents
Protected amino ketone compound and preparation method thereof Download PDFInfo
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- CN103772081A CN103772081A CN201210397025.0A CN201210397025A CN103772081A CN 103772081 A CN103772081 A CN 103772081A CN 201210397025 A CN201210397025 A CN 201210397025A CN 103772081 A CN103772081 A CN 103772081A
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- -1 amino ketone compound Chemical class 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 22
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 62
- 239000002904 solvent Substances 0.000 claims description 49
- 150000001414 amino alcohols Chemical class 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 38
- 125000000623 heterocyclic group Chemical group 0.000 claims description 32
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 28
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 claims description 23
- 229920006395 saturated elastomer Polymers 0.000 claims description 21
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000004215 Carbon black (E152) Substances 0.000 claims description 14
- 229930195733 hydrocarbon Natural products 0.000 claims description 14
- 150000002430 hydrocarbons Chemical class 0.000 claims description 14
- 230000003647 oxidation Effects 0.000 claims description 14
- 238000007254 oxidation reaction Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 13
- 239000012044 organic layer Substances 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 238000001953 recrystallisation Methods 0.000 claims description 10
- 150000008065 acid anhydrides Chemical class 0.000 claims description 8
- 150000001263 acyl chlorides Chemical class 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- ZNOKGRXACCSDPY-UHFFFAOYSA-N tungsten trioxide Chemical compound O=[W](=O)=O ZNOKGRXACCSDPY-UHFFFAOYSA-N 0.000 claims description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- 150000001721 carbon Chemical group 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- 239000012266 salt solution Substances 0.000 claims description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 6
- 235000011152 sodium sulphate Nutrition 0.000 claims description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 2
- PBYZMCDFOULPGH-UHFFFAOYSA-N tungstate Chemical group [O-][W]([O-])(=O)=O PBYZMCDFOULPGH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 5
- 229910052721 tungsten Inorganic materials 0.000 abstract description 4
- 239000010937 tungsten Substances 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 abstract 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 230000001590 oxidative effect Effects 0.000 abstract 1
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 18
- 238000000034 method Methods 0.000 description 15
- 230000006837 decompression Effects 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 238000010792 warming Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 238000009413 insulation Methods 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 230000002194 synthesizing effect Effects 0.000 description 6
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 5
- 229910052804 chromium Inorganic materials 0.000 description 5
- 239000011651 chromium Substances 0.000 description 5
- 238000010907 mechanical stirring Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 3
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 101000582914 Homo sapiens Serine/threonine-protein kinase PLK4 Proteins 0.000 description 2
- 108090000144 Human Proteins Proteins 0.000 description 2
- 102000003839 Human Proteins Human genes 0.000 description 2
- 241001062009 Indigofera Species 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-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
- 102100031463 Serine/threonine-protein kinase PLK1 Human genes 0.000 description 2
- 102100030267 Serine/threonine-protein kinase PLK4 Human genes 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000002240 furans Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical compound NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 description 2
- 108010056274 polo-like kinase 1 Proteins 0.000 description 2
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- BLGJHQMNSBYLEZ-UHFFFAOYSA-N 2-hydroxyethanesulfonamide Chemical class NS(=O)(=O)CCO BLGJHQMNSBYLEZ-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 150000000644 6-membered heterocyclic compounds Chemical class 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000004880 oxines Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a protected amino ketone compound which is shown in the formula (III) and preparation method thereof, wherein, R1, R2, R3, R4 and n have specific meanings, and the preparation method comprises the following step: 1) selectively acylating amino of aminoalcohol shown in formula (I), crystallizing and obtaining a protected aminoalcohol which is shown in the formula (II); 2) catalyzing by using a tungsten-containing reagent, oxidizing the protected aminoalcohol shown in the formula (II) by hydrogen peroxide, and obtaining the protected amino ketone shown in the formula (III). The obtained protected amino ketone compound shown in the formula (III) provided by the invention can be used as an important medicinal and chemical intermediate, and compared with prior art, the preparation method has the advantages of simple post-treatment, mild and controllable reaction condition, good yield, environmental friendly performance, etc. The obtained protected amino ketone compound is suitable for industrial large-scale production.
Description
Technical field
The present invention relates to keto-amine compound of a kind of protection and preparation method thereof; relate to particularly a kind of amino alcohol formula II that is obtained protection by amino alcohol formula (I) through acylation reaction; again through being oxidized the keto-amine formula III of synthetic protection, the keto-amine formula III of the synthetic protection of the method can be used as important pharmaceutical-chemical intermediate.
Background technology
Alzheimer's, Parkinson's disease and proliferative disease are three kinds in present the most common disease, as the medicine of these diseases for the treatment of, on market, have original sales volume, thereby the shared intermediate of developing these medicines have very wide market outlook.The keto-amine formula III of the present invention's protection is the key intermediate of these medicines of preparation, especially for treatment Parkinson disease drug pramipexole and synthetic for the hydroxyethyl sulfonamide derivatives intermediate 4-substituted amido pimelinketone of Alzheimer's, be used as the inhibitor of human protein kinase PLK1 to PLK4 with the 4-(9-(3 for the treatment of hyperplasia, 3-difluoro cyclopentyl)-5, 7, 7-trimethylammonium-6-oxo-6, 7, 8, 9-tetrahydrochysene-5H-Kui Linpyrimido quinoline [4, 5-B] [1, 4] diaza *-2-base amino)-3-methoxy benzamide derivatives intermediates 3-protection amide group cyclopentanone.
The acquisition of the keto-amine formula III of protection is obtained by alcohol oxidation often, if now amino is not protected, by having a strong impact on the yield of oxidation, can not get even required product.In present technique, amino protecting group adopts acyl group more, and agents useful for same is diacetyl oxide or Acetyl Chloride 98Min. (Journal of Heterocyclic Chemistry, 2000, vol., 37, # 2 p. 405 – 410; Meticulous and specialty chemicals 2005,13(2), 13-14; Journal of Organic Chemistry, 2010, vol., 75, # 10 p. 3515 – 3517; Journal of the American Chemical Society, 1958, vol. 80, p. 6412,6419; European Journal of Medicinal Chemistry; 1980; vol. 15, # 1 p. 77-84), benzoyl (CN101429173), tertbutyloxycarbonyl (WO2004050619, WO2009023269A2, WO2010/32009 A1, EP1403255 A1).Amino alcohol after amido protecting obtains the keto-amine of protection through oxidation, it is less that this step is reacted the method for having reported, great majority are for containing chromium reagent oxidation, as jones reagent (Journal of Medicinal Chemistry, 1986, vol., 29, # 8 p. 1452 – 1457; Liebigs Annalen der Chemie, 1990, # 8 p. 781 – 787; Journal of Heterocyclic Chemistry, 2000, vol., 37, # 2 p. 405 – 410; Chemical and Pharmaceutical Bulletin, 1976, vol. 24, p. 2876; US3895036) yield, at 50%-70%, also has potassium dichromate oxidation for bibliographical information (US4731374) simultaneously, in every case relates to all have certain problem containing chromium reagent oxidation, is difficult to industrialization.There is recently bibliographical information to adopt non-chromium process oxidation; by the method (CN102584618A) of TEMPO clorox and Sodium Bromide oxidation; although the method has been avoided containing chromium reagent; but cost costliness; have is exactly with Dess-Martin reagent oxidation (WO2009/23269 A2) again; this cost often industrialization is difficult to bear; therefore still need a kind of reaction conditions gentleness controlled; yield is good; more friendly to environment; be more suitable for the operational path of industrialized production, prepare the keto-amine formula III compound of protection lower cost.。
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiencies in the prior art, provides a kind of simple to operate, and raw material is easy to get, environmental friendliness, the synthetic method of the keto-amine formula III of protection with low cost.
Another object of the present invention is to provide the keto-amine formula III compound of the protection of this new texture.
For solving above technical problem, the present invention takes following technical scheme:
A kind of keto-amine compound formula III of protection:
（Ⅲ）
Wherein:
R1 represents the group of any formation in H, saturated alkane, alcoxyl hydrocarbon, aromatic ring, alcoxyl aromatic ring, fragrant heterocycle or heterocycle;
R2 represents the group of any formation in H, saturated alkane, alcoxyl hydrocarbon, aromatic ring, fragrant heterocycle or heterocycle;
R3 represents the group of any formation in saturated alkane, alcoxyl hydrocarbon, aromatic ring, fragrant heterocycle or heterocycle;
R4 represents the group of any formation in H, saturated alkane, alcoxyl hydrocarbon, aromatic ring, fragrant heterocycle or heterocycle;
Meanwhile, R2, R3 connects by carbon-carbon bond or carbon-oxygen bond;
N representative has the alkane of 1-20 carbon atom.
A preparation method for the keto-amine compound formula III of aforesaid protection, is characterized in that comprising the steps:
（Ⅲ）
1) under the condition existing at suitable solvent, by amino alcohol formula I and acid anhydrides or acyl chloride reaction complete after, be reduced to suitable temperature crystallization, solvent evaporated or filtration, make the amino alcohol formula II of protection;
2) under the condition existing at suitable solvent, with the catalysis of tungstenic reagent, through the oxidized keto-amine formula III that obtains protection of amino alcohol formula II of hydrogen peroxide oxidation protection.
Wherein, described step 1) in the mol ratio of amino alcohol formula I and acid anhydrides or acyl chlorides be 1:1 ~ 1:1.25.
Wherein, described step 1) described in the temperature of reaction of amino alcohol formula I and acid anhydrides or acyl chloride reaction be 50 ℃ ~ 120 ℃.
Wherein, described step 1) described in recrystallization temperature be 0 ℃ ~ 50 ℃.
Wherein, described step 1) described in the consumption of solvent be every mole of amino alcohol formula I 250mL-800mL solvent.
Wherein, described step 1) described in solvent be non-protonic solvent, be selected from toluene, dimethylbenzene, ethyl acetate, chloroform, acetonitrile any one, be preferably toluene or ethyl acetate.
Wherein, described step 1) reaction times be 0.5h ~ 8h.
Wherein, described step 2) described in tungstenic reagent be selected from tungstate, tungstic anhydride, wolframic acid and different hydrate thereof at interior+6 valency tungsten atom compounds.
Wherein, described step 2) described in amino alcohol (II) mol ratio of tungstenic reagent dosage and protection be 0.001:1-0.1:1, preferred proportion is 0.005:1-0.05:1.
Wherein, described step 2) described in the mass concentration of hydrogen peroxide be 20% ~ 80%.
Wherein, described step 2) described in protection amino alcohol formula II and the mol ratio of hydrogen peroxide be 1:1 ~ 1:3.
Wherein, described step 2) described in solvent be polar solvent, be selected from any one in water, toluene, chloroform, ethyl acetate, be preferably water.
Wherein, described step 2) temperature of reaction be 50 ℃ ~ 100 ℃.
Wherein, described step 2) reaction times be 2h ~ 48h.
Wherein, described step 2) described in the amino alcohol formula II mass ratio of solvent and protection be 0.5:1 ~ 10:1.
In a preferred embodiment; also comprise step 3) separation and purification: step 2) reaction finish after; after the excessive hydrogen peroxide of cancellation; boil off more than 50% water, with methylene dichloride or chloroform or ethyl acetate extraction, organic layer washing; again with saturated salt solution washing; with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, distillating recovering solvent, then recrystallization obtains the keto-amine formula III of protection.
Wherein, the solvent that recrystallization described in described step 3) adopts is selected from any one in acetonitrile, acetone, ethyl acetate, toluene, methyl tertiary butyl ether, isopropyl ether, is preferably acetone or ethyl acetate.
Preparation method of the present invention, compared with traditional technology, in the time of the amino alcohol formula II of synthetic protection, directly uses recrystallisation solvent as reaction solvent, has avoided the larger Glacial acetic acid of distillation smell, and the operation that can save recrystallization; In the time of the keto-amine compound formula III of synthetic protection, adopt non-chromium process, greatly improve environmental friendliness degree; adopt the catalysis of tungsten reagent simultaneously, compared with new clorox TEMPO Sodium Bromide technique, with low cost; simple to operate, yield is higher, is more suitable for suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, the present invention is done to further expansion explanation, but it is pointed out that invention of the present invention is not limited to the following examples, the scope that these embodiment do not limit the present invention in any way.Some change that those skilled in the art has done within the scope of the claims and adjust and also should think and belong to scope of the present invention.
The keto-amine compound formula III of the protection the present invention relates to:
（Ⅲ）
Wherein:
R1 represents the group of any formation in H, saturated alkane, alcoxyl hydrocarbon, aromatic ring, alcoxyl aromatic ring, fragrant heterocycle or heterocycle;
R2 represents the group of any formation in H, saturated alkane, alcoxyl hydrocarbon, aromatic ring, fragrant heterocycle or heterocycle;
R3 represents the group of any formation in saturated alkane, alcoxyl hydrocarbon, aromatic ring, fragrant heterocycle or heterocycle;
R4 represents the group of any formation in H, saturated alkane, alcoxyl hydrocarbon, aromatic ring, fragrant heterocycle or heterocycle;
Well known to those skilled in the art, saturated alkane refers to the chain hydrocarbon that only has carbon-carbon single bond and hydrocarbon key, between the carbon atom in alkane molecule, is combined into outside chain (straight chain or containing side chain) with singly-bound, and all the other valencys are all by hydrogen atom is saturated, and its general formula is C
nh
2n+2, for example, include but not limited to methyl, ethyl, propyl group, butyl, sec.-propyl, the tertiary butyl etc.Alcoxyl alkyl refers to the group that has R-O-structure, and wherein R is aforesaid saturated alkane, for example, include but not limited to methoxyl group CH3O-, oxyethyl group C2H5O-etc.Aromatic ring refers to the organic aromatic compound that contains phenyl ring, for example, include but not limited to phenyl ph-, aminomethyl phenyl CH3-ph-etc.Alcoxyl aromatic ring is the aromatic ring that alkoxyl group replaces, and structural formula can be expressed as RO-ph-, for example, include but not limited to p-methoxy-phenyl CH3O-ph-etc.Heterocycle is the organic compound that contains heterocycle structure in molecule, forms the atom of ring in compound except carbon atom, also at least contains a heteroatoms, and heteroatoms comprises oxygen, sulphur, nitrogen etc.Modal heterogeneous ring compound is five yuan and hexa-member heterocycle and Benzoheterocyclic compounds etc., and wherein, five member ring heterocyclic compound has: furans, thiophene, pyrroles, thiazole, imidazoles, azoles etc.6-membered heterocyclic compound has: pyridine, pyrazine, pyrimidine etc.And fragrant heterocycle refers to the heterogeneous ring compound with aromaticity, modal is five-ring and six-ring, or condenses and encircle by them the compound forming.Five yuan of main fragrant heterocycles have furans, thiophene, pyrans etc., and hexa-atomic fragrant heterocycle has pyridine, pyrimidine etc.
Meanwhile, R2, R3 connects by carbon-carbon bond or carbon-oxygen bond, and for example R2 is methyl, and R3 is ethyl, and R2 and R3 are by be connected to-CH2-CH2CH2-of carbon-carbon bond; For example R2 is methyl, and R3 is oxyethyl group, and R2 and R3 are by be connected to-CH2-OCH2CH2-of carbon-oxygen bond.
N representative has the alkane of 1-20 carbon atom, represents the structure of the straight-chain paraffin that has 1-20 carbon atom, is at least pentacyclic ring structure, for example structure of pentamethylene base ketone thereby form one; In the time that n is 2, be the structure of cyclohexyl ketone, by that analogy.
The method of preparing the keto-amine compound formula III of aforesaid protection, comprises the steps:
（Ⅲ）
1) under the condition existing at suitable solvent, by amino alcohol formula I and acid anhydrides or acyl chloride reaction complete after, be reduced to suitable temperature crystallization, solvent evaporated or filtration, make the amino alcohol formula II of protection;
2) under the condition existing at suitable solvent, with the catalysis of tungstenic reagent, through the oxidized keto-amine formula III that obtains protection of amino alcohol formula II of hydrogen peroxide oxidation protection.
In aforesaid method of the present invention:
Suitable solvent described in step 1) is mainly selected from non-protonic solvent, preferably toluene, dimethylbenzene, ethyl acetate, chloroform, acetonitrile etc., more preferably solvent is toluene or ethyl acetate, solvent load is the amino alcohol formula I 250mL-800mL of every mole, be preferably 300-500mL, the mol ratio of amino alcohol formula I and acylating reagent acid anhydrides or acyl chlorides is 1:1 ~ 1:1.25, reaction times is 0.5h ~ 8h, temperature of reaction is 50 ℃-120 ℃, preferably temperature is 70 ℃-110 ℃, Optimal Temperature solvent is that toluene temperature is 110 ℃, when solvent is ethyl acetate, temperature is 77 ℃.
Further, after reaction, separation and purification is: after reaction finishes, stir or be staticly cooled to suitable temperature, filtering, filter cake can obtain the amino alcohol of the protection shown in formula II with reaction solvent washing.
Further, said suitable temp crystallization in step 1), this recrystallization temperature is 0 ℃-50 ℃, is preferably 0 ℃-30 ℃, most preferably is 10 ℃-15 ℃.
Step 2) described in suitable solvent be mainly selected from polar solvent, preferably water, toluene, chloroform, ethyl acetate etc., most preferably be water.Amino alcohol (II) mass ratio of solvent for use and protection is 0.5:1-10:1, and preferred proportion is 1:1-8:1, and best proportion is 1.5:1-5:1.
Further, the present invention is used+6 valency tungsten reagent, comprise wolframic acid, tungstic anhydride and different hydrate thereof and the various salt (comprising the hydrate of salt) of wolframic acid, be preferably the various salt (comprising the hydrate of salt) of wolframic acid and wolframic acid, most preferably the various salt of wolframic acid (comprising the hydrate of salt).Wherein the amino alcohol of tungsten reagent dosage and protection (II) mol ratio is 0.001:1-0.1:1, and preferred proportion is 0.005:1-0.05:1.
Further again, the mass concentration of hydrogen peroxide of the present invention is 20% ~ 80%, and preferred concentration is 10%-50%, and most preferable concentrations is 20%-40%.Wherein the amino alcohol of hydrogen peroxide consumption and protection (II) mol ratio is 1:1-3:1, and preferred proportion is 1:1-2:1, and best proportion is 1:1-1.5:1.
In addition, after in the present invention, reaction finishes, excessive hydrogen peroxide needs cancellation, cancellation adopts two kinds of methods, one: add reductive agent, one class is that reductibility reagent is as S-WAT, sodium bisulfite, vat powder, Sulfothiorine etc., another kind of is easily oxidized alcohol reagent, as: methyl alcohol, ethanol, the primary alconols such as Virahol or secondary alcohol, preferred easy oxidized alcohol reagent in this two class, wherein most preferably be and add Virahol, it is terminal that continuation reaction does not make starch potassium iodide paper become indigo plant to reaction solution in 1 hour-3 hours, concrete, oxidized reagent dosage and the amino alcohol of protection (II) mol ratio are 1:1-5:1, be preferably 3:1-4:1, its two: add catalyzer, accelerating hydrogen peroxide self decomposes, as activated manganese dioxide, add the amount of activated manganese dioxide to depend on that reaction adds the amount of hydrogen peroxide, until stir after half an hour reaction solution, not make starch potassium iodide paper become indigo plant be terminal, add the temperature of activated manganese dioxide to be controlled at 0 ℃-50 ℃ and be advisable, Optimal Temperature is 0 ℃-30 ℃.
In addition; the amino alcohol (II) of the present invention's protection is oxidized to the keto-amine (III) of protection; be not only applicable to the amino alcohol (II) of the protection preparing of the present invention; also other additive methods be should comprise and the amino alcohol (II) of available protection, the 4-acetamido hexalin that such as paracetamol direct-reduction hydrogenation obtains etc. prepared or purchase.
Oxidation shown in formula III of the present invention obtains the keto-amine of protection, employing adds the method for reductive agent, described separation and purification is: after reaction finishes, control 0 ℃-50 ℃ of temperature, add reductibility reagent, do not make starch potassium iodide paper become blue to stirring reaction solution after half an hour, the solvent that pressure reducing and steaming is over half, with methylene dichloride or chloroform extraction, organic layer washing, again with saturated salt solution washing, anhydrous sodium sulphate or anhydrous magnesium sulfate drying for organic layer, filter, remove siccative, filtrate decompression reclaims solvent, crude product can obtain the keto-amine of the protection shown in formula III by re-crystallizing in ethyl acetate, employing adds easily the method for oxidized alcohol reagent, described separation and purification is: after reaction finishes, add easily 90 ℃-100 ℃ insulation 1-3 hour of oxidized alcohol reagent, do not make starch potassium iodide paper become blue to reaction solution, the solvent that pressure reducing and steaming is over half, with methylene dichloride or chloroform extraction, anhydrous sodium sulphate or anhydrous magnesium sulfate drying for organic layer, filter, remove siccative, filtrate decompression reclaims solvent, and crude product can obtain the keto-amine of the protection shown in formula III by re-crystallizing in ethyl acetate.
Oxidation shown in formula III of the present invention obtains the keto-amine of protection, employing adds the method for catalyzer, described separation and purification is: after reaction finishes, control 0 ℃-50 ℃ of temperature, add catalyst agents, do not make starch potassium iodide paper become blue to stirring reaction solution after half an hour, filter, filtrate decompression boils off solvent over half, with methylene dichloride or chloroform extraction, organic layer washing, again with saturated salt solution washing, anhydrous sodium sulphate or anhydrous magnesium sulfate drying for organic layer, filter, remove siccative, filtrate decompression reclaims solvent, crude product can obtain the keto-amine of the protection shown in formula III by re-crystallizing in ethyl acetate.
In addition, utilize the keto-amine formula III that the present invention relates to protection as intermediate application aspect synthetic at medicine, corresponding medicine is for example recorded in: WO2011021214.
In addition the keto-amine that, the present invention also relates to formula III protection as intermediate at the inhibitor of synthetic human protein kinase PLK1 to PLK4 with the application (CN200880111548.6) in the medicine for the treatment of hyperplasia.
Further, the present invention also relates to keto-amine application (wo2009023269A2) in the medicine for the treatment of Alzheimer's as intermediate of formula III protection.
In context, all temperature are all ℃ to represent.In the embodiment of online face, " conventional aftertreatment " represents: if needed, add water, regulate as required pH value to depend on the formation of product to 1-13(), ethyl acetate, chloroform or dichloromethane extraction for mixture, separation of phases, anhydrous sodium sulphate or anhydrous magnesium sulfate drying for organic phase, underpressure distillation, product is purified by silica gel chromatography and/or recrystallization, and Rf value obtains on silica gel.
Embodiment mono-: the amino alcohol formula II of protection synthetic
Synthesizing of embodiment 1:4-acetamido hexalin
Under mechanical stirring, in the ethyl acetate of 5L, add 4-amino piperidine alcohol (1.15kg, 10mol), then drip diacetyl oxide (1.122kg, 11mol), after dropwising, be warming up to backflow, insulation, to reacting completely, is stirred and is cooled to 0 ℃-30 ℃, filter, obtain the 4-acetamido hexalin white crystalline solid (1.5kg) shown in formula II.
Embodiment 2:3-hydroxycyclopent base ammonia t-butyl formate
Under stirring, in 25ml ethyl acetate and 25ml water, add 3-amino cyclopentyl alcohol (10g, 0.1mol), under room temperature, drip tert-Butyl dicarbonate (24g, 0.11mol), stirring at room temperature is to reacting completely, separatory, organic layer is dry, reclaims solvent, freezingly separates out the 3-hydroxycyclopent base ammonia t-butyl formate white solid (19.5g) shown in formula II
Synthesizing of embodiment 3:4-benzoylamino hexalin
Under mechanical stirring, in the toluene of 500mL, add 4-amino piperidine alcohol (115g, 1mol), then drip Benzoyl chloride (147.6g, 1.05mol), after dropwising, be warming up to backflow, insulation, to reacting completely, is stirred and is cooled to 0 ℃-30 ℃, filter, obtain the 4-benzoylamino hexalin white crystalline solid (205.9g) shown in formula II.
Embodiment bis-: the keto-amine formula III of protection synthetic
Synthesizing of embodiment 4:4-acetamido pimelinketone
Under mechanical stirring, in the water of 2.5L, add sodium wolframate (10g, 0.03mol), 4-kharophen piperidine alcohols (1.57kg, 10mol), then be warming up to 80 ℃, add 30% hydrogen peroxide (2.53L, 20mol), be warming up to backflow, insulation is to reacting completely, stirring is cooled to 0 ℃-30 ℃, add 200g Manganse Dioxide, stir, filter, filtrate decompression boils off 3L solvent, with chloroform extraction, organic layer washing, again with saturated salt solution washing, organic layer anhydrous sodium sulfate drying, filter, remove siccative, filtrate decompression reclaims solvent, obtain the 4-acetamido pimelinketone (1.8kg) shown in formula III.
Synthesizing of embodiment 5:4-acetamido pimelinketone
Under mechanical stirring, in the water of 250mL, add sodium wolframate (2g, 0.006mol), 4-kharophen piperidine alcohols (157g, 1mol), then be warming up to 80 ℃, add 30% hydrogen peroxide (190mL, 1.5mol), be warming up to backflow, insulation is to reacting completely, add 240ml Virahol, continuing to be incubated to reaction solution does not make starch potassium iodide paper become blue, filtrate decompression boils off 400mL solvent, with chloroform extraction, organic layer washing, again with saturated salt solution washing, organic layer anhydrous sodium sulfate drying, filter, remove siccative, filtrate decompression reclaims solvent, obtain the acetamido pimelinketone (172g) shown in formula III.
Synthesizing of embodiment 6:4-benzoylamino pimelinketone
Under mechanical stirring, in the water of 50mL, add tungstic oxide (1.7g, 0.0075mol), 4-benzamido piperidine alcohols (11g, 0.05mol), then be warming up to 80 ℃, add 30% hydrogen peroxide (1mL, 0.0083mol), be warming up to backflow, insulation is to reacting completely, be cooled to 0 ℃-30 ℃, add 0.5g S-WAT, filtrate decompression boils off solvent, with acetic acid ethyl dissolution, anhydrous sodium sulfate drying, filters, and removes siccative, filtrate decompression reclaims solvent, can obtain the 4-benzoylamino pimelinketone (10.1g) shown in formula III.
Synthesizing of embodiment 7:3-oxocyclopentyl t-butyl carbamate
Under agitation, in the water of 50mL, add sodium wolframate (1g, 0.003mol), 3-hydroxycyclopent base ammonia t-butyl formate (10g, 0.05mol), is then warming up to 50 ℃, add 30% hydrogen peroxide (1mL, 0.0083mol), insulation, to reacting completely, is cooled to 0 ℃-30 ℃, add 0.5g S-WAT, filtrate decompression boils off solvent, with acetic acid ethyl dissolution, and anhydrous sodium sulfate drying, filter, remove siccative, filtrate decompression reclaims solvent, can obtain the 3-oxocyclopentyl t-butyl carbamate (9.1g) shown in formula III.
Although above the specific embodiment of the present invention has been given to describe in detail and explanation; but what should indicate is; we can carry out various equivalences to above-mentioned embodiment according to conception of the present invention and change and revise; when its function producing does not exceed spiritual that specification sheets contains yet, all should be within protection scope of the present invention.
Claims (9)
1. the keto-amine compound formula III of a protection:
（Ⅲ）
Wherein:
R1 represents the group of any formation in H, saturated alkane, alcoxyl hydrocarbon, aromatic ring, alcoxyl aromatic ring, fragrant heterocycle or heterocycle;
R2 represents the group of any formation in H, saturated alkane, alcoxyl hydrocarbon, aromatic ring, fragrant heterocycle or heterocycle;
R3 represents the group of any formation in saturated alkane, alcoxyl hydrocarbon, aromatic ring, fragrant heterocycle or heterocycle;
R4 represents the group of any formation in H, saturated alkane, alcoxyl hydrocarbon, aromatic ring, fragrant heterocycle or heterocycle;
Meanwhile, R2, R3 connects by carbon-carbon bond or carbon-oxygen bond;
N representative has the alkane of 1-20 carbon atom.
2. a preparation method for the keto-amine compound formula III of protection claimed in claim 1, is characterized in that comprising the steps:
（Ⅲ）
1) under the condition existing at suitable solvent, by amino alcohol formula I and acid anhydrides or acyl chloride reaction complete after, be reduced to suitable temperature crystallization, solvent evaporated or filtration, make the amino alcohol formula II of protection;
2) under the condition existing at suitable solvent, with the catalysis of tungstenic reagent, through the oxidized keto-amine formula III that obtains protection of amino alcohol formula II of hydrogen peroxide oxidation protection.
3. the preparation method of the keto-amine compound formula III of protection according to claim 2, is characterized in that described step 1) in the mol ratio of amino alcohol formula I and acid anhydrides or acyl chlorides be 1:1 ~ 1:1.25; The temperature of reaction of described amino alcohol formula I and acid anhydrides or acyl chloride reaction is 50 ℃ ~ 120 ℃; Described recrystallization temperature is 0 ℃ ~ 50 ℃; The consumption of described solvent is every mole of amino alcohol formula I 250mL-800mL solvent.
4. the preparation method of the keto-amine compound formula III of protection according to claim 2; it is characterized in that described step 1) described in solvent be non-protonic solvent; be selected from toluene, dimethylbenzene, ethyl acetate, chloroform, acetonitrile any one, be preferably toluene or ethyl acetate.
5. the preparation method of the keto-amine compound formula III of protection according to claim 2, it is characterized in that described step 1) reaction times be 0.5h ~ 8h, described tungstenic reagent is selected from tungstate, tungstic anhydride, wolframic acid and different hydrate thereof at interior+6 valency tungsten atom compounds, and the mass concentration of described hydrogen peroxide is 20% ~ 80%; Amino alcohol (II) mol ratio of described tungstenic reagent dosage and protection is 0.001:1-0.1:1, and preferred proportion is 0.005:1-0.05:1, and the mol ratio of amino alcohol formula II and hydrogen peroxide is 1:1 ~ 1:3.
6. the preparation method of the keto-amine compound formula III of protection according to claim 2, is characterized in that described step 2) described in solvent be polar solvent, be selected from any one in water, toluene, chloroform, ethyl acetate, be preferably water; Described temperature of reaction is 50 ℃ ~ 100 ℃.
7. the preparation method of the keto-amine compound formula III of protection according to claim 2, is characterized in that described step 2) reaction times be 2h ~ 48h; The amino alcohol formula II mass ratio of described solvent and protection is 0.5:1 ~ 10:1.
8. the preparation method of the keto-amine compound formula III of protection according to claim 2; characterized by further comprising step 3) separation and purification: step 2) reaction finish after; after the excessive hydrogen peroxide of cancellation; boil off more than 50% water, with methylene dichloride or chloroform or ethyl acetate extraction, organic layer washing; again with saturated salt solution washing; with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, distillating recovering solvent, then recrystallization obtains the keto-amine formula III of protection.
9. the preparation method of the keto-amine compound formula III of protection according to claim 8; it is characterized in that the solvent that recrystallization described in described step 3) adopts is selected from any one in acetonitrile, acetone, ethyl acetate, toluene, methyl tertiary butyl ether, isopropyl ether, is preferably acetone or ethyl acetate.
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| CN1835953A (en) * | 2003-08-15 | 2006-09-20 | 默克专利 | 4-cycloalkylaminopyrazolo pyrimidine nmda/nr2b antagonists |
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| CN102584618A (en) * | 2012-01-18 | 2012-07-18 | 浙江工业大学 | Preparation method for 4-substituted acylamino cyclohexanone |
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| CN101429173A (en) * | 2007-11-09 | 2009-05-13 | 重庆医药工业研究院有限责任公司 | Process for producing pramipexole midbody 2,6-diamino-4,5,6,7-tetrahydrochysene-benzothiazole |
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