CN1051759C - 芳基乙醇胺的制备方法 - Google Patents
芳基乙醇胺的制备方法 Download PDFInfo
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- CN1051759C CN1051759C CN91108911A CN91108911A CN1051759C CN 1051759 C CN1051759 C CN 1051759C CN 91108911 A CN91108911 A CN 91108911A CN 91108911 A CN91108911 A CN 91108911A CN 1051759 C CN1051759 C CN 1051759C
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- Prior art keywords
- formula
- aryl
- definition
- acetal
- alcohol
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- 229960002052 salbutamol Drugs 0.000 title abstract description 20
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 title abstract description 19
- 150000002373 hemiacetals Chemical class 0.000 title abstract 2
- 239000000543 intermediate Substances 0.000 title abstract 2
- 150000004677 hydrates Chemical class 0.000 title 1
- 238000004519 manufacturing process Methods 0.000 title 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims abstract description 51
- 238000002360 preparation method Methods 0.000 claims abstract description 27
- 229910052796 boron Inorganic materials 0.000 claims abstract description 12
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 7
- -1 aryl ethanolamines Chemical class 0.000 claims description 85
- 238000000034 method Methods 0.000 claims description 46
- 239000011541 reaction mixture Substances 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 239000005864 Sulphur Substances 0.000 claims description 19
- 239000003153 chemical reaction reagent Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 150000003462 sulfoxides Chemical class 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 230000002140 halogenating effect Effects 0.000 claims description 9
- 239000004215 Carbon black (E152) Substances 0.000 claims description 8
- 238000009833 condensation Methods 0.000 claims description 8
- 230000005494 condensation Effects 0.000 claims description 8
- 229930195733 hydrocarbon Natural products 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- NYYDZOSYLUOKEM-UHFFFAOYSA-N oxaldehyde;hydrate Chemical compound O.O=CC=O NYYDZOSYLUOKEM-UHFFFAOYSA-N 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 238000005336 cracking Methods 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 6
- 238000010025 steaming Methods 0.000 claims 1
- 150000001241 acetals Chemical class 0.000 abstract description 62
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 19
- 125000003118 aryl group Chemical group 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 16
- 150000001721 carbon Chemical group 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 12
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N alpha-ketodiacetal Natural products O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 11
- 238000004821 distillation Methods 0.000 description 11
- 229940015043 glyoxal Drugs 0.000 description 11
- 229920000642 polymer Polymers 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000003710 aryl alkyl group Chemical group 0.000 description 9
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 125000003107 substituted aryl group Chemical group 0.000 description 8
- LWAQTCWTCCNHJR-UHFFFAOYSA-N 5-acetyl-2-hydroxybenzamide Chemical compound CC(=O)C1=CC=C(O)C(C(N)=O)=C1 LWAQTCWTCCNHJR-UHFFFAOYSA-N 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 229910000085 borane Inorganic materials 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 229960000581 salicylamide Drugs 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical group 0.000 description 5
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 125000000547 substituted alkyl group Chemical group 0.000 description 5
- 239000009637 wintergreen oil Substances 0.000 description 5
- JPJBSUGXMUDGIE-UHFFFAOYSA-N 5-(2,2-dihydroxyacetyl)-2-hydroxybenzamide Chemical compound NC(=O)C1=CC(C(=O)C(O)O)=CC=C1O JPJBSUGXMUDGIE-UHFFFAOYSA-N 0.000 description 4
- FNQAQEOXCBTUJN-UHFFFAOYSA-N 5-(2,2-dimethoxyacetyl)-2-hydroxybenzamide Chemical compound COC(OC)C(=O)C1=CC=C(O)C(C(N)=O)=C1 FNQAQEOXCBTUJN-UHFFFAOYSA-N 0.000 description 4
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 238000006116 polymerization reaction Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- XPFVYQJUAUNWIW-UHFFFAOYSA-N furfuryl alcohol Chemical compound OCC1=CC=CO1 XPFVYQJUAUNWIW-UHFFFAOYSA-N 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 3
- 150000003568 thioethers Chemical class 0.000 description 3
- SEXKDZSOKXPFFH-UHFFFAOYSA-N 1-(2-benzoylphenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 SEXKDZSOKXPFFH-UHFFFAOYSA-N 0.000 description 2
- PXACTUVBBMDKRW-UHFFFAOYSA-M 4-bromobenzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-M 0.000 description 2
- BQIBHWUKFFWROT-UHFFFAOYSA-N 5-(2,2-dibutoxyacetyl)-2-hydroxybenzamide Chemical compound CCCCOC(OCCCC)C(=O)C1=CC=C(O)C(C(N)=O)=C1 BQIBHWUKFFWROT-UHFFFAOYSA-N 0.000 description 2
- XXRBPWOLPCOKBS-UHFFFAOYSA-N 5-(2-butoxy-2-hydroxyacetyl)-2-hydroxybenzamide Chemical compound CCCCOC(O)C(=O)C1=CC=C(O)C(C(N)=O)=C1 XXRBPWOLPCOKBS-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 238000010533 azeotropic distillation Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 2
- 235000012970 cakes Nutrition 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- XLSMGNNWSRNTIQ-UHFFFAOYSA-N methyl 5-acetyl-2-hydroxybenzoate Chemical class COC(=O)C1=CC(C(C)=O)=CC=C1O XLSMGNNWSRNTIQ-UHFFFAOYSA-N 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- QLOKJRIVRGCVIM-UHFFFAOYSA-N 1-[(4-methylsulfanylphenyl)methyl]piperazine Chemical compound C1=CC(SC)=CC=C1CN1CCNCC1 QLOKJRIVRGCVIM-UHFFFAOYSA-N 0.000 description 1
- LOWMYOWHQMKBTM-UHFFFAOYSA-N 1-butylsulfinylbutane Chemical compound CCCCS(=O)CCCC LOWMYOWHQMKBTM-UHFFFAOYSA-N 0.000 description 1
- BQCCJWMQESHLIT-UHFFFAOYSA-N 1-propylsulfinylpropane Chemical compound CCCS(=O)CCC BQCCJWMQESHLIT-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- WVYWICLMDOOCFB-UHFFFAOYSA-N 4-methyl-2-pentanol Chemical compound CC(C)CC(C)O WVYWICLMDOOCFB-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- VXWSXLSUWGZOHD-UHFFFAOYSA-N 5-(2-bromoacetyl)-2-hydroxybenzamide Chemical compound NC(=O)C1=CC(C(=O)CBr)=CC=C1O VXWSXLSUWGZOHD-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- UIERETOOQGIECD-UHFFFAOYSA-N Angelic acid Natural products CC=C(C)C(O)=O UIERETOOQGIECD-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BVMWIXWOIGJRGE-UHFFFAOYSA-N NP(O)=O Chemical compound NP(O)=O BVMWIXWOIGJRGE-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 125000005360 alkyl sulfoxide group Chemical group 0.000 description 1
- UIERETOOQGIECD-ARJAWSKDSA-N angelic acid Chemical compound C\C=C(\C)C(O)=O UIERETOOQGIECD-ARJAWSKDSA-N 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- JLZQFKAOWJWGKZ-UHFFFAOYSA-N azane;butan-1-amine Chemical compound N.CCCCN JLZQFKAOWJWGKZ-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- BMRWNKZVCUKKSR-UHFFFAOYSA-N butane-1,2-diol Chemical compound CCC(O)CO BMRWNKZVCUKKSR-UHFFFAOYSA-N 0.000 description 1
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
- C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
- C07C215/60—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
- C07C69/88—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified carboxyl groups
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
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Abstract
本发明公开了芳基乙醇胺的制备方法,它包括将硼芳基乙醇胺络合物裂解。
Description
本发明涉及芳基乙醇胺的制备,尤其是沙丁胺醇和英国专利说明书第1,200,886号、1,214,012号和1,266,058号公开的此类型的其它芳基乙醇胺的制备。
英国专利说明书第1,200,886号公开了某些芳基乙醇胺及两种制备方法,芳基乙醇胺是药用活性化合物,可用作抗高血压剂和支气管扩张剂。
通过卤代乙酰苯酮与苄基保护的叔丁胺缩合来制备沙丁胺醇的方法在下列文献中已有报导:英国专利说明书1,200,886;“Pharmazeutische Wirkstoffe(Synthesen,Patente,Anwendungen)”,Vol.5,Kleeman和Engel著(2nd ed.New Yorkand Stuttgart)P.813,1982;和“Pharmaceutical ManufacturingEncyclopedia”,第2版,Vol.1,Marshall Sittig著,NoyesPublication,Park Ridge,New Jersey,USA,1988,pp.31-33。这些方法的缺点是,沙丁胺醇的产率低,同时还产生大量不需要的付产物。效率低的部分原因是必须使用多种还原剂(例如:氢化锂铝、硼氢化钠)和钯/碳催化剂的氢化,再加上多个提纯工序。效率低的另一原因是必须在胺上使用苄基保护基团,以免胺二烷基化,这样又需要进一步去保护和提纯工序。
英国专利说明书1,247,370指出了制备沙丁胺醇的方法,即叔丁胺与芳基乙二醛缩合,接着用氢化锂铝和硼氢化钠多次还原。该专利还指出了一种芳基乙二醛的制备方法,该方法是多步的,采用低温(例如:室温)和较长的反应时间(例如:长达一周),使不稳定的芳基乙二醛的聚合这一不利现象降至最小。该方法的缺点是沙丁胺氨醇的产率低并产生大量的不需要的付产物。
芳基乙二醛是制备药用化合物的常用中间体。芳基乙二醛化合物的常规制备方法是本领域公知的。N.Kornblum,J.W.Powers,G.J.Anderson,W.J.Jones,H.O.Larson,O.Levand和W.M.Weaver[JACS,Vol.79(1957)p.6562];J.March[AdvancedOrganic Chemistry,Reactions,Mechanisms and Structure,3rded.John Wiley & Sons;New York,New York,(1985)pp.1081-1083]和英国专利说明书1247370指出了用二甲基亚砜将伯卤化物和伯醇的酯氧化生成醛的方法。M.B.Floyd;M.T.Du,P.F.Fabio,L.A.Jacob和Berrard D.Johnson[J.Org.Chem.Vol.50(1985)pp.5022-5027]和R.Desmond,S.Mills,R.P.Volante和I.Shinkai[Synthetic Comm.Vol.19(3和4)(1989)pp.379-385]公开了将乙酰苯酮与氢溴酸水溶液在二甲基亚砜中反应生成乙二醛的方法。G.Cardillo,M.Orena和S.Sandi[J.C.S.Chem.Comm.(1976)pp.190]公开了通过卤化物与铬酸钾在六甲基膦酰胺中,在冠醚的存在下,反应制备醛的方法。K.R.Henery Logan和T.L.Fridinger[Chemical Communications(1968)pp.130-131]公开了α,α-二氯乙酰苯酮在甲醇中用甲醇钠处理转化为苯基乙二醛的方法。V.E.Gunn和J.P.Anselme[J.Org.Chem.Vol.42,No.4,(1977)pp.754-75]公开了用N,N-二乙基和N,N-二苄基羟胺将苯甲酰甲基溴转化为苯基乙二醛。H.A.Riley和A.R.Gray[OrganicSynth.Coll.Vol.2,pp.509-511]公开了以二氧化硒为氧化剂将乙酰苯酮转化为苯基乙二醛的方法。上述方法有严重的局限性。例如,大部分文献教授的都是芳基乙二醛的直接制备,芳基乙二醛是易变的或不稳定的。而且,这些方法也不适宜用广泛的底物或前体制备芳基乙二醛。此外,上述大部分方法都使用有毒性氧化剂如氧化硒、铬酸盐等,它们不适合用于制备药用化合物。
此外,我们发现用溴化氢水溶液作溴化剂对于某些芳基底物是不适宜的,这是因为采用水性试剂会导致不需要的环上溴代。
考虑到先有技术中教授的方法所存在的问题,显然有必要提供一种制备芳基乙醇胺(如沙丁胺醇)的方法,该方法产率较高,同时废物或付产物较少。也有必要提供一种制备沙丁胺醇的新中间体或衍生物,使所述化合物的制备方法得以简化。我们惊异地发现,上述目的可以通过使用制备芳基乙二醛水合物的特定前体达到,即:乙缩醛和半乙缩醛。这些乙缩醛和半乙缩醛比芳基乙二醛水合物稳定得多,可以在温和的条件下除去保护基而产生期望的芳基乙二醛水合物。此外,我们发现了一种单一的还原剂,它可以代替英国专利1,247,370和1,200,886所述的复合还原剂用于制备沙丁胺醇。也有必要提供一种比先有技术只需较少反应步骤和提纯步骤的方法。此外,还有必要提供一种制备乙缩醛和半乙缩醛衍生物的有效方法,乙缩醛和半乙缩醛可用作制备期望的芳基乙二醛水合物的底物或前体。采用这样的中间体和方法相信可以克服上述参考文献中制备沙丁胺醇方法中的局限和问题。
在第一实施例中,本发明目的在于新的硼芳基乙醇胺络合物,其单体形式如式(XIII)的A和B所示和
式中Y是OR17或OH2其中,R17是C-1至C-6烷基;R3和R5各自代表氢、烷基、芳基或取代芳基。最好Y是-OCH,R3代表H,R5代表叔丁基。硼芳基乙醇胺络合物(XIII)可用作制备芳基乙醇胺(如沙丁胺醇)的有价值的中间体。
在第二实施例中,本发明目的在于下式芳基乙醇胺的制备方法:式中R3和R5各自代表氢、烷基、芳基或取代芳基。该方法包括将第一实施例中硼芳基乙醇胺络合物(XIII)-A和-B裂解’,给出期望的芳基乙醇胺(XIV)。最好通过向反应混合物中加入酸和醇来裂解芳基乙醇胺络合物(XIII)-A和-B。将反应混合物蒸馏以除去用过的硼也是优选的。式中R3是H,R5是叔丁基的芳乙醇胺(XIV)称为沙丁胺醇。
在第三实施例中,本发的目的在于式(XIV)芳基乙醇胺的制备方法,该方法包括用硼烷-硫醚试剂还原下式Schiff碱,给出(XIV)。式中R3和R5与第二实施例的定义相同;Ar’是式中R9代表氢或酰基;R11代表氢或烷基。硼-硫醚试剂最好具有如下结构:其中R13和R15可以相同或不同,代表C-1至C-6烷基,或与硫原子一起代表含有3~6个碳原子和1或2个硫或氧原子的环;或者与硫原子一起代表聚合硫烃。
在本发明的第四实施例中,第三实施例的Schiff碱(XI)是通过将乙二醛水合物(IX)或半乙缩醛(V)与胺H2NR5(X)(其中R5如上文定义)接触制得的。式(IX)和式(V)如下:式中Ar’和R3的定义同第三实施例,R代表烷基、取代烷基、环烷基、环烷基烷基、羟烷基、芳基、取代芳基、芳烷基、取代芳烷基、杂环基或杂环烷基。
在本发明的第五实施例中,第四实施例的乙二醛水合物(IX)是通过水解乙缩醛(VII)或半乙缩醛(V)制得的:式中Ar’和R3的定义同第二和第三实施例,R代表烷基、取代烷基、环烷基、环烷基烷基、羟烷基、芳基、取代芳基、芳烷基、取代芳烷基、杂环基或杂环烷基。
在本发明的第六实施例中,第五实施例的乙二醛水合物(VII)或半乙缩醛(V)是通过将式(II)化合物与亚砜和醇ROH(R的定义同第四实施例)接触制得的,式(II)如下:式中,Ar’和R3的定义同第二或第三实施例,L是离去基,例如:溴、氯、碘、甲磺酰基、三氟甲磺酰基、对溴苯磺酸酯基、甲苯磺酸酯基,或者,将式(I)化合物与卤化剂、亚砜和醇ROH接触制得乙缩醛或半乙缩醛(VII)或(V),式(I)如下:其中Ar’和R3的定义同第二或第三实施例。
在第七实施例中,本发明的目的在于乙缩醛和半乙缩醛的制备方法。上式中Ar代表芳基或取代芳基,R代表烷基、取代烷基、环烷基、环烷基烷基、羟烷基、芳基、取代芳基、芳烷基、取代芳烷基、杂环基或杂环烷基,且,R3代表氢、烷基、芳基或取代芳基。该方法包括将式(II)化合物与亚砜和醇ROH(R如上文定义)接触,式(II)如下:其中Ar和R3如上文定义,L是离去基,例如:溴、碳、氯、甲磺酰基、三氟甲磺酰基、对溴苯磺酸酯基或甲苯磺酸酯基。或者,将式(I)化合物与卤化剂、亚砜和醇ROH接触制得乙缩醛或半乙缩醛(VII)或(V),式(I)如下:其中Ar和R3的定义同前。
在第八实施例中,本发明的目的在于式(IX)的乙二醛水合物的制备方法。式(IX)如下:其中Ar和R3的定义同第七实施例。该方法包括将第七实施例制得的乙缩醛(VII)或半乙缩醛(V)水解得到水合物(IX)。
在第九实施例中,本发明的目的在于下式化合物的制备方法:其中Z是-NH2,-OH或OR6,R6代表氢或1~10个碳原子的烷基;R7和R8各自代表氢,烷基、取代烷基、环烷基、环烷基烷基、羟烷基、芳基、芳烷基、取代芳烷基、杂环基或杂环烷基,其前提是R7和R8不都是氢,或R7和R8与氧原子一道形成五元或六元环。最好R7和R8代表氢或1~10个碳原子的烷基,但必须R7或R8只有一个是烷基,最好是1~4个碳原子的烷基。最佳的是Z是-OCH3,R7和R8各自代表甲基、异丙基或正丁基。
与其它已知方法比较,本发明的优点是它能够更高效更经济地通过乙缩醛、半乙缩醛和芳基乙二醛水合物中间体制得某些芳基乙醇胺,如沙丁胺醇,即产率高、纯度高、时间短、付产物少。本发明的优点是能提供新的中间体,如硼芳基乙醇胺络合物(XIII)、乙缩醛和半乙缩醛(XX),它们可用来简化沙丁胺醇的制备方法。在一个实施例中,本发明的优点是提供一种使用单一还原剂还原同一分子中三个不同基团的方法。在另一实施例中,本发明制备芳基乙二醛水合物的方法具有适用于广泛的制备底物的优点。本发明还有一优点是能够在高于室温的温度下制备芳基乙二醛化合物、乙缩醛和半乙缩醛,同时几乎没有或根本没有由不稳定芳基乙二醛聚合产生的付产物。当使用溴化剂时,本发明的优点是可以利用无水溴化氢或溴来减少或消除环上溴代。还有一个优点是,与其它已有的方法相比,它只需少得多的反应步骤或提纯步骤。
除非另有说明,本文所用的术语定义如下:烷基-代表具有1-10个碳原子的直链饱和烃基,最好具有1-6个碳原子;或者代表含3-10个碳原子的支链烃基,最好具有3-6个碳原子,例如:甲基、乙基、丙基、异丙基、正丁基、异丁基、戊基、己基、十二烷基等;“取代烷基”一词是指有一个或多个氢原子被卤素、羟基、芳基或环烷基取代的烷基;环烷基-代表含3-10个碳原子的饱和烃环,最好含3-6个碳原子,例如:环丙基、环丁基、环戊基、环己基等。酰基-代表-CO-J基团,其中J代表烷基、环烷基或芳基。芳基-代表含至少一个苯型环的碳环基团,芳环部分含6-14个碳原子,例如苯基、萘基、茚基、茚满基等;“取代芳基”一词是指被一至三个分别选自下列取代基取代的芳基:所述取代基是芳基、烷基、烷氧基、卤素、三卤甲基、氰基、硝基、-CONH2、羟基、保护的羟基、羟烷基、保护的羟烷基、巯基或羧基及其盐或酯。芳烷基或取代芳烷基-是指烷基与芳基或取代芳基键合而成的基团,例如:苯甲基、2-氯苯乙基等。杂环基-代表碳环中含至少一个O,S和/或N原子的环状基团,同时具有足够数目的离域π电子以提供芳香性,芳杂环基团有2-14个(2-16个更好)碳原子。例如2-,3-或4-吡啶基,2-或3-呋喃基,2-或3-噻吩基,2-,4-或5-噻唑基,1-,2-,4-或5-咪唑基,2-,4-或5-嘧啶基,2-吡嗪基,3-或4-哒嗪基,3-,5-或6-(1,2,4-三嗪基),3-或5-(1,2,4-噻二唑基),2-,3-,4-,5-,6-或7-苯并呋喃基,1-,2-,3-,4-,5-,6-,或7-吲哚基,1-,3-,4-或5-吡唑基,2-,4-或5-噁唑基等;杂环烷基-代表通过烷基与杂环基键接而成的基团;羟烷基-代表按上文定义的、其中一个氢原子被羟基取代的烷基基团,例如:羟甲基、2-羟乙基等;被护羟基或被护羟烷基-代表按上文定义的羟基或羟烷基,其中羟基被转化为被保护的基团例如-OCH3,-OCH2苯基,=OCOCH3,-OSi(CH3)3,-OSi(CH3)2(叔丁基),
等,以免参与反应。当然也可以使用本领域公知的其他保护基。经一次或多次反应后,保护基可用本领域公知的标准方法除去,例如用无机酸(如:盐酸)水解;卤素-代表氟、氯、溴或碘;三卤甲基-代表三氯甲基和三氟甲基;烷氧基-代表通过氧原子共键价连结的上文定义的烷基,例如:甲氧基、乙氧基、丙氧基、戊氧基、己氧基、癸氧基等;羧基-代表-COOH基团;且巯基-代表-SR’基团,其中R’代表烷基或芳基;聚合硫烃-代表含硫、氢和碳原子的聚合物,硫原子以硫醚构型存在于聚合硫烃中,即,-C-S-C构型。
式中Hal代表卤素(如氯、溴或碘)且R3代表氢、烷基或芳基的式(II)化合物可通过将式(I)化合物与卤化剂和亚砜如二甲基亚砜接触来制备。所用的卤化剂可选自能将一种卤素元素最好是氯或溴引入化合物(1)的一大类化合物。这样的卤化剂包括但并不限于溴(Br2),碘(I2)氯(Cl2),溴化氢(HBr)和氯化氢(HCl)。卤化剂的用量为每摩尔化合物(I)约2摩尔至催化量的卤化剂,优选约0.8-约0.4摩尔卤化剂。反应最好在无水的条件下进行。使用所述试剂的方法是公知的,可参见J.March,Advanced Organic Chemistry.Reactions,Mechanisms and Structure,第三版,John Wiley and Sons,New York,(1985),1346pp.所述。所用的亚砜可以是烷基亚砜,其中每个烷基取代基有一至四个碳原子,例如:二甲基亚砜(即CH3SOCH3或DMSO),二乙基亚砜,二丙基亚砜和二丁基亚砜,以DMSO最为优选。亚砜的用量从过量到大约2∶1摩尔化合物(1)[亚砜摩尔数∶1摩尔化合物(I)],以约20-4摩尔亚砜为好,约10-6摩尔亚砜更好,约6摩尔亚砜最好。式(II’)化合物可通过将化合物(I’)与式LCl的酸性氯化物在碱的存在下接触来制备,式中L是离去基团,典型的离去基有甲苯磺酰基、三氟甲磺酰基、对溴苯磺酰基和甲基磺酰基等,参见上述J.March,pp.444和628。
乙缩醛(VII)和半乙缩醛(V)可通过将化合物(II)或(II’)与亚砜和醇ROH(其中R是按上文定义的烷基、环烷基、羟烷基或芳基)接触制得,亚砜的用量与上述制备化合物(II)的用量相似。在制备乙缩醛(VII)和半乙缩醛(V)中所用的醇可以是含羟基的一大类有机化合物,见Condensed Chemical Dictionary(第10版,Gessner G.Hawley改写,Van Nostrand Reinhold Company,New York,1981)定义。醇可以是一羟基(一个-OH基团)或二羟基(两个-OH基团-二醇)醇。典型的一羟基醇包括甲醇(即CH3OH)、乙醇、丙醇、异丙醇、正丁醇、正己醇、4-甲基-2-戊醇等。一羟基醇还包括C-3至C-8环醇,如:环己醇,环庚醇等;C-6至C-15芳醇,如:苯酚、苄醇、1-萘酚等;和杂环醇,如;2-羟基吡啶、糠醇等。二醇可以包括C-2至C-10二醇,如:乙二醇、丙二醇、1,2-丁二醇、1,4-丁二醇、戊二醇等。适当时,也可使用上述醇的混合物,如两种或两种以上一羟基醇的混合物或一羟基醇与二羟基醇的混合物。醇的用量范围可由过量到约2∶1(乙醇摩尔数∶1摩尔化合物(II)),约30-10摩尔的醇更好,约20-15摩尔的醇最好。一般来说,使用较多量的醇易于使乙醛缩(VII)较半乙缩醛(V)更易生成。
在反应过程中通常要搅拌反应物。可以将反应物接触足够长的时间以完成期望的反应,这可由原料的消失观察到。该时间将取决于温度和所用的试剂,范围可由约15分钟到24小时或更长,优选约1小时。
乙缩醛(VII)和半乙缩醛(V)可通过常规的方法回收,例如:溶剂萃取、过滤、相分离、结晶等。一般是将混合物加入冰水中,将沉淀过滤,得到期望的乙缩醛(V)和半乙缩醛(VII)。
芳基乙二醛水合物(IX)可通过用无机或有机酸(如:盐酸、硫酸或乙酸)将反应混合物中的乙缩醛(VII)和半乙缩醛(V)水解的常规方法制备。酸的用量范围可以由过量至每摩尔乙缩醛(VII)或半乙缩醛(V)用约0.1mol酸,每摩尔乙缩醛(VII)或半乙缩醛(V)用约10-0.5摩尔酸更好。类似地,可将酸与任何分离的或回收的乙缩醛(VII)或半乙缩醛(V)接触给出芳基乙二醛水合物。当含有乙缩醛(VII)和半乙缩醛(V)的反应混合物中己有足够水解的酸时,便不必向反应混合物中再加酸了。
实施本发明方法最好除使用过量的反应物本身之外不使用任何溶剂。但当使用外加溶剂时,所述溶剂可包括芳香烃,如:二甲苯、苯、甲苯等;或6-10个碳原子的烷烃。使用外加溶剂时,溶剂的用量范围由与任一反应物比较均过量至足以至少使一种或多种反应物和/或或所需产物部分溶剂化。值得注意的是化合物(I)向乙二醛水合物(IX)的转化可以很方便地在单一釜或反应容器中高产率地进行,见下文实施例1所述。
Schiff碱(XI)可以通过半乙缩醛(V)或芳基乙二醛水合物(IX)与伯胺H2NR5(X)缩合而得,其中R5按前文定义。最好反应物是等摩尔或者使较廉价的反应物(通常是胺)过量。缩合可以在适当溶剂的存在下进行,包括C-1至C-6链烷醇,如甲醇、乙醇、己醇等;前文所述的芳香烃;C-5至C-10脂肪烃;醚类,如乙醚、乙二醇二甲醚(DME)或二噁烷;四氢呋喃(THF);或上述溶剂的任意混合物。或者缩合可以很简洁地进行,其中使用过的胺(X),最好使用DME或甲苯。用来制备Schiff碱(XI)的有机溶剂一般也应作为下步反应的溶剂,即用硼烷-硫醚试剂(XII)的还原反应的溶剂,这是因为在缩合之后,在单一釜中进行还原反应更经济。缩合可以在0℃至溶剂回流温度的范围内进行,最好在大约室温下进行。
用硼烷-硫醚试剂(XII)还原Schiff碱(XI),接着用醇和酸处理可制得新的硼-芳基乙醇胺络合物(XIII),硼烷-硫醚试剂可以是如下结构:式中R13和R15可以相同或不同,可以代表C-1至C-6烷基或与硫原子一起代表含3-6个碳原子的杂环,该杂环可以含1或2个硫或氧原子;或者R13和R15与硫一起代表聚合硫代烃。R13和R15是C-1至C-6烷基为好,是乙基更好,是甲基最好。R13和R15是甲基的硼烷-硫醚试剂称为硼烷-硫化二甲基(BMS3),是市售液体。优选的是R13和R15与硫原子一起代表美国专利4,029,706和3,928,293号所述的聚合硫烃。上述专利描述了硼烷硫聚合物络合物,即三氢化硼(BH3)与不溶性交联硫烃聚合物固体粒子的络合物,更具体地说后者是含大量硫原子的、固体的、粒子的、不溶的、交联的脂肪族、环脂族或芳香族硫烃聚合物,所述硫原子是硫醚构型。聚合硼烷硫聚合物络合物的特征是硫烃聚合物中的大部分硫原子(至少80%)都与BH3分子络合。硼烷硫聚合物络合物在室温下是稳定的。其稳定性及该络合物是固体的性质使其易于使用和回收(即通过过滤回收)。硼烷硫聚合物络合物可以通过将二硼烷气体与选定的聚醚接触制得,见美国专利4,029,706号和3,928,293号中所述,其中的关于制备方法的叙述作为对比文献并入本文。硼烷硫聚合物络合物的优点是大大减弱了含硫气味,Schiff碱与非聚合硼烷-硫醚试剂的反应会产生这种气味。而且,用过的硼烷硫聚合物试剂可以很方便地用常规方法(如过滤)从反应混合物中回收。
最好选择合适的硼烷-硫醚试剂(XII)使用过的硼和有机硫化物反应物易于除去:例如,用过的甲硫醚可通过蒸馏除去,用过的硼可在加入甲醇和乙酸后用蒸馏的方法以硼酸三甲酯的形式从反应混合物中除去。最好用无水疏质子溶剂,如甲苯,DME、THF、二噁烷、二甲苯等。硼烷-硫醚试剂(XII)的用量范围从过量到约1.7摩尔[硼烷-硫醚试剂(XII)摩尔数∶1摩尔Schiff碱(XI)],以约5-2摩尔为好、约3-2摩尔更好,约2摩尔最好。还原反应的温度范围可以由室温至溶剂的回流温度,例如:DME作溶剂84℃,反应足够长时间以完成期望的反应,例如2-12小时或更长时间。在Schiff碱(XI)和硼烷-硫醚试剂(XII)反应之后,硼烷-芳基乙醇胺络合物被认为是一种聚合的形式,如下式所示其中,波浪线(
)表示硼烷-芳基乙醇胺络合物可以通过硼原子与其它硼-芳基乙醇胺络合物聚合。该聚合络合物可断开成单个单体,如通过将含聚合络合物的反应混合物与适当的C-1至C-6醇接触。硼-芳基乙醇胺络合物(XIII)-A或-B单体最好在醇的存在下向反应混合物中加入酸的方法而裂解为芳基乙醇胺(XIV)。所用的酸可以是多种有机弱酸中的任一种,如乙酸、丙酸或丁酸,优选的是乙酸。优选的醇是C-1至C-6醇,最优选的是甲醇。酸的用量范围从过量到大约4当量[酸当量数:1当量硼-芳基乙醇胺络合物(XIII)],更优选约10-4当量酸。醇的用量范围从过量到大约10当量[醇当量数:1当量硼-芳基乙醇胺络合物(XIII)],优选的是用约1000-100当量醇。
硼-芳基乙醇胺络合物(XIII)一般以瞬间中间体的形式存在于反应介质中,如络合物结构中括号所示。式中Y是-OH的硼-芳基乙醇络合物(XIII)可以用任何方便的方法回收,例如:向反应混合物中加入水,接着用与水不混溶的溶剂(如乙酸乙酯)提取。式中Y是-OR6的硼-芳基乙醇胺(XIII)可通过向反应混合物中加入式HOR6的醇(其中R6按上文定义)接着除去过量溶剂的方法回收。
加入醇和酸后,将用过的硼,如硼酸三甲酯,从反应混合物中蒸出,剩下需要的芳基乙醇胺(XIV)。蒸馏在真空中进行,温度范围是大约35℃-40℃,应蒸馏足够长的时间,例如约2-12小时或更长,以完成期望的反应。
所需的芳基乙醇胺(XIV)可以用常规方法从反应混合物中回收,例如:溶剂萃取、过滤、相分离、蒸馏、结晶等方法。最好将稀硫酸与水不混溶的有机溶剂(如2-丙醇)一起加到含芳基乙醇胺(XIV)的反应混合物中。芳基乙醇胺(XIV)以硫酸酯的形式(例如:硫酸柳丁氨醇酯)沉析出来,接着过滤,将其从反应混合物中分离出。
值得注意的是5-乙醛酰基-水杨酸甲酯水合物向沙丁胺醇硫酸酯的转变可以很方便地在单一釜或反应容器中高产率地进行,见下文实施例7所述。
下述实施例说明本发明及其实施方法,而不是对本发明总范围的限定。实施例1:
5-(二羟乙酰基)-2-羟基苯甲酰胺(10)在步骤(a)中,将6.23g(0.077mol)溴化氢气体通入处于500ml园底烧瓶中的180ml分子筛干燥过的异丙醇中。将12.5g 5-乙酰基-2-羟基苯甲酰胺(1)(MW 179.17,0.0698mol)和29.3ml DMSO(32.3g,0.413mol)加入该溶液中,得到的悬浮液在适当的搅拌下加热到约85℃,平缓蒸馏。在整个反应过程中蒸出的异丙醇循环入反应瓶中。反应过程用1H-核磁谱(NMR)和高压液相色谱(HPLG)监控。反应在三小时内完成,得到含70%的5-[双(1-甲基乙氧基)乙酰基]-2-羟基苯甲酰胺(2)和2-羟基-5-[羟基(1-甲基乙氧基]苯甲酰胺(3)的反应混合物。在步骤(b)中向反应混合物中加入1.8g波硫酸和100ml水组成的溶液。同时,加热混合物馏出异丙醇。馏出90%的异丙醇后,另加入100ml水,将混合物冷却至50℃。剩下的异丙醇在减压下(300mmHg)馏出。搅拌下冷却至室温,出现结晶。滤出白色晶体,用水充分洗涤,在60℃的鼓风烘箱中干燥16小时,得12.2g标题化合物(10)(83%产率)。实施例2:
在250ml的园底三颈瓶上装上短冷凝管、加料漏斗和温度计,在氮气氛中将12.5g(0.07mol)5-乙酰基-2-羟基-苯甲酰胺(1)、30ml DMSO和50ml正丁醇加入瓶中。将所得浆液在搅拌下加热至95℃。通过加料漏斗加入4.5g(0.056mol)HBr气体和50ml正丁醇组成的溶液,20分钟加完。在加料过程中反应温度上升至98℃反应进程用HPLC(70∶30,乙腈∶水,加2.5%乙酸,1.5ml/mm,254nm,使用ZorbaxODS 4.6mm×25cm柱)通过5-乙酰基-2-羟基苯甲酰胺(1)(保留时间(tr)=2.23分钟)的消失跟踪。20分钟后,移去热源,用100ml冰急冷该含有5-(二丁氧基乙酰基)-2-羟基苯甲酰胺(5)和5-(丁氧基羟基乙酰基)-2-羟基苯甲酰胺(6)的反应混合物搅拌3分钟。分离出所得的正丁醇层,再用100ml水洗涤,接着加入150ml水。正丁醇在32℃下真空恒沸蒸馏,直至收集到200ml馏出物。向所得溶液中加50ml异丙醇,将悬浮液搅拌10分钟,冷却至20℃。通过加料漏斗向所得浆液中加50ml浓盐酸,同时温度控制在20-25℃之间,然后在室温下搅拌反应混合物。当用HPLC探测剩下少于0.5%5-(二丁氧基乙酰基)-2-羟基苯甲酰胺(5)(tr=6.7min)时,便认为水解是完全的(9.5小时),这时用30min时间加入250ml水。将反应混合物冷却至大约5℃,搅拌20分钟,过滤,滤饼用150ml水、50ml异丙醇/水(1/1),最后用100ml水洗涤。在45℃的烘箱中干燥滤饼得12.6g标题化合物(10),浅黄色固体(产率85.5%)。实施例3:
向瓶口装有机械搅拌和回流冷凝器的2升三颈园度烧瓶中先后加入180ml DMSO和100g(0.388mol)5-(溴代乙酰基)-2-羟基苯甲酰胺(7)。搅拌反应混合物直至得到均相溶液。向反应混合物中加入1升甲醇,将混合物在氮气氛下于油浴中加热至85-90℃回流。反应进程用HPLC或1HNMR监控,当反应物消耗完毕后(大约回流22小时),反应被认为已经完全,这时,反应混合物含大约70%5-(二甲氧基乙酰基)-2-羟基苯甲酰胺和大约30%2-羟基-5-(羟基甲氧基乙酰基)苯甲酰胺。减压蒸馏出大约1升甲醇,残留物注入1.5升冰水中,5-(二甲氧基乙酰基)-2-羟基苯甲酰胺优先沉淀出来,将其滤出,用水洗涤,真空干燥得66g(产率71%)标题化合物(8)实施例4:
向瓶口装有机械搅拌和回流冷凝器的500ml三颈园底烧瓶中加入33ml DMSO和200ml分子筛干燥的异丙醇,接着加入20g(0.077mol)5-(溴乙酰基)-2-羟基苯甲酰胺,反应混合物在油浴中加热回流5小时,保持反应混合物内部温度为85-90℃。加入200ml水,常压下将异丙醇以恒沸混合物(130ml)的形式蒸出。再加130ml水,继续在减压下蒸馏,直至又馏出70ml馏出物。将反应混合物冷却,滤出灰白色晶体,用水洗涤,在45℃的鼓风烘箱中干燥过夜,得15.14g标题化合物(10)(产率92%)实施例5:
用HBr气体制备
5-乙醛酰基-水杨酸甲酯水合物
将盛有40g(0.206mol)5-乙酰基水杨酸甲酯的60ml二氯甲烷的三颈瓶浸入油浴中,加入70ml异丙醇。蒸馏除去过量的二氯甲烷。当内部温度达77℃时,向混合物中加入126ml(1.77mol)DMSO,将反应混合物加热至80℃。保持油浴温度在约85-90℃,用20分钟的时间向混合物中加入溶有HBr气体(10.85g,0.134mol或0.65当量)的40ml异丙醇溶液(放热),当加入一半HBr溶液时,搅拌混合物,蒸出二甲硫醚((CH3)2S)和异丙醇,监测馏出物体积,蒸馏出82ml溶剂后,缓慢加入异丙醇(IPA),同时保持稳定的馏出速率。当HPLC测定出反应完全后,向反应混合物中加入81ml 2.4N硫酸(H2SO4),降低温度至75℃,真空蒸馏除去残留异丙醇、整个蒸馏过程中保持70-75℃的油浴温度。总共收集到120ml馏出物后,标题化合物开始沉析。75℃下加入水同时搅拌。搅拌30分钟后,用90分钟的时间将反应混合物冷却至15℃使沉淀完全。过滤反应混合物,用水(3×60ml)洗涤滤饼,50℃下干燥16小时,得39.6g标题酮醛水合物(产率85%)。实施例6:
用HBr水溶液制备
将盛有40g(0.206mol)5-乙酰基水杨酸甲酯的6ml二氯甲烷的三颈瓶浸入油浴中,加入82ml异丙醇。蒸馏除去过量的二氯甲烷当内部温度达77℃时,向混合物中加入126ml(1.77mol或8.6当量)DMSO,将反应混合物加热至85℃-90℃。保持油浴温度在约95-100℃,用20分钟的时间向混合物中加入33ml(0.29mol或1.4当量)HBr水溶液(48%)(放热),当快加完HBr水溶液时,开始蒸馏除去甲硫醚和异丙醇。搅拌混合物并监测馏出物体积。蒸馏出82ml溶剂后,缓慢加入20ml IPA以保持稳定的馏出速率。用HPLC测定反应完全后,向反应混合物中加入70ml 2.4N硫酸(H2SO4),降低温度至75℃,真空蒸馏除去残留异丙醇总共收集到165ml馏出物后,标题化合物开始沉析。在75℃和搅拌下加入30ml乙腈(CH3CN)与70ml水的混合物。搅拌30分钟后,用90分钟的时间将反应混合物冷却至15℃使沉淀完全。过滤反应混合物,用水(3×300ml)洗涤滤饼并在50℃的鼓风烘箱中干燥16小时,得39.5g标题化合物(产率85%)。实施例7:
从5-乙醛酰基-水杨酸甲酯水合物制备沙丁胺醇
在室温下,将叔丁胺(16.2g,O.221mol)加入5-乙醛酰基水杨酸甲酯水合物(50g,0.221mol)的DME(乙二醇二乙醚,400ml)溶液中。将所得淡橙色溶液搅拌5分钟,直至形成澄清溶液。将此澄清溶液加热回流。水和DME共沸蒸馏除去。总共收集到200ml馏出物后,将反应溶液冷却至25℃。在70℃下将反应混合物徐徐加入含49ml(0.49mol)10.0M甲硼烷-二甲硫醚(BMS)的200ml DME溶液中。所得混合物进一步回流25小时。用HPLC监测,反应完全后真空蒸馏除去过量DME。含硼和芳基乙醇胺络合物的残留物随后冷却至0℃。用300ml甲醇处理残留物,得到芳基乙醇胺的硼酸甲酯。恒沸蒸馏将硼酸酯以硼酸三甲酯(B(OCH3)3)的形式除去,在反应混合物中剩下所需的芳基乙醇胺。再加入300ml甲醇和乙酸(85ml)以确保能完全除去硼酸三甲酯,真空蒸馏至接近干燥。含无硼芳基乙醇胺的残留物冷却至25℃,再先后加入浓硫酸(10.4g,0.221mol)的水(64ml)溶液和570ml异丙醇。沙丁胺醇以白色固体析出。在室温下将反应混合物搅拌12小时、在0℃搅拌30分钟后滤出柳丁氨醇硫酸酯,用异丙醇(2×50ml)洗涤,50℃下干燥12小时,得49.75g标题化合物(产率78%)。
Claims (6)
2.权利要求1的方法,其中芳基乙醇胺(XIV)是通过将用过的硼从反应混合物中蒸除后而回收的。
6.权利要求5的方法,其特征在于:乙缩醛(VII)或半乙缩醛(V)是通过将式(II)化合物与亚砜和醇ROH接触制得的,其中R如权利要求4中的定义,式(II)如下:式中,Ar’和R3如权利要求3中的定义,L是离去基,或者将式(I)化合物与卤化剂、亚砜和上文定义的醇ROH接触而制得,式(I)如下:其中Ar’和R3如权利要求3中的定义。
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US5545745A (en) * | 1994-05-23 | 1996-08-13 | Sepracor, Inc. | Enantioselective preparation of optically pure albuterol |
US5399765A (en) * | 1994-05-23 | 1995-03-21 | Sepracor, Inc. | Enantioselective preparation of optically pure albuterol |
WO2005113481A1 (en) | 2004-05-20 | 2005-12-01 | Teva Pharmaceutical Fine Chemicals S.R.L. | Preparation of levalbuterol hydrochloride |
US8070044B1 (en) * | 2010-12-02 | 2011-12-06 | Rohm And Haas Electronic Materials Llc | Polyamine flux composition and method of soldering |
US8070045B1 (en) * | 2010-12-02 | 2011-12-06 | Rohm And Haas Electronic Materials Llc | Curable amine flux composition and method of soldering |
CN107110573B (zh) | 2014-11-25 | 2019-12-24 | B医疗系统有限公司 | 冷却装置 |
CN105001100A (zh) * | 2015-06-11 | 2015-10-28 | 山西云鹏制药有限公司 | 一种精制硫酸沙丁胺醇的方法 |
CN109072171A (zh) | 2016-05-12 | 2018-12-21 | 三得利控股株式会社 | 含有l-羟脯氨酸的解脂耶氏酵母的菌体或菌体培养物或者它们的提取物及其用途以及l-羟脯氨酸的制造方法 |
CN108863819B (zh) * | 2018-06-26 | 2021-01-15 | 南京逐陆医药科技有限公司 | 一种游离的消旋沙丁胺醇的制备方法 |
CN110734382B (zh) * | 2019-10-09 | 2024-02-20 | 苏州弘森药业股份有限公司 | 一种合成特布他林的方法 |
CN112341373B (zh) * | 2020-11-30 | 2022-04-08 | 山东嘉成医药科技有限公司 | 一种酞丁安的制备方法 |
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