CN1320114A - 新颖的6－(4－苯基丁氧基)己胺衍生物和获得沙美特罗的方法 - Google Patents
新颖的6－(4－苯基丁氧基)己胺衍生物和获得沙美特罗的方法 Download PDFInfo
- Publication number
- CN1320114A CN1320114A CN99811432A CN99811432A CN1320114A CN 1320114 A CN1320114 A CN 1320114A CN 99811432 A CN99811432 A CN 99811432A CN 99811432 A CN99811432 A CN 99811432A CN 1320114 A CN1320114 A CN 1320114A
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- CN
- China
- Prior art keywords
- compound
- alkoxy carbonyl
- benzyl
- acid
- hexylamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 32
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229960004017 salmeterol Drugs 0.000 title claims abstract description 17
- GNSOSZKMHANCMP-UHFFFAOYSA-N 6-(4-phenylbutoxy)hexan-1-amine Chemical class NCCCCCCOCCCCC1=CC=CC=C1 GNSOSZKMHANCMP-UHFFFAOYSA-N 0.000 title abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- -1 cyclic acetals Chemical class 0.000 claims abstract description 17
- 125000002252 acyl group Chemical group 0.000 claims abstract description 16
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 16
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims abstract description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 16
- 239000012442 inert solvent Substances 0.000 claims abstract description 15
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 10
- 150000002902 organometallic compounds Chemical class 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 21
- 239000000460 chlorine Substances 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 230000000903 blocking effect Effects 0.000 claims description 11
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 150000002576 ketones Chemical group 0.000 claims description 5
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical class CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 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 claims description 4
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- 238000003776 cleavage reaction Methods 0.000 claims description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- 229960002317 succinimide Drugs 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 2
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 150000004982 aromatic amines Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims 3
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims 1
- 239000000010 aprotic solvent Substances 0.000 claims 1
- PIZLBWGMERQCOC-UHFFFAOYSA-N dibenzyl carbonate Chemical compound C=1C=CC=CC=1COC(=O)OCC1=CC=CC=C1 PIZLBWGMERQCOC-UHFFFAOYSA-N 0.000 claims 1
- 229940043279 diisopropylamine Drugs 0.000 claims 1
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 claims 1
- 125000001033 ether group Chemical group 0.000 claims 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 16
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 10
- OCKPCBLVNKHBMX-UHFFFAOYSA-N butylbenzene Chemical compound CCCCC1=CC=CC=C1 OCKPCBLVNKHBMX-UHFFFAOYSA-N 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 238000004821 distillation Methods 0.000 description 5
- 150000002118 epoxides Chemical class 0.000 description 5
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 5
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- NHZPWFUYBUSPHT-UHFFFAOYSA-N benzyl n-(2,2-dimethoxyethyl)-n-[6-(4-phenylbutoxy)hexyl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)N(CC(OC)OC)CCCCCCOCCCCC1=CC=CC=C1 NHZPWFUYBUSPHT-UHFFFAOYSA-N 0.000 description 3
- WHDNTMUSIDMLHG-UHFFFAOYSA-N benzyl n-(2-oxoethyl)-n-[6-(4-phenylbutoxy)hexyl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)N(CC=O)CCCCCCOCCCCC1=CC=CC=C1 WHDNTMUSIDMLHG-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000010908 decantation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- UTTFDCWJAKGSQZ-UHFFFAOYSA-N n-(2,2-diethoxyethyl)-6-(4-phenylbutoxy)hexan-1-amine Chemical compound CCOC(OCC)CNCCCCCCOCCCCC1=CC=CC=C1 UTTFDCWJAKGSQZ-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- OYCVIHNVPFDNLD-UHFFFAOYSA-N 1-(2,2-dimethyl-4h-1,3-benzodioxin-6-yl)-2-[6-(4-phenylbutoxy)hexylamino]ethanol Chemical compound C=1C=C2OC(C)(C)OCC2=CC=1C(O)CNCCCCCCOCCCCC1=CC=CC=C1 OYCVIHNVPFDNLD-UHFFFAOYSA-N 0.000 description 2
- LILXDMFJXYAKMK-UHFFFAOYSA-N 2-bromo-1,1-diethoxyethane Chemical compound CCOC(CBr)OCC LILXDMFJXYAKMK-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- SXDOZUBVNVZPCM-UHFFFAOYSA-N benzyl n-(2,2-diethoxyethyl)-n-[6-(4-phenylbutoxy)hexyl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)N(CC(OCC)OCC)CCCCCCOCCCCC1=CC=CC=C1 SXDOZUBVNVZPCM-UHFFFAOYSA-N 0.000 description 2
- ZMYLKHCNPQKIIG-UHFFFAOYSA-N benzyl n-[2-(2,2-dimethyl-4h-1,3-benzodioxin-6-yl)-2-hydroxyethyl]-n-[6-(4-phenylbutoxy)hexyl]carbamate Chemical compound C=1C=C2OC(C)(C)OCC2=CC=1C(O)CN(C(=O)OCC=1C=CC=CC=1)CCCCCCOCCCCC1=CC=CC=C1 ZMYLKHCNPQKIIG-UHFFFAOYSA-N 0.000 description 2
- 150000003944 halohydrins Chemical class 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- JWLIKZBRVQRFNF-UHFFFAOYSA-N n-benzyl-6-(4-phenylbutoxy)hexan-1-amine Chemical compound C=1C=CC=CC=1CNCCCCCCOCCCCC1=CC=CC=C1 JWLIKZBRVQRFNF-UHFFFAOYSA-N 0.000 description 2
- OUAYLCUKLZVMPS-UHFFFAOYSA-N n-benzyl-6-(4-phenylbutoxy)hexan-1-amine;hydrobromide Chemical compound Br.C=1C=CC=CC=1CNCCCCCCOCCCCC1=CC=CC=C1 OUAYLCUKLZVMPS-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- LDZLXQFDGRCELX-UHFFFAOYSA-N 4-phenylbutan-1-ol Chemical class OCCCCC1=CC=CC=C1 LDZLXQFDGRCELX-UHFFFAOYSA-N 0.000 description 1
- FEMDDCVZFBLCLI-UHFFFAOYSA-N C(C)NCCCCC(C)OCCCCC1=CC=CC=C1 Chemical compound C(C)NCCCCC(C)OCCCCC1=CC=CC=C1 FEMDDCVZFBLCLI-UHFFFAOYSA-N 0.000 description 1
- DSAPOVSCQLPSQC-UHFFFAOYSA-N C(C1=CC=CC=C1)N(CCCCCC(OCCCCC1=CC=CC=C1)(OCC)OCC)CC Chemical compound C(C1=CC=CC=C1)N(CCCCCC(OCCCCC1=CC=CC=C1)(OCC)OCC)CC DSAPOVSCQLPSQC-UHFFFAOYSA-N 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- LUNDKKXHGUCOSP-UHFFFAOYSA-N N-(4-phenylbutoxy)hexan-1-amine Chemical class C1(=CC=CC=C1)CCCCONCCCCCC LUNDKKXHGUCOSP-UHFFFAOYSA-N 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- UTZLYIFQYGQUPA-UHFFFAOYSA-N benzyl 2,5-dioxopyrrolidine-1-carboxylate Chemical compound O=C1CCC(=O)N1C(=O)OCC1=CC=CC=C1 UTZLYIFQYGQUPA-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229940124630 bronchodilator Drugs 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
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 125000006182 dimethyl benzyl group Chemical group 0.000 description 1
- SNQXJPARXFUULZ-UHFFFAOYSA-N dioxolane Chemical compound C1COOC1 SNQXJPARXFUULZ-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
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- 150000002828 nitro derivatives Chemical class 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003786 synthesis reaction 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
- 230000009466 transformation Effects 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
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Abstract
本发明涉及新颖的通式(Ⅰ)的6－(4－苯基丁氧基)己胺衍生物:其中:－.R1是CHO或CHOR3OR4,其中的R3和R4独立地是C1－C6烷基、芳烷基,或者它们形成5或6元环状缩醛;和－.R2是H、苄基或烷氧基羰基、芳氧基羰基、芳烷氧基羰基或酰基;及其获得方法。本发明也涉及获得沙美特罗或其药学上可接受的盐的新方法,其特征在于在惰性溶剂中,在低温下,进行通式(13)有机金属化合物与通式(Ⅰ)合成中间体的反应,其中R1是CHO,R2是烷氧基羰基、芳氧基羰基、芳烷氧基羰基或酰基。
Description
发明领域
本发明涉及新颖的通式(Ⅰ)的6-(4-苯基丁氧基)己胺衍生物及其获得方法。本发明还涉及从所述新颖的衍生物获得沙美特罗的方法。
新颖的6-(4-苯基丁氧基)己胺衍生物是由通式(Ⅰ)所代表的：
其中：-R1是CHO或CHOR3OR4，其中的R3和R4独立地是C1-C6烷基、芳烷基，或者它们形成5或6元环状缩醛；和-R2是H、苄基或烷氧基羰基、芳氧基羰基、芳烷氧基羰基或酰基。
所述衍生物可用作沙美特罗合成中的中间体。
发明背景
沙美特罗在治疗领域、具体在哮喘治疗中的用途是已知的，它具有支气管扩张剂的性质。在描述沙美特罗的获得方法的文献中可以找到若干篇参考文献。
法国专利FR 2545482公开了下列获得沙美特罗的方法：
·将通式1的胺用通式2的烷化剂进行烷基化：其中的R3、R5和R6各自代表氢原子或保护基团，L代表离去基团，例如氯、溴、碘、甲磺酰氧基或对甲苯磺酰氧基；进一步除去最后存在的保护基团。
或者，烷基化作用可以通过醛3与胺1的还原性胺化加以进行(R3=H或在反应条件下可转化为H的基团)。·通式4化合物的还原：
其中R5是氢原子或保护基团，X、X1、X2、X3和X4原子团中至少有一个是可还原的基团；进一步除去最后存在的保护基团。
适合的可还原基团是：X:COOH或COOR7(其中的R7是H、烷基、芳基或芳烷基)，和CHO。X1:C=O。X2:CH2NY(其中的Y通过氢化作用可转化为H)、CH=N和CONH。X3:CO(CH2)5、CH=CH-(CH2)4、CH2CH=CH(CH2)3等。X2-X3:CH2N=CH(CH2)5。X4:CH=CH(CH2)2、CH2CH=CHCH2等。
·环氧化物5或卤代醇6与胺7的反应：其中的Y1是H或通过氢化作用可转化为氢的基团；进一步除去最后存在的保护基团。
另一方面，世界专利WO 9824753公开了胺10的不对称合成及其在旋光活性沙美特罗合成中的应用。
硝基甲烷向醛8的不对称加成提供了旋光活性的硝基衍生物9，后者的还原生成胺10。
其中的R1和R2是适合的保护基团。
不过，现有技术所述这些操作存在一些缺点。起始化合物是高度官能化的小分子量中间体，因此其获得方法涉及颇为复杂的反应，特别是在工业化水平上，这主要是由于生成了所不需要的副产物，而且副产物降低了反应收率。
例如，所述化合物1的获得方法(GB 1200886)包括很多步骤，其中有溴化反应和氯甲基化作用，继而可能分别生成二溴化衍生物和异构体。
另一方面，卤代醇6是稳定性非常弱的化合物，由于在碱性条件下有转化为环氧化物5的趋势，因此是难以分离的。获得环氧化物的反应既非易事，环氧化物5的使用也存在另外的缺点，即沙美特罗的获得是通过环氧化物的开环得以实现的，该反应是不太可取的，因为得到了很多副产物(Randall等《四面体快报》(1986),2451-2454)。
本发明提供了新颖的6-(4-苯基丁氧基)己胺衍生物，它们可用作获得沙美特罗的新制备方法的起始化合物。借助简单的反应，例如醇或胺的水解或烷化，所述新颖的衍生物易于从工业上可得到的化合物获得。
发明的说明
本发明涉及新颖的通式(Ⅰ)的6-(4-苯基丁氧基)己胺衍生物：其中：-R1是CHO或CHOR3OR4，其中的R3和R4独立地是C1-C6烷基、芳烷基，或者它们形成5或6元环状缩醛；和-R2是H、苄基或烷氧基羰基、芳氧基羰基、芳烷氧基羰基或酰基。
若R1是CHO，则R2优选为烷氧基羰基、芳氧基羰基、芳烷氧基羰基或酰基。
优选地，R2是叔丁氧基羰基、苄氧基羰基或乙氧基羰基、乙酰基、苯甲酰基或三氟乙酰基；R3和R4独立地是甲基、乙基、苄基，或者它们形成1,2-二氧戊环或1,3-二噁烷。
本发明的目的也是所述6-(4-苯基丁氧基)己胺衍生物的获得方法。所述方法概述在下列流程Ⅰ中。 其中：
-R3和R4具有上述相同含义；
-Z1和Z2各自是不同的，与L或NHR2相同，L是离去基团，例如氯、溴、碘、甲磺酰氧基或对甲苯磺酰氧基，优选为溴；R2是H或苄基。
所述通式(Ⅰ)的6-(4-苯基丁氧基)己胺衍生物的获得方法按照下列步骤进行：
(ⅰ)在惰性溶剂中，在有机或无机碱的存在下，在25℃至100℃的温度范围内，优选为80℃至100℃，式(11)化合物与式(12)化合物进行胺的烷基化反应，得到式(Ⅰ)化合物，其中R1=CHOR3OR4,R2=H或苄基：其中：
-R3和R4独立地是C1-C6烷基、芳烷基，或者它们形成5或6元环状缩醛；
-Z1和Z2各自是不同的，与L或NHR2相同，L是离去基团，例如氯、溴、碘、甲磺酰氧基或对甲苯磺酰氧基，优选为溴；R2是H或苄基；
得到通式(Ⅰ)化合物：
其中R1=CHOR3OR4,R3=H或苄基。
惰性溶剂可以是高沸点的非质子惰性溶剂，例如N,N-二甲基甲酰胺、N-甲基吡咯烷酮或二甲基亚砜，卤代溶剂，例如二氯甲烷或氯仿，醚，例如四氢呋喃或二噁烷，或芳烃，例如苯、甲苯或二甲苯。
有机碱可以是叔胺，例如三乙胺或二异丙基乙胺，芳胺，例如N,N-二甲基苯胺，或杂环胺，例如吡啶。无机碱可以是碳酸盐或碳酸氢盐。
(ⅱ)若R2是苄基，则在氢化之前将步骤(ⅰ)所得化合物(Ⅰ)用适合的试剂保护起来，得到其中R1=CHOR3OR4、R2=烷氧基羰基、芳氧基羰基、芳烷氧基羰基或酰基的式(Ⅰ)化合物。
提到式(Ⅰ)化合物(R1=CHCOR3OR4,R2=烷氧基羰基、芳氧基羰基、芳烷氧基羰基或酰基)，必须对R2、R3和R4加以选择，以便应当存在这样的可能性，在不影响R2的前提下除去R3和R4。
用烷氧基羰基、芳氧基羰基和芳烷氧基羰基保护氨基是通过其中R1=CHOR3OR4、R2=H的式(Ⅰ)化合物与下列化合物的反应加以进行的：氯甲酸酯，例如氯甲酸乙酯、氯甲酸叔丁酯或氯甲酸苄基酯；二碳酸酯，例如二碳酸二叔丁酯或二碳酸二苄酯；或特殊的试剂，例如N-(苄氧基羰基)琥珀酰亚胺。用酰基保护氨基是利用常规试剂进行的，例如酰氯或酸酐。
保护反应是这样完成的：在惰性溶剂中，最终在有机或无机碱的存在下，在0℃至50℃的温度范围内。
惰性溶剂可以是酮，例如丙酮；卤代衍生物，例如二氯甲烷或氯仿；酯，例如乙酸乙酯；醚，例如四氢呋喃或二噁烷；或高沸点溶剂，例如N,N-二甲基乙酰胺或N,N-二甲基甲酰胺。
用于该反应的碱可以与上述步骤(ⅰ)所提到的碱相同。
(ⅲ)步骤(ⅱ)所得式(Ⅰ)化合物通过缩醛基的水解作用、缩醛转移作用或氢解作用转化为相应的醛，应注意在选择程序时，要考虑与基团R2的相容性。该转化作用得到其中R1=CHO、R2=烷氧基羰基、芳氧基羰基、芳烷氧基羰基或酰基的式(Ⅰ)化合物。
水解是这样进行的：在有机溶剂中，在至少为化学计算量的水和有机或无机酸的存在下，酸例如盐酸、硫酸、甲磺酸、对甲苯磺酸或三氟乙酸，优选在15℃至50℃的温度范围内。
溶剂可以是酮，例如丙酮，醇，例如甲醇、乙醇或异丙醇，酰胺，例如N,N-二甲基甲酰胺或N,N-二甲基乙酰胺等。
缩醛转移作用是这样实现的：在酮的存在下，例如丙酮，此时它也充当溶剂，并且在有机或无机酸的存在下，例如甲磺酸、对甲苯磺酸、氯化氢或硫酸，优选在15℃至50℃的温度范围内。
氢解作用是这样进行的：在典型的脱苄基作用条件下，在催化剂的存在下，在惰性溶剂中，在10℃至50℃的温度范围内。催化剂优选为吸附在炭上的钯。
溶剂可以是C1至C4脂族醇，例如甲醇、乙醇、异丙醇或丁醇，酯，例如乙酸乙酯，或醚，例如四氢呋喃。
反应温度优选在15℃与25℃之间。
按照上述程序所得式(Ⅰ)化合物可用作沙美特罗合成中的中间体。
本发明的目的也是从通式(Ⅰ)化合物获得沙美特罗或其药学上可接受的盐的方法。所述操作的特征在于使通式(13)的有机金属化合物与通式(Ⅰ)化合物进行反应：
其中：
-R3和R4独立地是C1-C6烷基、芳烷基或者它们形成1,3-二氧戊环类型的环状缩醛；
-M是含有金属的基团，例如锂、镁或铜，优选地，M是Li、MgBr或MgCl；和
-R1是CHO,R2是烷氧基羰基、芳氧基羰基、芳烷氧基羰基或酰基。
优选地，R3和R4独立地是甲基、乙基或苄基，或者它们形成环状缩醛，例如2,2-二甲基-1,3-二噁烷或2-甲基-1,3-二噁烷。
优选地，R2是叔丁氧基羰基、苄氧基羰基、乙氧基羰基、乙酰基、苯甲酰基或三氟乙酰基。
该反应是这样进行的：在醚样惰性溶剂中，优选为乙醚或四氢呋喃，在低温下，优选从-40℃至40℃，更优选从-40℃至10℃。式13有机金属化合物可以按照文献所述方法得到(Effenberger,F.；Jger,J.《有机化学杂志》(1977),62,3867-3873.Seebach,D.,Neumann,H.，《化学报告》Chem.Ber.(1974),107,874-853)。
如流程Ⅱ所示，化合物(Ⅰ)与有机金属化合物13的反应在进一步的水解后得到醇14，随后除去保护基团R2、R3和R4，得到沙美特罗。其中：- R3和R4独立地是C1-C6烷基、芳烷基，或者它们形成1,3-二噁烷类型的环状缩醛，例如2,2-二甲基-1,3-二噁烷或2-甲基-1,3-二噁烷；和- R2是烷氧基羰基、芳氧基羰基、芳烷氧基羰基或酰基。
醇14的分离涉及反应粗产物在酸性介质中的水性处理。
从式15化合物中除去前述定义的保护基团R2、R3和R4，得到沙美特罗。该阶段可以分一步或几步进行。反应条件取决于不同保护基团的性质，可以按照常规方法，通过酸或碱水解、或氢解进行反应(例如参见：《有机合成中的保护基团》第2版，John Wiley&Sons Ed.,Inc.1991)。
按照常规程序，沙美特罗可以转化为它的药学上可接受的加成盐，例如盐酸盐、富马酸盐、马来酸盐或xynaphoate。
实验
实施例1:4-(6-溴己氧基)丁基苯
向5ml(32.75 mmol)4-苯基丁醇与10.1ml(65.66 mmol)1,6-二溴己烷的混合物中加入8g(121.2 mmol)KOH粉末和1.112g(3.28 mmol)四丁基硫酸氢铵。悬浮液在室温下搅拌20 hr后，过滤，将滤液溶于50 ml Et2O。所得溶液用水洗涤，在无水Na2SO4上干燥，蒸发Et2O，残余物减压(0.1 mmHg)中蒸馏，在100℃下收集第一部分，为起始产物的混合物，在150℃下收集第二部分，为4-(6-溴己氧基)丁基苯，重7.60g(74.4％)。NMR1H(CDCl3),δ(ppm):1.3-2.0(m,12H),2.6(t,2H,-CH2-C6H5),3.4(m,6H,-CH2-O-CH2-+-CH2Br),7.1-7.4(m,5H,-C6H5).实施例2：氢溴酸N-二甲氧基乙基-6-(4-苯基丁氧基)己胺
在回流下，向8.7ml(79.85 mmol)氨基乙醛二甲基缩醛的60ml甲苯溶液中滴加10g(31.94 mmol)4-(6-溴己氧基)丁基苯的40ml甲苯溶液。反应混合物在回流下保持4hr后，在减压下蒸去甲苯，向其中加入50ml CH2Cl2。所得溶液与用20ml H2O稀释过的20ml 47％HBr一起搅拌15min。滗析反应混合物，蒸发CH2Cl2相至于所得粗产物用Et2O研磨，过滤，由此得到4.31g(32.3％)氢溴酸N-二甲氧基乙基-6-(4-苯基丁氧基)己胺。NMR1H(CDCl3),δ(ppm):1.3(m,4H),1.6(m,6H),1.9(m,2H),2.6(t,2H,-CH2-C6H5),3.0(m,4H,-CH2-NH-CH2-),3.4(c,4H,-CH2-O-CH2-),3.45(s,6H,2*CH3),4.95(t,1H,-CH(OCH3)2),7.1-7.3(m,5H,-C6H5).实施例3：氢溴酸N-苄基-6-(4-苯基丁氧基)己胺
将包含7.34g(25.53 mmol)4-(6-溴己氧基)丁基苯与10.3ml(94.30 mmol)苄胺的混合物在125℃下加热8hr。蒸馏除去过量的苄胺，将残余物溶于30ml甲乙酮。向加热至50℃的所得溶液中加入7.43ml47％HBr的50 ml H2O溶液，然后搅拌15 min，滗析。有机相蒸发至干，所得残余物用Et2O研磨，过滤，得到5.9g(59.8％)氢溴酸N-苄基-6-(4-苯基丁氧基)己胺。NMR1H(CDCl3),δ(ppm):1.2-2.0(m,12H),2.6(t,2H,-CH2-C6H5),2.8(m,2H,-NH-CH2-CH2-),3.35(m,4H,-CH2-O-CH2-),4.05(t,2H,-NH-CH2-C6H5),7.1-7.7(m,10H,2*-C6H5),9.35(s,2H).IR(KBr,cm-1):2930,2830,2785,1430,1105,750,690.实施例4:6-(4-苯基丁氧基)己胺.
将4.02g(11.86 mmol)N-苄基-6-(4-苯基丁氧基)己胺的40mlEtOH溶液在室温和大气压下用0.4g 5％Pd/C氢化。当已经吸收300mlH2后，将混合物在decalite上过滤，滤液浓缩，得到2.89g(97.9％)6-(4-苯基丁氧基)己胺，为油状。NMR1H(CDCl3),δ(ppm):1.2-1.8(m,12H),2.65(c,4H,-CH2-C6H5+-CH2-NH2),3.4(c,4H,-CH2-O-CH2-),7.1-7.4(m,5H,-C6H5).实施例5:N-苄基-6-N-二乙氧基乙基-6-(4-苯基丁氧基)己胺。
向25ml DMF中加入5g(11.90 mmol)N-苄基-6-(4-苯基丁氧基)己胺、1.85ml(11.93mmol)溴乙醛二乙基缩醛和3.29g(23.84 mmol)K2CO3。悬浮液在80℃下加热22 hr，此后在减压下蒸馏除去DMF。向粗产物加入30ml CH2Cl3，混合物用30ml H2O洗涤。滗析CH2Cl2后，在无水Na2SO4上干燥，浓缩至干，通过硅胶柱层析法纯化(梯度CH2Cl2至CH2Cl2/AcOEt 9∶1)，得到2.25g(51％)N-苄基-N-二乙氧基乙基-6-(4-苯基丁氧基)己胺，为油状。NMR1H(CDCl3),δ(ppm):1.2(t,6H,2*-CH3),1.2-1.8(m,12H),2.45(t,2H,-CH2-C6H5),2.6(m,4H,-CH2-N-CH2-),3.3-3.7(m,8H.-CH2-O-CH2-+2*-CH2-CH3),4.55(t,1H,-CH(OCH2CH3)2),7.1-7.4(m,10H,2*-C6H5).实施例6:N-二乙氧基乙基-5-(4-苯基丁氧基)己胺
向2.77g(11.12 mmol)6-(4-苯基丁氧基)己胺的20ml DMF溶液中加入1.54g(11.16mmol)K2CO3和1,68g(11,17 mmol)溴乙醛二乙基缩醛。混合物在80℃下保持20 hr后，在减压下蒸馏除去DMF，将所得粗产物的30 ml CH2Cl2溶液用30 ml H2O洗涤。CH2Cl2相在无水Na2SO4上干燥，浓缩至干，残余物通过硅胶柱层析法纯化(梯度CH2Cl2/AcOEt1∶1至AcOEt)由此得到1.73g(42.6％)N-二乙氧基乙基-6-(4-苯基丁氧基)己胺，为油状。
或者，通过3.24g(7.53 mmol)N-苄基-二乙氧基乙基-6-(4-苯基丁氧基)己胺与0.32g 5％Pd/C在35 ml EtOH中的混合物在室温和大气压下的氢化作用，也得到2.39g(90.3％)N-二乙氧基乙基-6-(4-苯基丁氧基)己胺。NMR1H(CDCl3),δ(ppm):1.2(t,6H,2*CH3),1.25-1.8(m,12H),2.6(c,2H,-CH2-C6H5),2.7(d,1H,-NH-),3.4(c,4H,2*-OCH2CH3),3.5-3.8(m,4H,-CH2-O-CH2-),4.6(t,1H,-CH(OCH2CH3)2),7.1-7.3(m,5H,-C6H5).实施例7:N-苄氧基羰基-N-二甲氧基乙基-6-(4-苯基丁氧基)己胺.
向4.15g(9.93 mmol)氢溴酸N-二甲氧基乙基-6-(4-苯基丁氧基)己胺的40ml丙酮溶液中加入1.4ml三乙胺和2.41 g(10,71 mmol)N-(苄氧基羰基氧基)琥珀酰亚胺。混合物在室温下搅拌2 hr后，蒸发除去丙酮，向其中加入40ml Et2O。所得混合物用40ml H2O洗涤三次。相分离之后，醚相在无水Na2SO4上干燥，蒸发至于，得到4.46g(95.3％)N-苄氧基羰基-N-二甲氧基乙基-6-(4-苯基丁氧基)己胺，为油状。NMR1H(CDCl3),δ(ppm):1.2-1.8(m,12H),2.65(t,2H,-CH2-C6H5),3.2-3.5(m,14H,2*CH3+-CH2-N-CH2-+-CH2-O-CH2-),4.3-4.6(dt,1H,-CH(OCH3)2),5.15(s,2H,-O-CH2-C6H5),7.1-7.4(m,10H,2*C6H5).实施例8:N-苄氧基羰基-N-二乙氧基乙基-6-(苯基丁氧基)己胺
向2.39g(6.55 mmol)N-二乙氧基乙基-6-(4-苯基丁氧基)己胺的25 ml丙酮溶液中加入1.59g(7.07 mmol)N-(苄氧基羰基氧基)琥珀酰亚胺。混合物在室温下搅拌2 hr后，蒸发除去丙酮，向其中加入30 ml AcOEt。所得混合物用30 ml H2O洗涤三次。相分离之后，AcOEt相在无水Na2SO4上干燥，蒸发至干，由此得到3.28g(99％)N-苄氧基羰基-N-二乙氧基乙基-6-(苯基丁氧基)己胺，为油状。NMR1H(CDCl3),δ(ppm):1.1-1.8(m,18H),2.65(t,2H,-CH2-C6H5),3.3-3.8(m,12H,2*-O-CH2CH3+-CH2-N-CH2-+-CH2-O-CH2-),4.4-4.7(dt,1H,-CH(OCH2CH3)2),5.15(s,2H,-O-CH2-C6H5),7.1-7.4(m,10H,2*－C6H5)。实施例9:N-苄氧基羰基-N-(2-氧代乙基)-6-(4-苯基丁氧基)己胺
向3.89g(8.26 mmol)N-苄氧基羰基-N-二甲氧基乙基-6-(4-苯基丁氧基)己胺的50 ml丙酮溶液中加入对甲苯磺酸一水合物(0.786g4.13 mmol)。溶液在室温下保持4 hr后，蒸发除去丙酮，将粗产物溶于50 ml Et2O，用50 ml H2O洗涤一次。分离Et2O相，在无水Na2SO4上干燥，蒸发至干，所得残余物通过硅胶柱层析法纯化(梯度CH2Cl2至CH2Cl2/AcOEt 4∶1)，由此得到2.66g(75.7％)N-苄氧基羰基-N-(2-氧代乙基)-6-(4-苯基丁氧基)己胺，为油状。
或者，按照上述方法，从2.70g(5.4l mmol)N-苄氧基羰基-N-二乙氧基乙基-6-(4-苯基丁氧基)己胺也可以得到1.66g(72.3％)N-苄氧基羰基-N-(2-氧代乙基)-6-(4-苯基丁氧基)己胺。NMR1H(CDCl3),δ(ppm):1.2-1.8(m,12H),2.65(t,2H,-CH2-C6H5),3.4(m,6H,-CH2-N＜,-CH2-O-CH2-),4.0(d,2H,-O-CH2-C6H5),5.15(d,2H,-CH2-CHO),7.1-7.4(m,10H,2*C6H5),9.6(d,1H,-CHO).实施例10:2,2-二甲基-6-溴苯并-1,3-二噁烷
向冷却至0℃的5.0g(24.63 mmol)3-溴-6-羟基苯甲醇的30ml丙酮溶液中滴加1.15g(8.62 mmol)AlCl3的20 ml Et2O溶液。所得混合物在室温下保持1 hr，此后冷却至0℃，向其中加入预先冷却至5℃的50ml 10％NaOH水溶液。分离Et2O相，用20 ml H2O洗涤两次，在无水Na2SO4上干燥，蒸发至干，在减压下蒸馏，得到4.85g(81％)2,2-二甲基-6-溴苯并-1,3-二噁烷，为油状。NMR1H(CDCl3),δ(ppm):1.5(s,6H,2*CH3),4.8(s,2H,-O-CH2-),6.7(d,1H),7.1(d,2H),7.25(dd,1H).
实施例11:N-[2-(2,2-二甲基-4H-苯并[1,3]二噁烯-6-基)-2-羟基乙基]-N-苄氧基羰基-6-(4-苯基丁氧基)己胺
向0.166g(6.83 mmol)Mg的1 ml THF溶液中滴加几滴1.51g(6.21 mmol)2,2-二甲基-6-溴苯并-1,3-二噁烷的20 ml溶液和催化量的1,2-二溴乙烷。一旦反应开始，加入剩余的2,2-二甲基-6-溴苯并-1,3-二噁烷溶液，同时保持温度在40℃。加入一经完成(15 min)，进一步在40℃下保持反应30分钟。混合物然后冷却至-7℃，向其中加入2.64g(6.21 mmol)N-苄氧基羰基-N-2-氧代乙基-6-(4-苯基丁氧基)己胺的5 ml THF溶液。在0℃下保持反应1 hr，反应混合物的温度升至室温，加入30 ml饱和NH4Cl溶液，混合物搅拌15 min。最后，加入30 ml AcOEt，分离EtOAc相，用30 ml H2O洗涤，在无水Na2SO4上干燥，浓缩至干，残余物通过硅胶柱层析法纯化(梯度CH2Cl2至CH2Cl2/EtOAc 4∶1)，得到1.50g(40.9％)N-[2-(2,2-二甲基-4H-苯并[1,3]二噁烯-6-基)-2-羟基乙基]-N-苄氧基羰基-6-(4-苯基丁氧基)己胺。NMR1H(CDCl3),δ(ppm):1.4-1.8(m,18H),2.65(t,2H,-CH2-C6H5),3.1-3.6(m,9H),4.8(m,3H,-CH(OH)-,-CH2-O-),5.15(s,2H,-O-CH2-C6H5),6.8(d,1H),7.0-7.4(m,12H).IR(KBr,cm-1):3430,2930,2860,1695,1500,1265,1120.实施例12:N-[2-(2,2-二甲基-4H-苯并[1,3]二噁烯-6-基)-2-羟基乙基]-6-(4-苯基丁氧基)己胺
将0.9g(1.53 mmol)N-[2-(2,2-二甲基-4H-苯并[1,3]二噁烯-6-基)-2-羟基乙基]-N-苄氧基羰基-6-(4-苯基丁氧基)己胺在大气压和室温下用0.1g 5％Pd/C在30 ml MeOH中氢化。一旦已经吸收50mlH2后，在decalite上过滤除去催化剂，滤液浓缩至干，得到0.69 g(99％)N-[2-(2,2-二甲基-4H-苯并[1,3]二噁烯-6-基)-2-羟基乙基]-6-(4-苯基丁氧基)己胺。NMR1H(CDCl3),δ(ppm):1.3-2.0(m,12H),1.55(s,6H,2*CH3),2.6(t,2H,-CH2-C6H5),2.9-3.2(m,4H,-CH2-N-CH2-),3.35(c,4H,-CH2-O-CH2-),4.8(s,2H,-CH2-O-),5.25(dd,1H,-CH(OH)-),6.75(d,1H),7.05(d,1H),7.1-7.3(m,6H).IR(KBr,cm-1):3355,2930,2855,1630,1595,1490,1260,1120.实施例13:4-羟基-a1-[[[6-(4-苯基丁氧基)己基]氨基]甲基]-1,3-苯二甲醇
向0.6g(1.32 mmol)[2-(2,2-二甲基-4H-苯并[1,3]二噁烯-6-基)-2-羟基乙基]-6-[4-苯基丁氧基]己胺在20 ml 1∶1 H2O/MeOH混合物中的溶液中加入0.15 ml(1,75 mmol)35％HCl。反应物在室温下搅拌48 hr后，在减压下蒸发除去MeOH。所得水性混合物用20 ml CH2Cl2萃取。有机相按顺序用20 ml饱和NaHCO3溶液和20 ml H2O洗涤，在无水Na2SO4上干燥，蒸发至干，得到0.24g(43.9％)2-羟甲基-4-{1-羟基-2-[6-(4-苯基丁氧基)己氨基]乙基}苯酚。NMR1H(CDCl3),δ(ppm):1.2-1.8(m,12H),2.4-2.7(m,6H,-CH2-N-CH2-+-CH2-C6H5),3.3-3.5(m,4H,-CH2-O-CH2-),4.4-4.6(m,3H,-CH2-OH+-CH(OH)-),5.1(s,4H,3*OH+NH),6.7(d,1H),6.8-7.0(m,2H),7.1-7.3(m,5H,-C6H5).
Claims (20)
1．通式(Ⅰ)的6-(4-苯基丁氧基)己胺衍生物：
其中：- R1是CHO或CHOR3OR4，其中的R3和R4独立地是C1-C6烷基、芳烷基，或者它们形成5或6元环状缩醛；和- R2是H、苄基或烷氧基羰基、芳氧基羰基、芳烷氧基羰基或酰基。
2．如权利要求1的化合物，其特征在于R1等于CHO,R2是烷氧基羰基、芳氧基羰基、芳烷氧基羰基或酰基。
3．如权利要求1的化合物，其特征在于R3和R4独立地是甲基、乙基、苄基，或者它们形成1,3-二氧戊环或1,3-二噁烷。
4．如权利要求1或2任意一项的化合物，其特征在于R2是叔丁氧基羰基、苄氧基羰基、乙氧基羰基、乙酰基、苯甲酰基或三氟乙酰基。
5．获得沙美特罗或其药学上可接受的盐的方法，其特征在于在惰性溶剂中，在低温下，进行通式(13)有机金属化合物与通式(Ⅰ)合成中间体的反应： 
其中：
-R1和R4独立地是C1-C6烷基、芳烷基，或者它们形成1,3-二氧戊环类型的环状缩醛；
-M是含有选自锂、镁或铜的金属的基团；和
-R1是CHO,R2是烷氧基羰基，芳氧基羰基，芳烷氧基羰基或酰基；然后是水解和除去保护基团。
6．如权利要求5的方法，其特征在于所述惰性溶剂是醚，例如乙醚或四氢呋喃。
7．如权利要求5的方法，其特征在于所述反应在-40℃至40℃的温度范围内进行，优选为-40℃至10℃。
8．如权利要求5的方法，其特征在于R3和R4独立地是甲基、乙基、苄基、2,2-二甲基-1,3-二噁烷或2-甲基-1,3-二噁烷。
9．如权利要求5的方法，其特征在于M是Li、MgBr或MgCl。
10．获得如权利要求1至4任意一项的通式(Ⅰ)6-(4-苯基丁氧基)己胺衍生物的方法，其特征在于进行下列步骤：
(ⅰ)在惰性溶剂中，在有机或无机碱的存在下，在25℃至100℃的温度范围内，优选为80℃至100℃，式(11)化合物与式(12)化合物进行胺的烷基化反应，
其中：
-R3和R4独立地是C1-C6烷基、芳烷基，或者它们形成5或6元环状缩醛；
-Z1和Z2各自是不同的，与L或NHR2相同，L是离去基团，例如氯、溴、碘、甲磺酰氧基或对甲苯磺酰氧基，优选为溴；R2是H或苄基；得到其中R1=CHOR3OR4、R3=H或苄基的通式(Ⅰ)化合物
(ⅱ)若R2是苄基，则在惰性溶剂中，可选地在有机或无机碱的存在下，在从0℃至50℃的温度范围内，在氢化之前将步骤(ⅰ)所得化合物(Ⅰ)用适合的试剂保护起来，得到其中R1=CHOR3OR4、R2=烷氧基羰基、芳氧基羰基、芳烷氧基羰基或酰基的通式(Ⅰ)化合物；
(ⅲ)步骤(ⅱ)所得式(Ⅰ)化合物通过缩醛基的水解作用、缩醛转移作用或氢解作用转化为相应的醛，得到其中R1=CHO、R2=烷氧基羰基、芳氧基羰基、芳烷氧基羰基或酰基的通式(Ⅰ)化合物。
11．如权利要求10的方法，其特征在于在步骤(ⅰ)中，惰性溶剂选自高沸点质子惰性溶剂，例如N,N-二甲基甲酰胺、N-甲基吡咯烷酮或二甲基亚砜，或卤代溶剂，例如二氯甲烷或氯仿，或醚，例如四氢呋喃或二噁烷，芳族烃，例如苯、甲苯或二甲苯。
12．如权利要求10的方法，其特征在于在步骤(ⅰ)和(ⅱ)中，有机碱选自叔胺，例如三乙胺或二异丙基胺，芳族胺，例如N,N-二甲基苯胺，或杂环胺，例如吡啶，或碳酸盐或碳酸氢盐。
13．如权利要求10的方法，其特征在于在步骤(ⅱ)中，所述试剂选自氯甲酸酯，例如氯甲酸乙酯、氯甲酸叔丁酯或氯甲酸苄基酯；重碳酸酯，例如重碳酸二叔丁酯或重碳酸二苄酯；或特殊的试剂，例如N-(苄氧基羰基氧基)琥珀酰亚胺；或酰氯或酸酐。
14．如权利要求10的方法，其特征在于在步骤(ⅱ)中，惰性溶剂选自酮，例如丙酮，卤代衍生物，例如二氯甲烷或氯仿，酯，例如乙酸乙酯，醚，例如四氢呋喃或二噁烷，或高沸点溶剂，例如N,N-二甲基乙酰胺或N,N-二甲基甲酰胺。
15．如权利要求10的方法，其特征在于在步骤(ⅲ)中，水解反应是这样进行的：在有机溶剂中，在至少为化学计算量的水和有机或无机酸的存在下。
16．如权利要求10的方法，其特征在于在步骤(ⅲ)中，缩醛转移反应是在酮和有机或无机酸的存在下进行的。
17．如权利要求15或16任意一项的方法，其中该反应是这样进行的：在盐酸、硫酸、甲磺酸、对甲苯磺酸或三氟乙酸的存在下，在15℃至50℃的温度范围内。
18．如权利要求10的方法，其特征在于在步骤(ⅲ)中，氢解反应是这样进行的：在催化剂的存在下，在惰性溶剂中，在10℃至50℃的温度范围内。
19．如权利要求18的方法，其中该催化剂是钯。
20．如权利要求18的方法，其中该溶剂选自C1至C4脂族醇，例如甲醇、乙醇、异丙醇或丁醇，酯，例如乙酸乙酯，或醚，例如四氢呋喃。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES009802014A ES2142771B1 (es) | 1998-09-28 | 1998-09-28 | Nuevos derivados de la 6-(4-fenil-butoxi) hexilamina y procedimiento para la obtencion de salmeterol. |
| ESP9802014 | 1998-09-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1320114A true CN1320114A (zh) | 2001-10-31 |
| CN1189446C CN1189446C (zh) | 2005-02-16 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB998114324A Expired - Fee Related CN1189446C (zh) | 1998-09-28 | 1999-09-20 | 6－(4－苯基丁氧基)己胺衍生物和获得沙美特罗的方法 |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US6388134B1 (zh) |
| EP (1) | EP1132373B1 (zh) |
| JP (1) | JP3786834B2 (zh) |
| KR (1) | KR100479256B1 (zh) |
| CN (1) | CN1189446C (zh) |
| AT (1) | ATE254596T1 (zh) |
| AU (1) | AU756042B2 (zh) |
| BR (1) | BR9913989A (zh) |
| CA (1) | CA2344647C (zh) |
| CZ (2) | CZ296902B6 (zh) |
| DE (1) | DE69912984D1 (zh) |
| EA (1) | EA003397B1 (zh) |
| ES (2) | ES2142771B1 (zh) |
| HU (1) | HUP0103969A3 (zh) |
| IL (1) | IL141991A (zh) |
| IS (1) | IS2016B (zh) |
| NO (2) | NO327780B1 (zh) |
| NZ (1) | NZ511157A (zh) |
| OA (1) | OA11660A (zh) |
| PL (1) | PL196116B1 (zh) |
| PT (1) | PT1132373E (zh) |
| SK (1) | SK284366B6 (zh) |
| TR (1) | TR200100862T2 (zh) |
| WO (1) | WO2000018722A2 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101712622B (zh) * | 2009-11-10 | 2012-10-03 | 浙江万里学院 | 抗哮喘药物沙美特罗的制备方法 |
| CN103435505A (zh) * | 2013-09-05 | 2013-12-11 | 南京工业大学 | 一种合成(r)-沙美特罗的方法 |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6835857B2 (en) | 2002-03-05 | 2004-12-28 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for the manufacture of 4-(6-bromohexyloxy)-butylbenzene |
| DE10209583B4 (de) * | 2002-03-05 | 2006-01-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung von 4-(6-Bromhexyloxy)-butylbenzol |
| PL1937626T3 (pl) * | 2005-10-17 | 2016-08-31 | Generics Uk Ltd | Sposób i związki do otrzymywania salmeterolu |
| ES2288114B1 (es) * | 2006-04-26 | 2008-12-01 | Quimica Sintetica S.A. | Nuevo procedimiento de sintesis de (6-(4-fenilbutoxi)hexil)aminas n-sustituidas y su uso en la sintesis de salmeterol xinafoato. |
| EP2127641A1 (en) | 2008-05-26 | 2009-12-02 | Inke, S.A. | Micronisable form of salmeterol xinafoate |
| US9447067B2 (en) * | 2014-10-03 | 2016-09-20 | Amphastar Pahmaceuticals, Inc. | Method of preparing intermediate of salmeterol |
| KR20230001708U (ko) | 2022-02-17 | 2023-08-24 | 유기택 | 재접착식 슬림 평면형 액자 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZW6584A1 (en) * | 1983-04-18 | 1985-04-17 | Glaxo Group Ltd | Phenethanolamine derivatives |
| AU581887B2 (en) * | 1984-04-17 | 1989-03-09 | Glaxo Group Limited | Ethanolamine compounds |
| ES2065269B1 (es) * | 1993-05-11 | 1995-10-01 | S A L V A T Lab Sa | 6-(4-(fenilbutoxi) hexilaminometil-4-hidroxi-a1,a3-bencenodimetanol. procedimiento para la obtencion del mismo y nuevos intermedios utilizados en su preparacion. |
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1998
- 1998-09-28 ES ES009802014A patent/ES2142771B1/es not_active Expired - Fee Related
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- 1999-09-20 AU AU59839/99A patent/AU756042B2/en not_active Ceased
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- 1999-09-20 CZ CZ20033118A patent/CZ296902B6/cs not_active IP Right Cessation
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- 1999-09-20 EP EP99969711A patent/EP1132373B1/en not_active Expired - Lifetime
- 1999-09-20 AT AT99969711T patent/ATE254596T1/de not_active IP Right Cessation
- 1999-09-20 KR KR10-2001-7003977A patent/KR100479256B1/ko not_active IP Right Cessation
- 1999-09-20 HU HU0103969A patent/HUP0103969A3/hu unknown
- 1999-09-20 DE DE69912984T patent/DE69912984D1/de not_active Expired - Lifetime
- 1999-09-20 CZ CZ20010958A patent/CZ296901B6/cs not_active IP Right Cessation
- 1999-09-20 PL PL348572A patent/PL196116B1/pl not_active IP Right Cessation
- 1999-09-20 IL IL14199199A patent/IL141991A/en not_active IP Right Cessation
- 1999-09-20 JP JP2000572184A patent/JP3786834B2/ja not_active Expired - Fee Related
- 1999-09-20 NZ NZ511157A patent/NZ511157A/xx not_active IP Right Cessation
- 1999-09-20 WO PCT/ES1999/000294 patent/WO2000018722A2/es active IP Right Grant
- 1999-09-20 BR BR9913989-8A patent/BR9913989A/pt not_active Application Discontinuation
- 1999-09-20 EA EA200100391A patent/EA003397B1/ru not_active IP Right Cessation
- 1999-09-20 ES ES99969711T patent/ES2212672T3/es not_active Expired - Lifetime
- 1999-09-20 TR TR2001/00862T patent/TR200100862T2/xx unknown
- 1999-09-20 CN CNB998114324A patent/CN1189446C/zh not_active Expired - Fee Related
- 1999-09-20 SK SK386-2001A patent/SK284366B6/sk not_active IP Right Cessation
- 1999-09-20 OA OA1200100079A patent/OA11660A/en unknown
- 1999-09-20 PT PT99969711T patent/PT1132373E/pt unknown
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101712622B (zh) * | 2009-11-10 | 2012-10-03 | 浙江万里学院 | 抗哮喘药物沙美特罗的制备方法 |
| CN103435505A (zh) * | 2013-09-05 | 2013-12-11 | 南京工业大学 | 一种合成(r)-沙美特罗的方法 |
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