CN100406456C - 莨菪品酯的制备方法 - Google Patents
莨菪品酯的制备方法 Download PDFInfo
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- CN100406456C CN100406456C CNB028265610A CN02826561A CN100406456C CN 100406456 C CN100406456 C CN 100406456C CN B028265610 A CNB028265610 A CN B028265610A CN 02826561 A CN02826561 A CN 02826561A CN 100406456 C CN100406456 C CN 100406456C
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- FIMXSEMBHGTNKT-RZVDLVGDSA-N scopine Chemical class C([C@@H]1N2C)[C@H](O)C[C@@H]2[C@@H]2[C@H]1O2 FIMXSEMBHGTNKT-RZVDLVGDSA-N 0.000 title abstract description 6
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims description 40
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 27
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 27
- 229910052794 bromium Inorganic materials 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 21
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 20
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 15
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- -1 methoxyl group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000001544 thienyl group Chemical group 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- 125000002541 furyl group Chemical group 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 229960002317 succinimide Drugs 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims description 2
- 229910021536 Zeolite Inorganic materials 0.000 claims description 2
- RFMFOBISNWTLTK-UHFFFAOYSA-N [O].[N+](=O)([O-])C1=C(C(=C(OC2=C(C(=C(C(=C2F)F)F)F)F)C=C1)F)OC1=CC=CC=C1 Chemical compound [O].[N+](=O)([O-])C1=C(C(=C(OC2=C(C(=C(C(=C2F)F)F)F)F)C=C1)F)OC1=CC=CC=C1 RFMFOBISNWTLTK-UHFFFAOYSA-N 0.000 claims description 2
- 230000003213 activating effect Effects 0.000 claims description 2
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 239000010457 zeolite Substances 0.000 claims description 2
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 150000002460 imidazoles Chemical class 0.000 description 9
- 230000001078 anti-cholinergic effect Effects 0.000 description 8
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 7
- XQJMXPAEFMWDOZ-UHFFFAOYSA-N 3exo-benzoyloxy-tropane Natural products CN1C(C2)CCC1CC2OC(=O)C1=CC=CC=C1 XQJMXPAEFMWDOZ-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 description 6
- QIZDQFOVGFDBKW-DHBOJHSNSA-N Pseudotropine Natural products OC1C[C@@H]2[N+](C)[C@H](C1)CC2 QIZDQFOVGFDBKW-DHBOJHSNSA-N 0.000 description 6
- 229910052744 lithium Inorganic materials 0.000 description 6
- CYHOMWAPJJPNMW-JIGDXULJSA-N tropine Chemical compound C1[C@@H](O)C[C@H]2CC[C@@H]1N2C CYHOMWAPJJPNMW-JIGDXULJSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- FIMXSEMBHGTNKT-UHFFFAOYSA-N Scopine Natural products CN1C2CC(O)CC1C1C2O1 FIMXSEMBHGTNKT-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000007822 coupling agent Substances 0.000 description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 229910052728 basic metal Inorganic materials 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FIGYYXIYTVBRJV-UHFFFAOYSA-N 1h-imidazole;lithium Chemical compound [Li].C1=CNC=N1 FIGYYXIYTVBRJV-UHFFFAOYSA-N 0.000 description 1
- NMGODFWGUBLTTA-UHFFFAOYSA-N 3-amino-1h-quinazoline-2,4-dione Chemical compound C1=CC=C2C(=O)N(N)C(=O)NC2=C1 NMGODFWGUBLTTA-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- PKSYYKNMVZIREQ-UHFFFAOYSA-N N1N=CN=C1.C(=O)(NC(=O)OCC)NC(=O)OCC Chemical compound N1N=CN=C1.C(=O)(NC(=O)OCC)NC(=O)OCC PKSYYKNMVZIREQ-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- KQUXDEQEVXTYHW-UHFFFAOYSA-M [Br+].CS([O-])(=O)=O Chemical compound [Br+].CS([O-])(=O)=O KQUXDEQEVXTYHW-UHFFFAOYSA-M 0.000 description 1
- BQODPTQLXVVEJG-UHFFFAOYSA-N [O].C=C Chemical compound [O].C=C BQODPTQLXVVEJG-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000003153 cholinolytic effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 235000019628 coolness Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- VTTKBFMNVGIDQJ-UHFFFAOYSA-N nonane;hydrobromide Chemical compound Br.CCCCCCCCC VTTKBFMNVGIDQJ-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010010 raising Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 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 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Polyethers (AREA)
Abstract
本发明涉及一种制备通式(1)的莨菪品酯的新方法，其中X-以及R1和Ar基具有权利要求和说明书中所述定义。
Description
本发明涉及一种制备通式1的莨菪品酯的新方法
其中X-以及R1和Ar基具有权利要求和说明书中所述定义。
发明背景
抗胆碱能药可适合用于治疗多种疾病。这里着重指出的例如治疗哮喘病或COPD(慢性的阻塞性肺病)。为治疗该疾病，例如WO92/16528建议具有莨菪品、莨菪醇(Tropenol)或者莨菪碱基结构的抗胆碱能药。
WO92/16528的目的是制备抗胆碱能的有效化合物，其特征在于长时期的效力。为实现该目的，WO92/16528公开了除了其它的莨菪品、莨菪醇或者莨菪碱的联苯甲酰酯。
为治疗慢性疾病，常常希望制备具有较长有效的药物。这通常确保能够在较长期间内在体内提供达到治疗效果所必要的活性物质浓度，而不必非常频繁地屡次给以药物。此外，以较长的时间间隔服用高计量的活性物质有助于病人的良好感觉。特别合乎愿望的是提供一种药物，通过每天服用一次(一次剂量)该药物有治疗的良好作用。每天一次地使用的优点在于，病人能相对快地养成在白天的确定时间有规律服药的习惯。
为了能够作为每天一次地使用的药物，使用的有效药物要满足特别要求。首先，服药后应很快产生预期效果，理想情况下，在随后的较长时间内其具有尽可能恒定的效力。另一方面，药物的作用时间应基本上不超过约一天。理想情况下，有效物质表现出类似这样的效果特征，使其能够可控地制备每天使用一次的药物，并含有治疗有效剂量的活性物质。
实验发现，WO92/16528公开的莨菪品、莨菪醇或者莨菪碱的酯不能够满足这些提高的要求。因为其特别长的有效期明显超出了上述约一天的时间间隔，所以不能用于每天服用一次的治疗。
不同于WO92/16528公开的示例性化合物，如果使用式1的莨菪品酯，可以制备每天一次给药的抗胆碱有效的药物：
其中X-以及取代基R1和Ar具有下面所述的定义。
除了WO92/16528公开的制备莨菪品酯的合成方法，例如EP418716A1中也公开了一种制备莨菪品酯的方法。现有技术已知的方法也可用于制备式1的化合物。然而这些合成途径涉及部分复杂的、是由多步合成步骤组成的做法。
本发明的目的是提供一种合成方法，该方法可以更简单的合成通式1化合物。
发明详述
令人惊讶地发现，可以在一个反应步骤中得到式1的化合物，
其中，X-以及R1和Ar具有下面所述的定义，是使用式2化合物作为原料。
相应地，本发明涉及一种制备式1化合物的方法
其中
X-为氯、溴、碘、甲磺酸盐或三氟甲磺酸盐；
R1为羟基、C1-C4-烷基、C1-C4-烷氧基、CF3或氟；
Ar为选自苯基、萘基、噻吩基和呋喃基的取代基，其可以被一个或两个选自C1-C4-烷基、C1-C4-烷氧基、羟基、氟、氯、溴或CF3中的取代基所取代，
其特征在于，式2的化合物在一步骤中与式3的化合物反应
式2中
Y-为氯、溴、碘、甲磺酸盐或三氟甲磺酸盐
式3中
R为选自羟基、甲氧基、乙氧基、O-N-琥珀酰亚胺、O-N-邻苯二甲酰亚胺、苯氧基、硝基苯氧基、氟苯氧基、五氟苯氧基、乙烯氧基、2-烯丙氧基、-S-甲基、-S-乙基和-S-苯基中的取代基并且取代基R1和Ar具有上述定义。
优选本发明涉及一种制备式1化合物的方法
其中
X-为溴、甲磺酸盐或三氟甲磺酸盐；
R1为羟基、甲基、CF3或氟；
Ar为选自苯基、噻吩基和呋喃基中的取代基
其特征在于，式2的化合物在一个步骤中与式3的化合物反应
式2中
Y-为溴、甲磺酸盐或三氟甲磺酸盐
式3中
R为选自羟基、O-N-琥珀酰亚胺、O-N-邻苯二甲酰亚胺、乙烯氧基和2-烯丙氧基的取代基并且R1和Ar具有上述定义。
特别优选本发明涉及一种制备式1化合物的方法
其中
X-为溴、甲磺酸盐或三氟甲磺酸盐；
R1为羟基或甲基；
Ar为苯基或噻吩基，
其特征在于，式2的化合物在一个步骤中与式3的化合物反应，
式2中
Y-为溴甲磺酸盐或三氟甲磺酸盐
式3中
R为选自羟基、O-N-琥珀酰亚胺、O-N-邻苯二甲酰亚胺、乙烯氧基和2-烯丙氧基中的取代基，优选乙烯氧基和2-烯丙氧基并且R1和Ar具有上述定义，反应。
本发明方法按如下所述进行。
在第一步中，式3化合物溶于合适的有机溶剂中，优选在极性有机溶剂中，特别优选在选自乙腈、硝基甲烷、甲酰胺、二甲基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜和二甲基乙酰胺的溶剂中，上述溶剂中特别优选为二甲基甲酰胺、N-甲基吡咯烷酮和二甲基乙酰胺。按照本发明特别优选的是二甲基甲酰胺和N-甲基吡咯烷，其中特别优选后者。
每摩尔所使用的式3化合物优选加入0.5～2L，特别优选0.75～1.5L的所述溶剂。
式3化合物的选择是有用的，在其与式2化合物反应前使之活化。作为式3化合物使用其中R＝OH的衍生物，例如本发明优选使用的相应的活化试剂，如羰基二咪唑、羰基二-1，2，4-三唑、二环己基碳化二亚胺或乙基二甲基氨基丙基碳化二亚胺，其中在本文中特别优选使用羰基二咪唑。每摩尔使用的R＝羟基的化合物3，使用1～2摩尔的偶联剂。优选使用1～1.5摩尔的偶联剂。优选如在R＝羟基情况下使用上述偶联剂，在进行下述的进一步反应前，所得的反应混合物优选在15～35℃温度范围内，优选在20～25℃下搅拌1～8小时，优选3～7小时。
上述溶剂中的3的反应混合物，当R＝羟基情况下任选地加入一种上述偶联剂后，然后调节其温度小于30℃，优选为-20～20℃的温度，特别优选为-10～5℃的温度，并加入式2化合物。以最初使用的化合物3计，可以化学计量加入式2化合物。不过根据本发明，优选是3比2过量。根据本发明，每摩尔使用的化合物3使用的2为0.5～1摩尔，优选0.7～0.95摩尔，特别优选0.75～0.9摩尔。
然后，上述反应混合物中加入溶解在上述溶剂中的合适的碱。这里可以使用有机碱或无机碱。作为有机碱优选使用碱金属的咪唑化物(imidazolide)，例如它可以由碱金属和咪唑或者碱金属氢化物和咪唑就地生成。作为碱金属咪唑化物优选为锂、钠或钾的咪唑化物，其中根据本发明优选咪唑化钠或咪唑化锂。特别优选使用咪唑化锂。作为无机碱优选为锂、钠或钾的氢化物。特别优选使用氢化钠作为无机碱。上述所有碱中特别优选使用咪唑化锂。
如要得到其中R1表示羟基的式1的化合物，代替上述的碱催化反应，在温和反应条件下的酯交换反应是有利的。在此可以有利地使用沸石作为催化剂。
使用一种上述的碱进行反应，每摩尔使用的化合物2至少使用化学计量的碱。优选每摩尔使用的化合物2使用1～1.5摩尔，优选1.1～1.3摩尔的碱。以溶液形式加入碱，特别是在本发明优选情况下和预先就地生成的碱性咪唑化锂的情况下，为此优选使用的溶剂，就是已经使用于进行上述步骤的溶剂。每摩尔反应的碱优选使用0.3～1.3升，特别优选0.5～1升上述的溶剂。加碱结束后，在15～35℃温度范围内，优选在20～25℃下搅拌4～48小时，优选8～36小时。
在恒定温度下向这样形成的悬浮液中加入酸H-X。根据所要求的通式1最终产物中的离子X-确定所选择的酸。就本发明而言，优选合成其中X-表示溴的通式1化合物，以下描述制备本发明优选的含溴的通式1最终产物。对于技术人员来说，通过适当选择试剂H-X而可按类似技术和方式制备X-不是溴的化合物的相应方法是明显的。
为了制备其中X-＝溴的式1化合物，在恒定温度下，以使用的式3化合物计，优选加入的溴化氢2～4摩尔，更优选2～3摩尔，最优选2.2～2.6摩尔。所使用的溴化氢既可以气态形式，也可以溶液，优选是以饱和溶液形式加入。本发明优选以溴化氢溶解在冰醋酸的形式加入。这里特别优选使用33％溴化氢的冰醋酸溶液。加入结束后，在恒定温度下，也可以在冰冷却下搅拌(0.5～6小时)。
然后得到的溶液与非极性的有机溶剂混合，优选与选自丙酮、甲苯、乙酸正丁酯。二氯甲烷、二乙基醚、四氢呋喃和二噁烷，特别优选甲苯或丙酮中的一种溶剂进行混合。
充分混合后，分离结晶产物，并用上述非极性溶剂洗涤。为了分离水溶性杂质，用水溶性的溴化物溶液，例如溴化钠或溴化钾溶液处理粗产物。
如果需要，可以继续纯化这样得到的式1化合物，通过使用硅胶的层析法，或借助重结晶从适合的溶剂，例如低级醇，如异丙醇进行纯化。
通过使用现有技术中已知的式2化合物作为起始原料合成结构式1，只经一步反应的步骤就成功得到了有抗胆碱能效果的结构。
相应地，本发明的另一方面涉及使用式2的化合物
其中
Y-为氯、溴、碘、甲磺酸盐或三氟甲磺酸盐
作为原料，来合成式1的化合物
其中
X-为氯、溴、碘、甲磺酸盐或三氟甲磺酸盐；
R1为羟基、C1-C4-烷基、C1-C4-烷氧基、CF3或氟；
Ar为选自苯基、萘基、噻吩基和呋喃基的取代基，其可以被一个或两个选自C1-C4-烷基、C1-C4-烷氧基、羟基、氟、氯、溴或CF3的取代基一取代或两取代。
本发明优选涉及使用式2的化合物
其中
Y-为溴、甲磺酸盐或三氟甲磺酸盐作为起始原料来合成式1的化合物
其中
X-为溴、甲磺酸盐或三氟甲磺酸盐；
R1为羟基、甲基、CF3或氟；
Ar为选自苯基、噻吩基和呋喃基中的取代基。
本发明特别优选涉及使用式2的化合物
其中
Y-为溴、甲磺酸盐或三氟甲磺酸盐作为起始原料来合成式1的化合物
其中
X-为溴、甲磺酸盐或三氟甲磺酸盐；
R1为羟基或甲基；
Ar为苯基或噻吩基。
以下实施例用于示范性说明进行的合成方法。其只可理解为示范性说明上述方法，而不是在内容上限定本发明。
实施例1：2，2-二苯基丙酸莨菪品酯-甲基溴：
向2，2-二苯基丙酸(1629g，7.2mol)的N-甲基吡咯烷酮(9L)溶液中分批加入羰基二咪唑(1206g，7.44mol)，然后室温(约23℃)下搅拌5小时。反应混合物在-3℃冷却。向反应混合物中加入莨菪品甲基溴(1501g，6.0mol)。然后滴加咪唑化锂(由氢化锂(59.6g；7.12mol)及咪唑(490.2g，7.2mol)制备)在5L N-甲基吡咯烷酮中的溶液。室温下搅拌17小时。在18-28℃冷却下向所得悬浮液中加入溴化氢溶液(33％在冰醋酸中；2460ml，14.25mol)。悬浮液在冰浴中搅拌，随后和甲苯(14L)混合。过滤，得到的滤饼用5500ml的30％溴化钾溶液悬浮两次并抽滤。这样得到的物质在40℃干燥箱中干燥。
产量：2359.3g＝85.8％d.Th(理论值)。
为了纯化，将粗产物(2100g)从35.7L异丙醇中重结晶。
产量：1562.2g；无色片状。
用类似技术和方式可以一步的合成步骤得到：
实施例2：(1α，2β，4β，5α，7β)-7-[(羟基二-2-噻吩乙酰)氧]-9，9-二甲基-3-氧杂
-9-氮鎓环[3.3.1.0
2.4
]壬烷-溴化物
Claims (10)
1.制备式1化合物的方法
其中
X-为氯、溴、碘、甲磺酸盐或三氟甲磺酸盐；
R1为羟基、C1-C4-烷基、C1-C4-烷氧基、CF3或氟；
Ar为选自苯基、萘基、噻吩基和呋喃基中的取代基，其可以被一个或两个选自C1-C4-烷基、C1-C4-烷氧基、羟基、氟、氯、溴或CF3的取代基进行一取代或者二取代，
其特征在于，式2的化合物在一个步骤中与式3的化合物反应
式2中
Y-为氯、溴、碘、甲磺酸盐或三氟甲磺酸盐，
式3中
R为选自羟基、甲氧基、乙氧基、O-N-琥珀酰亚胺、O-N-邻苯二甲酰亚胺、苯氧基、硝基苯氧基、氟苯氧基、五氟苯氧基、乙烯氧基、2-烯丙氧基、-S-甲基、-S-乙基和-S-苯基的取代基并且
R1为羟基、C1-C4-烷基、C1-C4-烷氧基、CF3或氟；
Ar为选自苯基、萘基、噻吩基和呋喃基中的取代基，其可以被一个或两个选自C1-C4-烷基、C1-C4-烷氧基、羟基、氟、氯、溴或CF3的取代基进行一取代或者二取代。
2.根据权利要求1的方法，为了制备式1化合物
其中
X-为溴、甲磺酸盐或三氟甲磺酸盐；
R1为羟基、甲基、CF3或氟；
Ar为选自苯基、噻吩基和呋喃基的取代基
其特征在于，式2的化合物在一个步骤中与式3的化合物反应，
式2中Y-为溴、甲磺酸盐或三氟甲磺酸盐，
式3中R为选自羟基、O-N-琥珀酰亚胺、O-N-邻苯二甲酰亚胺、乙烯氧基和2-烯丙氧基中的取代基并且
R1为羟基、甲基、CF3或氟；
Ar为选自苯基、噻吩基和呋喃基。
3.根据权利要求1或2制备式1化合物的方法，其中
X-为溴、甲磺酸盐或三氟甲磺酸盐；
R1为羟基或甲基；
Ar为苯基或噻吩基，
其特征在于，式2的化合物在一个步骤中与式3的化合物反应，
式2中，Y-为溴、甲磺酸盐或三氟甲磺酸盐，
式3中，R为选自羟基、O-N-琥珀酰亚胺、O-N-邻苯二甲酰亚胺、乙烯氧基和2-烯丙氧基中的取代基，并且Ar为选自苯基或噻吩基，R1为羟基或甲基。
4.根据权利要求1至2中之一的方法，其特征在于，反应是在一种有机溶剂中进行，有机溶剂选自乙腈、硝基甲烷、甲酰胺、二甲基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜和二甲基乙酰胺。
5.根据权利要求1至2中之一的方法，其特征在于，在使用其中R＝OH的式3化合物情况下，使用选自羰基二咪唑、羰基二-1，2，4-三唑、二环己基碳化二亚胺和乙基二甲基氨基丙基碳化二亚胺中的活化试剂。
6.根据权利要求1至2中之一的方法，其特征在于，反应在温度小于30℃下进行。
7.根据权利要求1至2中之一的方法，其特征在于，反应在温度在-20至20℃下进行。
8.根据权利要求1至2中之一的方法，其特征在于，反应是在有有机碱或无机碱的存在下进行。
9.根据权利要求1至2中之一的方法，其特征在于，在其中R1表示羟基的式1化合物情况下，反应是在有沸石作为催化剂的存在情况下进行。
10.使用式2化合物作为起始原料合成式1化合物
式2中
Y-为氯、溴、碘、甲磺酸盐或三氟甲磺酸盐，
式1中
X-为氯、溴、碘、甲磺酸盐或三氟甲磺酸盐；
R1为羟基、C1-C4-烷基、C1-C4-烷氧基、CF3或氟；
Ar为选自苯基、萘基、噻吩基和呋喃基中的取代基，其可以被一个或两个选自C1-C4-烷基、C1-C4-烷氧基、羟基、氟、氯、溴或CF3中的取代基进行一取代或者二取代。
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