CN1413976A - New process for preparing levo-albuterol - Google Patents
New process for preparing levo-albuterol Download PDFInfo
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- CN1413976A CN1413976A CN02131215A CN02131215A CN1413976A CN 1413976 A CN1413976 A CN 1413976A CN 02131215 A CN02131215 A CN 02131215A CN 02131215 A CN02131215 A CN 02131215A CN 1413976 A CN1413976 A CN 1413976A
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- Prior art keywords
- statement
- chirality
- phenyl amine
- salbutamol
- amine alcohol
- Prior art date
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- Granted
Links
- 229960002052 salbutamol Drugs 0.000 title claims description 27
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 32
- 229950008204 levosalbutamol Drugs 0.000 claims abstract description 9
- 125000006239 protecting group Chemical group 0.000 claims abstract description 9
- NDAUXUAQIAJITI-LBPRGKRZSA-N (R)-salbutamol Chemical compound CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-LBPRGKRZSA-N 0.000 claims abstract description 7
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 19
- -1 phenyl aldehyde Chemical class 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 102000014974 beta2-adrenergic receptor activity proteins Human genes 0.000 claims description 7
- 108040006828 beta2-adrenergic receptor activity proteins Proteins 0.000 claims description 7
- 230000003287 optical effect Effects 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000005516 engineering process Methods 0.000 claims description 4
- 150000003333 secondary alcohols Chemical class 0.000 claims description 4
- 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 4
- YUCBLVFHJWOYDN-HVLQGHBFSA-N 1,4-bis[(s)-[(2r,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]phthalazine Chemical compound C1=C(OC)C=C2C([C@H](OC=3C4=CC=CC=C4C(O[C@H]([C@@H]4N5CC[C@H]([C@H](C5)CC)C4)C=4C5=CC(OC)=CC=C5N=CC=4)=NN=3)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 YUCBLVFHJWOYDN-HVLQGHBFSA-N 0.000 claims description 3
- 150000003141 primary amines Chemical class 0.000 claims description 3
- YUCBLVFHJWOYDN-PPIALRKJSA-N 4-[(r)-[(2r,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]-1-[(r)-[(2r,4r,5s)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]phthalazine Chemical compound C1=C(OC)C=C2C([C@@H](OC=3C4=CC=CC=C4C(O[C@@H]([C@@H]4N5CC[C@@H]([C@@H](C5)CC)C4)C=4C5=CC(OC)=CC=C5N=CC=4)=NN=3)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 YUCBLVFHJWOYDN-PPIALRKJSA-N 0.000 claims description 2
- 125000005504 styryl group Chemical group 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 6
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 abstract description 4
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 abstract description 3
- 238000005906 dihydroxylation reaction Methods 0.000 abstract 1
- 125000003011 styrenyl group Chemical class [H]\C(*)=C(/[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 239000002243 precursor Substances 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 description 4
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000005425 toluyl group Chemical group 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 2
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- LJOQGZACKSYWCH-UHFFFAOYSA-N dihydro quinine Natural products C1=C(OC)C=C2C(C(O)C3CC4CCN3CC4CC)=CC=NC2=C1 LJOQGZACKSYWCH-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000011916 stereoselective reduction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229960000195 terbutaline Drugs 0.000 description 2
- BYGOPQKDHGXNCD-UHFFFAOYSA-N tripotassium;iron(3+);hexacyanide Chemical compound [K+].[K+].[K+].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] BYGOPQKDHGXNCD-UHFFFAOYSA-N 0.000 description 2
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 1
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- IWNGJPYVYJDENJ-UHFFFAOYSA-N 2-(2-ethenyl-6,6-dimethylcyclohexa-2,4-dien-1-yl)-1,3-dioxane Chemical compound CC1(C(C(=CC=C1)C=C)C1OCCCO1)C IWNGJPYVYJDENJ-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 241000254171 Curculionidae Species 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical group CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 241001635574 Sabatia angularis Species 0.000 description 1
- 101000924984 Salmonella typhimurium (strain LT2 / SGSC1412 / ATCC 700720) 3-dehydroquinate dehydratase Proteins 0.000 description 1
- 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 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229940124748 beta 2 agonist Drugs 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
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- 239000003640 drug residue Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000003754 fetus Anatomy 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
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- ULNFTUJQIGMSAY-UHFFFAOYSA-N iodomethane;triphenylphosphane Chemical compound IC.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 ULNFTUJQIGMSAY-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
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- 239000012071 phase Substances 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
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- 239000000741 silica gel Substances 0.000 description 1
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- 150000003440 styrenes Chemical class 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for preparing levo-salbutamol includes such steps as asymmetrical dihydroxylation reaction of properly substituted and protected styrene derivative, converting the class-one hydroxy of asymmetrical glycol to proper dessociative group, replacing the dessociative group by tert-butylamine, and removing protecting group.
Description
Technical field the present invention relates to a kind of novel preparation process of Levalbuterol, and the structure of Levalbuterol as shown in Figure 3.
Synthesis step of the present invention comprises: (1) suitably replaces and the asymmetric dihydroxy reaction of the styrene derivatives protected; (2) the one-level hydroxyl with asymmetric ethylene glycol is transformed into suitable leavings group; (3) replace this leavings group with TERTIARY BUTYL AMINE, remove protecting group thereupon, promptly get Levalbuterol.
Background technology The present invention be more particularly directed to have the antasthmatic of significant curative effect effect---Levalbuterol.Modern age, experiment showed to have the drug molecule at optical activity center, and its single optical activity isomer has stronger activity and reduces side effect than raceme.
About the preparation of the optical activity isomer of theme of the present invention-phenyl amine alcohol, reported in literature is much about the part recrystallization method of synthetic intermediate or final product.For example, the preparation method of known optically pure chirality salbutamol of people and Fu Mateluo; Can often in building-up process, run into a lot of problems as the optically pure product of medicine yet will synthesize in this way, comprise the costliness of raw material reagent, the part recrystallization solvent reclaims repeatedly, a large amount of manpowers expend loss of yield 50%, the generation of the enantiomorph of non-expectation.
Salbutamol, its chemistry α by name-{ [(1, the 1-methylethyl) amine] methyl }-4 hydroxyls-1, the 3-xylyl alcohol is the beta-2 adrenoceptor excitomotor, as bronchodilator.It is at β
1Acceptor (being present in heart) and β
2Acceptor has high selectivity between (being present in bronchial tissue and other positions), because this reason, the salbutamol of therapeutic dose is wanted much less than many other beta-2-agonists Side effects of pharmaceutical drugs, and it is widely used for treating asthma.Salbutamol still be one efficiently domestic animal urge longly plain, be used for the raising of chicken at large at some national salbutamols in Europe.
As everyone knows, exist chiral centre in many medicines, the wherein a kind of enantiomorph in the raceme in therapeutic process often than another enantiomorph drug effect height.Data show that the drug effect of salbutamol levo form (R type) enantiomorph exceeds 80 times approximately than dextrorotatory form (S type) recently.(Hartley and Middlemis, J.Med.Chem.14,895-896,1971) are taken optically pure R type salbutamol and can be improved therapeutic index.All β
2In the receptor stimulant, have only levo form that the effect of beta receptor agonist is arranged.Salbutamol S type isomer does not have avidity to beta-2 adrenoceptor.Yet S type salbutamol has identical acute toxicity with the salbutamol of R type, and biological half-life longer than having of R type in human body of S type.S type salbutamol can cause the overreaction of segmental bronchus and uterine smooth muscle, is easy to enter in the fetus body by the placenta barrier film.Because of R type salbutamol sulfate has higher curative effect and less side effect, it is by food and drug administration (FDA) approval, as the new drug of treatment asthma.In addition R type salbutamol also developed into one efficiently domestic animal urge longly plain, avoided potential side effect and the drug residue relevant with S type salbutamol.
Article at least two, synthetic method is used to control the stereochemistry of salbutamol and relevant amine alcohol chiral centre.First kind is used at preparation pure salbutamol R type and the method for S type enantiomorph, the i.e. chiral separation method of synthetic intermediate or final product raceme mixture.(with reference to Bakale etc., Clinical Reviewin Allergy and Immmunology vol 14 pp 7-35,1996).Second method is to adopt asymmetric catalysis synthesis, from the chiral precurser synthesizing chiral compound.
One of method that chemistry splits is with chiral acid and racemic salbutamol, or its precursor form diastereoisomeric salt (USP 5,399,765; 5,545,745; Ferrayoli etc., Enantiomer vol 5 pp289-291,2000).With salt with pure recrystallization repeatedly after, the salbutamol (or precursor) of R or S type discharges from salt with alkali.Chiral acid can use (-)-two-(to toluyl)-L-tartrate, (+)-two-(to toluyl)-D-tartrate, (-)-two-benzoyl-L-tartrate, (+)-two-benzoyl-D-tartrate.The shortcoming of this method is: (1) poor efficiency, as, the salbutamol of R type and S type (or its precursor) is a racemic mixture, contains 50% R type isomer and 50% S type isomer, the maximum yield of R type isomer just 50%.And reality is more much smaller than 50%.(2) costliness, chiral acid as described above particularly is used for preparing (+)-two-(to toluyl)-D-tartrate of the salbutamol (or precursor) of R type, and (+)-two-benzoyl-D-tartrate is too expensive, and technology is not to gather very much effect.
In laboratory study, the chirality synthetic method of the steric isomer of at present the most successful salbutamol is to be based upon utilization homogeneous phase chirality organic boron as on the Stereoselective reduction technical foundation of catalyzer.(J.Org.Chem vol 60, pp 41-46,1995) racemic secondary alcohol obtains by an achirality reductive agent reduction precursor ketone (being connected to different groups on the carbonyl).When adding resembles the such catalyzer of the organic boron of chirality, the S type that obtains that often can highly selective or the alcohol of R type.But, this Stereoselective reduction method also is not applied in the production of R type salbutamol on a large scale, because chiral catalyst is too expensive.
So people need seek the synthetic method that obtains optically pure phenyl amine alcohol or its intermediate with the stereoselectivity chemical reaction.
The synthetic needs that obtain optically pure phenyl amine alcohol or its intermediate with the stereoselectivity chemical reaction have been satisfied in this invention of goal of the invention.
Purpose of the present invention just provides terrible synthetic method to optically pure phenyl amine alcohol or its intermediate, comprises following step:
(a) one is suitably replaced and the vinylbenzene of due care contains the two pure of a primary alconol and a secondary alcohol by what asymmetric dihydroxy was deformed into a chirality.
(b) primary alconol with ethylene glycol is transformed into a suitable leavings group,
(c) generate a chirality phenyl amine alcohol with suitably replacing and protecting primary amine to replace leavings group.Technical scheme method provided by the invention mainly is the preparation about the single optical isomer of a phenyl amine alcohol, and this compound is by a phenylglycol that suitably replaces, and promptly the precursor of phenyl amine alcohol obtains high optical activity.General method of the present invention is as follows:
(a) one is suitably replaced and the vinylbenzene of due care by becoming the ethylene glycol that contains a primary alconol and a secondary alcohol of a chirality.
(b) primary alconol with ethylene glycol is transformed into a suitable leavings group.
(c) primary amine with suitable substituting group and protection replaces chirality phenyl amine alcohol of leavings group generation.
For the purpose of the present invention, suitable substituting group and suitable technical term be meant occur in the literary composition can generate the useful final product and the substituting group that compound is with of intermediate thereof.To chirality phenyl amine alcohol; useful final product is the beta-2 adrenoceptor excitomotor of phenyl amine alcohols, comprises salbutamol, Fu Mateluo; the useful especially intermediate that special sieve of husky benzene, terbutaline etc. resemble these compounds comprises the chirality phenylglycol of corresponding protection.
So-called suitable protecting group is meant that a group is being used for protecting a special compound to be vulnerable to attack and the position of react with in indivedual reactions or reaction, this group can be removed under existing other group situations not destroying in the compound afterwards.The optimal protecting group of hydroxyl has similar groups such as ester, carbonic ether, carbamate, ketal.The best protection base of amido has acid amides, amino-carbon acid esters and relevant group.A large amount of suitable protecting groups and lose protective reaction description to some extent in " organic chemistry protecting group " accordingly.(JohnWiley and Sons; Inc., New York, 1991; ISBN0-471-62301-6) (" Greene ")) (GeorgThieme Verlag Stuttgart; New York, 1994) this book chapter 1 particularly, blocking group: summary 1-20 page or leaf; chapter 2, hydroxyl protecting group 21-94 page or leaf; chapter 3, glycerol protection base 95-117 page or leaf, chapter 4 carboxyl-protecting group 118-154 page or leaf, chapter 5 carbonyl-protection base 155-184 page or leaf.
So-called good leavings group is meant under the situation that does not influence other functional groups in the compound, is easy to be substituted by reaction immediately generate desired product.The corresponding leavings group of hydroxyl has tosic acid base, methylsulfonyl, trifluoroacetic acid base and relevant group.
In the present invention, suitably the vinylbenzene that replaces is made by corresponding phenyl aldehyde by the known method of author, and the multistep operation steps by subsequently makes target compound.For example as Fig. 1, among this figure, crucial asymmetric dihydroxy reagent is: the mixture for preparing R type ethylene glycol is the Tripotassium iron hexacyanide, salt of wormwood, four hydration potassium osmates, dihydro quinoline Ni Ding-2, the 3-dihydro naphthalene catalyzer (DHQD) of mixing
2-PHAL, this mixture is called as AD-mix-β; The mixture of preparation S type ethylene glycol is the Tripotassium iron hexacyanide, salt of wormwood, four hydration potassium osmates, dihydroquinine-2, the 3-dihydro naphthalene catalyzer (DHQ) of mixing
2-PHAL, this mixture is called as AD-mix-α.These reagent are used to synthesis of chiral glycol (Sharpless et al.J.Org.Chem.57,2768-2771,1992 usually; And can be Marko et al.USP 4,965,364), from having bought on the market or the professional and technical personnel under lab prepares.
Along with the primary alconol in the chiral diol intermediate changes its corresponding leavings group into, replaced the protected product of generation by a primary amino as this leavings group of toluenesulphonic acids base.As requested, protecting group can upward be left away from corresponding substituent X, Y and/or Z, generates the finished product phenyl amine alcohol of high chiral purity, and photolytic activity purity reaches 99.5%.
X, Y and/or Z group are the substituting groups useful to the phenyl amine alcohol moiety, resemble beta-2 adrenoceptor excitomotor and domestic animal and urge long plain effect.X, Y substituting group are as hydroxyl, methylol, amido, N, relevant groups such as N-dimethyl methyl imide.Represent the better substituting group of Z such as the tertiary butyl, (CH
2) O (CH
2)
4-C
6H
5, CH (CH
3)-C
6H
4-p-OCH
3Etc. relevant group.
The acid salt that also can prepare chirality phenyl amine alcohol with method of the present invention.Suitable salt has inorganic acid salt to resemble hydrochloride, vitriol and some organic acid salt weevil benzene sulfonates, fumarate, benzoate.
Description of drawings Fig. 1: make target compound by multistep operation steps subsequently by phenyl aldehyde
Fig. 2: prepare left-handed salbutamol sulfate with method of the present invention
Fig. 3: the structure of Levalbuterol
Embodiment is equipped with R type salbutamol with this legal system, is an example of invention purposes, urges long plain important use as the good medicine and the domestic animal of treatment asthma, has promoted R-many preparation methods' of type salbutamol investigation.Fig. 2 has described with method of the present invention and has prepared left-handed salbutamol sulfate.
Synthesizing of example-Levalbuterol
The first step .4-hydroxyl-3-methylol-phenyl aldehyde
Stable hydrogen chloride gas is fed the 4-hydroxy benzaldehyde, and (24.4g, 0.2mol), (40% the aqueous solution 18ml), in the hydrochloric acid (110ml), keeps interior temperature to be lower than 40 ℃ (cooling off with frozen water) to formaldehyde, reacts 4 hours, and suction filtration is washed, and gets solid product.
Wet cake is dissolved in the mixed solution of 80ml tetrahydrofuran (THF) 50ml water.Branch adds 20g lime carbonate, stirring at room 12 hours.Tell organic phase, twice of extracted with diethyl ether of water.Organic phase merges, and washes anhydrous magnesium sulfate drying with water, filters, concentrate crude product.Crude product water recrystallization gets the rose pink crystallization of 26.5g, productive rate 86%.Mp.130-132 ℃;
1HNMR (CDCl
3), confirm structure.
The second step .2,2-dimethyl-6-aldehyde radical-phenyl [1,3]-dioxane
Under keeping 5-10 ℃, (26g, anhydrous propanone solution 80ml 0.17mol) and DMF 25ml join Vanadium Pentoxide in FLAKES, and (72g is 0.5mol) and in the toluene mixture of 50ml with 4-hydroxyl-3-methylol-phenyl aldehyde.Stir under the room temperature and spend the night.Add the 70g Vanadium Pentoxide in FLAKES again, continued to stir 2 hours.Mixture is filtered, and solid washs with acetone and ether.Filtrate decompression concentrates, residue water dissolution, extracted with diethyl ether.Organic phase is washed salt water washing, anhydrous magnesium sulfate drying with the sodium hydroxide of 1N.Filter evaporate to dryness.Residue vacuum-drying gets 26.8g white crystals product, productive rate 82%.Mp.58 ℃;
1HNMR (CDCl
3), confirm structure.
The 3rd step 2,2-dimethyl-6-vinyl-phenyl-[1,3]-dioxane
In nitrogen protection; under 0 ℃; with 2.5M n-Butyl Lithium/normal hexane (109ml; 0.27mol) drips of solution be added to the triphenyl phosphorus methyl iodide (109.2g, in the mixed solution of anhydrous tetrahydro furan 0.27mol) (100ml), 0 ℃ is stirred down 15min; then this mixture is added drop-wise under 0 ℃ in the solution of tetrahydrofuran (THF) (50ml) of aldehyde (26g0.135mol) of the second step gained; stir under the mixture room temperature and spend the night, use water treatment, petroleum ether extraction.Filter through the organic phase anhydrous magnesium sulfate drying, filtrate concentrates, oily matter, silicagel column is crossed post, (with 1: 9 ethyl acetate than sherwood oil towards post) must white paraffin shape compound 21.5g, productive rate 84%.
1HNMR (CDCl
3), confirm structure.
The 4th step 2,2-dimethyl-6-(1, the 2-dihydroxy ethyl)-phenyl [1,3] dioxane
AD-mix-β 154g is dissolved in the water of the trimethyl carbinol of 550ml and 550ml, stirs under the room temperature, is cooled to 0 ℃ then.(21g 0.11mol), forms heterogeneous muddy mixture, 0 ℃ of following vigorous stirring 8hr (thin plate monitoring level of response) to add above-mentioned paraffin shape compound in this mixture.Under 0 ℃ of stirring, add the 165g solid sodium sulfite, be raised to room temperature, restir 30min.Mixture extracts with ethyl acetate (3*150ml).Gained organic layer anhydrous magnesium sulfate drying filters, concentrate solid.Crude product gets 1,2 glycol with ethyl acetate and sherwood oil recrystallization, 22.2g, productive rate 90%.Specific rotation, R/S=98.5/1.5 (chirality HPLC),
1HNMR (CDCl
3), confirm structure.
The 5th step 2,2-dimethyl-6-(1-hydroxyl-2-(tolysulfonyl oxygen base) ethyl)-phenyl [1,3] dioxane
Under 0 ℃ with Tosyl chloride (19.8g, 104mol) join above-mentioned preparation 1,2 glycol (21g, 95mol) and exsiccant pyridine (150ml) in.Stir under the room temperature and spend the night, concentrate under the vacuum.The gained residue dissolves with frozen water, extracted with diethyl ether.Organic phase saturated common salt water washing, anhydrous magnesium sulfate drying filters.Vacuum concentration.Crude product gets corresponding tosylate white crystals, 29.3g, productive rate 82% with ethyl acetate and sherwood oil recrystallization.
1HNMR (CDCl
3), confirm structure.
The 6th step 2,2-dimethyl-6-(1-hydroxyl-2-(tert-butylamine) ethyl)-phenyl [1,3] dioxane
(28g, the mixture of tert-butylamine 74mol) (120ml) stir under reflux and spend the night above-mentioned tosylate, concentrate gained residue water dissolution, dichloromethane extraction under the vacuum.Organic phase saturated common salt water washing, anhydrous magnesium sulfate drying filters.Vacuum concentration.Crude product gets corresponding phenyl amine alcohol white crystals with chloroform and sherwood oil recrystallization, 16g, and productive rate 78%,
1HNMR (CDCl
3), confirm structure.
The 7th step sulfuric acid Levalbuterol
Above-mentioned phenyl amine alcohol (16g) joins in the dilute sulphuric acid of 100ml 3% and stirs 2hr under the room temperature.The reaction mixture extracted with diethyl ether, the water vacuum concentration.Residue gets the salbutamol sulfate white powder with recrystallizing methanol, 13.7g, productive rate 88%.Purity HPLC 99.6%.Specific rotation R/S=99.52/0.48 (chirality HPLC).
1H and
13CNMR (D
2O), confirm structure.α [25 ℃]=～35.2 (cl.0, water).
Use similar method, the professional can make other pure chipal compounds, resembles phenyl amine alcohol precursor, includes, but is not limited to salbutamol, Fu Mateluo, Salmeterol, terbutaline.
Claims (8)
1, the preparation method of the single optical isomer of a kind of phenyl amine alcohol (salbutamol) comprises the following steps:
(a) with the ethylene glycol that contains a primary alconol and a secondary alcohol of a vinylbenzene that suitably replaces by a chirality of asymmetric dihydroxy formation.
(b) primary alconol with ethylene glycol is transformed into a suitable leavings group,
(c) replace the chirality phenyl amine alcohol that this leavings group generates a band protecting group with the primary amine that suitably replaces.
(d) go protecting group, the chirality phenyl amine alcohol of protecting is converted into chirality phenyl amine alcohol.
2. according to statement 1, (a) styryl that suitably replaces in the step obtains by the phenyl aldehyde base is transformed into styryl.
3. according to statement 1, (b) leavings group in the step is the tosic acid base.
4. according to statement 1, comprised also in addition and changed chirality phenyl amine alcohol into acid salt this step that its acid salt is vitriol or hydrochloride.
5. according to the technology in arbitrary statement in the 1-4 item, (a) step is by carrying out with the styryl reaction of suitable replacement, prepares R type enantiomorph and prepares the enantiomorph of S type with AD-mix-α with AD-mix-β.
6. according to the technology in the statement of 1-4 item, its chirality phenyl amine alcohol is the beta-2 adrenoceptor excitomotor of phenyl amine alcohols.
7. according to statement 6, its beta-2 adrenoceptor excitomotor is a Levalbuterol.
8. according to statement 7, its beta-2 adrenoceptor excitomotor is the dextrorotation salbutamol.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2311793A1 (en) | 2004-12-17 | 2011-04-20 | Cipla Ltd. | Crystalline levosalbutamol sulphate (Form II) |
| CN104478740A (en) * | 2014-11-19 | 2015-04-01 | 上海化工研究院 | Synthesis method of stable isotope-labeled beta receptor agonist type compound |
| CN113666906A (en) * | 2021-09-23 | 2021-11-19 | 安徽有吉医药科技有限公司 | Synthesis method of 2-chloro-1- (2, 2-dimethyl-4H-benzo [1,3] dioxin-6-yl) ethanone |
| CN114539077A (en) * | 2022-04-07 | 2022-05-27 | 南京恒道医药科技有限公司 | Synthesis method of levalbuterol hydrochloride |
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2002
- 2002-09-13 CN CNB02131215XA patent/CN100432044C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2311793A1 (en) | 2004-12-17 | 2011-04-20 | Cipla Ltd. | Crystalline levosalbutamol sulphate (Form II) |
| CN104478740A (en) * | 2014-11-19 | 2015-04-01 | 上海化工研究院 | Synthesis method of stable isotope-labeled beta receptor agonist type compound |
| CN113666906A (en) * | 2021-09-23 | 2021-11-19 | 安徽有吉医药科技有限公司 | Synthesis method of 2-chloro-1- (2, 2-dimethyl-4H-benzo [1,3] dioxin-6-yl) ethanone |
| CN114539077A (en) * | 2022-04-07 | 2022-05-27 | 南京恒道医药科技有限公司 | Synthesis method of levalbuterol hydrochloride |
| CN114539077B (en) * | 2022-04-07 | 2023-12-08 | 南京恒道医药科技股份有限公司 | Synthesis method of levosalbutamol hydrochloride |
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