GB1598668A - Indolyloxymethyl-2-oxazolidinone derivatives and their use in the preparation of 1-amino-3-(indolyloxy)-2-propanols - Google Patents
Indolyloxymethyl-2-oxazolidinone derivatives and their use in the preparation of 1-amino-3-(indolyloxy)-2-propanols Download PDFInfo
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- GB1598668A GB1598668A GB20036/80A GB2003680A GB1598668A GB 1598668 A GB1598668 A GB 1598668A GB 20036/80 A GB20036/80 A GB 20036/80A GB 2003680 A GB2003680 A GB 2003680A GB 1598668 A GB1598668 A GB 1598668A
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- HNAKTPCVTOXAAE-UHFFFAOYSA-N 3-(1H-indol-2-yloxymethyl)-1,3-oxazolidin-2-one Chemical class N1C(=CC2=CC=CC=C12)OCN1C(OCC1)=O HNAKTPCVTOXAAE-UHFFFAOYSA-N 0.000 title description 2
- 238000002360 preparation method Methods 0.000 title description 2
- VPOYCNSBWBCOEK-UHFFFAOYSA-N 1-amino-3-(1H-indol-2-yloxy)propan-2-ol Chemical class OC(COC=1NC2=CC=CC=C2C1)CN VPOYCNSBWBCOEK-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 51
- 238000000034 method Methods 0.000 claims description 31
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical group C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000002346 iodo group Chemical group I* 0.000 claims description 2
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims description 2
- 125000005905 mesyloxy group Chemical group 0.000 claims description 2
- 229910052717 sulfur Chemical group 0.000 claims description 2
- 239000011593 sulfur Chemical group 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- BHNHHSOHWZKFOX-UHFFFAOYSA-N 2-methyl-1H-indole Chemical compound C1=CC=C2NC(C)=CC2=C1 BHNHHSOHWZKFOX-UHFFFAOYSA-N 0.000 claims 1
- WDGCBNTXZHJTHJ-UHFFFAOYSA-N 2h-1,3-oxazol-2-id-4-one Chemical group O=C1CO[C-]=N1 WDGCBNTXZHJTHJ-UHFFFAOYSA-N 0.000 claims 1
- 239000012458 free base Substances 0.000 claims 1
- 238000007142 ring opening reaction Methods 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000011734 sodium Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- -1 indol-4-yl Chemical group 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000000725 suspension Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- JGRPZAGOYKNIAC-UHFFFAOYSA-N ethyl n-propan-2-ylcarbamate Chemical compound CCOC(=O)NC(C)C JGRPZAGOYKNIAC-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- RXRVCSDDGFQDOJ-LURJTMIESA-N (5s)-5-(hydroxymethyl)-3-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)N1C[C@@H](CO)OC1=O RXRVCSDDGFQDOJ-LURJTMIESA-N 0.000 description 3
- SIJBDWPVNAYVGY-UHFFFAOYSA-N 2,2-dimethyl-1,3-dioxolane Chemical compound CC1(C)OCCO1 SIJBDWPVNAYVGY-UHFFFAOYSA-N 0.000 description 3
- GOEGYHBXKPIDJE-UHFFFAOYSA-N 3-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)N1CCOC1=O GOEGYHBXKPIDJE-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- RNFDZDMIFOFNMC-UHFFFAOYSA-N 1-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NCC(C)O RNFDZDMIFOFNMC-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
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CLPYLBMXTAOERP-QMMMGPOBSA-N N-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]propan-2-amine Chemical compound C(C)(C)NC[C@@H]1OC(OC1)(C)C CLPYLBMXTAOERP-QMMMGPOBSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- VSBCXARDKFKTHY-LBPRGKRZSA-N [(5s)-2-oxo-3-propan-2-yl-1,3-oxazolidin-5-yl]methyl 4-methylbenzenesulfonate Chemical compound O1C(=O)N(C(C)C)C[C@H]1COS(=O)(=O)C1=CC=C(C)C=C1 VSBCXARDKFKTHY-LBPRGKRZSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000001165 hydrophobic group Chemical group 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- YSGPYVWACGYQDJ-YFKPBYRVSA-N (4r)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde Chemical compound CC1(C)OC[C@H](C=O)O1 YSGPYVWACGYQDJ-YFKPBYRVSA-N 0.000 description 1
- ODYBCPSCYHAGHA-UHFFFAOYSA-N 1,2-bis(2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol Chemical compound O1C(C)(C)OCC1C(O)C(O)C1OC(C)(C)OC1 ODYBCPSCYHAGHA-UHFFFAOYSA-N 0.000 description 1
- 150000000180 1,2-diols Chemical class 0.000 description 1
- DAFLOHLGKOOTKU-UHFFFAOYSA-N 1,3-dioxolane-4-carbaldehyde Chemical compound O=CC1COCO1 DAFLOHLGKOOTKU-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004797 2,2,2-trichloroethoxy group Chemical group ClC(CO*)(Cl)Cl 0.000 description 1
- YSGPYVWACGYQDJ-UHFFFAOYSA-N 2,2-dimethyl-1,3-dioxolane-4-carbaldehyde Chemical compound CC1(C)OCC(C=O)O1 YSGPYVWACGYQDJ-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
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- NLMQHXUGJIAKTH-UHFFFAOYSA-N 4-hydroxyindole Chemical compound OC1=CC=CC2=C1C=CN2 NLMQHXUGJIAKTH-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 description 1
- PWAPCRSSMCLZHG-UHFFFAOYSA-N cyclopentylidene Chemical group [C]1CCCC1 PWAPCRSSMCLZHG-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/38—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system containing rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/28—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/93—Spiro compounds
- C07C2603/94—Spiro compounds containing "free" spiro atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Indole Compounds (AREA)
Description
PATENT SPECIFICATION
Application No 20036/80 ( 22) Filed 21 March 1978 Divided out of No 1598667 Convention Application No 3754/77 Filed 24 March 1977 in Switzerland (CH) Complete Specification published 23 Sept 1981
INT CL 3 C 07 D 263/24 263/16 Index at acceptance C 2 C 1343 1371 213 215 247 250 251 255 25 Y 28 X 305 30 Y 351 352 360 361 364 36 Y 388 624 625 652 672 761 768 AA TX ( 72) Inventor EDOUARD LIER ( 54) NOVEL INDOLYLOXYMETHYL-2-OXAZOLIDINONE DERIVATIVES, AND THEIR USE IN THE PREPARATION OF l-AMINO-3(INDOLYLOXY)-2-PROPANOLS.
( 71) We, SANDOZ LTD, of 35 Lichtstrasse, 4002 Basle Switzerland, a Swiss Body Corporate, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
The invention provides a process for the o 10 production of a compound of formula I Ar-OCH 2 CH(OH)CH 2 NH-Rl I wherein Ar is indol-4-yl or 2-methylinol-4-yl and R, is isopropyl or tert-butyl and esters thereof, which comprises splitting off the group \ C=X / from a corresponding compound of formula II Ar O-CH 2-CH H 2 O c N-R 1 Ix X II wherein Ar and R, are as defined above and X is oxygen or sulfur and, if desired, esterifying the hydroxy group of the resultant compound of formula I.
The compounds of formula I are in general known The compounds of formula I and esters thereof are pharmacteutically active, possessing 5-blocking activity.
The compounds of formula I or an ester thereof may be in optically active (R) or (S) form or in racemic form.
The above process is applicable not only to the production of racemic compounds, but also, and preferably, to the production of optically active compounds in R or S form, because the configuration of the 2carbon of the propyl moiety is maintained in the above reaction and in the reactions described hereinafter.
The process is particularly useful for the production of optically active compounds.
Thus 2 S-isomers, which in general are the more active optical as regards beta-blocking activity, may be produced, in which case the intermediates have the following configuration:H O -OCH 2 C CH N 2 2 \ The process according to the invention may be effected in conventional manner, e.g under basic conditions, e g with an alkali metal hydroxide Alternatively strong acidic or reductive conditions, where appropriate, may be used.
An advantage of the process is that it may be effected under a wide range of conditions, e g acidic, basic or reductive conditions.
If desired the hydroxy group of the resultant compound of formula I may be esterified, e g by an aryl carboxylic acid, an aliphatic carboxylic acid or an alicyclic carboxylic acid of, e g up to 10 carbon atoms.
A compound of formula II may be produced by a process comprising condensing a compound of formula III Ar OH III wherein Ar is as defined above with a compound of formula IV, ( 21) ( 62) ( 31) ( 32) ( 33) ( 44) ( 51) ( 52) ( 11) 1 598 668 V-CH 2 _CH CH 2 II X N-R X IV wherein X and R, are as defined above and Z' is a leaving group.
This reaction may be effected in conventional manner The compound of formula IV may be obtained by introducing a leaving group Z' into a compound of formula V R 0.CHCH CH 2 \ N-R 1 X V wherein X and R 1 are as defined above.
The introduction of a leaving group Z' may be effected in conventional manner It is to be appreciated that Z' will be appropriately chosen bearing in mind the nature of the compounds Z' may be, for example, chloro, bromo or iodo or especially mesyloxy or tosyloxy.
A compound of formula V may be produced by a process comprising intramolecularly cyclizing a compound of formula VI.
HOCH 2-CH(OH-CH 2-NR,-C(X)R 2 VI wherein X and R, are as defined above and R 2 is a leaving group.
The process may be effected in conventional manner for such intromolecular cyclizations, e g of urethanes Conveniently X is oxygen R 2 is conveniently alkoxy (C 1 _ 4), haloalkoxy (C,4), phenoxy or benzyloxy unsubstituted or substituted by halogen, alkyl (C,_ 4) or alkoxy (C 1 _ 4) (halogen is preferably fluorine, bromine or especially chlorine) Preferred examples of R 2 include 2,2,2-trichloroethoxy, and especially methoxy, ethoxy, and unsubstituted benzyloxy or phenoxy The reaction is conveniently effected under basic conditions, e g in the presence of sodium hydroxide, pyridine or triethylamine Suitable reaction temperatures may be from O to 50 C, e g.
room temperature Suitable solvents include tetrahydrofuran, dioxane, ethanol or methanol, or water.
A compound of formula VI may be produced by a process comprising splitting off the protecting group A from a compound of formula VII H 2-CH-CH 2-N Rc -C (X) -R 2 VII 0 O A wherein R, R 2 and X are as defined above 50 and A is a protecting group.
The reaction may be effected in conventional manner for deprotecting a 1,2diol without splitting off the moiety 55 C(=X) R 2 The protecting group A is conviently a hydrophobic group and may, as will be appreciated from the reactions described hereinafter, for example be a base-stable group For example A may be 60 alkylidene, e g of I to 5 carbon atoms, which is preferably symmetrical, e g.
methylene or preferably isopropylidene.
Alternatively A may be a cycloalkylidene, e.g such as cyclohexylidene or 65 cyclopentylidene, or a benzylidene group which may be substituted in the ring, e g by nitro The reaction may be effected with an organic acid, e g aqueous acetic acid, or preferably with a mineral acid such as 70 aqueous hydrochloric acid An appropriate solvent such as methanol may be present.
Suitable temperatures are between O and C, e g 10 C It is to be appreciated that the resultant compound of formula VI may 75 be further converted into a compound of formula III directly without purification.
A compound of formula VII may be produced by a process comprising reacting a compound of formula VIII 80 CH 2 CH CH 2NHR O N.
VIII wherein A and R, are as defined above, with a compound of formula IX Y.C(=X) R 2 IX 85 wherein R 2 and X are as defined above and Y is a group capable of being split off with the hydrogen of an amine.
The reaction may be effected in conventional manner, e g for a SchottenBaumann reaction Y is, for example, chlorine Alternatively Y may be alkoxy (which may conveniently be the same as R, when this is alkoxy) The reaction may be effected at a temperature of from O to C.
A compound of formula VIII may be obtained by reductively aminating a compound of formula X H 2 CH CHO o O A/ 1, X 100 wherein A is as defined above The above process steps, in general, may lead to high yields of optically active or racemic products with the formation of few side products, or side products which may 105 be easily removed using conventional 1,598 668 1,598,668 purification procedures, e g crystallization, chromatography or distillation.
Naturally two or more of the above steps may be effected without isolating and/or purifying the intermediate product(s).
A particular advantage of this process as a whole is that when A is a hydrophobic group, then the intermediates of formulae VII and VIII are less water soluble than the corresponding diols with the result that working up of the reaction mixtures using extraction of aqueous solutions with organic solvents or washing of organic solutions with aqueous solvents is more efficient than with the corresponding diols Such an advantage is particularly useful when the intermediates of formulae VII and VIII are oils at room temperatures.
Insofar as the production of any compound is not particularly described, then this is known or may be prepared according to conventional methods.
The compounds of formula VII, their production and use as described above are described and claimed in Application No.
11113/78 (Patent Specification No.
1598667).
In the following examples all temperatures are in degree Centigrade and are uncorrected Unless otherwise mentioned all optical rotations are expressed as a 1 % (w/v) solution in methanol.
EXAMPLE 1 ( 2 S) I (Indol 4 yloxy) 3isopropylamino 2 propanol A suspension of 19 5 g of ( 55) 5 (indol 4 yloxy methyl) 3 isopropyl 2 oxazolidinone, 200 ml of ethanol and 180 ml of 4 N Na OH are heated at reflux overnight, the solvent is distilled off and the residue is taken up in methylene choride/water The aqueous phase is extracted with methylene chloride The combined organic phases are washed neutral with water, dried over Na 25 O 4 and concentrated by evaporation The residue is crystallized from benzene The title compound is obtained (M P 939450) li 120-7 8 ( 1 % CHCI 3) la 120 o 4 80 ( 1 %/ methanol).
The starting material may be obtained as follows:
a) ( 4 S) 4 Isopropylaminomethyl 2,2 dimethyl 1,3 dioxolane (Compound of formula VIII) 52.5 g of ( 4 R) 2,2 dimethyl 1,3 dioxolane 4 carbaldehyde in 400 ml methanol lobtained by treating 1,2,5,6diiso propylidene D mannitol with lead tetracetatel are added dropwise to a suspension of 5 25 g of 10 / palladium-oncharcoal in 150 ml of methanol and 86 ml of isopropylamine in the presence of hydrogen over 2 hours The mixture is hydrogenated overnight at I atmosphere.
The catalyst is filtered off and the methanol is distilled off The residue is stirred for 5 minutes with a solution of 95 g of Na 2 CO 3 in 500 ml of water and is extracted thrice with methylene chloride The organic phases are dried with Na 2 SO 4 and the filtrate is concentrated by evaporation.
The yellowish oil is subsequently distilled at 42 ( 0 1 mm Hg) to give the heading compound lcalo -7 2 ( 2 % methanol).
b) N l 4 S) 2,2 Dimethyl 1,3dioxolan 4 ylmethyll N isopropyl carbamic acid ethyl ester (Compound of formula VII) g of ( 4 S) 4 isopropylaminomethyl 2,2 dimethyl 1,3 dioxolane are dissolved in 1 5 1 of methylene chloride and are cooled to 0 To this solution there are added dropwise during the course of one hour simultaneously 92 ml of ethyl chloroformate and 240 ml of 4 N sodium hydroxide and the suspension is thoroughly stirred for 30 minutes at 0 The suspension is then made acid with cold 10 % tartaric acid, the phases are separated and the aqueous phase is extracted thrice with methylene chloride The combined organic phases are shaken twice with cold 2 N Na OH, washed with water, dried over Na 2 SO 4 and concentrated by evaporation.
Distillation of the residue yields pure N l( 4 S)2,2 dimethyl 1,3 dioxolan 4 ylmethyll N isopropylcarbamic acid ethyl ester of B P 96 ( 0 6 mm Hg), (a)J O -19 20.
c) ( 2 S)N ( 2,3 Dihydroxypropyl) N isopropylcarbamic acid ethyl ester (Compound of formula VI) 7 g of N l( 4 S) 2,2 dimethyl 1,3 dioxolan 4 ylmethyll N isopropylcarbamic acid ethyl ester are stirred in 500 ml of methanol and 115 ml of 4 N HCI for two hours at 10 and are concentrated by evaporation in a vacuum.
( 2 S) N ( 2,3 dihydroxypropyl) Nisopropyl carbamic acid ethyl ester is obtained, lal 20-19 9 %Y, which is further reacted in crude form.
d) ( 5 S) 5 Hydroxymethyl 3 isopropyl 2 oxazolidinone (Compound of formula V) 4 N Na OH are added to 98 7 g of crude ( 2 S) N ( 2,3 dihydroxypropyl) N-isopropylcarbamic acid ethyl ester until the p H is 13 The mixture is allowed to stand for 2 hours at 20 and then extracted thrice with methylene chloride The organic phases are washed with 6 M Na CI, dried 1,598,668 over Na 2 SO 4 and the solvent is distilled off.
The title compound is obtained (M P 5659 -from methylene chloride/ether).
lt 12 + 49 1 0.
Instead of ethyl chloroformate, either benzyl chloroformate or phenyl chloroformate may be used in step b) to produce the corresponding benzyl ester of formula VII B P 130-133 ( 0 03 mm Hg) lal -20 1 ( 2 % methanol) or phenyl ester of formula VII B P 123-125 ( 0 1 mm Hg) la 20 _ 33 7 , respectively, which may be further reacted according to steps c) and d) to produce ( 5 S) 5 hydroxymethyl 3 isopropyl 2 oxazolidinone.
e) ( 5 S) 3 isopropyl 5 tosyloxymethyl 2 oxazolidinone (Compound of formula IV) 32.8 g of p-toluenesulfonyl chloride are added over 30 minutes to a solution of 24 8 g of ( 5 S) 5 hydroxymethyl 3 isopropyl 2 oxazolidinone in 60 ml of pyridine at -5 and are kept overnight at 00.
The mixture is poured onto ice, the oil is extracted with methylene chloride and the organic phases are washed with 2 N HCI and water After the phases have been dried over Na SO 4 the methylene chloride is removed and the residue is crystallized from methylene chloride/ether ( 5 S) 3 Isopropyl 5 tosyloxymethyl 2oxazolidinone is obtained (M P 77-79 ) la 1 l 20 + 51 8 f) ( 5 S)5 (indol 4 yloxymethyl) 3 isopropyl 2 oxazolidinone (Compound of formula II) A solution of 17 4 g of 4 hydroxyindole in ml of N,N dimethylformamide is added dropwise during one hour to a suspension of 6 3 g of sodium hydride ( 50 % dispersion) and 50 ml of N,N dimethylformamide under argon The temperature is kept below 35 The suspension is stirred for 1.5 hours at room temperature, 41 g of ( 5 S) 3 isopropyl 5 tosyloxymethyl 2 oxazolidinone in 50 ml of N,N-dimethylformamide are added dropwise and stirred at 80 overnight under argon.
The suspension is poured onto ice and shaken with methylene chloride The organic phases are washed with 2 N Na OH and water, dried over Na 2 SO 4 and concentrated by evaporation The residue is crystallized from methylene chloride/ether ( 5 S) 5 (Indol 4 yloxymethyl) 3 isopropyl 2 oxazolidinone is obtained (M P 139142 -from CH 2 CI 2/ether) lal 20 + 56 7 .
EXAMPLE 2
In analogous manner to that described in Example 1, racemic 2,2 dimethy 1,3 dioxolane 4 carbaldehyde may be converted into racemic I (indol 4yloxy) 3 isopropylamino 2 propanol.
M.P 171-173 (from ethanol).
EXAMPLE 3
In analogous manner to that described in Example 1, 4 S 2,2 dimethyl 1,3 dioxolane 4 carbaldehyde may be converted into ( 2 R) I (indol 4yloxy) 3 isopropylamino 2 propanol.
M.P 93-95 O la 1 46 + 77 ( 1 % CHCI 3).
lal 546 + 4 8 ( 1 % methanol).
Claims (17)
- WHAT WE CLAIM IS:-I A process for the production of a compound of formula I Ar-OCH 2 CH(OH)CH 2 NH-R, I wherein Ar is indol 4 yl or 2 methylindol 4 yl and R, is isopropyl or tert-butyl, and esters thereof, which comprises splitting off the group C=X / from a corresponding compound of formula II Ar O-CH 2-CH HH 2 O O CN-R x X II wherein Ar and R 1 are as defined above and X is oxygen or sulfur, and, if desired, esterifying the hydroxy group of the resultant compound of formula I.
- 2 A process according to claim I wherein X is 0.
- 3 A process according to claim I wherein the compound of formula II is produced by condensing a compound of formula III Ar OH III wherein Ar is as defined in claim 1 with a compound of formula IV :-% l CH CH 2 c N-R 1 11 1 IIX X IV wherein X and R, are as defined in claim I and Z' is a leaving group.
- 4 A process according to claim 3 wherein 100 Z' is mesyloxy or tosyloxy and X is 0.
- A process according to claim 3 wherein Z' is chloro, bromo or iodo and X is 0 and wherein the subsequent oxazolidone ring opening step is effected in the presence of 105 an alkali metal hydroxide.
- 6 A process according to any one of claims 3, 4 or 5 wherein the compound of 1,598,668 5 formula IV is produced by introducing a group Z' into a compound of formula V HO.CH 2 CH CH 2 1, N-R 1 II X V wherein X and R, are as defined in claim 1.
- 7 A process according to claim 6, wherein the compound of formula V is produced by a process comprising intramolecularly cyclising a compound of formula VI HOCH 2-CH(OH)-CH 2 N Ri C(=X)-R 2 VI wherein R 1 and X are as defined in claim 1 and R 2 is a leaving group.
- 8 A process according to claim 7, wherein the compound of formula VI is produced by a process comprising splitting off the protecting group A from a compound of formula VII H 2-CH-CH 2-NR 1-C (=X) -R 2 0 \ O A VII wherein R, and X are as defined in claim 3, R 2 is a leaving group and A is a protecting group.
- 9 A process according to claim 8, wherein X is O and A is isopropylidene.
- A process as claimed in claim 1 substantially as hereinbefore described with reference to any one of the Examples.
- 11 A process according to any one of claims 1 to 10, wherein the compound produced is in racemic form.
- 12 A process according to any one of claims 1 to 10 wherein the compound produced is in S optically active form.
- 13 A process according to any one of claims 1 to 12, wherein the compound produced is in free base form.
- 14 A compound of formula I as defined in claim 1 or an ester thereof, whenever obtained by a process of any one of claims 1 to 13.
- A compound of formula I, wherein Ar is indol 4 yl and R 2 is isopropyl, whenever produced by a process of any one of claims 1 to 13.
- 16 A compound of formula II as defined in claim 1 in optically active or racemic form.
- 17 A compound of formula I as stated in claim 1, whenever produced by a process as claimed in claim 8.B A YORKE & CO, Chartered Patent Agents, 98 The Centre, Feltham, Middlesex TW 13 4 EP Agents for the applicants.Printed for Her Majesty's Stationery Office, by the Courier Press, Leamington Spa, 1981 Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.1,598,668
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH375477A CH635573A5 (en) | 1977-03-24 | 1977-03-24 | Process for preparing novel 1,2-dihydroxypropane derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1598668A true GB1598668A (en) | 1981-09-23 |
Family
ID=4262769
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB11113/78A Expired GB1598667A (en) | 1977-03-24 | 1978-03-21 | 1,3-dioxolane derivatives and their use in the preparation of 1-amino-3-aryloxy-2-propanols |
GB20036/80A Expired GB1598668A (en) | 1977-03-24 | 1978-03-21 | Indolyloxymethyl-2-oxazolidinone derivatives and their use in the preparation of 1-amino-3-(indolyloxy)-2-propanols |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB11113/78A Expired GB1598667A (en) | 1977-03-24 | 1978-03-21 | 1,3-dioxolane derivatives and their use in the preparation of 1-amino-3-aryloxy-2-propanols |
Country Status (8)
Country | Link |
---|---|
JP (3) | JPS53119824A (en) |
BE (1) | BE865201A (en) |
CH (4) | CH635573A5 (en) |
DE (1) | DE2810732A1 (en) |
FR (1) | FR2401148A1 (en) |
GB (2) | GB1598667A (en) |
IT (1) | IT1104182B (en) |
NL (1) | NL7802986A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070265451A1 (en) * | 2001-10-18 | 2007-11-15 | Board Of Trustees Of Michigan State University | Process for the preparation of oxazolidinones and method of use thereof |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS574969A (en) * | 1980-06-13 | 1982-01-11 | Paamakemu Asia:Kk | Preparation of indole derivative |
JPS577465A (en) * | 1980-06-13 | 1982-01-14 | Paamakemu Asia:Kk | Preparation of indole derivative |
JPS5973223U (en) * | 1982-11-06 | 1984-05-18 | ブラザー工業株式会社 | Jusa |
JPS59227238A (en) * | 1983-06-06 | 1984-12-20 | Tetsuya Nishikura | Rot-proof paste food and its preparation |
DE3330005A1 (en) * | 1983-08-19 | 1985-02-28 | Wolfgang Dr. Graz Lindner | TONIC ACID MONOESTERS OF OPTICALLY ACTIVE ALKANOLAMINES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
JPS60261586A (en) * | 1984-06-09 | 1985-12-24 | Fuiruton Internatl Kk | Method for removing metal, metallic ion, and organic chlorine from water |
SE8404073D0 (en) * | 1984-08-13 | 1984-08-13 | Haessle Ab | METHOD FOR THE SYNTHESIS OF PHARMACOLOGICALLY ACITVE COMPOUNDS AND INTERMEDIATES FOR SUCH SYNTHESIS |
JPS61192268A (en) * | 1985-02-19 | 1986-08-26 | Yagira Suisan:Kk | Preparation of boiled fish paste having taste and flavor of sushi |
CH674843A5 (en) * | 1988-01-26 | 1990-07-31 | Lonza Ag | |
SE8801518D0 (en) * | 1988-04-22 | 1988-04-22 | Astra Pharma Prod | A NOVEL PROCESS |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH572924A5 (en) * | 1972-04-19 | 1976-02-27 | Frosst & Co Charles E | Thiadiazole derivs - for treating angina pectoris |
GB1435276A (en) * | 1974-04-10 | 1976-05-12 | Pfizer Ltd | Oxazolidines and conversion to propanolamines |
-
1977
- 1977-03-24 CH CH375477A patent/CH635573A5/en not_active IP Right Cessation
-
1978
- 1978-03-13 DE DE19782810732 patent/DE2810732A1/en not_active Withdrawn
- 1978-03-20 NL NL7802986A patent/NL7802986A/en not_active Application Discontinuation
- 1978-03-21 GB GB11113/78A patent/GB1598667A/en not_active Expired
- 1978-03-21 GB GB20036/80A patent/GB1598668A/en not_active Expired
- 1978-03-22 BE BE186192A patent/BE865201A/en not_active IP Right Cessation
- 1978-03-23 IT IT48559/78A patent/IT1104182B/en active
- 1978-03-23 JP JP3246378A patent/JPS53119824A/en active Granted
- 1978-03-24 FR FR7808660A patent/FR2401148A1/en active Granted
-
1981
- 1981-03-25 JP JP4260381A patent/JPS5716853A/en active Pending
- 1981-03-25 JP JP4260281A patent/JPS579781A/en active Pending
- 1981-08-19 CH CH535681A patent/CH639953A5/en not_active IP Right Cessation
-
1982
- 1982-04-02 CH CH205982A patent/CH640212A5/en not_active IP Right Cessation
- 1982-05-27 CH CH326982A patent/CH642646A5/en not_active IP Right Cessation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070265451A1 (en) * | 2001-10-18 | 2007-11-15 | Board Of Trustees Of Michigan State University | Process for the preparation of oxazolidinones and method of use thereof |
Also Published As
Publication number | Publication date |
---|---|
CH639953A5 (en) | 1983-12-15 |
IT7848559A0 (en) | 1978-03-23 |
CH635573A5 (en) | 1983-04-15 |
BE865201A (en) | 1978-09-22 |
CH640212A5 (en) | 1983-12-30 |
JPS5716853A (en) | 1982-01-28 |
CH642646A5 (en) | 1984-04-30 |
GB1598667A (en) | 1981-09-23 |
DE2810732A1 (en) | 1978-09-28 |
JPS579781A (en) | 1982-01-19 |
FR2401148A1 (en) | 1979-03-23 |
IT1104182B (en) | 1985-10-21 |
NL7802986A (en) | 1978-09-26 |
JPS53119824A (en) | 1978-10-19 |
FR2401148B1 (en) | 1983-01-28 |
JPS5730113B2 (en) | 1982-06-26 |
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Legal Events
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PS | Patent sealed [section 19, patents act 1949] | ||
PCNP | Patent ceased through non-payment of renewal fee |