NO179450B - Analogous process for the preparation of 4-substituted 2-aminoalk-3-eno acids - Google Patents
Analogous process for the preparation of 4-substituted 2-aminoalk-3-eno acids Download PDFInfo
- Publication number
- NO179450B NO179450B NO904169A NO904169A NO179450B NO 179450 B NO179450 B NO 179450B NO 904169 A NO904169 A NO 904169A NO 904169 A NO904169 A NO 904169A NO 179450 B NO179450 B NO 179450B
- Authority
- NO
- Norway
- Prior art keywords
- amino
- phosphonomethyl
- enoic acid
- hydroxy
- ethyl ester
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 230000008569 process Effects 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 239000002253 acid Substances 0.000 title abstract description 20
- 150000007513 acids Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 150000003839 salts Chemical class 0.000 claims abstract description 46
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 26
- 239000000203 mixture Substances 0.000 claims abstract description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical class NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000007858 starting material Substances 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- BDIISILJKJGWEW-UHFFFAOYSA-N [4-amino-5-ethoxy-2-(2-fluoroethyl)-5-oxopent-2-enyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CCF)CP(O)(O)=O BDIISILJKJGWEW-UHFFFAOYSA-N 0.000 claims description 3
- DNMKUTJZKQHZJX-UHFFFAOYSA-N [4-amino-5-ethoxy-2-(2-hydroxyethyl)-5-oxopent-2-enyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CCO)CP(O)(O)=O DNMKUTJZKQHZJX-UHFFFAOYSA-N 0.000 claims description 3
- FDAGOTTWUNLLOP-UHFFFAOYSA-N [4-amino-5-ethoxy-2-(2-methoxyethyl)-5-oxopent-2-enyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CP(O)(O)=O)CCOC FDAGOTTWUNLLOP-UHFFFAOYSA-N 0.000 claims description 3
- ZWECDLATICDICM-UHFFFAOYSA-N [4-amino-5-ethoxy-2-(3-hydroxypropyl)-5-oxopent-2-enyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CP(O)(O)=O)CCCO ZWECDLATICDICM-UHFFFAOYSA-N 0.000 claims description 3
- GAMAQLIMMSMPNA-UHFFFAOYSA-N [8-amino-2-(2-amino-3-ethoxy-3-oxopropylidene)octyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CP(O)(O)=O)CCCCCCN GAMAQLIMMSMPNA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000004494 ethyl ester group Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- CTVZYLFMXUAAQZ-UHFFFAOYSA-N 2-amino-6-hydroxy-4-(phosphonomethyl)hex-3-enoic acid Chemical compound OC(=O)C(N)C=C(CCO)CP(O)(O)=O CTVZYLFMXUAAQZ-UHFFFAOYSA-N 0.000 claims description 2
- RFPJMDKTBMDVFE-UHFFFAOYSA-N 2-amino-6-methoxy-4-(phosphonomethyl)hex-3-enoic acid Chemical compound COCCC(CP(O)(O)=O)=CC(N)C(O)=O RFPJMDKTBMDVFE-UHFFFAOYSA-N 0.000 claims description 2
- PTYIQTMXSJCCIC-UHFFFAOYSA-N 2-amino-7-hydroxy-4-(phosphonomethyl)hept-3-enoic acid Chemical compound OC(=O)C(N)C=C(CP(O)(O)=O)CCCO PTYIQTMXSJCCIC-UHFFFAOYSA-N 0.000 claims description 2
- WKCQTPLGPMICCC-UHFFFAOYSA-N [4-amino-5-ethoxy-2-(ethoxymethyl)-5-oxopent-2-enyl]phosphonic acid Chemical compound CCOCC(CP(O)(O)=O)=CC(N)C(=O)OCC WKCQTPLGPMICCC-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- BCSPXGHLTKQWAB-UHFFFAOYSA-N 2,10-diamino-4-(phosphonomethyl)dec-3-enoic acid Chemical compound NCCCCCCC(CP(O)(O)=O)=CC(N)C(O)=O BCSPXGHLTKQWAB-UHFFFAOYSA-N 0.000 claims 1
- NBPWJAAXBIRKQO-UHFFFAOYSA-N 2-amino-4-(hydroxymethyl)-5-phosphonopent-3-enoic acid Chemical compound OC(=O)C(N)C=C(CO)CP(O)(O)=O NBPWJAAXBIRKQO-UHFFFAOYSA-N 0.000 claims 1
- WSTSEHBPVVVXHA-UHFFFAOYSA-N 2-amino-6-(methylamino)-4-(phosphonomethyl)hex-3-enoic acid Chemical compound CNCCC(CP(O)(O)=O)=CC(N)C(O)=O WSTSEHBPVVVXHA-UHFFFAOYSA-N 0.000 claims 1
- GLTVTLNNHBUFOL-UHFFFAOYSA-N 2-amino-8-hydroxy-4-(phosphonomethyl)oct-3-enoic acid Chemical compound OC(=O)C(N)C=C(CP(O)(O)=O)CCCCO GLTVTLNNHBUFOL-UHFFFAOYSA-N 0.000 claims 1
- VYQKONACMHXMLZ-UHFFFAOYSA-N [2-(2-amino-3-ethoxy-3-oxopropylidene)-6-hydroxyhexyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CP(O)(O)=O)CCCCO VYQKONACMHXMLZ-UHFFFAOYSA-N 0.000 claims 1
- DTRJVCAKYINYSZ-UHFFFAOYSA-N [2-(2-amino-3-ethoxy-3-oxopropylidene)-8-hydroxyoctyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CP(O)(O)=O)CCCCCCO DTRJVCAKYINYSZ-UHFFFAOYSA-N 0.000 claims 1
- WDNUXVXTSKURHQ-UHFFFAOYSA-N [4-amino-5-ethoxy-2-(hydroxymethyl)-5-oxopent-2-enyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CO)CP(O)(O)=O WDNUXVXTSKURHQ-UHFFFAOYSA-N 0.000 claims 1
- 239000000470 constituent Substances 0.000 claims 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 abstract description 7
- 125000001931 aliphatic group Chemical group 0.000 abstract description 7
- 239000004215 Carbon black (E152) Substances 0.000 abstract description 4
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- 102000018899 Glutamate Receptors Human genes 0.000 abstract description 2
- 108010027915 Glutamate Receptors Proteins 0.000 abstract description 2
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- 230000003042 antagnostic effect Effects 0.000 abstract description 2
- 125000004432 carbon atom Chemical group C* 0.000 abstract 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 abstract 1
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 35
- -1 5-hydroxypentyl Chemical group 0.000 description 34
- 239000000243 solution Substances 0.000 description 28
- 239000003921 oil Substances 0.000 description 21
- 235000019198 oils Nutrition 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
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- 238000003756 stirring Methods 0.000 description 16
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- SJHCUXCOGGKFAI-UHFFFAOYSA-N tripropan-2-yl phosphite Chemical compound CC(C)OP(OC(C)C)OC(C)C SJHCUXCOGGKFAI-UHFFFAOYSA-N 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
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- 125000000217 alkyl group Chemical group 0.000 description 12
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 8
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- 238000000746 purification Methods 0.000 description 7
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- 125000003545 alkoxy group Chemical group 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- FPULFENIJDPZBX-UHFFFAOYSA-N ethyl 2-isocyanoacetate Chemical compound CCOC(=O)C[N+]#[C-] FPULFENIJDPZBX-UHFFFAOYSA-N 0.000 description 6
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- 239000013543 active substance Substances 0.000 description 5
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- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
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- 239000000047 product Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
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- 241000699670 Mus sp. Species 0.000 description 3
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- 125000004423 acyloxy group Chemical group 0.000 description 3
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
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- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
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- WVHVBYLHVDIPBY-UHFFFAOYSA-N benzyl n-(7-formyloct-7-enyl)carbamate Chemical compound O=CC(=C)CCCCCCNC(=O)OCC1=CC=CC=C1 WVHVBYLHVDIPBY-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/44—Amides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3826—Acyclic unsaturated acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Description
Oppfinnelsen vedrører en analogifremgangsmåte for fremstilling av terapeutisk aktive, substituerte 2-aminoalk-3-ensyrederivater med formel I The invention relates to an analogous method for the production of therapeutically active, substituted 2-aminoalk-3-enoic acid derivatives of formula I
hvor R^ står for hydroksy-C^-Cy-alkyl, Ci-C^alkoksy-C-L-Cy-alkyl, amino.-Cjj-Cy-alkyl eller halogen-C^-Cy-alkyl, hvorved halogen betyr klor eller fluor og R2 betyr karboksy eller C±-C4~alkoksykarbonyl og salter derav. where R^ stands for hydroxy-C₁-Cy-alkyl, C₁-C₁-alkyl-C-L-Cy-alkyl, amino-C₁-Cy-alkyl or halogen-C₁-Cy-alkyl, whereby halogen means chlorine or fluorine and R 2 means carboxy or C±-C 4 ~ alkoxycarbonyl and salts thereof.
Hydroksy-C^-C7-alkyl er eksempelvis hydroksymetyl, 2-hydroksyetyl, 3-hydroksypropyl, 4-hydroksybutyl, 5-hydroksy-pentyl eller 6-hydroksyheksyl. Hydroxy C 1 -C 7 alkyl is, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or 6-hydroxyhexyl.
Ci-C4-alkoksy-C^-C7-alkyl betyr eksempelvis metoksymetyl, etoksymetyl, 2-metoksyetyl, 2-etoksyetyl, 3-metoksypropyl, 4-metoksybutyl, 5-metoksypentyl eller 6-metoksyheksyl. C1-C4-Alkoxy-C1-C7-alkyl means, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl or 6-methoxyhexyl.
Halogen-C^-C7-alkyl er eksempelvis halogenmetyl, 2-halogen-etyl, 3-halogenpropyl, 4-halogenbutyl, 5-halogenpentyl eller 6-halogenheksyl, hvorved halogen betyr klor eller spesielt fluor. Halogen-C1-C7-alkyl is, for example, halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl, 5-halopentyl or 6-halohexyl, whereby halogen means chlorine or especially fluorine.
Amino-C4-Cy-alkyl er eksempelvis 4-aminobutyl, 5-aminopentyl eller 6-aminoheksyl. Amino-C4-Cy-alkyl is, for example, 4-aminobutyl, 5-aminopentyl or 6-aminohexyl.
Ci~C4-alkoksykarbonyl er eksempelvis etoksykarbonyl, propoksykarbonyl, isopropoksykarbonyl eller butoksykarbonyl. C1~C4-Alkoxycarbonyl is, for example, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or butoxycarbonyl.
Forbindelsene med formel I foreligger pga. deres amfotære karakter i form av indre salter og kan såvel danne syreaddisjonssalter som også salter med baser. The compounds with formula I exist because their amphoteric character in the form of internal salts and can form acid addition salts as well as salts with bases.
Syreaddisjonssalter av forbindelser med formel I er eksempelvis de farmasøytisk anvendbare saltene med egnede mineralsyrer, som halogenhydrogensyrer, svovelsyre eller fosforsyre, f.eks. hydroklorider, hydrobromider, sulfater, hydrogensulfåter eller fosfater, eller salter med egnede alifatiske eller aromatiske sulfonsyrer eller N-substituerte sulfaminsyrer, f.eks. metansulfonater, benzensulfonater, p-toluensulfonater eller N-cykloheksylsulfaminater (cykla-mater). Acid addition salts of compounds of formula I are, for example, the pharmaceutically usable salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, e.g. hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, e.g. methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfaminates (cycla-mates).
Salter av forbindelser med formel I med baser er eksempelvis deres salter med farmasøytisk anvendbare baser, som ikke-toksiske, fra metaller fra gruppe Ia, Ib, Ila og Ilb avledede metallsalter, f.eks. alkalimetall-, spesielt natrium- eller kaliumsalter, jordalkalimetall-, spesielt kalsium- eller magnesiumsalter, videre ammoniumsalter med ammoniakk eller organiske aminer eller kvaternære ammoniumbaser, som eventuelt C-hydroksylerte alifatiske aminer, spesielt mono-, di- eller trilaverealkylaminer, f.eks. metyl-, etyl-, dietyl-eller trietylamin, mono-, di- eller tri-(hydroksylavere-alkyl)aminer, som etanol-, dietanol- eller trietanolamin, tris-(hydroksymetyl)metylamin eller 2-hydroksytertiær-butylamin, eller N-(hydroksylaverealkyl)-N,N-dilaverealkyl-aminer hhv. N-(polyhydroksylaverealkyl)-N-laverealkylaminer, som 2-(dimetylamino)etanol eller D-glukamin, eller kvaternære alifatiske ammoniumhydroksyder, f.eks. tetrabutylammonium-hydroksyd. Salts of compounds of formula I with bases are, for example, their salts with pharmaceutically usable bases, such as non-toxic metal salts derived from metals from groups Ia, Ib, Ila and Ilb, e.g. alkali metal, especially sodium or potassium salts, alkaline earth metal, especially calcium or magnesium salts, further ammonium salts with ammonia or organic amines or quaternary ammonium bases, such as optionally C-hydroxylated aliphatic amines, especially mono-, di- or tri-lower alkylamines, e.g. methyl, ethyl, diethyl or triethylamine, mono-, di- or tri-(hydroxylower alkyl)amines, such as ethanol, diethanol or triethanolamine, tris-(hydroxymethyl)methylamine or 2-hydroxytertiary-butylamine, or N -(hydroxylower alkyl)-N,N-dilower alkyl amines or N-(polyhydroxylower alkyl)-N-lower alkylamines, such as 2-(dimethylamino)ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxides, e.g. tetrabutylammonium hydroxide.
For isolering eller rensing kan det også anvendes farma-søytisk uegnede salter. For terapeutisk anvendelse anvendes bare de farmasøytisk anvendbare, ikke-toksiske saltene, som derfor er foretrukket. Pharmaceutically unsuitable salts can also be used for isolation or purification. For therapeutic use, only the pharmaceutically usable, non-toxic salts are used, which are therefore preferred.
Forbindelsene med formel I oppviser verdifulle farmakologiske egenskaper. Spesielt har de en utpreget og selektiv antagonistisk virkning overfor N-metyl-D-asparaginsyre-følsomme (NMDA-sensitive) eksitatoriske aminosyrereseptorer hos varmblodige dyr. Denne kan in vitro eksempelvis bestemmes ved forsøksanordningen ifølge G. Fagg og Å. Matus, Proe. Nat. Acad. Sei., USA, 81, 6876-80 (1984). Herved bestemmes det i hvilken grad bindingen av L-^H-glutaminsyre til NMDA-sensitive reseptorer hemmes. De NMDA-antagonistiske egenskapene for de nye forbindelsene kan imidlertid også demonstreres in vivo, f.eks. på mus, på bakgrunn av hemme-virkningen på NMDA-induserte konvulsjoner. The compounds of formula I exhibit valuable pharmacological properties. In particular, they have a pronounced and selective antagonistic action against N-methyl-D-aspartic acid-sensitive (NMDA-sensitive) excitatory amino acid receptors in warm-blooded animals. This can be determined in vitro, for example, by the test device according to G. Fagg and Å. Matus, Proe. Nat. Acad. Sci., USA, 81, 6876-80 (1984). This determines the extent to which the binding of L-^H-glutamic acid to NMDA-sensitive receptors is inhibited. However, the NMDA-antagonistic properties of the new compounds can also be demonstrated in vivo, e.g. in mice, based on the inhibitory effect on NMDA-induced convulsions.
På grunn av disse egenskapene er forbindelsene med formel I og deres farmasøytisk anvendbare salter fremragende egnet for behandling av patologiske tilstander som viser respons på en blokkering av NMDA-sensitive reseptorer, eksempelvis ischemiske sykdomstilstander, som cerebral ischemi og av ischemiske sykdomstilstander i øyet, av vevs- og muskel-spasmer, samt av migrene eller av lokal eller generell spastisitet, og spesielt av konvulsjoner som epilepsi. Because of these properties, the compounds of formula I and their pharmaceutically usable salts are eminently suitable for the treatment of pathological conditions which show a response to a blockade of NMDA-sensitive receptors, for example ischemic disease states, such as cerebral ischemia and of ischemic disease states of the eye, of tissue - and muscle spasms, as well as from migraines or from local or general spasticity, and especially from convulsions such as epilepsy.
De antikonvulsive egenskapene for forbindelsene ifølge oppfinnelsen kan eksempelvis bestemmes på mus på bakgrunn av deres utpregede beskyttelsesvirkning overfor, ved elektro-sjokk utløste eller audiogent fremkalte, konvulsjoner, hvorved man f.eks. kan anvende den etablerte elektrosjokk-musemodellen hhv. forsøksanordningen ifølge Chapman et al., Arzneimittel-Forsch. 34» 1261 (1984). Forbindelsene fremstilt ifølge oppfinnelsen utmerker seg derved, spesielt i elektro-sjokk -musemodellen , ved en virkning som er forbedret overfor strukturelt beslektede forbindelser. The anticonvulsant properties of the compounds according to the invention can, for example, be determined on mice on the basis of their pronounced protective effect against electroshock-triggered or audiogenically induced convulsions, whereby e.g. can use the established electroshock mouse model or the test device according to Chapman et al., Arzneimittel-Forsch. 34» 1261 (1984). The compounds produced according to the invention are thereby distinguished, especially in the electro-shock mouse model, by an effect that is improved compared to structurally related compounds.
De antispastiske egenskapene som begrunner egnetheten av forbindelsene fremstilt ifølge oppfinnelsen for behandling av migrene, kan eksempelvis vises på rotte på bakgrunn av den depresjonshemmende virkningen i den frontale cortex ifølge forsøksanordningen beskrevet av R. Marannes et al., Brain Res. 457, 226 (1988). I denne modellen reduserer de ved oppfinnelsen fremstilte forbindelsene i doseområdet fra ca. 3 til 30 mg/kg ip. , terskelverdien for "spreading depression" og forkorter dens varighet. The antispastic properties which justify the suitability of the compounds produced according to the invention for the treatment of migraine can, for example, be shown in rats on the basis of the depression-inhibiting effect in the frontal cortex according to the experimental device described by R. Marannes et al., Brain Res. 457, 226 (1988). In this model, the compounds produced by the invention reduce the dose range from approx. 3 to 30 mg/kg ip. , the threshold value for "spreading depression" and shortens its duration.
I NO-søknadene nr. 870577 og nr. 883444, samt i Br. J. Pharmacol. 99, 791-797 (1990) beskrives forbindelser med formel I med NMDA-antagonistiske egenskaper, som istedenfor R^L oppviser en alkylrest. Sammenlignet med de i de nevnte publikasjonene med navn nevnte strukturelt nærmestliggende forbindelsene oppnås ved forbindelsene med formel I fremstilt ifølge oppfinnelsen fordelen med en forhøyet anti-epileptisk virksomhet. Følgelig ga sammenligningsforsøk i elektrosjokk-modellen på mus, Chapman et al., Arzneimittel-Forsch. 34, 1261 (1984) de nedenfor angitte ED50-verdiene: In the NO applications no. 870577 and no. 883444, as well as in Br. J. Pharmacol. 99, 791-797 (1990) describes compounds of formula I with NMDA-antagonistic properties, which instead of R 1 L have an alkyl residue. Compared to the structurally closest compounds mentioned in the aforementioned publications by name, the compounds of formula I produced according to the invention have the advantage of increased anti-epileptic activity. Accordingly, comparative experiments in the electroshock model on mice, Chapman et al., Arzneimittel-Forsch. 34, 1261 (1984) the ED50 values given below:
Forbindelser ifølge patentsøknad nr. 870577 Compounds according to patent application no. 870577
Oppfinnelsen vedrører i første rekke forbindelser med formel I,, hvori Ri betyr 2-hydroksyetyl, 3-hydroksypropyl, hydroksymetyl, metoksymetyl, etoksymetyl, 2-metoksyetyl, 4-aminobutyl, 6-aminoheksyl eller 2-fluoretyl, og Rg betyr karboksy eller C^-C4-alkoksykarbonyl og deres salter. The invention primarily relates to compounds of formula I, in which Ri means 2-hydroxyethyl, 3-hydroxypropyl, hydroxymethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 4-aminobutyl, 6-aminohexyl or 2-fluoroethyl, and Rg means carboxy or C ^-C4-Alkoxycarbonyl and their salts.
Oppfinnelsen vedrører spesielt de i eksemplene angitte forbindelser med formel I og deres salter, spesielt deres farmasøytisk anvendbare salter. The invention relates in particular to the compounds of formula I indicated in the examples and their salts, in particular their pharmaceutically usable salts.
Fremgangsmåten for fremstilling av forbindelsen ifølge oppfinnelsen er kjennetegnet ved at man The method for producing the compound according to the invention is characterized by the fact that
i en forbindelse med formel II in a compound of formula II
hvor Z^, Z2 står for eventuelt beskyttet hydroksy, Z3 står for en eventuelt beskyttet rest R^ og Z4 betyr beskyttet amino, overfører beskyttet amino Z4 og, om tilstedeværende, som bestanddel av Z3 til amino og, dersom tilstedeværende, overfører beskyttet hydroksy Z^, 1% og/eller som bestanddel av Z3 til hydroksy og, om tilstedeværende, settes en beskyttet 5— til 7-leddet azacykloalkylrest Z3 fri og, om where Z^, Z2 stands for optionally protected hydroxy, Z3 stands for an optionally protected residue R^ and Z4 means protected amino, transfers protected amino Z4 and, if present, as a component of Z3 to amino and, if present, transfers protected hydroxy Z ^, 1% and/or as a component of Z3 to hydroxy and, if present, a protected 5- to 7-membered azacycloalkyl residue Z3 is set free and, if
ønsket, overføres en oppnådd forbindelse til en annen forbindelse med formel I, en ved fremgangsmåten oppnådd isomerblanding oppdeles i komponentene og den i ethvert tilfelle foretrukne isomeren fraskilles og/eller en ved fremgangsmåten oppnådd fri forbindelse overføres til et salt eller et ved fremgangsmåten oppnådd salt til den tilsvarende frie forbindelsen. desired, a compound obtained is transferred to another compound of formula I, an isomer mixture obtained by the method is divided into its components and the isomer preferred in any case is separated and/or a free compound obtained by the method is transferred to a salt or a salt obtained by the method to the corresponding free compound.
I utgangsstoffer med formel II betyr beskyttet hydroksy Z± og/eller Z2 eksempelvis foretret, spesielt alifatisk eller aromatisk foretret hydroksy, beskyttet hydroksy som bestanddel av Z3 eksempelvis acylert eller silylert hydroksy, og beskyttet amino Z4 og, om tilstedeværende, som bestanddel av Z3 eksempelvis acylert amino. In starting substances of formula II, protected hydroxy Z± and/or Z2 means, for example, etherified, especially aliphatic or aromatic etherified hydroxy, protected hydroxy as a component of Z3, for example acylated or silylated hydroxy, and protected amino Z4 and, if present, as a component of Z3 for example acylated amino.
Alifatisk foretret hydroksy er eksempelvis laverealkoksy, som metoksy, etoksy eller spesielt isopropyloksy. Aromatisk foretret hydroksy er eksempelvis eventuelt med laverealkyl, laverealkoksy, halogen, cyano og/eller nitro substituert fenoksy. Aliphatic etherified hydroxy is, for example, lower alkoxy, such as methoxy, ethoxy or especially isopropyloxy. Aromatic etherified hydroxy is, for example, phenoxy optionally substituted with lower alkyl, lower alkoxy, halogen, cyano and/or nitro.
Acylert hydroksy oppviser som acylgruppe eksempelvis acyl-resten av en aralifatisk karboksylsyre eller en halvester av karbonsyre og betyr eksempelvis laverealkanoyloksy, eller en i fenyldelen eventuelt med laverealkyl, laverealkoksy, halogen, cyano og/eller trifluormetyl substituert fenyl-laverealkanoyloksy- eller fenyllaverealkoksykarbonyloksy-gruppe , f.eks. benzyloksykarbonyloksy. Acylated hydroxy shows as an acyl group, for example, the acyl residue of an araliphatic carboxylic acid or a half-ester of a carboxylic acid and means, for example, lower alkanoyloxy, or a phenyl-lower alkanoyloxy or phenyl lower alkanoyloxy group optionally substituted in the phenyl part with lower alkyl, lower alkoxy, halogen, cyano and/or trifluoromethyl, e.g. benzyloxycarbonyloxy.
Silylert hydroksy er eksempelvis trilaverealkylsilyloksy, f.eks. trimetyl- eller tributylsilyloksy. Silylated hydroxy is, for example, trilower alkylsilyloxy, e.g. trimethyl or tributylsilyloxy.
Acylert amino oppviser som acylgruppe eksempelvis fra en egnet organisk syre, som maursyre eller en aralifatisk eller aromatisk halvester av karbonsyreavledet acyl. Acylert amino betyr følgelig eksempelvis formylamino, laverealkoksy-karbonylamino, som metoksy-, etoksy- eller tertiærbutyloksy-karbonylamino, eventuelt i fenyldelen med laverealkyl, laverealkoksy, halogen, cyano og/eller nitro substituert fenyllaverealkoksykarbonylamino, som benzyloksykarbonylamino, eller med laverealkyl, laverealkoksy, halogen, cyano og/eller nitro substituert fenoksykarbonylamino. Acylated amino exhibits as acyl group, for example, from a suitable organic acid, such as formic acid or an araliphatic or aromatic half-ester of carboxylic acid-derived acyl. Acylated amino therefore means, for example, formylamino, lower alkoxycarbonylamino, such as methoxy, ethoxy or tertiary butyloxycarbonylamino, optionally in the phenyl part with lower alkyl, lower alkoxy, halogen, cyano and/or nitro substituted phenyl lower oxycarbonylamino, such as benzyloxycarbonylamino, or with lower alkyl, lower alkoxy, halogen , cyano and/or nitro substituted phenoxycarbonylamino.
Frigivelsen av de beskyttede gruppene fra forbindelser med formel II, dvs. av hydroksy fra beskyttede hydroksygrupper Zi, Z2 og/eller beskyttede hydroksygrupper som bestanddel av Z3 hhv. av amino fra beskyttede aminogrupper Z4 og, om tilstedeværende, av beskyttede aminogrupper som bestanddel av Z3, foregår eksempelvis ved behandling med surt middel, eksempelvis med en trilaverealkylhalogensilan, som trimetylbromsilan, tributylbromsilan eller trimetyljodsilan. Derved arbeider man fortrinnsvis i et inert oppløsningsmiddel som et halogenert alifatisk hydrokarbon, f.eks. i diklormetan eller i andre rekke tri- eller tetraklormetan, trikloretan eller tetrakloretan, eksempelvis i temperaturområde fra ca. -25° til ca. +50°C, fortrinnsvis fra ca. 0° til 30°C, f.eks. ved romtemperatur, dvs. ved ca. 15" til 25°C, fordelaktig under idet vesentlige vannfrie betingelser og under inertgass, som argon eller nitrogen. Opparbeidelsen foregår fordelaktig under tilsetning av et hydrogenhalogenidoppfangende middel, spesielt en alifatisk epoksyforbindelse, som en epoksylavere-alkan, f.eks. av propylenoksyd eller i en laverealkanol, som etanol. The release of the protected groups from compounds of formula II, i.e. of hydroxy from protected hydroxy groups Zi, Z2 and/or protected hydroxy groups as a component of Z3 or of amino from protected amino groups Z4 and, if present, of protected amino groups as a component of Z3, takes place for example by treatment with an acidic agent, for example with a trilower alkylhalosilane, such as trimethylbromosilane, tributylbromosilane or trimethyliodosilane. Thereby, one preferably works in an inert solvent such as a halogenated aliphatic hydrocarbon, e.g. in dichloromethane or in other tri- or tetrachloromethane, trichloroethane or tetrachloroethane, for example in a temperature range from approx. -25° to approx. +50°C, preferably from approx. 0° to 30°C, e.g. at room temperature, i.e. at approx. 15" to 25°C, advantageously under substantially anhydrous conditions and under inert gas, such as argon or nitrogen. The work-up advantageously takes place with the addition of a hydrogen halide scavenger, in particular an aliphatic epoxy compound, such as an epoxy lower alkane, e.g. of propylene oxide or in a lower alkanol, such as ethanol.
I en foretrukket utførelsesform går man eksempelvis ut fra forbindelser med formel II, hvor Z^ og Zg betyr laverealkoksy, f.eks. isopropyloksy, og Z4 betyr laverealkanoyl-amino, som formylamino, og behandler disse i et alifatisk hydrogen-hydrokarbon, som diklormetan, ved 15" til 25°C med en trilaverealkylbromsilan, som trimetylbromsilan eller tributylbromsilan, lar dette utreagere noen tid, f.eks. 2 til 30 timer, tilsetter deretter en etanolisk oppløsning av propylenoksyd og frafUtrerer produktet. In a preferred embodiment, one starts, for example, from compounds of formula II, where Z 1 and Z 2 mean lower alkoxy, e.g. isopropyloxy, and Z4 means lower alkanoylamino, such as formylamino, and treating these in an aliphatic hydrogen hydrocarbon, such as dichloromethane, at 15" to 25°C with a trilower alkyl bromosilane, such as trimethylbromosilane or tributylbromosilane, allowing this to react for some time, e.g. 2 to 30 hours, then add an ethanolic solution of propylene oxide and filter the product.
Utgangsstoffer med formel II fremstilles eksempelvis ved at man omsetter et a,<g->umettet aldehyd med formel Ila Starting substances with formula II are prepared, for example, by reacting an α,<g->unsaturated aldehyde with formula IIa
med en a-isocyaneddiksyreester med formel Hb på i og for seg kjent måte, eksempelvis i nærvær av en kobber- eller gullkatalysator, f.eks. av kobber-I-oksyd eller bis(cykloheksylisocyanid)gull-I-tetrafluorborat, til den tilsvarende 5-substituerte 2-oksazolin-4-karboksylsyreesteren med formel lic denne overføres ved hydrolyse, f.eks. i vandig tetrahydrofuran, til den tilsvarende åpenkjedede esteren med formel Ild denne omvandles ved behandling med tionylbromid på i og for seg kjent måte til den tilsvarende u-bromesteren med formel Ile og denne omsettes videre på i og for seg kjent måte med en fosforsyrlingstriester med formel P(Za)()(Zc), hvor Za, Z^ og Zc står for like eller forskjellige i en eterform beskyttede hydroksygrupper, som en trilaverealkylfosfitt, f.eks. med triisopropylfosfitt, til tilsvarende forbindelser med formel II' with an α-isocyanoacetic acid ester of formula Hb in a manner known per se, for example in the presence of a copper or gold catalyst, e.g. of copper I-oxide or bis(cyclohexyl isocyanide)gold I-tetrafluoroborate, to the corresponding 5-substituted 2-oxazoline-4-carboxylic acid ester of formula lic this is transferred by hydrolysis, e.g. in aqueous tetrahydrofuran, to the corresponding open-chain ester of formula Ild, this is converted by treatment with thionyl bromide in a manner known per se to the corresponding u-bromo ester of formula Ile and this is further reacted in a manner known per se with a phosphoric acid triester of formula P(Za)()(Zc), where Za, Z^ and Zc stand for the same or different hydroxy groups protected in an ether form, such as a tri-lower alkyl phosphite, e.g. with triisopropyl phosphite, to corresponding compounds of formula II'
Ved fremgangsmåten oppnådde forbindelser kan på vanlig måte overføres til andre forbindelser med formel I. Compounds obtained by the method can be transferred in the usual way to other compounds of formula I.
Følgelig kan man overføre frie og forestrede karboksygrupper R2 på vanlig måte til hverandre. Spesielt kan man overføre forestret karboksy R2 ved hydrolyse til karboksy hhv. fritt karboksy R2 ved omsetning med en alkohol i forestret karboksy. Videre kan man omestre forestret karboksy R2 til en annen forestret karboksygruppe. Herved arbeider man på vanlig måte under hydrolytiske, alkoholytiske eller omestrende betingelser. Consequently, free and esterified carboxy groups R2 can be transferred to each other in the usual way. In particular, esterified carboxy R2 can be transferred by hydrolysis to carboxy or free carboxy R2 by reaction with an alcohol in esterified carboxy. Furthermore, esterified carboxy R2 can be transesterified to another esterified carboxy group. This is done in the usual way under hydrolytic, alcoholytic or reesterifying conditions.
Hydrolysen av karboksylsyreestere (I; R2 = C1-C4-alkoksy-karbonyl) foregår på vanlig måte, om nødvendig i nærvær av et surt eller basisk middel, som en mineralsyre, f.eks. av hydrogenklorid eller svovelsyre, eller en base, som et alkalimetallhydroksyd, f.eks. natriumhydroksyd. The hydrolysis of carboxylic acid esters (I; R 2 = C 1 -C 4 -alkoxycarbonyl) takes place in the usual way, if necessary in the presence of an acidic or basic agent, such as a mineral acid, e.g. of hydrogen chloride or sulfuric acid, or a base, such as an alkali metal hydroxide, e.g. sodium hydroxide.
Ved omestrlngen av estere (I; R2 = C1-C4~alkoksykarbonyl) med alkoholer, arbeider man vanligvis under syre- eller base-katalytiske betingelser, eksempelvis i nærvær av en katalytisk mengde av en mineralsyre, som av hydrogenklorid eller svovelsyre, eller en metallbase, som av natriumhydroksyd, eller ved at man anvender alkoholkomponenten i form av et metallalkoholat, f.eks. et alkalimetallalkoholat. In the transesterification of esters (I; R2 = C1-C4~alkoxycarbonyl) with alcohols, one usually works under acid or base catalytic conditions, for example in the presence of a catalytic amount of a mineral acid, such as hydrogen chloride or sulfuric acid, or a metal base , such as from sodium hydroxide, or by using the alcohol component in the form of a metal alcoholate, e.g. an alkali metal alcoholate.
Videre kan man i med alifatisk foretret hydroksy substituerte alifatiske hydrokarbonrester, som a-fenyllaverealkoksylavere-alkylrester, overføre R-^ i a-f enyllaverealkoksygruppen reduktivt, f.eks. ved behandling med hydrogen i nærvær av en hydreringskatalysator, som palladium på kull eller Raney-nikkel, til hydroksy. Furthermore, in aliphatic etherified hydroxy substituted aliphatic hydrocarbon residues, such as α-phenyl lower alkyl lower alkyl residues, R-^ in the α-phenyl lower alkyl group can be reductively transferred, e.g. by treatment with hydrogen in the presence of a hydrogenation catalyst, such as palladium on carbon or Raney nickel, to hydroxy.
Oppnådde salter kan på i og for seg kjent måte omvandles til de frie forbindelsene, f.eks. ved behandling med en base, som et alkalimetallhydroksyd, et metallkarbonat eller -hydrogen-karbonat, eller ammoniakk, eller en annen innledningsvis nevnt saltdannende base hhv. med en syre, som en mineralsyre, f.eks. med hydrogenklorid, eller en annen innledningsvis nevnt saltdannende syre. Obtained salts can be converted in a manner known per se to the free compounds, e.g. by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or hydrogen carbonate, or ammonia, or another initially mentioned salt-forming base or with an acid, such as a mineral acid, e.g. with hydrogen chloride, or another initially mentioned salt-forming acid.
Oppnådde salter kan på i og for seg kjent måte overføres til andre salter, syreaddisjonssalter, f.eks. ved behandling med et egnet metallsalt som et natrium-, barium- eller sølvsalt, eller annen syre i et egnet oppløsningsmiddel, hvori et uorganisk salt som dannes, er uoppløselig og dermed ved reaksjonslikevekt utskilles, og basesalter ved frigivelse av den frie syren og fornyet saltdannelse. Obtained salts can be transferred in a manner known per se to other salts, acid addition salts, e.g. by treatment with a suitable metal salt such as a sodium, barium or silver salt, or other acid in a suitable solvent, in which an inorganic salt that is formed is insoluble and is thus separated at reaction equilibrium, and base salts by release of the free acid and renewed salt formation .
Forbindelsene med formel I, innbefattende deres salter, kan også oppnås i form av hydrater, eller inneslutte det for krystallisasjon anvendte oppløsningsmiddel. The compounds of formula I, including their salts, can also be obtained in the form of hydrates, or contain the solvent used for crystallization.
På grunn av den nære relasjonen mellom de nye forbindelsene i fri form og i form av deres salter, forstås ovenfor og i det følgende under fri forbindelse og deres salter, hensikts-messig eventuelt også de tilsvarende saltene hhv. de frie forbindelsene. Due to the close relationship between the new compounds in free form and in the form of their salts, above and in the following, free compound and their salts are understood, where appropriate, also the corresponding salts or the free connections.
Oppnådde diastereomerblandinger og racematblandinger kan oppdeles på bakgrunn av fysikalsk-kjemiske forskjeller for bestanddelene, på kjent måte til de rene diastereomerene hhv. racematene, eksempelvis ved kromatografi og/eller fraksjonert krystall isasjon. Obtained diastereomer mixtures and racemate mixtures can be divided on the basis of physico-chemical differences for the components, in a known manner into the pure diastereomers or the racemates, for example by chromatography and/or fractional crystallization.
Oppnådde racemater kan videre ved kjente fremgangsmåter dekomponeres i de optiske antipodene, eksempelvis ved omkrystallisasjon fra et optisk aktivt oppløsningsmiddel, ved hjelp av mikroorganismer eller ved omsetning av den oppnådde diastereomerblanding, f.eks. racematet med en optisk aktiv hjelpeforbindelse, f.eks. tilsvarende de i forbindelsene med formel I inneholdte sure, basiske eller funksjonelt avledede gruppene med en optisk aktiv syre, base eller en optisk aktiv alkohol, i blandinger av diastereomere salter hhv. funksjonelle derivater, som estere, oppdeling av disse i diastereomerene, hvorfra den i ethvert tilfelle ønskede enantiomeren kan settes fri på vanlig måte. For dette formålet egnede baser, syrer hhv. alkoholer er eksempelvis aminosyrer, spesielt D- eller L-lysin, optisk aktive alkaloidbaser, som stryknin, kinkonin eller brucin, eller D-eller L-(1-fenyl)etylamin, 3-pipekolin, efedrin, amfetamin og lignende syntetisk tilgjengelige baser, optisk aktive karboksyl- eller sulfonsyrer, som kinasyre eller D- eller L-vinsyre, D- eller L-di-o-toluylvinsyre, D- eller L-eplesyre, D- eller L-mandelsyre, eller D- eller L-kamfersulfonsyre, hhv. optisk aktive alkoholer, som borneol eller D- eller L-(1-fenyl)etanol. Obtained racemates can further be decomposed into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, with the help of microorganisms or by reacting the obtained diastereomer mixture, e.g. the racemate with an optically active auxiliary compound, e.g. corresponding to the acidic, basic or functionally derived groups contained in the compounds of formula I with an optically active acid, base or an optically active alcohol, in mixtures of diastereomeric salts or functional derivatives, such as esters, splitting these into the diastereomers, from which the enantiomer desired in any case can be set free in the usual way. For this purpose suitable bases, acids or alcohols are, for example, amino acids, especially D- or L-lysine, optically active alkaloid bases, such as strychnine, cinchonine or brucine, or D- or L-(1-phenyl)ethylamine, 3-pipecoline, ephedrine, amphetamine and similar synthetically available bases, optically active carboxylic or sulfonic acids, such as quinic acid or D- or L-tartaric acid, D- or L-di-o-toluyltartaric acid, D- or L-malic acid, D- or L-mandelic acid, or D- or L-camphorsulfonic acid, respectively optically active alcohols, such as borneol or D- or L-(1-phenyl)ethanol.
De nye forbindelsene med formel I kan f.eks. finne anvendelse i form av farmasøytiske preparater som inneholder en terapeutisk virksom mengde av det aktive stoffet, eventuelt sammen med uorganiske eller organiske, faste eller flytende, farmasøytisk anvendbare bærerstoffer, som egner seg for enteral, f.eks. oral eller parenteral administrering. Følgelig anvender man tabletter eller gelatinkapsler som inneholder det virksomme stoffet sammen med fortynnings-midler, f.eks. laktose, dekstrose, sakkarose, mannitt, sorbitt, cellulose og/eller smøremidler, f.eks. kiseljord, talk, stearinsyre eller salter derav, som magnesium- eller kalsiumstearat, og/eller polyetylenglykol. Tabletter kan også inneholde bindemidler, f.eks. magnesiumaluminiumsilikat, stivelser, som mais-, hvete-, ris- eller pilrotstivelse, gelatin, tragant, metylcellulose, natriumkarboksymetyl-cellulose og/eller polyvinylpyrrolidon, og om ønsket, sprengmidler, f.eks. stivelser, agar, alginsyrer eller et salt derav, f.eks. natriumalginat, og/eller bruseblandinger eller absorpsjonsmidler, fargestoffer, smaksstoffer og søtningsmidler. Videre kan man anvende de nye forbindelsene med formel I i form av parenteralt administrerbare preparater eller av infusjonsoppløsninger. Slike oppløsninger er fortrinnsvis isotonisk vandige oppløsninger eller suspen-sjoner, hvorved disse f.eks. ved lyofiliserte preparater som inneholder det virksomme stoffet alene eller sammen med et bærermateriale, f.eks. mannitt, kan fremstilles før bruk. De farmasøytiske preparatene kan være steriliserte og/eller inneholde hjelpestoffer, f.eks. konserverings-, stabili-serings-, fukte- og/eller emulgeringsmidler, oppløselighets-formidlere, salter for regulering av det osmotiske trykket og/eller buffere. De foreliggende farmasøytiske preparatene som om ønsket kan inneholde ytterligere farmakologisk virksomme stoffer, fremstilles på i og for seg kjent måte, f.eks. ved hjelp av konvensjonelle blande-, granulerings-, dragéerings-, oppløsnings- eller lyofiliseringsfremgangsmåter og inneholder fra 0,1 % til 100 Sé, spesielt fra 1 % til 50 %, lyofilisater inntil 100 1o av det aktive stoffet. The new compounds of formula I can e.g. find use in the form of pharmaceutical preparations containing a therapeutically effective amount of the active substance, possibly together with inorganic or organic, solid or liquid, pharmaceutically usable carriers, which are suitable for enteral administration, e.g. oral or parenteral administration. Consequently, tablets or gelatin capsules are used which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or lubricants, e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets may also contain binders, e.g. magnesium aluminum silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if desired, explosives, e.g. starches, agar, alginic acids or a salt thereof, e.g. sodium alginate, and/or fizzy mixes or absorbents, colourants, flavorings and sweeteners. Furthermore, the new compounds of formula I can be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonically aqueous solutions or suspensions, whereby these e.g. in the case of lyophilized preparations containing the active substance alone or together with a carrier material, e.g. mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preserving, stabilizing, wetting and/or emulsifying agents, solubility mediators, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations, which if desired may contain further pharmacologically active substances, are produced in a manner known per se, e.g. by means of conventional mixing, granulating, coating, dissolving or lyophilizing methods and containing from 0.1% to 100%, especially from 1% to 50%, lyophilisates up to 100 1o of the active substance.
Doseringen kan avhenge av forskjellige faktorer, som til-førselsmåte, spesies, alder og/eller individuell tilstand. De daglige dosene som administreres ligger ved oral tilførsel mellom 0,25 og 10 mg/kg og for varmblodige dyr med en kroppsvekt på 70 kg fortrinnsvis mellom 20 mg og 500 mg. The dosage may depend on various factors, such as method of administration, species, age and/or individual condition. The daily doses that are administered are for oral administration between 0.25 and 10 mg/kg and for warm-blooded animals with a body weight of 70 kg preferably between 20 mg and 500 mg.
De etterfølgende eksemplene tjener til illustrasjon av oppfinnelsen. The following examples serve to illustrate the invention.
Eksempel 1 Example 1
3,57 g (8,5 mmol) 6-acetoksy-4-diisopropylfosfonometyl-2-formylaminoheks-3-ensyreetylester oppløses i 22 ml diklormetan og blandes ved romtemperatur dråpevis med 4,4 ml (34 mmol) trimetylbromsilan. Blandingen får stå ved romtemperatur i 22 timer, det tilsettes dråpevis 22 ml etanol, blandingen får igjen stå i 22 timer, det inndampes på rotasjonsfordamper, resten oppløses i 22 ml etanol og tilsettes dråpevis en blanding av 22 ml propylenoksyd og 22 ml etanol. Det danner seg en suspensjon som omrøres i ytterligere 90 minutter og deretter frasuges. Man oppnår 2-amino-6-hydroksy-4-fosfonometyl-heks-3-ensyreetylester med smp. 195"C (dekomponering). 3.57 g (8.5 mmol) of 6-acetoxy-4-diisopropylphosphonomethyl-2-formylaminohex-3-enoic acid ethyl ester are dissolved in 22 ml of dichloromethane and mixed at room temperature dropwise with 4.4 ml (34 mmol) of trimethylbromosilane. The mixture is allowed to stand at room temperature for 22 hours, 22 ml of ethanol is added dropwise, the mixture is again allowed to stand for 22 hours, it is evaporated on a rotary evaporator, the residue is dissolved in 22 ml of ethanol and a mixture of 22 ml of propylene oxide and 22 ml of ethanol is added dropwise. A suspension is formed which is stirred for a further 90 minutes and then sucked off. 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is obtained with m.p. 195"C (decomposition).
Utgangsmaterialet kan f.eks. fremstilles på følgende måte: 13,0 g (100 mmol) eddiksyre-(4-okso)butylester, 92,0 g (112,6 mmol) dimetylammoniumklorid og 10,8 ml (117 mmol) 37 % formaldehydoppløsning oppvarmes under omrøring i 1 time til 100°C. Blandingen får avkjøle og ekstraheres 3 ganger, hver gang med 30 ml dietyleter. De organiske fasene samles, vaskes med mettet koksaltoppløsning, tørkes over magnesiumsulfat og inndampes til tørrhet. Man oppnår eddiksyre-(3-formyl)but-3-enylester som fargeløs olje, som kan omsettes videre uten ytterligere rensing. The starting material can e.g. is prepared as follows: 13.0 g (100 mmol) acetic acid-(4-oxo)butyl ester, 92.0 g (112.6 mmol) dimethylammonium chloride and 10.8 ml (117 mmol) 37% formaldehyde solution are heated with stirring for 1 hour to 100°C. The mixture is allowed to cool and extracted 3 times, each time with 30 ml of diethyl ether. The organic phases are collected, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. Acetic acid (3-formyl)but-3-enyl ester is obtained as a colorless oil, which can be reacted further without further purification.
13,5 g (95 mmol) eddiksyre-(3-formyl)but-3-enylester og 10,4 g (95 mmol) isocyaneddiksyreetylester tilsettes dråpevis til en suspensjon av 0,38 g kobber-I-oksyd i 50 ml benzen. Etter avslutning av den eksoterme reaksjonen omrøres det i ytterligere 45 minutter ved romtemperatur, filtreres over "Hyflo" og inndampes til tørrhet. Resten opptas i 75 ml tetrahydrofuran, blandes med 25 ml vann og oppvarmes under omrøring i 4 timer til tilbakeløp. Det inndampes til tørrhet og kromatograferes på silikagel med toluen/isopropanol (9:1) som elueringsmiddel. Man oppnår 6-acetoksy-2-formylamino-3-hydroksy-4-metylen-heksansyreetylester som brunlig olje. 13.5 g (95 mmol) of acetic acid (3-formyl)but-3-enyl ester and 10.4 g (95 mmol) of isocyanoacetic acid ethyl ester are added dropwise to a suspension of 0.38 g of copper I oxide in 50 ml of benzene. After completion of the exothermic reaction, it is stirred for a further 45 minutes at room temperature, filtered over "Hyflo" and evaporated to dryness. The residue is taken up in 75 ml of tetrahydrofuran, mixed with 25 ml of water and heated with stirring for 4 hours to reflux. It is evaporated to dryness and chromatographed on silica gel with toluene/isopropanol (9:1) as eluent. 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester is obtained as a brownish oil.
9,19 g (35,9 mmol) 6-acetoksy-2-formylamino-3-hydroksy-4-metylen-heksansyreetylester oppløses i 100 ml diklormetan og blandes ved romtemperatur dråpevis med 3,34 ml (43,1 mmol) tionylbromid. Etter 1 time tilsettes det 10 ml vann og omrøres intenst i 10 minutter. Den organiske fasen fraskilles, vaskes trinnvis med vann, mettet kaliumhydrogen-karbonatoppløsning og nok en gang med vann, tørkes over magnesiumsulfat, filtreres og inndampes. Man oppnår 6-acetoksy-4-brommetyl-2-formylamino-heks-3-ensyreetylester som brunlig olje. 9.19 g (35.9 mmol) of 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 100 ml of dichloromethane and mixed at room temperature dropwise with 3.34 ml (43.1 mmol) of thionyl bromide. After 1 hour, 10 ml of water is added and stirred intensively for 10 minutes. The organic phase is separated, washed step by step with water, saturated potassium hydrogen carbonate solution and once again with water, dried over magnesium sulfate, filtered and evaporated. 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a brownish oil.
8,7 g (25 mmol) 6-acetoksy-4-brommetyl-2-formylamino-heks-3-ensyreetylester og 21 ml (75 mmol) triisopropylfosfitt (90 %) oppvarmes til 80 til 90°C og omrøres under et trykk på ca. 100 mbar i 19 timer. Det overskytende triisopropylfosfitt fradestilleres og inndampingsresten kromatograferes på 150 g silikagel med først eddiksyreetylester og deretter eddiksyreetylester/etanol (9:1) som elueringsmiddel. Man oppnår 6-acetoksy-4-di i sopropylf osf onometyl-2-f ormylamino-heks-3-ensyreetylester som gulaktig olje. 8.7 g (25 mmol) of 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 21 ml (75 mmol) of triisopropylphosphite (90%) are heated to 80 to 90°C and stirred under a pressure of about. 100 mbar for 19 hours. The excess triisopropyl phosphite is distilled off and the evaporation residue is chromatographed on 150 g of silica gel with first ethyl acetate and then ethyl acetate/ethanol (9:1) as eluent. 6-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a yellowish oil.
Eksempel 2 Example 2
0,415 g (1,55 mmol) 2-amino-6-hydroksy-4-fosfonometyl-heks-3-ensyreetylester oppvarmes i 3 ml vann i 24 timer til tilbake-løp. Reaksjonsblandingen inndampes, renses kromatografisk på 10 g silikagel med etanol/vann (1:1) som elueringsmiddel og utkrystalliseres fra etanol. Man oppnår 2-amino-6-hydroksy-4-fosfonometyl-heks-3-ensyre med smp. >300°C. 0.415 g (1.55 mmol) of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is heated in 3 ml of water for 24 hours to reflux. The reaction mixture is evaporated, purified chromatographically on 10 g of silica gel with ethanol/water (1:1) as eluent and crystallized from ethanol. 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid is obtained with m.p. >300°C.
Eksempel 3 Example 3
0,5 g (1,0 mmol) 8-(N-benzyloksykarbonylamino)-4-dietyl-fosfonometyl-2-formylamino-okt-3-ensyremetylester oppvarmes i 5,0 ml 6n-saltsyre i 6 timer til tilbakeløp. Inndamping til tørrhet gir 2,8-diamino-4-fosfonometyl-okt-3-ensyre-dihydro-klorid i form av et gummiaktig faststoff som omkrystalliseres fra acetonitril; smp. 128°C (dekomponering). 0.5 g (1.0 mmol) of 8-(N-benzyloxycarbonylamino)-4-diethyl-phosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is heated in 5.0 ml of 6n-hydrochloric acid for 6 hours to reflux. Evaporation to dryness gives 2,8-diamino-4-phosphonomethyl-oct-3-enoic acid dihydrochloride as a gummy solid which is recrystallized from acetonitrile; m.p. 128°C (decomposition).
Utgangsmaterialet kan fremstilles på følgende måte: The starting material can be produced in the following way:
Til en oppløsning av 5,52 g (47 mmol) 6-aminoheksan-l-ol og 3,95 g (47 mmol) natriumhydrogenkarbonat i 100 ml aceton og 50 ml vann tilsettes det dråpevis 7,06 ml (47 mmol) klor-maursyrebenzylester. Det omrøres i 18 timer ved romtemperatur, inndampes til ca. 70 ml, det hvite bunnfallet frafiltreres, dette vaskes med 20 ml vann, opptas i 250 ml metylenklorid, tørkes over magnesiumsulfat, dette frafiltreres og resten inndampes til tørrhet. Man oppnår 6-(N-benzyloksykarbonylamino)heksan-l-ol i form av hvite krystaller med smp. 58-60°C. To a solution of 5.52 g (47 mmol) 6-aminohexan-1-ol and 3.95 g (47 mmol) sodium bicarbonate in 100 ml acetone and 50 ml water, 7.06 ml (47 mmol) chlorine formic acid benzyl ester. It is stirred for 18 hours at room temperature, evaporated to approx. 70 ml, the white precipitate is filtered off, this is washed with 20 ml of water, taken up in 250 ml of methylene chloride, dried over magnesium sulphate, this is filtered off and the residue is evaporated to dryness. 6-(N-benzyloxycarbonylamino)hexan-1-ol is obtained in the form of white crystals with m.p. 58-60°C.
Til en ved -50° C omrørt oppløsning av 0,19 ml (2,20 mmol) oksalylklorid i 10 ml metylenklorid tilsettes det under nitrogen dråpevis 0,32 ml (4,40 mmol) dimetylsulfoksyd. Det omrøres i 15 minutter og tilsettes deretter 0,5 g (2 mmol) 6-(N-benzyloksykarbonylamino)heksan-l-ol. Det omrøres i 25 minutter ved -50°C, tilsettes dråpevis 1,78 ml (10 mmol) N-etyl-N,N-diisopropylamin og helles i 10 ml isvann. Den organiske fasen fraskilles, og vannfasen ekstraheres med 10 ml metylenklorid. De organiske fasene forenes, vaskes 2 ganger, hver gang med 5 ml n-saltsyre og 1 gang med 10 ml mettet koksaltoppløsning, tørkes over magnesiumsulfat og inndampes til tørrhet. Den oppnådde oljen renses kromatografisk på silikagel med heksan/eddiksyreetylester (1:1) som elueringsmiddel. Man oppnår 6-(N-benzyloksykarbonylamino)-heksanal. To a solution of 0.19 ml (2.20 mmol) of oxalyl chloride in 10 ml of methylene chloride stirred at -50° C., 0.32 ml (4.40 mmol) of dimethylsulfoxide is added dropwise under nitrogen. It is stirred for 15 minutes and then 0.5 g (2 mmol) of 6-(N-benzyloxycarbonylamino)hexan-1-ol is added. It is stirred for 25 minutes at -50°C, 1.78 ml (10 mmol) of N-ethyl-N,N-diisopropylamine are added dropwise and poured into 10 ml of ice water. The organic phase is separated, and the aqueous phase is extracted with 10 ml of methylene chloride. The organic phases are combined, washed twice, each time with 5 ml of n-hydrochloric acid and once with 10 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. The oil obtained is purified chromatographically on silica gel with hexane/acetic acid ethyl ester (1:1) as eluent. 6-(N-benzyloxycarbonylamino)-hexanal is obtained.
Til en oppløsning av 1,5 g (17 mmol) vannfritt piperazin og 2.03 g (34 mmol) eddiksyre i 18,7 ml vann tilsettes det 2,44 g (30 mmol) 37 # vandig formaldehydoppløsning. Det omrøres i 15 minutter ved 25°C og deretter tilsettes 7,48 g (30 mmol) 6-(N-benzyloksykarbonylamino)heksanal. Reaksjons-blandingen oppvarmes i 2 timer til tilbakeløp, avkjøles deretter med isvann og ekstraheres to ganger, hver gang med 50 ml metylenklorid. "Uttrekkene forenes, vaskes to ganger, hver gang med 25 ml mettet natriumhydrogenkarbonatoppløsning og med 25 ml mettet koksaltoppløsning, tørkes og inndampes til tørrhet. Man oppnår 6-(N-benzyloksykarbonylamino)-2-metylen-heksanal som gulaktig væske. To a solution of 1.5 g (17 mmol) anhydrous piperazine and 2.03 g (34 mmol) acetic acid in 18.7 ml water is added 2.44 g (30 mmol) 37 # aqueous formaldehyde solution. It is stirred for 15 minutes at 25°C and then 7.48 g (30 mmol) of 6-(N-benzyloxycarbonylamino)hexanal are added. The reaction mixture is heated to reflux for 2 hours, then cooled with ice water and extracted twice, each time with 50 ml of methylene chloride. "The extracts are combined, washed twice, each time with 25 ml of saturated sodium bicarbonate solution and with 25 ml of saturated sodium bicarbonate solution, dried and evaporated to dryness. 6-(N-benzyloxycarbonylamino)-2-methylene-hexanal is obtained as a yellowish liquid.
4,0 g (15,3 mmol) 6-(N-benzyloksykarbonylamino)-2-metylen-heksanal og 1,62 ml (16,8 mmol) isocyaneddiksyremetylester oppløses i 50 ml toluen og tilsettes ved 40°C dråpevis til en suspensjon av 0,12 g 96,4 % kobber-I-oksyd i 50 ml toluen. Det omrøres i 2,5 timer ved romtemperatur, filtreres, helles på en med 60 g silikagel fylt søyle og ekstraheres først med heksan/eddiksyreetylester (1:1) og deretter med eddiksyreetylester. Man oppnår 5-[6-(N-benzyloksykarbonylamino)heks-l-en-2-yl]-oksazolin-4-karboksylsyremetylester; olje. 4.0 g (15.3 mmol) 6-(N-benzyloxycarbonylamino)-2-methylene-hexanal and 1.62 ml (16.8 mmol) isocyanoacetic acid methyl ester are dissolved in 50 ml toluene and added at 40°C dropwise to a suspension of 0.12 g of 96.4% copper I oxide in 50 ml of toluene. It is stirred for 2.5 hours at room temperature, filtered, poured onto a column filled with 60 g of silica gel and extracted first with hexane/ethyl acetate (1:1) and then with ethyl acetate. 5-[6-(N-benzyloxycarbonylamino)hex-1-en-2-yl]-oxazoline-4-carboxylic acid methyl ester is obtained; oil.
9.4 g (26,1 mmol) 5-[6-(N-benzyloksykarbonylamino )heks-l-en-2-yl]-oksazolin-4-karboksylsyremetylester oppløses i 40 ml tetrahydrofuran og 20 ml vann, blandes med noen dråper trietylamin og oppvarmes i 18 timer til tilbakeløp. Opp-løsningsmidlet fjernes under redusert trykk og den tilbake-blivende oljen opptas i totalt 125 ml metylenklorid, tørkes over magnesiumsulfat og inndampes til tørrhet. Man oppnår 8-(N-benzyloksykarbonylamino )-2-f ormylamino-3-hydroksy-4-metylen-oktansyremetylester. 9.4 g (26.1 mmol) of 5-[6-(N-benzyloxycarbonylamino)hex-l-en-2-yl]-oxazoline-4-carboxylic acid methyl ester are dissolved in 40 ml of tetrahydrofuran and 20 ml of water, mixed with a few drops of triethylamine and heated for 18 hours to reflux. The solvent is removed under reduced pressure and the remaining oil is taken up in a total of 125 ml of methylene chloride, dried over magnesium sulphate and evaporated to dryness. 8-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-octanoic acid methyl ester is obtained.
2,46 g (6,5 mmol) 8-(N-benzyloksykarbonylamino)-2-formylamino-3-hydroksy-4-metylen-oktansyremetylester i 25 ml tetrahydrofuran blandes med 5,5 ml (46 mmol) heksa-1,5-dien og deretter ved -50°C dråpevis med 2,6 ml (32,5 mmol) tionylbromid. Det omrøres i 2 timer ved 0 til 5°C, helles i 25 ml iskald mettet natriumhydrogenkarbonatoppløsning og ekstraheres 2 ganger, hver gang med 20 ml metylenklorid. Den organiske fasen vaskes med 10 ml mettet koksaltoppløsning, tørkes over magnesiumsulfat og inndampes til tørrhet. Den oppnådde oljen renses kromatografisk på silikagel med heksan/eddiksyreetylester (3:1). Man oppnår 8-(N-benzyl-oksykarbonyl amino ) -4 -br omme tyl - 2-f ormylamino-okt-3-ensyre-metylester. 2.46 g (6.5 mmol) of 8-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-octanoic acid methyl ester in 25 ml of tetrahydrofuran are mixed with 5.5 ml (46 mmol) of hexa-1,5 -diene and then at -50°C dropwise with 2.6 ml (32.5 mmol) of thionyl bromide. It is stirred for 2 hours at 0 to 5°C, poured into 25 ml of ice-cold saturated sodium bicarbonate solution and extracted twice, each time with 20 ml of methylene chloride. The organic phase is washed with 10 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. The oil obtained is purified chromatographically on silica gel with hexane/ethyl acetate (3:1). 8-(N-benzyl-oxycarbonylamino)-4-bromomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained.
1,45 g (3,3 mmol) 8-(N-benzyloksykarbonylamino)-4-brommetyl-2-formylamino-okt-3-ensyremetylester blandes med 5 ml trietylfosfitt og oppvarmes under omrøring i 8 timer til 75° C. Det overskytende trietylfosfitt avdestilleres under redusert trykk og gir en oljeformig rest. Denne renses kromatografisk på en silikagelsøyle med først eddiksyreetylester og deretter eddiksyreetylester/metanol (9:1). Man oppnår 8-(N-benzyloksykarbonylamino)-4-dietyl-fosfonometyl-2-formylamino-okt-3-ensyremetylester. 1.45 g (3.3 mmol) of 8-(N-benzyloxycarbonylamino)-4-bromomethyl-2-formylamino-oct-3-enoic acid methyl ester are mixed with 5 ml of triethyl phosphite and heated with stirring for 8 hours at 75° C. The excess triethyl phosphite is distilled off under reduced pressure and gives an oily residue. This is purified chromatographically on a silica gel column with first acetic acid ethyl ester and then acetic acid ethyl ester/methanol (9:1). 8-(N-benzyloxycarbonylamino)-4-diethyl-phosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained.
Eksempel 4 Example 4
1,77 g (4,5 mmol) 4-diisopropylfosfonometyl-2-formylamino-6-metoksy-heks-3-ensyreetylester oppløses i 12 ml diklormetan og blandes ved romtemperatur dråpevis med 2,32 ml (18,0 mmol) trimetylbromsilan. Man lar det stå i 22 timer ved romtemperatur, tilsetter dråpevis 12 ml etanol, lar det på nytt stå i 24 timer, inndamper på rotasjonsfordamper, oppløser resten i 10 ml etanol og tilsetter en blanding av 2 ml propylenoksyd og 2 ml etanol. Det danner seg en suspensjon som omrøres ytterligere 2 timer ved romtemperatur og 2 timer under isavkjøling og deretter frasuges. Man oppnår 2-amino-6-metoksy-4-fosfonometyl-heks-3-ensyreetylester med smp. 242°C (dekomponering). 1.77 g (4.5 mmol) of 4-diisopropylphosphonomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester are dissolved in 12 ml of dichloromethane and mixed at room temperature dropwise with 2.32 ml (18.0 mmol) of trimethylbromosilane. It is allowed to stand for 22 hours at room temperature, 12 ml of ethanol is added dropwise, it is left to stand again for 24 hours, evaporated on a rotary evaporator, the residue is dissolved in 10 ml of ethanol and a mixture of 2 ml of propylene oxide and 2 ml of ethanol is added. A suspension is formed which is stirred for a further 2 hours at room temperature and 2 hours under ice cooling and then suctioned off. 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is obtained with m.p. 242°C (decomposition).
Utgangsmaterialet kan f.eks. fremstilles som følger: The starting material can e.g. produced as follows:
19,7 g (193 mmol) 4-metoksybutanal, 17,7 g (217 mmol) dimetylammoniumklorid og 17,0 ml (226 mmol) 37 # formaldehyd-oppløsning oppvarmes under omrøring i 3 timer til 100°C. Dette får avkjøles og ekstraheres 3 ganger med dietyleter. De organiske fasene vaskes med mettet koksaltoppløsning, forenes, tørkes over natriumsulfat, filtreres og inndampes til tørrhet. Man oppnår 4-metoksy-2-metylenbutanal som gulaktig olje, som videre omsettes uten ytterligere rensing. 19.7 g (193 mmol) of 4-methoxybutanal, 17.7 g (217 mmol) of dimethylammonium chloride and 17.0 ml (226 mmol) of 37 # formaldehyde solution are heated with stirring for 3 hours at 100°C. This is allowed to cool and extracted 3 times with diethyl ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over sodium sulfate, filtered and evaporated to dryness. 4-Methoxy-2-methylenebutanal is obtained as a yellowish oil, which is further reacted without further purification.
16,5 g (144,5 mmol) 4-metoksy-2-metylen-butanal og 15,8 ml (144,5 mmol) isocyaneddiksyreetylester oppløses i 145 ml toluen og blandes med 400 mg kobber-I-oksyd. Etter avslutning av den eksoterme reaksjonen etteromrøres det i ytterligere 2 timer, filtreres over "Hyflo" og inndampes til tørrhet. Resten opptas i 145 ml tetrahydrofuran, blandes med 33 ml vann og oppvarmes under omrøring i 2 timer til tilbakeløp. Man inndamper til tørrhet, blander med toluen og inndamper på nytt. Kromatografi på silikagel med toluen/etanol (95:5) som elueringsmiddel gir 2-formylamino-3-hydroksy-6-metoksy-4-metylen-heksansyreetylester som rødbrun olje. 16.5 g (144.5 mmol) of 4-methoxy-2-methylene-butanal and 15.8 ml (144.5 mmol) of isocyanoacetic acid ethyl ester are dissolved in 145 ml of toluene and mixed with 400 mg of copper I oxide. After completion of the exothermic reaction, it is stirred for a further 2 hours, filtered over "Hyflo" and evaporated to dryness. The residue is taken up in 145 ml of tetrahydrofuran, mixed with 33 ml of water and heated with stirring for 2 hours to reflux. Evaporate to dryness, mix with toluene and evaporate again. Chromatography on silica gel with toluene/ethanol (95:5) as eluent gives 2-formylamino-3-hydroxy-6-methoxy-4-methylene-hexanoic acid ethyl ester as a red-brown oil.
19,0 g (77,5 mmol) 2-formylamino-3-hydroksy-6-metoksy-4-metylen-heksansyreetylester oppløses i 190 ml 1,2-dikloretan og blandes ved romtemperatur dråpevis med 7,20 ml (93,0 mmol) tionylbromid. Etter 45 minutter tilsettes det 100 ml vann og omrøres intenst i 10 minutter. Den organiske fasen fraskilles, vaskes trinnvis med vann, 1 N kaliumhydrogen-karbonatoppløsning og nok en gang med vann, tørkes over natriumsulfat, filtreres og inndampes. Man oppnår 4-brom-metyl-2-formylamino-6-metoksy-heks-3-ensyreetylester som rødbrun olje. 19.0 g (77.5 mmol) of 2-formylamino-3-hydroxy-6-methoxy-4-methylene-hexanoic acid ethyl ester are dissolved in 190 ml of 1,2-dichloroethane and mixed at room temperature dropwise with 7.20 ml (93.0 mmol) thionyl bromide. After 45 minutes, 100 ml of water is added and stirred intensively for 10 minutes. The organic phase is separated, washed step by step with water, 1 N potassium hydrogen carbonate solution and once again with water, dried over sodium sulphate, filtered and evaporated. 4-Bromo-methyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained as a reddish-brown oil.
3,38 g (11,0 mmol) 4-brommetyl-2-formylamino-6-metoksy-heks-3-ensyreetylester og 12,0 ml (44 mmol) triisopropylfosfitt 3.38 g (11.0 mmol) 4-bromomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester and 12.0 ml (44 mmol) triisopropyl phosphite
(96 %) oppvarmes til 80'C og omrøres under et trykk på ca. 130 mbar i 18 timer. Den overskytende triisopropylfosfitt avdestilleres under redusert trykk og inndampingsresten renses kromatografisk på silikagel med eddiksyreetylester. Man oppnår 4-diisopropylfosfonometyl-2-formylamino-6-metoksy-heks-3-ensyreetylester som gulaktig olje. (96%) is heated to 80°C and stirred under a pressure of approx. 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified chromatographically on silica gel with acetic acid ethyl ester. 4-Diisopropylphosphonomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained as a yellowish oil.
Eksempel 5 Example 5
0,98 g (3,5 mmol) 2-amino-6-metoksy-4-fosfonometyl-heks-3-ensyreetylester oppvarmes i 7 ml vann i 17 timer til tilbake-løp. Reaksjonsblandingen inndampes og utkrystalliseres fra en blanding av vann og etanol. Man oppnår 2-amino-6-metoksy-4-fosfonometyl-heks-3-ensyre med smp. 214°C (dekomponering). 0.98 g (3.5 mmol) of 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is heated in 7 ml of water for 17 hours to reflux. The reaction mixture is evaporated and crystallized from a mixture of water and ethanol. 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid is obtained with m.p. 214°C (decomposition).
Eksempel 6 Example 6
0,52 g (1,36 mmol) 4-diisopropylfosfonometyl-6-fluor-2-formylamino-heks-3-ensyreetylester oppløses i 3,5 ml diklormetan, og blandes ved romtemperatur dråpevis med 0,7 ml (5,45 mmol) trimetylbromsilan. Dette får stå i 24 timer ved romtemperatur, det tilsettes dråpevis 3,5 ml etanol, blandingen får igjen stå i 24 timer, inndampes på rotasjonsfordamper, resten oppløses i 2,4 ml etanol og det tilsettes en blanding av 0,6 ml propylenoksyd og 0,6 ml etanol. Det danner seg en suspensjon som omrøres ytterligere 2 timer ved romtemperatur og 2 timer under isavkjøling, og deretter frasuges. Man oppnår 2-amino-6-fluor-4-fosfonometyl-heks-3-ensyreetylester med smp. 222°C (dekomponering). 0.52 g (1.36 mmol) of 4-diisopropylphosphonomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is dissolved in 3.5 ml of dichloromethane, and mixed at room temperature dropwise with 0.7 ml (5.45 mmol ) trimethylbromosilane. This is allowed to stand for 24 hours at room temperature, 3.5 ml of ethanol is added dropwise, the mixture is again allowed to stand for 24 hours, evaporated on a rotary evaporator, the residue is dissolved in 2.4 ml of ethanol and a mixture of 0.6 ml of propylene oxide and 0.6 ml of ethanol. A suspension is formed which is stirred for a further 2 hours at room temperature and 2 hours under ice cooling, and then suctioned off. 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester is obtained with m.p. 222°C (decomposition).
Utgangsmaterialet kan f.eks. fremstilles på følgende måte: 2,4 g (26,6 mmol) 4-fluorbutanal, 2,44 g (30,0 mmol) dimetylammoniumklorid og 2,34 ml (31,1 mmol) 37 % formaldehyd-oppløsning oppvarmes under omrøring i 2 timer til 100°C. Man lar blandingen avkjøle og ekstraherer 3 ganger med dietyleter. De organiske fasene vaskes med mettet koksaltopp-løsning, forenes, tørkes over natriumsulfat, filtreres og inndampes til tørrhet. Man oppnår 4-fluor-2-metylen-butanal som gulaktig olje, som kan omsettes videre uten ytterligere rensing. The starting material can e.g. is prepared as follows: 2.4 g (26.6 mmol) 4-fluorobutanal, 2.44 g (30.0 mmol) dimethylammonium chloride and 2.34 ml (31.1 mmol) 37% formaldehyde solution are heated with stirring in 2 hours at 100°C. The mixture is allowed to cool and extracted 3 times with diethyl ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over sodium sulfate, filtered and evaporated to dryness. 4-fluoro-2-methylene-butanal is obtained as a yellowish oil, which can be reacted further without further purification.
1,43 g (14,0 mmol) 4-f luor-2-metylen-butanal og 1,53 ml (14,0 mmol) isocyaneddiksyreetylester oppløses i 14 ml toluen og blandes med 40 mg kobber-I-oksyd. Etter avslutning av den eksoterme reaksjonen omrøres det i ytterligere 2 timer, filtreres over "Hyflo" og inndampes til tørrhet. Resten opptas i 14 ml tetrahydrofuran, blandes med 3,1 ml vann og oppvarmes under omrøring i 2 timer til tilbakeløp. Man inndamper til tørrhet, blander med toluen og inndamper på nytt. Kromatografi på silikagel med toluen/eddiksyreetylester (1:1) som elueringsmiddel, gir 6-fluor-2-formylamino-3-hydroksy-4-metylen-heksansyreetylester som mørkegul olje. 1.43 g (14.0 mmol) of 4-fluoro-2-methylene-butanal and 1.53 ml (14.0 mmol) of isocyanoacetic acid ethyl ester are dissolved in 14 ml of toluene and mixed with 40 mg of copper I oxide. After completion of the exothermic reaction, it is stirred for a further 2 hours, filtered over "Hyflo" and evaporated to dryness. The residue is taken up in 14 ml of tetrahydrofuran, mixed with 3.1 ml of water and heated with stirring for 2 hours to reflux. Evaporate to dryness, mix with toluene and evaporate again. Chromatography on silica gel with toluene/acetic acid ethyl ester (1:1) as eluent gives 6-fluoro-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester as a dark yellow oil.
1,40 g (6,0 mmol) 6-fluor-2-formylamino-3-hydroksy-4-metylen-heksansyreetylester oppløses i 14 ml 1,2-dikloretan og blandes ved romtemperatur dråpevis med 0,56 ml (7,2 mmol) tionylbromid. Etter 45 minutter tilsetter man 12 ml vann og omrører intenst i 15 minutter. Den organiske fasen fraskilles, vaskes trinnvis med vann, 1 N kaliumhydrogen-karbonatoppløsning og nok en gang med vann, tørkes over natriumsulfat, filtreres og inndampes. Man oppnår 4-brom-metyl-6-fluor-2-formylamino-heks-3-ensyreetylester som brun-gul olje. 1.40 g (6.0 mmol) of 6-fluoro-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester is dissolved in 14 ml of 1,2-dichloroethane and mixed at room temperature dropwise with 0.56 ml (7.2 mmol) thionyl bromide. After 45 minutes, add 12 ml of water and stir vigorously for 15 minutes. The organic phase is separated, washed step by step with water, 1 N potassium hydrogen carbonate solution and once again with water, dried over sodium sulphate, filtered and evaporated. 4-bromo-methyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a brown-yellow oil.
1,43 g (4,82 mmol) 4-brommetyl-6-fluor-2-formylamino-heks-3-ensyreetylester og 5,3 ml (19 mmol) triisopropylfosfitt (96 $ >) oppvarmes til 80°C og omrøres under et trykk på ca. 130 mbar i 18 timer. Det overskytende triisopropylfosfitt avdestilleres under redusert trykk og inndampingsresten renses kromatografisk på silikagel med eddiksyreetylester. Man oppnår 4-diisopropylfosfonometyl-6-fluor-2-formylamino-heks-3-ensyreetylester som gulaktig olje. 1.43 g (4.82 mmol) of 4-bromomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester and 5.3 ml (19 mmol) of triisopropyl phosphite (96 $>) are heated to 80°C and stirred under a pressure of approx. 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified chromatographically on silica gel with acetic acid ethyl ester. 4-Diisopropylphosphonomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained as a yellowish oil.
Eksempel 7 Example 7
0,5 g (1,86 mmol) 2-amino-6-fluor-4-fosfonometyl-heks-3-ensyreetylester oppvarmes i 4 ml vann i 17 timer til tilbake-løp. Reaksjonsblandingen inndampes og oppdeles på sterkt sur ionebytter ("Dowex 50Wx8"; H<®->form) med vann. Man oppnår 2-amino-6-fluor-4-fosfonometylheks-3-ensyre med smp. 160-162°C (dekomponering). 0.5 g (1.86 mmol) of 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester is heated in 4 ml of water for 17 hours to reflux. The reaction mixture is evaporated and partitioned on strongly acidic ion exchanger ("Dowex 50Wx8"; H<®->form) with water. 2-amino-6-fluoro-4-phosphonomethylhex-3-enoic acid is obtained with m.p. 160-162°C (decomposition).
Eksempel 8 Example 8
På tilsvarende måte som beskrevet i eksempel 3 oppnår man med utgangspunkt i 8-aminooktan-l-ol, 2,10-diamino-4-fosfono-metyl-dec-3-ensyre-dihydroklorid, smp. 126°C. In a similar manner as described in example 3, starting from 8-aminooctan-1-ol, 2,10-diamino-4-phosphono-methyl-dec-3-enoic acid dihydrochloride is obtained, m.p. 126°C.
Eksempel 9 Example 9
8,63 g (15,2 mmol) 10-(N-benzyloksykarbonylamino)-4-diiso-propylfosfonometyl-2-f ormyl amino-dec-3-ensyreetylester oppløses i 22 ml diklormetan, og blandes ved romtemperatur dråpevis med 9,82 ml (75,9 mmol) trimetylbromsilan. Det omrøres i 22 timer ved romtemperatur, deretter tilsettes dråpevis 22 ml absolutt etanol, det omrøres i ytterligere 22 timer og inndampes på rotasjonsfordamper. Resten overhelles med 20 ml toluen og inndampes i vakuum. Denne prosessen gjentas 3 ganger. Det oppnådde klart gule skummet oppløses i 150 ml absolutt etanol og blandes i løpet av 90 minutter dråpevis med en oppløsning av 7,5 ml propylenoksyd i 7,5 ml etanol. Det danner seg en krystallsuspensjon som omrøres over natten ved romtemperatur. Produktet frafiltreres og vaskes med etanol og eter. Etter tørking i høyvakuum ved romtemperatur oppnår man 4,70 g råprodukt som klart gule krystaller. For ytterligere rensing utrøres det med 46 ml vann. Etter frafiltrering fra litt uoppløst materiale (0,33 g) inndampes det klare gule filtratet totalt i vakuum. Resten blandes med 20 ml etanol og 20 ml toluen og inndampes på nytt til tørrhet. Denne prosessen gjentar man ytterligere 2 ganger med toluen. Resten suspenderes etter tørking i høyvakuum i 150 ml absolutt etanol og blandes under omrøring dråpevis med en 5 N oppløsning av hydrogenkloridgass i etanol, inntil blandingen reagerer kongosurt. Den dannede 8.63 g (15.2 mmol) of 10-(N-benzyloxycarbonylamino)-4-diiso-propylphosphonomethyl-2-formyl amino-dec-3-enoic acid ethyl ester are dissolved in 22 ml of dichloromethane, and mixed at room temperature dropwise with 9.82 ml (75.9 mmol) of trimethylbromosilane. It is stirred for 22 hours at room temperature, then 22 ml of absolute ethanol is added dropwise, it is stirred for a further 22 hours and evaporated on a rotary evaporator. The residue is poured over with 20 ml of toluene and evaporated in vacuo. This process is repeated 3 times. The clear yellow foam obtained is dissolved in 150 ml of absolute ethanol and mixed dropwise over 90 minutes with a solution of 7.5 ml of propylene oxide in 7.5 ml of ethanol. A crystal suspension is formed which is stirred overnight at room temperature. The product is filtered off and washed with ethanol and ether. After drying in high vacuum at room temperature, 4.70 g of crude product is obtained as bright yellow crystals. For further purification, it is stirred with 46 ml of water. After filtering off some undissolved material (0.33 g), the clear yellow filtrate is completely evaporated in vacuo. The residue is mixed with 20 ml of ethanol and 20 ml of toluene and evaporated again to dryness. This process is repeated a further 2 times with toluene. After drying in a high vacuum, the residue is suspended in 150 ml of absolute ethanol and mixed with stirring dropwise with a 5 N solution of hydrogen chloride gas in ethanol, until the mixture reacts congo acid. It formed
klare oppløsningen blandes i løpet av 1 time dråpevis med en blanding av 7,4 ml propylenoksyd i 7,4 ml etanol. Det danner seg en krystallsuspensjon som omrøres i ytterligere 15 timer og deretter frasuges. Etter vasking med etanol og eter tørkes produktet 48 timer i høyvakuum ved 50°C. Man oppnår på denne måten 2,86 g 2,10-diamino-4-fosfonometyl-dec-3-ensyreetylester, som begynner å sintre ved 157°C og smelter ved 194° C under dekomponering. the clear solution is mixed dropwise over the course of 1 hour with a mixture of 7.4 ml of propylene oxide in 7.4 ml of ethanol. A crystal suspension forms which is stirred for a further 15 hours and then suctioned off. After washing with ethanol and ether, the product is dried for 48 hours in a high vacuum at 50°C. In this way, 2.86 g of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester is obtained, which begins to sinter at 157°C and melts at 194°C during decomposition.
Dette produktet inneholder som forurensninger ca. 5-10 vekt-# av den tilsvarende, i 10-stilling N-benzylerte samt N-(2-hydroksy)propylerte, forbindelsen. This product contains as contaminants approx. 5-10 wt-# of the corresponding, in the 10-position N-benzylated and N-(2-hydroxy)propylated, compound.
Utgangsmaterialet fremstilles som følger: The starting material is produced as follows:
På tilsvarende måte som i eksempel 3 oppnår man med utgangspunkt i 8-aminooktan-l-ol via 8-(N-benzyloksykarbonylamino)-oktan-l-ol og 8-(N-benzyloksykarbonylamino)oktanal, 8-(N-benzyloksykarbonylamino)-2-metylen-oktanal. In a similar way as in example 3, starting from 8-aminooctan-l-ol via 8-(N-benzyloxycarbonylamino)-octan-l-ol and 8-(N-benzyloxycarbonylamino)octanal, 8-(N-benzyloxycarbonylamino) -2-methylene-octanal.
15,30 g (52,9 mmol) 8-(N-benzyloksykarbonylamino)-2-metylen-oktanal og 7,37 ml (67,4 mmol) isocyaneddiksyreetylester oppløses i 78 ml toluen og tilsettes dråpevis til en suspensjon av 0,30 g kobber-I-oksyd i 76 ml toluen under argon i løpet av 75 minutter. Det omrøres i 90 minutter ved 30° C, avkjøles til romtemperatur, filtreres og det klart skarprøde filtratet helles på en med 250 g silikagel (kornstørrelse 0,04 - 0,063 mm) fylt søyle og elueres med heksan/eddiksyreetylester (2:1). Man oppnår etter inndamping av de egnede fraksjonene 8,15 g 5-[8-(N-benzyloksykarbonylamino)okt-l-en-2-yl]oksazolin-4-karboksylsyreetylester som fargeløs honning. 15.30 g (52.9 mmol) of 8-(N-benzyloxycarbonylamino)-2-methylene-octanal and 7.37 ml (67.4 mmol) of isocyanoacetic acid ethyl ester are dissolved in 78 ml of toluene and added dropwise to a suspension of 0.30 g of copper I oxide in 76 ml of toluene under argon during 75 minutes. It is stirred for 90 minutes at 30° C, cooled to room temperature, filtered and the bright bright red filtrate is poured onto a column filled with 250 g of silica gel (grain size 0.04 - 0.063 mm) and eluted with hexane/ethyl acetate (2:1). After evaporation of the suitable fractions, 8.15 g of 5-[8-(N-benzyloxycarbonylamino)oct-1-en-2-yl]oxazoline-4-carboxylic acid ethyl ester are obtained as colorless honey.
8,15 g (20,25 mmol) 5-[8-(N-benzyloksykarbonylamino)okt-l-en-2-yl]oksazolin-4-karboksylsyreetylester oppvarmes i 40 ml tetrahydrofuran og 20 ml vann under omrøring i 4 timer til tilbakeløp. Reaksjonsblandingen inndampes i vakuum ved 55° C til tørrhet, og den honningaktige resten inndampes ytter- 8.15 g (20.25 mmol) of 5-[8-(N-benzyloxycarbonylamino)oct-1-en-2-yl]oxazoline-4-carboxylic acid ethyl ester is heated in 40 ml of tetrahydrofuran and 20 ml of water with stirring for 4 hours more backflow. The reaction mixture is evaporated in vacuo at 55° C to dryness, and the honey-like residue is further evaporated
ligere 2 ganger etter toluentilsats. Råproduktet oppløses i diklormetan, tørkes med natriumsulfat, filtreres og inndampes. Etter tørking i høyvakuum ved romtemperatur oppnår man 9,03 g 10-(N-benzyloksykarbonylamino)-2-formylamino-3-hydroksy-4-metylen-dekansyreetylester som gulaktig honning. more than 2 times after toluene addition. The crude product is dissolved in dichloromethane, dried with sodium sulphate, filtered and evaporated. After drying in high vacuum at room temperature, 9.03 g of 10-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester are obtained as yellowish honey.
13,70 g (32,60 mmol) rå 10-(N-benzyloksykarbonylamino)-2-formylamino-3-hydroksy-4-metylen-dekansyreetylester i 137 ml tetrahydrofuran blandes under argon med 18,5 ml (156,4 mmol) heksa-1,5-dien og deretter ved 10° C dråpevis i løpet av 15 minutter med 6,1 ml (78,2 mmol) tionylbromid. Det etter-omrøres i 1 time ved 10" C og 2 timer ved romtemperatur, helles i 200 ml iskald, mettet natriumhydrogenkarbonat-oppløsning, den organiske fasen fraskilles og ekstraheres 1 gang med diklormetan. Den organiske fasen vaskes med iskald 0,5 N natriumhydrogenkarbonatoppløsning og deretter mettet koksaltoppløsning, tørkes over natriumsulfat og inndampes ved 40° C i vakuum til tørrhet. Den oppnådd rå 10-(N-benzyloksy-karbony 1 am i no ) - 4 - br omme ty 1 - 2 - f ormylamino-dec-3-ensyreetylester (27 g, gul honning) blandes straks med 64 ml (260 mmol) triisopropylfosfitt (96 $ >) og omrøres under et trykk på ca. 100 mbar i 17 timer ved 80°C, hvorved det dannede isopropylbromidet oppfanges i kjølefelle (COg). Deretter avdestilleres det overskytende triisopropylfosfitt under redusert trykk og inndampingsresten (23 g) renses kromatografisk på en søyle med 650 g silikagel (0,04 - 0,063 mm) med eddiksyreetylester/metanol (95:5). Man oppnår 8,73 g 10-(N-benzyl ok sykarbonylamino)-4-diisopropylfosfonometyl-2-formylamino-dec-3-ensyreetylester som gulaktig honning. 13.70 g (32.60 mmol) of crude 10-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester in 137 ml of tetrahydrofuran are mixed under argon with 18.5 ml (156.4 mmol) hexa-1,5-diene and then at 10° C dropwise over 15 minutes with 6.1 ml (78.2 mmol) of thionyl bromide. It is then stirred for 1 hour at 10°C and 2 hours at room temperature, poured into 200 ml of ice-cold, saturated sodium bicarbonate solution, the organic phase is separated and extracted once with dichloromethane. The organic phase is washed with ice-cold 0.5 N sodium bicarbonate solution and then saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness at 40° C. in vacuum. 3-monoacid ethyl ester (27 g, yellow honey) is immediately mixed with 64 ml (260 mmol) of triisopropyl phosphite (96 $ >) and stirred under a pressure of about 100 mbar for 17 hours at 80°C, whereby the formed isopropyl bromide is collected in a cooling trap (COg). The excess triisopropyl phosphite is then distilled off under reduced pressure and the evaporation residue (23 g) is purified chromatographically on a column with 650 g of silica gel (0.04 - 0.063 mm) with ethyl acetate/methanol (95:5). 8.73 is obtained g 10-(N-benzyloxycarbonylamino)-4-diisopro pylphosphonomethyl-2-formylamino-dec-3-enoic acid ethyl ester as yellowish honey.
Eksempel 10 Example 10
2,25 g (6,98 mmol) 2,10-diamino-4-fosfonometyl-dec-3-ensyreetylester oppløses under argon i 45 ml 2 N saltsyre og omrøres i 17 timer ved en badtemperatur på 120°C. Den klare, lysebrune oppløsningen inndampes på rotasjonsfordamper. Resten oppløses i 20 ml etanol og inndampes etter tilsats av 30 ml toluen i vakuum. Denne prosessen gjentar man ytter- 2.25 g (6.98 mmol) of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester are dissolved under argon in 45 ml of 2 N hydrochloric acid and stirred for 17 hours at a bath temperature of 120°C. The clear, light brown solution is evaporated on a rotary evaporator. The residue is dissolved in 20 ml of ethanol and evaporated after adding 30 ml of toluene in vacuum. This process is repeated further
ligere 3 ganger. Det oppnådde, beige skummet oppløses i 75 ml absolutt etanol og blandes i løpet av 35 minutter dråpevis med en oppløsning av 15 ml propylenoksyd i 15 ml etanol. Den dannede krystallsuspensjonen, som oppviser en pH-verdi på 3, frafiltreres etter 1,5 times omrøring og vaskes godt med etanol og eter. Etter tørking i vakuum oppnår man 1,65 g beige råprodukt som oppløses i den minimale mengden vann (ca. 2 ml), og kromatograferes på en søyle, fylt med 67 g reversed-phase kiselgel ("Opti-Up C^g"» kornstørrelse 40 pm), med rent vann som elueringsmiddel ved svakt overtrykk (0,2 bar). Man oppnår en ren fraksjon, Rf-verdi på kiselgel = 0,37 med n-propanol/vann/pyridin/eddiksyre (15:12:10:3) som elueringsmiddel, og flere blandefraksjoner med et biprodukt av Rf-verdi = 0,48. Fornyet kromatografi av denne blandefraksjonen og forenelse av de rene fraksjonene etter-fulgt av lyofilisering fra vann, gir 2,10-diamino-4-fosfono-metyl-dec-3-ensyre-hemihydrokloridhydrat som amorft glass, som fra 134°C langsomt sintrer og som dekomponeres ved 149°C under oppskumming. more than 3 times. The resulting beige foam is dissolved in 75 ml of absolute ethanol and mixed dropwise over the course of 35 minutes with a solution of 15 ml of propylene oxide in 15 ml of ethanol. The formed crystal suspension, which exhibits a pH value of 3, is filtered off after stirring for 1.5 hours and washed well with ethanol and ether. After drying in vacuum, 1.65 g of beige crude product is obtained, which is dissolved in the minimal amount of water (approx. 2 ml), and chromatographed on a column filled with 67 g of reversed-phase silica gel ("Opti-Up C^g"» grain size 40 pm), with pure water as eluent at slight excess pressure (0.2 bar). One obtains a pure fraction, Rf value on silica gel = 0.37 with n-propanol/water/pyridine/acetic acid (15:12:10:3) as eluent, and several mixed fractions with a by-product of Rf value = 0, 48. Re-chromatography of this mixed fraction and pooling of the pure fractions followed by lyophilization from water gives 2,10-diamino-4-phosphono-methyl-dec-3-enoic acid hemihydrochloride hydrate as an amorphous glass, which from 134°C slowly sinters and which decomposes at 149°C during foaming.
Eksempel 11 Example 11
4,3 g (9,9 mmol) 7-acetoksy-4-diisopropylfosfonometyl-2-formylaminohept-3-ensyreetylester oppløses i 25 ml diklormetan og blandes ved romtemperatur dråpevis med 5,1 ml (39,5 mmol) trimetylbromsilan. Det får stå i 24 timer ved romtemperatur, 25 ml etanol tilsettes dråpevis og det hele får stå i ytterligere 24 timer, inndampes, resten oppløses i 25 ml etanol og det tilsettes dråpevis en blanding av 25 ml propylenoksyd og 25 ml etanol. Det danner seg en suspensjon som omrøres 1 time ved romtemperatur og 1 time i isbad og deretter frasuges. Etter tørking oppnår man 2-amino-7-hydroksy-4-fosfonometyl-hept-3-ensyreetylester med smp. 210°C (dekomponering). 4.3 g (9.9 mmol) of 7-acetoxy-4-diisopropylphosphonomethyl-2-formylaminohept-3-enoic acid ethyl ester are dissolved in 25 ml of dichloromethane and mixed at room temperature dropwise with 5.1 ml (39.5 mmol) of trimethylbromosilane. It is allowed to stand for 24 hours at room temperature, 25 ml of ethanol is added dropwise and the whole is allowed to stand for a further 24 hours, evaporated, the residue is dissolved in 25 ml of ethanol and a mixture of 25 ml of propylene oxide and 25 ml of ethanol is added dropwise. A suspension is formed which is stirred for 1 hour at room temperature and 1 hour in an ice bath and then suctioned off. After drying, 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester is obtained with m.p. 210°C (decomposition).
Utgangsmaterialet kan f.eks. fremstilles på følgende måte: 10 g (69,4 mmol) 5-acetoksypentanal, 6,37 g (78,2 mmol) dimetylammoniumklorid og 6,1 ml (81,2 mmol) 37 # formaldehyd-oppløsnlng holdes under omrøring i 1,5 time ved tilbakeløp (badtemperatur ~ 110°C). Dette får avkjøle, ekstraheres tre ganger med eter, de organiske fasene forenes, tørkes over MgS04, filtreres og inndampes. 5-acetoksy-2-metylen-pentanal oppnås som gulaktig olje som kan omsettes uten ytterligere rensing. The starting material can e.g. is prepared as follows: 10 g (69.4 mmol) of 5-acetoxypentanal, 6.37 g (78.2 mmol) of dimethylammonium chloride and 6.1 ml (81.2 mmol) of 37 # formaldehyde solution are kept under stirring for 1, 5 hours at reflux (bath temperature ~ 110°C). This is allowed to cool, extracted three times with ether, the organic phases are combined, dried over MgSO 4 , filtered and evaporated. 5-acetoxy-2-methylene-pentanal is obtained as a yellowish oil which can be reacted without further purification.
9,6 g (61,5 mmol) 5-acetoksy-2-metylen-pentanal og 7,38 ml (67,6 mmol) isocyaneddiksyreetylester anbringes i 70 ml toluen ved romtemperatur og blandes med 250 mg kobber-I-oksyd. Etter opphør av den eksoterme reaksjonen omrøres det i ytterligere 1 time, filtreres over "Hyflo" og inndampes. Resten opptas i 50 ml tetrahydrofuran, blandes med 10 ml vann og holdes i 3 timer ved tilbakeløp. Man inndamper til tørrhet, blander med toluen og inndamper ytterligere én gang. Kromatografi på silikagel med toluen/eddiksyreetylester (4:1) gir 7-acetoksy-2-formylamino-3-hydroksy-4-metylen-heptansyre-etylester som orange olje. 9.6 g (61.5 mmol) of 5-acetoxy-2-methylene-pentanal and 7.38 ml (67.6 mmol) of isocyanoacetic acid ethyl ester are placed in 70 ml of toluene at room temperature and mixed with 250 mg of copper I oxide. After cessation of the exothermic reaction, it is stirred for a further 1 hour, filtered over "Hyflo" and evaporated. The residue is taken up in 50 ml of tetrahydrofuran, mixed with 10 ml of water and kept at reflux for 3 hours. Evaporate to dryness, mix with toluene and evaporate once more. Chromatography on silica gel with toluene/acetic acid ethyl ester (4:1) gives 7-acetoxy-2-formylamino-3-hydroxy-4-methylene-heptanoic acid ethyl ester as an orange oil.
5,9 g (20,5 mmol) 7-acetoksy-2-formylamino-3-hydroksy-4-metylen-heptansyreetylester oppløses i 60 ml diklormetan og blandes ved romtemperatur dråpevis med 1,9 ml (24,6 mmol) tionylbromid. Etter 1 time tilsetter man 40 ml vann og omrører intenst i 10 minutter. Den organiske fasen fraskilles, vaskes trinnvis med vann, 1 N KHC03-oppløsning og ytterligere én gang med vann, tørkes over MgS04, filtreres og inndampes. Man oppnår 7-acetoksy-4-brommetyl-2-formylamino-hept-3-ensyreetylester som brun olje, som kan omsettes videre i rå tilstand. 5.9 g (20.5 mmol) of 7-acetoxy-2-formylamino-3-hydroxy-4-methylene-heptanoic acid ethyl ester are dissolved in 60 ml of dichloromethane and mixed at room temperature dropwise with 1.9 ml (24.6 mmol) of thionyl bromide. After 1 hour, add 40 ml of water and stir vigorously for 10 minutes. The organic phase is separated, washed step by step with water, 1 N KHCO 3 solution and once more with water, dried over MgSO 4 , filtered and evaporated. 7-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained as a brown oil, which can be reacted further in the crude state.
6,1 g (17,4 mmol) 7-acetoksy-4-brommetyl-2-formylamino-hept-3-ensyreetylester og 19,1 ml (69,6 mmol) triisopropylfosfitt (90 %) oppvarmes til 80° C og omrøres i 18 timer under et trykk på ca. 130 mbar. Det overskytende triisopropylfosfitt fradestilleres og resten renses på silikagel med eddiksyre- 6.1 g (17.4 mmol) 7-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoic acid ethyl ester and 19.1 ml (69.6 mmol) triisopropylphosphite (90%) are heated to 80° C and stirred for 18 hours under a pressure of approx. 130 mbar. The excess triisopropyl phosphite is distilled off and the residue is purified on silica gel with acetic acid
etylester. Man oppnår 7-acetoksy-4-diisopropylfosfonometyl-2-formylamino-hept-3-ensyreetylester som gul olje. ethyl ester. 7-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained as a yellow oil.
Eksempel 12 Example 12
1,1 g (3,9 mmol) 2-amino-7-hydroksy-4-fosfonometyl-hept-3-ensyreetylester i 8 ml vann omrøres i 18 timer ved 130°C i bomberør. Den mørke reaksjonsoppløsningen behandles med aktivt kull og filtreres over "Hyflo". Det fargeløse filtratet inndampet til ~3 ml og blandes med ~25 ml etanol. Den dannede suspensjonen frafiltreres og tørkes i høyvakuum ved 50°C. Man oppnår 2-amino-7-hydroksy-4-fosfonometyl-hept-3-ensyre med smp. fra 190°C (dekomponering). 1.1 g (3.9 mmol) of 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester in 8 ml of water is stirred for 18 hours at 130°C in a bomb tube. The dark reaction solution is treated with activated carbon and filtered over "Hyflo". The colorless filtrate is evaporated to ~3 ml and mixed with ~25 ml of ethanol. The resulting suspension is filtered off and dried in a high vacuum at 50°C. 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid is obtained with m.p. from 190°C (decomposition).
Eksempel 13 Example 13
1,10 g (2,8 mmol) 5-etoksy-4-diisopropylfosfonometyl-2-formylamino-pent-3-ensyreetylester oppløses i 20 ml diklormetan og blandes ved romtemperatur dråpevis med 1,6 ml (12,3 mmol) trimetylbromsilan. Dette får stå ved romtemperatur i 7 timer, tilsettes dråpevis 20 ml etanol og får igjen stå i 15 timer, inndampes, resten oppløses i 10 ml etanol og det tilsettes dråpevis en blanding av 10 ml propylenoksyd og 10 ml etanol. Det danner seg en suspensjon som omrøres i 2 timer ved romtemperatur, og deretter frasuges. Etter tørking oppnår man 5-etoksy-2-amino-4-fosfonometyl-pent-3-ensyreetylester med smp. 217-218°C (dekomponering). 1.10 g (2.8 mmol) of 5-ethoxy-4-diisopropylphosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester are dissolved in 20 ml of dichloromethane and mixed at room temperature dropwise with 1.6 ml (12.3 mmol) of trimethylbromosilane. This is allowed to stand at room temperature for 7 hours, 20 ml of ethanol is added dropwise and left to stand for 15 hours, evaporated, the residue is dissolved in 10 ml of ethanol and a mixture of 10 ml of propylene oxide and 10 ml of ethanol is added dropwise. A suspension is formed which is stirred for 2 hours at room temperature, and then suctioned off. After drying, 5-ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid ethyl ester is obtained with m.p. 217-218°C (decomposition).
Utgangsmaterialet kan f.eks. fremstilles som følger: The starting material can e.g. produced as follows:
50 g (283 mmol) 3-etoksy-propionaldehyd-dietylacetal, 27,3 g (335 mmol) dimetylammoniumklorid og 30 ml (392 mmol) 36 # formaldehydoppløsning oppvarmes under omrøring i 2 timer til 110°C. Man avkjøler og ekstraherer 3 ganger med dietyleter. De organiske fasene vaskes med mettet koksaltoppløsning, forenes, tørkes over natriumsulfat, filtreres og inndampes til tørrhet. Man oppnår 2-etoksypropanal som gul væske, som kan omsettes videre uten ytterligere rensing. 50 g (283 mmol) of 3-ethoxy-propionaldehyde diethyl acetal, 27.3 g (335 mmol) of dimethylammonium chloride and 30 ml (392 mmol) of 36 # formaldehyde solution are heated with stirring for 2 hours at 110°C. It is cooled and extracted 3 times with diethyl ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over sodium sulfate, filtered and evaporated to dryness. 2-ethoxypropanal is obtained as a yellow liquid, which can be reacted further without further purification.
4,2 g (36,1 mmol) 2-etoksypropanal og 4,4 ml (40 mmol) isocyaneddiksyreetylester oppløses i 50 ml toluen og blandes med 200 mg kobber-I-oksyd. Etter opphør av den eksoterme reaksjonen etteromrøres det 1 1 time, filtreres over "Eyflo" og inndampes til tørrhet. Resten opptas i 50 ml tetrahydrofuran, blandes med 12 ml vann og oppvarmes under omrøring i 1 time til tilbakeløp. Man inndamper til tørrhet, blander med toluen og inndamper på nytt. Kromatografi på silikagel med toluen/isopropanol (9:1) som elueringsmiddel gir 5-etoksy-2-formylamino-3-hydroksy-4-metylen-pentansyreetylester som gul olje. 4.2 g (36.1 mmol) of 2-ethoxypropanal and 4.4 ml (40 mmol) of isocyanoacetic acid ethyl ester are dissolved in 50 ml of toluene and mixed with 200 mg of copper I oxide. After the end of the exothermic reaction, it is stirred for 11 hours, filtered over "Eyflo" and evaporated to dryness. The residue is taken up in 50 ml of tetrahydrofuran, mixed with 12 ml of water and heated with stirring for 1 hour to reflux. Evaporate to dryness, mix with toluene and evaporate again. Chromatography on silica gel with toluene/isopropanol (9:1) as eluent gives 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester as a yellow oil.
3,70 g (15,1 mmol) 5-etoksy-2-formylamino-3-hydroksy-4-metylen-pentansyreetylester oppløses i 100 ml 1,2-dikloretan og blandes ved romtemperatur dråpevis med 1,8 ml (22,8 mmol) tionylbromid. Etter 1 time tilsetter man 100 ml vann og omrører intenst i 15 minutter. Den organiske fasen fraskilles, vaskes trinnvis med 1 N kaliumhydrogenkarbonat-oppløsning og sol, tørkes over natriumsulfat, filtreres og inndampes. Man oppnår 5-etoksy-4-brommetyl-2-formylamino-pent-3-ensyreetylester som gulbrun olje, som omsettes videre i rå tilstand. 3.70 g (15.1 mmol) of 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester are dissolved in 100 ml of 1,2-dichloroethane and mixed at room temperature dropwise with 1.8 ml (22.8 mmol) thionyl bromide. After 1 hour, add 100 ml of water and stir vigorously for 15 minutes. The organic phase is separated, washed step by step with 1 N potassium hydrogen carbonate solution and sol, dried over sodium sulphate, filtered and evaporated. 5-ethoxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained as a yellow-brown oil, which is reacted further in the crude state.
3,12 g (10,1 mmol) 5-etoksy-4-brommetyl-2-formylamino-pent-3-ensyreetylester og 30 ml (118 mmol) triisopropylfosfitt (90 %) oppvarmes til 80° C og omrøres under et trykk på ca. 130 mbar i 7 timer. Det overskytende triisopropylfosfitt avdestilleres og resten renses kromatografisk på silikagel med metylenoksyd/metanol (97:3 til 95:5). Man oppnår 5-etoksy-r4-diisopropylfosf on onre ty 1-2-f ormylamino-pent-3-ensyreetylester som gul olje. 3.12 g (10.1 mmol) 5-ethoxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester and 30 ml (118 mmol) triisopropyl phosphite (90%) are heated to 80° C and stirred under a pressure of about. 130 mbar for 7 hours. The excess triisopropyl phosphite is distilled off and the residue is purified chromatographically on silica gel with methylene oxide/methanol (97:3 to 95:5). 5-ethoxy-r4-diisopropylphosphon onrety 1-2-formylamino-pent-3-enoic acid ethyl ester is obtained as a yellow oil.
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FI97231B (en) | 1996-07-31 |
DE59009368D1 (en) | 1995-08-10 |
EP0420806A1 (en) | 1991-04-03 |
IE903452A1 (en) | 1991-04-10 |
FI904690A0 (en) | 1990-09-24 |
IL95729A0 (en) | 1991-06-30 |
FI97231C (en) | 1996-11-11 |
CA2026038A1 (en) | 1991-03-27 |
IL95729A (en) | 1998-02-22 |
PT95401A (en) | 1991-05-22 |
ES2074153T3 (en) | 1995-09-01 |
AU6315290A (en) | 1991-04-11 |
HU906210D0 (en) | 1991-03-28 |
KR910006312A (en) | 1991-04-29 |
AU638057B2 (en) | 1993-06-17 |
ATE124700T1 (en) | 1995-07-15 |
HUT56110A (en) | 1991-07-29 |
DK0420806T3 (en) | 1995-10-16 |
NO904169L (en) | 1991-03-27 |
EP0420806B1 (en) | 1995-07-05 |
PT95401B (en) | 1997-07-31 |
NZ235427A (en) | 1992-10-28 |
DD298105A5 (en) | 1992-02-06 |
NO179450C (en) | 1996-10-09 |
ZA907641B (en) | 1991-05-29 |
MX22528A (en) | 1994-02-28 |
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