IE842268L - Process for preparation of nucleoside alkyl-,aralkyl- and¹aryl phosphonites and phosphonates - Google Patents
Process for preparation of nucleoside alkyl-,aralkyl- and¹aryl phosphonites and phosphonatesInfo
- Publication number
- IE842268L IE842268L IE842268A IE226884A IE842268L IE 842268 L IE842268 L IE 842268L IE 842268 A IE842268 A IE 842268A IE 226884 A IE226884 A IE 226884A IE 842268 L IE842268 L IE 842268L
- Authority
- IE
- Ireland
- Prior art keywords
- general formula
- denotes
- see diagramm
- compound
- meanings given
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 21
- 239000002777 nucleoside Substances 0.000 title claims abstract description 17
- 230000008569 process Effects 0.000 title claims abstract description 15
- 150000003833 nucleoside derivatives Chemical class 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title abstract description 8
- XRBCRPZXSCBRTK-UHFFFAOYSA-N phosphonous acid Chemical class OPO XRBCRPZXSCBRTK-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 239000000460 chlorine Chemical group 0.000 claims abstract description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 9
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims abstract description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 9
- 125000006239 protecting group Chemical group 0.000 claims abstract description 9
- 229910052711 selenium Inorganic materials 0.000 claims abstract description 9
- 239000011669 selenium Substances 0.000 claims abstract description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 8
- 239000011593 sulfur Substances 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- 239000005549 deoxyribonucleoside Substances 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 6
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 4
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 4
- 239000011737 fluorine Substances 0.000 claims abstract description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 4
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 239000001301 oxygen Substances 0.000 claims abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract 3
- -1 di(p-anisoyl)phenylmethyl Chemical group 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000003835 nucleoside group Chemical group 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229940116254 phosphonic acid Drugs 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000004679 31P NMR spectroscopy Methods 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- WFPZPJSADLPSON-UHFFFAOYSA-N dinitrogen tetraoxide Chemical compound [O-][N+](=O)[N+]([O-])=O WFPZPJSADLPSON-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical class CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 2
- SCLFRABIDYGTAZ-UHFFFAOYSA-N methylphosphonic acid dichloride Chemical compound CP(Cl)(Cl)=O SCLFRABIDYGTAZ-UHFFFAOYSA-N 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- LKPFWCPZERQLFI-UHFFFAOYSA-N 2,4,6-trimethylpyridine;hydrochloride Chemical compound Cl.CC1=CC(C)=NC(C)=C1 LKPFWCPZERQLFI-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000005654 Michaelis-Arbuzov synthesis reaction Methods 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- CDPKWOKGVUHZFR-UHFFFAOYSA-N dichloro(methyl)phosphane Chemical compound CP(Cl)Cl CDPKWOKGVUHZFR-UHFFFAOYSA-N 0.000 description 1
- LWNLXVXSCCLRRZ-UHFFFAOYSA-N dichlorophosphane Chemical compound ClPCl LWNLXVXSCCLRRZ-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 231100000065 noncytotoxic Toxicity 0.000 description 1
- 230000002020 noncytotoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- RARSHUDCJQSEFJ-UHFFFAOYSA-N p-Hydroxypropiophenone Chemical compound CCC(=O)C1=CC=C(O)C=C1 RARSHUDCJQSEFJ-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 150000003008 phosphonic acid esters Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
-
- 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
- C07F9/48—Phosphonous acids [RP(OH)2] including [RHP(=O)(OH)]; Thiophosphonous acids including [RP(SH)2], [RHP(=S)(SH)]; Derivatives thereof
- C07F9/4883—Amides or esteramides thereof, e.g. RP(NR'2)2 or RP(XR')(NR''2) (X = O, S)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Saccharide Compounds (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Silicon Polymers (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
1. Claims for the contracting states : BE, CH, LI, DE, FR, GB, IT, LU, NL, SE A process for the preparation of deoxyribonucleoside phosphonates of the general formula I see diagramm : EP0136543,P14,F1 in which T denotes a protecting group for a primary hydroxyl group, B denotes a nucleoside base radical in which any exoamino group present is protected, G denotes a protecting group for a secondary hydroxyl group, Z denotes oxygen, sulfur or selenium and R denotes alkyl having up to 8 C atoms, cyclohexyl, benzyl, or phenyl which is optionally substituted by fluorine, chlorine, bromine, lower alkyl, lower alkoxy or trifluoromethyl, characterized in that a difunctional phosphonylating reagent of the general formula II see diagramm : EP0136543,P14,F2 in which X denotes chlorine or Y and Y denotes a group of the formula see diagramm : EP0136543,P14,F3 R**1 and R**2 representing identical or different alkyl or cycloalkyl radicals having up to 8 C atoms, or phenyl radicals, or R**1 and R**2 , together with the nitrogen, representing a saturated or unsaturated heterocyclic ring which can contain further hetero atoms, being reacted with a nucleoside of the general formula III see diagramm : EP0136543,P14,F4 in which T and B have the meanings given above, the resulting compound of the general formula IV see diagramm : EP0136543,P14,F5 being reacted with a compound of the general formula V see diagramm : EP0136543,P15,F1 in which B and G have the meanings given above, and the resulting compounds of the general formula VI see diagramm : EP0136543,P15,F2 in which T, R, B and G have the meanings given above, being oxidatively converted to compound of the general formula I. 1. Claims for the contracting state AT A process for the preparation of deoxyribonucleoside phosphonates of the general formula I see diagramm : EP0136543,P15,F3 in which T denotes a protecting group for a primary hydroxyl group, B denotes a nucleoside base radical in which any exoamino group present is protected, G denotes a protecting group for a secondary hydroxyl group, Z denotes oxygen, sulfur or selenium and R denotes alkyl having up to 8 C atoms, cyclohexyl, benzyl, or phenyl which is optionally substituted by fluorine, chlorine, bromine, lower alkyl, lower alkoxy or trifluoromethyl, characterized in that a difunctional phosphonylating reagent of the general formula II see diagramm : EP0136543,P16,F1 in which X denotes chlorine or Y and Y denotes a group of the formula see diagramm : EP0136543,P16,F2 R**1 and R**2 representing identical or different alkyl or cycloalkyl radicals having up to 8 C atoms, or phenyl radicals, or R**1 and R**2 , together with the nitrogen, representing a saturated or unsaturated heterocyclic ring which can contain further hetero atoms, being reacted with a nucleoside of the general formula III see diagramm : EP0136543,P16,F3 in which T and B have the meanings given above, the resulting compound of the general formula IV see diagramm : EP0136543,P16,F4 being reacted with a compound of the general formula V see diagramm : EP0136543,P16,F5 in which B and G have the meanings given above, and the resulting compounds of the general formula VI see diagramm : EP0136543,P17,F1 in which T, R, B and G have the meanings given above, being oxidatively converted to compound of the general formula I.
Description
1 H U 4 - 2 - This invention relates to a process for the preparation of nucleoside alkyl-, aralkyl- and ary1-phosphonites and -phosphonates.
Non-ionic analogs of deoxyribonucleic acids (DNA) are important for the investigation of DNA-DNA and DNA-protein interactions. Of particular interest are phos-phonic acid esters of deoxyribonucleotides as a result of their chemical stability and on the basis of their capability to enter into cells and their high resistance to cell nucleases. Hitherto, four different strategies have been described for the synthesis of methylphosphonate analogs ofnucleotides: 1. Ogilvie et al. (M.J. Nemer and K.K. Ogilvie, Tetrahedron Lett. 21, Page 4149 (1980)) prepared a completely protected uridyl-3', 5 1-uridine methylphosphonate by Michaelis-Arbuzov rearrangement of the corresponding phosphite intermediates. This reaction (methyl iodide, 20 hours at 50°C) might not be generally applicable as a result of its drastic conditions, because, for example, methylation of the purine bases is to be expected. 2. Ts'o et al. (F.S. Miller, J. Yano, E. Yano, C. Caroll, K. Jayaraman and P.O.P. Ts'o, Biochemistry 18, 5134 (1979); Proc. Natl. Acad. Sci. USA 73, 1537 (1 981 ); ■P.S. Miller, N. Drean, S.M. Pulford and K.B. McParland, J. Biol. Chem. 225, 9659 (1 980)) developed a synthesis strategy which is analogous to the phosphotriester method in oligonucleotide synthesis. Here, a protected nucleotide 3'-O-methylphosphonic acid ^?-cyanoethyI ester is used as the most important intermediate. This method has the known advantages and disadvantages of the phosphotriester method, the low reactivity of the phosphor us (V) compound being mentioned in particular as a disadvantage. 3. Agarwal et al. (K. L. Agarwal and F. Riftina, Nucl. 5 Acid Res. 6_, 3009 (1979)) used methylphosphonic acid di-chloride as a difunctional phosphonylating agent. In the second step, the chloride has to be activated by means of tetrazole. The crude product obtained can only be purified by efficient chromatography. 10 4. J. Engels and A. Jager, Angew. Chem. Suppl. 1982, 2010, and N.D. Sin ha, V. Grossbruchhaus and H. Ko'ster, Tetrahedron Lett. 2_4, 887 (1 983) used methy I d i ch lorophosphane as the starting material. The latter authors synthesized the nucleotide methylphosphonates on a polymeric support. 15 The products obtained are yet to be characterized.
Whereas the reactivity of the second halogen of methylphosphonic acid dichloride is generally too low and additional activation is necessary, the activity in the case of phosphinic acid dichlorides is if anything too 20 high. Thus, handling difficulties arise (extremely anhydrous medium) and, in addition, the symmetrical phos-phonous acid ester is unavoidably formed.
By contrast, the invention relates to a process for the preparation of deoxyribonucleoside phosphonates of 25 the general formula I 20 (I) - 4 - *-0T$ 0 1 Z = P - R G~0 in which T denotes a protecting group for a primary hydroxyl group, preferably triphenyImethyI ( = Tr), p-anisoyl-5 diphenylmethyl or di(p-anisoyl)phenylmethyl, B denotes a nucleoside base radical in which any exo-amino group present is protected, preferably 1 -thyminyl, 1 -(N-4-benzoyIcytosinyI), 9-(N-6-berizoy l-adeninyl) or 9 - (N-2-isobutyroyIguaninyI), 'i0 G denotes a protecting group for a secondary hydroxy I group, Z denotes oxygen, sulfur or selenium and R denotes alkyl having up to 8 C atoms, cyclohexyl, benzyl,or phenyl optionally substituted by fluorine, 15 chlorine, bromine, lower alkyl, lower alkoxy or tri- f luoromethyI, and preferably denotes methyl, ethyl, phenyl or benzyl, especially methyl, •wherein a difunctional phosphonylating reagent of the general formula II X R- PC Y (II) wherein X denotes chlorine or Y and Y denotes a group of the formula - 5 -R1 VR2 1 ? R 1 and Rc representing identical or different alkyl or cycloalkyl radicals having up to 8 C atoms, or phenyl 1 5 radicals, or R and R , together with the nitrogen, representing a saturated or unsaturated heterocyclic ring which can contain further heteroatoms, is reacted with a nucleoside of the general formula III B r-°XJ (III) H-0 wherein T and D have the meanings given above, preferably 10 at -80 to +100°C, in particular at -20 to 0°C, the resulting compound of the general formula IV T -—O—1/ 0nJ ^Y_j/ (iv) 0 1 R - P y is reacted with a compound of the general formula V B H-°X7 (V) G-0 wherein B and G have the meanings given above, preferably at -20 to +100°C, in particular at room temperature, and the resulting compound of the general formula VI I - 6 - R - ^ B (VI) > The compounds of the general formula I in which 2 denotes sulfur or selenium are new. The intermediates of the general formula IV are also new and form a subject of the i nverit ion. 10 In principle, the radical R in the difunctional phosphcnylating reagent of the general formula II can be any non-cytotoxic organic radical which is inert towards the compounds of the general formulae II to VI and which does not hinder the reactions. 15 Examples of possible groups of the general formula -NR^R^ are: dimethylamino, diethylamino, diisopropyl-amino, methylethyl amino, methylpropylafiiino, methylhexyl-amino, methyIcyc lohexyI amino, methy I benzyI amino, morpholino, pyrrolidine, piperidino, methyI aniIino, dipheny I ami no, 20 imidazolo, triazolo, benzotriazolo and tetrazolo.
The starting materials of the general formula II in which X denotes chlorine can be obtained by reacting the corresponding dichlorophosphane, preferably Riethyldi-chlorophotphane, with a secondary amine of the general 25 formula VII - 7 - H-NR1R2 (VII) 1 ? in which R and R have the meanings given above. Correspondingly, compounds of the general formula II in which X denotes a group of the formula Y are accessible 5 by further reaction with the sane secondary amine or a different secondary amine of the general formula VII. The compounds of the formula II can be purified by vacuum distiIlation.
The reaction of the phosphonylating reagent of the 10 general formula II with a suitably protected nucleoside of the general formula III is carried out in a moderately polar solvent, preferably chloroform, with the exclusion of moisture. Tertiary amines, preferably ethyldiisopropyl- li amine (Hunig's base), can be used as auxiliary bases for 15 this reaction. Working-up is carried out by aqueous extraction and precipitation of the products of the general formula IV with a non-polar solvent such as petroleum ether or pentane. The phosphonous acid ester-amides of the general formula IV obtained in this way precipitate as 20 colorless powders and can be characterized by spectroscopic data such as ^P-NMR or UV and elementary analysis. Furthermore, they can also be converted, by direct oxidation, to the phosphonic acid ester-amides of -the general formula VIII B 25 O (VIII) Z = p — R I Y T, B, Z, R and Y having the meanings given above, which can then be isolated and characterized.
Remarkably, no symmetrical dinucleoside 3',3'-phosphonite is formed within the limit of detection. 5 As shown by '"'p-NMR, the compounds of the general formula I are stable for at least 1 month in powder form, when stored dry and at a maximum of -20°C. This great stability of the phosphonous acid ester-amides is astonishing and emphasizes the value of this method. Its 10 universal applicability in the synthesis of phosphonic acid diesters of nucleosides is shown by the reaction with suitably 3'-protected nucleosides: In this reaction, the 5'-protected nucleoside phosphonites of the general formula IV are dissolved in a 15 moderately polar solvent, preferably acetonitri le, chloroform or tetrahydrofuran, and mixed with the nucleoside of the general formula V (protected in the 31-position) . Suitable protecting groups G in the compounds of the general formula V are acyl groups such as benzoyl, acetyl, 20 pivaloyl or levulonyl, or silyl groups such as t-butyl-dimethy Isi ly I. The reaction is catalyzed by an acid, preferably an azole or amine hydrochloride. Benzotriazole is particularly suitable. It is remarkable that HPLC analysis of the product shows no symmetrical S'^'-isomer 25 and only traces of the 3 ' ,3 '-isomeric phosphonate.
The labile intermediate, namely the phosphonous acid triester of the general formula VI, is oxidized directly to the phosphonate of the general formula I. In addition to the oxidizing agents usually employed for this purpose, such as dinitrogen tetroxide or iodine, peroxides, in particular anhydrous t-butyl hydroperoxide, have proved valuable. The reaction is preferably carried out in a moderately polar solvent, particular preference being 5 afforded to acetonitrile or chloroform. Particular consideration should be given to the known acid-catalyzed transesterification of the diacylalkylphosphonites ( F. W „ Hoffmann, R.G. Roth and T.C. Simmons, J. Amcr. Chem. Soc. 80, 5937 - 40 (1 958)) . 10 The compounds (some of which are already known) 31 1 are characterized by means of P-NMR and H-NMR and also chromatographic comparisons with authentic material.
The compounds of the general formula I in which Z denotes sulfur or selenium are prepared by direct reaction 15 of the compounds of the general formula VI with elemental sulfur or selenium. Stirring with the stoichiometric quantity of sulfur or selenium, in a polar solvent such as tetrahydrofuran, leads to good yields of the corresponding thiophosphonates or seIenophosphonates of the general 20 formula I. Characterization is carried out by means of 31p_NMR and ^ H-NMR as well as elementary analysis.
Because of the presence of a center of asymmetry in the nucleoside moiety and the production of another on the phosphorus, the phosphates of the general formula I 25 exist as mixtures of diastereomers (see Table 6, isomers 1 and 2) .
The isomer ratio, which is close to the statistical ratio of 1:1, is only very slightly influenced by a variation in the parameters such as the solvent, the tern- - 10 - perature and the sequence of addition.
The examples which follow describe the invention in greater detail: Ex amp Ie 1: Starting material HjC-'P CN (CHj) 2^2 5 In a 1000 ml three-necked flask fitted with a dropping funnel and a mechanical stirrer, 125 ml (1.9 mol) of dimethyI amine are introduced into 400 in I of anhydrous diethyl ether and reacted, over a period of 60 minutes, with a solution of 60 ml (0.40 mol) 10 of methyldichlorophosphane in 200 ml of anhydrous ether, while cooling with ice. After stirring for 2 hours at room temperature and for 1 hour at 50°C, the precipitate is filtered off under a protective gas and rinsed twice with 100 ml of ether and the filtrate is concentrated at 15 about 0.1 bar. The remaining residue is rapidly distilled over at 0.5 bar/124°C. Precision distillation with a Vigreux column (50 cm) at 64-65°C/65 mbar gives 36.6 g (66% of theory) of a colorless liquid.
Analysis: Cl^~^ < 0.2% 20 31P-NMR (THF) % = 87 ppm 1H-NMR (COCI3) S = 1.23 ppm (d, 7Hz, P-CU3) % = 2.66 ppm (d, 7Hz, N(CH3)2) Example 2: The S'-tritylnucleosides III (1 mmol) are dissolved 25 in 6 ml of anhydrous chloroform under an inert nitrogen atmosphere nnd H3 CP CN (C ) 2^2 (2 i s added. The reaction is complete after 12 hours at room temperature (stirring) or after only 2 hours if catalytic quantities (0.1 mmol) of collidine hydrochloride are added. - 11 - The solution is then transferred with 100 ml of methylene chloride to a 250 ml separating funnel and extracted twice by shaking with 50 ml of saturated sodium chloride solution (containing 0.1 ml of triethy I amine). The organic phase is dried over anhydrous sodium sulfate and concentrated to a foam. This is stirred for 2 hours with 50 ml of pentane. The residue is filtered off and dissolved in 2 ml of diethyl ether and the solution is slowly added dropwise to 50 ml of thoroughly stirred pentane. The fine precipitate is filtered off and dried to give an 85-95% yield of the compound of the general formula IV (Tables 2 and 3).
The compounds can be identified directly by 31 P nuclear magnetic resonance spectroscopy or, after oxidation with t-butyl hydroperoxide, as phosphonic acid este:— amides of the general formula VIII (Tables 4 and 5).
In the ^P-NMR spectrum, these substances show up to 3% of hydrolyzed product (nucleoside methylphos-phinate), but no detectable quantity of symmetrical di-nucleoside 31,31-phosphonite. This demonstrates the superiority of the method compared with former methods, which always yielded about 5-10% of these products. When stored as dry powders at -20°C, no decomposition can be observed within a month.
The following reagents were also employed analogously: - 12 - „ r I)/N(C2H5>2 ,n ZCHtCIl >,_? n e - pf ii c - * 2 3 ^C1 3 x CI CaHC; N II C - p' 3 HC - P 652 CI 3 ^ CI Example 3: The 5 1 -1rityInucIeoside III (1.00 mmcl) and 1.71 ml (10 mmol) of N, N , N-e t hy Id i i sop ropy I am i ne are 5 introduced into 6 ml of TH F , and 2.,00 mmol of phosphonyla-ting agent II are then slowly added dropwise. After stirring at room temperature overnight, the reaction solution is added dropwise to ice-cold water (50 ml, saturated with NaCl). After extraction with twice 20 ml 10 of methylene chloride, the organic phase is dried with sodium sulfate and the solvent is removed in vacuo.
Further purification is carried out by precipitation as above (Tables 2 and 3).
E xamp le 4; 15 3 *-0-3e nzoy 11 li yrn i d i ne (0.20 mmol) and 1-H-benzo- triazole (0.80 mmol) are dried in a round-bottomed flask and then dissolved in 1.0 ml of dry acetonitrile. The reaction is complete within one minute, a very air-labile and acid-labile phosphonite VI being formed; this is 20 converted directly to the phosphonates I, with 80-90% yield, by oxidation with anhydrous t-butyl hydroperoxide (0.25 mmol) (according to H. Langhals, E. Fritz and J. Mergelsberg, Chen. Ber. 113, 3662 (1980)) dissolved in - 13 - acetonitrile or tetrahydrofuran.
Alternatively/ 30 mg (0.95 mmol) of sulfur are added to 0.7 mmol of VI at -20°C and the mixture is stirred overnight at room temperature. The reaction is generally already complete after a few hours. 20 ml of chloroform are then added and the organic phase is extracted three times by shaking with water. After drying over sodium sulfate and removal of the solvent, a crude product is obtained which is purified by silica gel chromatography to give the compound I in 80-90% yield (Table 6).
A11ernativeIy/ 118 mg (1.5 mmol) of black selenium are added to 0.7 mmol of VI and the mixture is stirred overnight. After working-up (as above), the compound I is obtained in 60% yield (Table 6).
HPLC analysis of the reaction mixture (in the case where Z ~ 0 by comparison with the authentic reference, P.O.P. T1so et al., Biochemistry 18, 5134 (1979)) showed about 1% of the 3',3'-phosphonates and no 5',5'-isomer.
TABLE 1: Conpounds (II) H^C-PXY 1H-NMR (CDClj), cf(ppm) X Y 31 P-NMR £ Cppm)3 ^ B .p.
°C/bar p-ch3 Other protons - Cl ch3 "N\ 6^5 - 141.2b) 44-47/10~8 1.61 d (J=13.1 Hz) 7.41-7.18 3.20 (m, 5H, aromatic H,d (J=8.3 Hz)) - Cl -N(C6H5)2 - 132.2b) 92-44/10-8 1.53 d (J=14 Hz) 7.5-6.9 (m, 10 H, aromatic H) /^N -N ! -N ' -i " NiSsW /=^N "VN yN-S^-NC ~v - 62C) n ^ - 72w _.c) - 91 92/l0~5 CM.p.: 60°C) (M. p.: 110°C) - 81 d) 2.20 d(J=10 Hz) 2.32 d(J=9 Hz) 2.49 d(J=9 Hz) 2.60 d(J=9 Hz) 7.45 (s, 2H) 6.95 (s, 4H) 8.51 (s, 2H) 8.07
Claims (12)
1. A process for the preparation of a deoxyribonucleoside phosphonate of the general formula I O * - P - K E o— ' °' (I) '1 G-0 in v/ h i c h T denotes a protecting group for a primary hydroxyl g roup, B denotes a nucleoside base radical in which one exo-amino group present is protected, G denotes a protecting group for a secondary hydroxyl group, Z denotes oxygen, sulfur or selenium and R denotes alkyl having up to 8 C atoms, cyclohexyl, benzyl, or phenyl optionally substituted by fluorine, chlorine, bromine, lower alkyl, lower alkoxy or tri-fluoromethyl, which comprises reacting a difunctional phosphonylating reagent of the general formula II X R - ^ Y (II) wherein X denotes chlorine or Y and Y denotes a group of the formula 1 R " 2 x R 10 - 21 - 1 ? R1 and representing identical or different alkyl or cycloalkyl radicals having up to 8 C atoms, or phenyl 1 ? radicals, or R and R , together with the nitrogen, representing a saturated or unsaturated heterocyclic ring which can contain further heteroatoms, with a nucleoside of the general formula III t — o- (iii) H-0 wherein T and B have the meanings given above, reacting the resulting compound of the general formula IV 9 (iv) r - p Y with a compound of the general formula V H-°Or G-0 (v) wherein B and G have the meanings given above, and oxidat-ively converting the resulting compounds of the general formula VI ,o B t—0 15 r~f 0 (vi) 1 R - P B 4-o G—O wherein T, ft, B and G have the meanings given above, to compounds of the general formula - 22 - 1.
2. A process as claimed in claim 1, wherein compounds of the formulae II to IV are used in which T denotes tripheny ImethyI, p-anisoy IdiphenyImethyI or di(p-anisoyl)phenylmethyl, B denotes 1-thyminyl, 1-, 9-(N~ 6-benzoyladeniny I) or 9-(N-2-isobutyroy Iguaniny I) and R denotes methyl, ethyl, phenyl or benzyl.
3. A process as claimed in claim 1 or 2, wherein the compounds of the formulae II and III are reacted at -80 to +100°C.
4. A process as claimed in claim 3, wherein the reaction takes place at -20 to 0°C.
5. A process as claimed in one or more of the preceding claims, wherein the compounds of the formulae IV and V are reacted at -20 to +100°C.,
6. A process as claimed in claim 5, wherein the reaction takes place at room temperature.
7. A process as claimed in one or more of the preceding claims, wherein the compound of the formula VI is oxida-tively converted to a compound of the formula I at -80 to +100°C.
8. A process as claimed in claim 7, wherein the oxidation takes place at -20°C to room temperature.
9. A compound of the formula IV in which T, B, R and Y have the meanings given in claim 1. - 23 -
10. A process as claimed in Claim 1 for the preparation of a deoxyribonucleoside phosphonate of the general formula I given and defined therein, substantially as hereinbefore described and exemplified. 5
11. A deoxyribonucleoside phosphonate of the general formula I given and defined in Claim 1, whenever prepared by a process claimed in preceding claim.
12. A compound of the formula IV according to Claim 9, substantially as hereinbefore described and exemplified. F . R. KELLY & CO . , AGENTS FOR THE APPLICANTS.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19833332068 DE3332068A1 (en) | 1983-09-06 | 1983-09-06 | METHOD FOR PRODUCING NUCLEOSIDALKYL, ARALKYL AND ARYLPHOSPHONITES AND PHOSPHONATES |
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| IE842268L true IE842268L (en) | 1985-03-06 |
| IE57904B1 IE57904B1 (en) | 1993-05-05 |
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| IE2268/84A IE57904B1 (en) | 1983-09-06 | 1984-09-05 | Process for the preparation of nucleoside alkyl-,aralkyl-and aryl-phosphonites and-phosphonates |
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| Country | Link |
|---|---|
| EP (1) | EP0136543B1 (en) |
| JP (2) | JPS6072899A (en) |
| AT (1) | ATE38839T1 (en) |
| AU (2) | AU570266B2 (en) |
| CA (1) | CA1235079A (en) |
| DE (2) | DE3332068A1 (en) |
| DK (3) | DK162895C (en) |
| ES (1) | ES8505384A1 (en) |
| GR (1) | GR80287B (en) |
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| PT (1) | PT79172B (en) |
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| US4959463A (en) * | 1985-10-15 | 1990-09-25 | Genentech, Inc. | Intermediates |
| DE3916871A1 (en) * | 1989-05-24 | 1990-11-29 | Boehringer Mannheim Gmbh | MODIFIED PHOSPHORAMIDITE PROCESS FOR THE PREPARATION OF MODIFIED NUCLEIC ACIDS |
| EP0464638B1 (en) * | 1990-07-02 | 1997-04-02 | Hoechst Aktiengesellschaft | Oligonucleotide analogues with terminal 3'-3' or 5'-5'-internucleotide linkages |
| US5512668A (en) * | 1991-03-06 | 1996-04-30 | Polish Academy Of Sciences | Solid phase oligonucleotide synthesis using phospholane intermediates |
| JPH08502723A (en) * | 1992-07-27 | 1996-03-26 | ハイブライドン インコーポレイテッド | Oligonucleotide alkylphosphonothioate |
| ATE150464T1 (en) * | 1993-01-08 | 1997-04-15 | Hybridon Inc | SYNTHESIS OF DIMER BLOCKS AND THEIR USE IN THE COMPOSITION OF OLIGONUCLEOTIDES |
| US6087491A (en) | 1993-01-08 | 2000-07-11 | Hybridon, Inc. | Extremely high purity oligonucleotides and methods of synthesizing them using dimer blocks |
| DK0677056T3 (en) * | 1993-01-25 | 1996-08-05 | Hybridon Inc | Oligonucleotide alkyl phosphonates and alkyl phosphonothioates |
| US6417138B1 (en) * | 1994-07-26 | 2002-07-09 | Sony Corporation | Method for transcribing an image and a support for transcription and ink ribbon employed therefor |
| AU707369B2 (en) * | 1995-05-26 | 1999-07-08 | Genta Incorporated | Compositions and methods for the synthesis of organophosphorus derivatives |
| ATE254627T1 (en) * | 1996-05-03 | 2003-12-15 | Avecia Biotechnology Inc | IN SITU PRODUCTION OF NUCLEOSIDE PHOSPHORAMIDITES AND THEIR USE IN OLIGONUCLEOTIDE SYNTHESIS |
| DE102004049339A1 (en) | 2004-10-08 | 2006-04-13 | Basf Ag | Process for the purification of phosphorus-containing chelate ligands |
| DE102007038930B4 (en) * | 2007-08-13 | 2013-12-05 | Universität Leipzig | New chemical compound and its use in medicine, in particular for use in tumor therapy |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| IL62834A0 (en) * | 1980-05-14 | 1981-07-31 | Ens Bio Logicals Inc | Polynucleotide synthesis |
| US4415732A (en) * | 1981-03-27 | 1983-11-15 | University Patents, Inc. | Phosphoramidite compounds and processes |
| EP0090789A1 (en) * | 1982-03-26 | 1983-10-05 | Monsanto Company | Chemical DNA synthesis |
| DE3239888A1 (en) * | 1982-10-28 | 1984-05-03 | Hubert Prof. Dr. 2000 Hamburg Köster | METHOD FOR PRODUCING OLIGONUCLEOSIDE PHOSPHONATES |
-
1983
- 1983-09-06 DE DE19833332068 patent/DE3332068A1/en not_active Withdrawn
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- 1984-08-30 AT AT84110314T patent/ATE38839T1/en not_active IP Right Cessation
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- 1984-09-04 PT PT79172A patent/PT79172B/en active IP Right Revival
- 1984-09-04 GR GR80287A patent/GR80287B/en unknown
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- 1984-09-05 JP JP59184717A patent/JPS6072899A/en active Granted
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- 1991-07-05 DK DK131691A patent/DK167359B1/en active IP Right Grant
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Also Published As
| Publication number | Publication date |
|---|---|
| GR80287B (en) | 1985-01-07 |
| AU3275684A (en) | 1985-03-14 |
| DK131691A (en) | 1991-07-05 |
| JPH05262787A (en) | 1993-10-12 |
| DK166585C (en) | 1993-10-25 |
| DE3332068A1 (en) | 1985-03-21 |
| DE3475307D1 (en) | 1988-12-29 |
| PT79172B (en) | 1986-09-10 |
| ES535627A0 (en) | 1985-05-16 |
| EP0136543B1 (en) | 1988-11-23 |
| CA1235079A (en) | 1988-04-12 |
| JPH0531560B2 (en) | 1993-05-12 |
| PT79172A (en) | 1984-10-01 |
| DK162895C (en) | 1992-05-11 |
| DK167359B1 (en) | 1993-10-18 |
| AU601257B2 (en) | 1990-09-06 |
| ATE38839T1 (en) | 1988-12-15 |
| DK131591A (en) | 1991-07-05 |
| AU570266B2 (en) | 1988-03-10 |
| DK162895B (en) | 1991-12-23 |
| DK424784A (en) | 1985-03-07 |
| JPH0662662B2 (en) | 1994-08-17 |
| AU1138488A (en) | 1988-07-14 |
| EP0136543A2 (en) | 1985-04-10 |
| JPS6072899A (en) | 1985-04-24 |
| DK166585B (en) | 1993-06-14 |
| DK131591D0 (en) | 1991-07-05 |
| DK131691D0 (en) | 1991-07-05 |
| IE57904B1 (en) | 1993-05-05 |
| EP0136543A3 (en) | 1986-07-16 |
| DK424784D0 (en) | 1984-09-05 |
| ES8505384A1 (en) | 1985-05-16 |
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