GB2125399A - Process for the preparation of (E)-5-(2-bromovinyl)-2'- deoxyuridine and new derivatives thereof - Google Patents
Process for the preparation of (E)-5-(2-bromovinyl)-2'- deoxyuridine and new derivatives thereof Download PDFInfo
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- GB2125399A GB2125399A GB08321081A GB8321081A GB2125399A GB 2125399 A GB2125399 A GB 2125399A GB 08321081 A GB08321081 A GB 08321081A GB 8321081 A GB8321081 A GB 8321081A GB 2125399 A GB2125399 A GB 2125399A
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- deoxyuridine
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- ODZBBRURCPAEIQ-DJLDLDEBSA-N Brivudine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=CBr)=C1 ODZBBRURCPAEIQ-DJLDLDEBSA-N 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 title claims description 22
- 238000002360 preparation method Methods 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 10
- 125000000950 dibromo group Chemical group Br* 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 2
- 239000000203 mixture Substances 0.000 claims description 46
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 238000005893 bromination reaction Methods 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- 238000002955 isolation Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 230000031709 bromination Effects 0.000 claims description 3
- 230000020176 deacylation Effects 0.000 claims description 3
- 238000005947 deacylation reaction Methods 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 238000006704 dehydrohalogenation reaction Methods 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- 125000004423 acyloxy group Chemical group 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 150000003512 tertiary amines Chemical class 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000001589 carboacyl group Chemical group 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 230000002503 metabolic effect Effects 0.000 abstract 1
- 239000002243 precursor Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000000463 material Substances 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229910001873 dinitrogen Inorganic materials 0.000 description 5
- XACKNLSZYYIACO-DJLDLDEBSA-N edoxudine Chemical compound O=C1NC(=O)C(CC)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XACKNLSZYYIACO-DJLDLDEBSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- NRTLTGGGUQIRRT-UHFFFAOYSA-N triethylazanium;bromide Chemical compound [Br-].CC[NH+](CC)CC NRTLTGGGUQIRRT-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- BLXGZIDBSXVMLU-OWOJBTEDSA-N 5-[(e)-2-bromoethenyl]-1h-pyrimidine-2,4-dione Chemical compound Br\C=C\C1=CNC(=O)NC1=O BLXGZIDBSXVMLU-OWOJBTEDSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- MXHRCPNRJAMMIM-SHYZEUOFSA-N 2'-deoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-SHYZEUOFSA-N 0.000 description 2
- YNYDWEIQSDFDLK-UHFFFAOYSA-N 5-acetyl-1h-pyrimidine-2,4-dione Chemical compound CC(=O)C1=CNC(=O)NC1=O YNYDWEIQSDFDLK-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229950005499 carbon tetrachloride Drugs 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- MXHRCPNRJAMMIM-UHFFFAOYSA-N desoxyuridine Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-UHFFFAOYSA-N 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000008259 solid foam Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- HFEXWXMEGUJTQB-OWOJBTEDSA-N (e)-3-(2,4-dioxo-1h-pyrimidin-5-yl)prop-2-enoic acid Chemical compound OC(=O)\C=C\C1=CNC(=O)NC1=O HFEXWXMEGUJTQB-OWOJBTEDSA-N 0.000 description 1
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 1
- ZRYZBEQILKESAW-UHFFFAOYSA-N 5-ethenyl-1h-pyrimidine-2,4-dione Chemical compound C=CC1=CNC(=O)NC1=O ZRYZBEQILKESAW-UHFFFAOYSA-N 0.000 description 1
- RHIULBJJKFDJPR-UHFFFAOYSA-N 5-ethyl-1h-pyrimidine-2,4-dione Chemical compound CCC1=CNC(=O)NC1=O RHIULBJJKFDJPR-UHFFFAOYSA-N 0.000 description 1
- OHAMXGZMZZWRCA-UHFFFAOYSA-N 5-formyluracil Chemical compound OC1=NC=C(C=O)C(O)=N1 OHAMXGZMZZWRCA-UHFFFAOYSA-N 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- 229910021547 Lithium tetrachloropalladate(II) hydrate Inorganic materials 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- WIKQEUJFZPCFNJ-UHFFFAOYSA-N carbonic acid;silver Chemical compound [Ag].[Ag].OC(O)=O WIKQEUJFZPCFNJ-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- -1 ethylacrylate (E)-5-(2-carbethoxyvinyl)-2'deoxyuridine Chemical compound 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- NGYIMTKLQULBOO-UHFFFAOYSA-L mercury dibromide Chemical compound Br[Hg]Br NGYIMTKLQULBOO-UHFFFAOYSA-L 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- KLVOSHOFGYMCCP-UHFFFAOYSA-N n,n-di(propan-2-yl)butan-1-amine Chemical compound CCCCN(C(C)C)C(C)C KLVOSHOFGYMCCP-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- KQTXIZHBFFWWFW-UHFFFAOYSA-L silver(I) carbonate Inorganic materials [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
Classifications
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- 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
- C07H19/06—Pyrimidine radicals
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
(E)-5-(2-bromovinyl)-2'- deoxyuridine and its derivatives of general formula VI <IMAGE> (where R is H or as defined below) are prepared from 3,5'-di-O-acyl-5-ethyl- 2'-deoxyuridines of general formula IV <IMAGE> (wherein R is C1-8 alkanoyl, benzoyl or benzoyl group substituted in para position by C1-4 alkyl or halogen) by reaction with bromine to give a dibromo derivative of general formula V <IMAGE> which is then dehydrohalogenated and if desired deacylated to give the compound of formula of formula (VI) in which R is H. The compounds of formula (VI) in which R is other than H are new compounds and are metabolic precursors for (E)-5-(2-bromovinyl-2'- deoxyuridine. These compounds are thus useful in medicine.
Description
SPECIFICATION
Process for the preparation of (E)-5-(2-bromovinyl)-2'-deoxyuridine and new derivatives thereof
The present invention relates to a new process for preparing (E)-5-(2-bromovinyl)-2'deoxyuridine and its derivatives of general formula VI.
wherein
R is a hydrogen atom or a C18 alkanoyl group, or benzoyl or a benzoyl group substituted in para position by alkyl group of 1-4 carbon atoms or a halogen atom.
Furthermore this invention relates to new compounds of general formula VI and their use.
Two processes are described in the literature for the preparation of the compound of formula VI where R=H.
The first process is based on condensation of 2,4-bis-O-trimethylsilyl derivative of (E)-5-(2bromovinyl)-uracil with 1-chloro-2-deoxy-3,5-di-0-p-toluyl-.l-D-Erythro-pentafuranose [A. S. Jones, R.
T. Walker, P. J. Barr and E. DeClercq: Ger. Offen. 2,915,254]. A disadvantage of this method is that synthesis of the starting material (E)-5-(2-bromovinyl)uracil is very elaborate and yields are low.
Furthermore the compound of formula VI where R=H obtained in this way is not pure; it is a mixture of alpha and beta isomers. Only the beta isomer has a practical value. (E)-5-(2-bromovinyl)uracil is prepared from 5-acetyluracil through 5-vinyluracil. The total yield for compound of formula VI where
R=H is less than 1 0% based on 5-acetyluracil, and chromatographic separation of the isomeric mixture is also required [see introductory remarks in A. S. Jones, G. Verhelst and R. T. Walker: Tetrahedron
Letters 45,4415-4418 (1979)]. Recently, (E)-5-(2-bromovinyl)uracil has been made from 5formyluracil through (E)-5-(2-carboxyvinyl)uracil in higher yields. Condensation results, of course, in an isomeric mixture (alpha/beta=1.3) for the compound of formula VI [P. J. Barr, A. S. Jones, G. Verhelst and R.T. Walker: J. Chem. Soc. Perkin 1,1665-1670(1981)].
A Modified version [A. S. Jones, G. Verhelst and R. T. Walker: Tetrahedron Letters 45, 441 5- 4418 (1979)] of the Bergström procedure [D. E. Bergström and J. L. Ruth: J. Am. Chem. Soc. 98, 1587 (1976) and D. E. Bergstrnm, M. K. Ogawa: J. Am. Chem. Soc. 1008106(1978)] seemstobe more advantageous than the condensation process: C-5-mercury-2'-deoxyuridine is prepared from 2'deoxyuridine and then treated with Li2PdCI4 and ethylacrylate (E)-5-(2-carbethoxyvinyl)-2'deoxyuridine is prepared which can be hydrolysed to the corresponding compound of formula VI. Since the starting material is beta-2'-deoxyuridine, an isomeric mixture is not formed in the course of the synthesis.Disadvantages of this process are that Li2PdCl4 and 2'-deoxyuridine are expensive compounds and silica gel column chromatography is required for the purification of the final product.
These facts make industrial production expensive and elaborate.
(E)-5-(2-bromovinyl)-2'-deoxyuridine of general formula VI where R=H can be prepared also by bromination of 5-ethyl-2'-deoxyuridine [D. BMlolff and P. Langen: Nucleic Acids Res, Spec. Publ. No.
1,2931 (1979)]: 3',5'-di-O-acyl-5-ethyl-2'-deoxyuridine is prepared from the beta-isomer of 5- ethyl-2'-deoxyuridine, it is then reacted with bromine, dehydrohalogenated in the presence of a tertiary base, and finally deacylated to yield compound of formula VI, where R=H. Disadvantages of this process are that prior to the bromination reaction pure beta-isomer of 5-ethyl-2'-deoxyuridine has to be separated from the isomeric mixture formed in the course of synthesis of 5-ethyl-2'-deoxyuridine, and that under conditions of the bromination reaction isomerization of 5-ethyl-2'-deoxyuridine derivative can occur. That is, starting with pure beta-isomer of diacyl compound of formula IV
an isomeric mixture with 9 ratio of alpha/beta=1 for the compound of formula VI, where R=H, was obtained.
(E)-5-(2-bromovinyl)-2'-deoxyuridine of general formula VI where R;H, is the most active and most selective (non-toxic to the host cell) chemotherapeutic agent so far known against herpes simplex virus type 1 and varicella zooster virus in vitro and in vivo [E. DeClercq, et al: Proc. Natl. Acad. Sci. USA 76, 2947-2951(1979), P. P. C. Maudgal, et al: Graefes Arch. Ophtalmol. 216, 261-268 (1981) and E. DeClercq et al: British Med. J. 281, 1178 (1980)]. This is why a synthetic process using a new starting material is desirable.
We have now found that compounds of general formula IV, wherein R is an acyl group e.g. an alkanoyl group of 1-8 carbon atoms, benzoyl or a benzoyl group substituted in para position with an alkyl group of 1-4 carbon atoms or a halogen atom, can be used as a target for bromination. The protecting groups of the compound of general formula IV are not brominated under conditions applied.
In this way the whole reaction becomes more simple since two steps can be omitted: deacylation and reacylation of the compound of general formula IV. Other great advantage of this new process is that the bromination reaction can be carried out with the alpha-beta isomeric mixture of formula IV formed in the condensation reaction. In this way the yield can considerably be increased. Under the conditions applied in the dehydrohalogenation reaction the majority of the beta isomer of the compound of general formula VI separates out from the mixture together with triethylammonium-hydrobromide, whereas the alpha isomer of compound of general formula VI together with a small amount of beta isomer remains in the solution.Based on the starting halogenose of formula III
the yield for the compound of formula VI obtained via reaction with pure beta isomer of formula IV is 22.5% whereas with the (14)' isomeric mixture of formula IV it is 35.4%.
The invention relates to a process for the preparation of (E)-5-(2-bromovinyl)-2'-deoxyuridine and its derivatives of general formula VI in which the alpha-beta isomeric mixture of 3',5'-di-O-acyl-5-ethyl2'-deoxyuridine of general formula IV (wherein R is an alkanoyl group of 1-8 carbon atoms, benzoyl or benzoyl group substituted in para position by an alkyl group of 1-4 carbon atoms or a halogen atom, is reacted with bromine, and the compound of formula V below which is obtained is dehydrohalogenated and then deacylated.
Preferably, 1 mole of the alpha-beta isomeric mixture of 3',5'-di-O-acyl-5-ethyl-2'-deoxyuridine of general formula IV (preferably the 3',5'-di-O-p-chlorobenzoyl derivative) is reacted photolytically in a halogenated hydrocarbon (preferably dichloromethane, chloroform or carbontetrachloride or a mixture thereof) with 2-3 moles of bromine. The dibromo derivative of formula V formed is then reacted, without isolation or, optionally, after isolation and resolution, in a halogenated organic solvent (preferably in dichioroethane) with an appropriate tertiary base used in excess (for instance diisopropylbutylamine or triethylamine, preferably triethylamine in dichloroethane), to dehydrohalogenate it.The compound of general formula VI is then deacylated in an alkanol (e.g. Cm~4) with a lower (e.g. C1~4) alkali metal alcoholate. The compound of general formula VI where R=H, either alone or in combination with other active ingredients and/or carriers, fillers, solvents, flavouring agents and/or other additives, can be prepared in the usual way for pharmaceutical purposes.
In a preferred aspect of the invention the compounds of general formula VI (wherein R is an acyl group) are used as active ingredients. The acyl groups are removed in the course of the metabolism of the compound of formula VI.
New compounds of the present invention are those of formula VI where R is other than H, particularly p-chlorobenzoyl and -COCH3. These new compounds may of course be prepared by the process of the invention, with the omission of the final deacylation step.
The process according to the invention is illustrated in the following examples.
Starting materials for the first and second examples,3',5'-di-0-chlorobenzoyl-5-ethyl-2'- deoxyuridine alpha-beta isomers and pure beta isomer, respectively, were prepared as follows.
a. 2,4-Bis-O-trimethylsilyl-5-ethyluracil of formula II
To 100 g (0.71 mole) of 5-ethyluracil of formula I dried at 1 500C in vacuum, 200 ml (1.25 moles) of 1,1,1,3,3,3,-hexamethylene-disilasane are added and mixture is refluxed
for 24 hours under anhydrous conditions. The resulting clear solution is distilled at atmospheric pressure. The remaining syrup is distilled in vacuum. Boiling point for the product is 1 340C at 1 733 Pa.
Yield is 197.4 g (97%).
b. 2-Deoxy-3,5-di-O-p-chlorobenzoyl-alpha-beta-D-ribofuranosyl chloride of formula Ill
10 g of 2-deoxy-D-ribose is dissolved in 1 90 ml of anhydrous methanol, then 10 ml of anhydrous methanol containing 1% hydrochloric acid are added. After 20 minutes at 250C 5 g of freshly prepared
Ag2CO3 are added. The mixture is filtered on paper, filtrate is evaporated in vacuo at 400C on water bath. To the residual syrup 5 ml of anhydrous pyridine are then added, and evaporation repeated. 58 ml of an hydros pyridine are added to the syrupy residue and then 22.5 ml of p-chlorobenzoyl chloride under ice cooling. The temperature is held between 20--400C during the addition. The flask is equipped with CaCl2-tubing and is left for 16 hours at room temperature.After addition of 50 ml of water, the solution is extracted twice with 75 ml of dichloromethane. Dichloromethane solution is also extracted twice with water containing 1 0% KH CO3, then dried over Na2SO4. After filtering out Na2SO4, dichloromethane is evaporated in vacuo. 75 ml of anhydrous diethylether are mixed with the residue, the mixture cooled to OOC, and 100 ml of anhydrous acetic acid saturated with hydrochloric acid are added. Dry hydrochloric acid gas is bubbled through the mixture until a white dense material is formed.
It is quickly filtered, washed with ice-cool anhydrous diethylether and dried over P2Os and KOH in vacuum desiccator. This material can be used without recrystallisation. Yield: 24 g (75%), melting point: 11 80C. Based on chromatographic separation on Silica gel He254 (Type 60, Merck) sheets with a mixture of chloroform-diethylether (7:3), the product is a 1:1 mixture of alpha and beta isomers.
c. 3',5'-Di-O-p-chlorobenzoyl-5-ethyl-2'-deoxyuridine (IV)
88.5 g of 2,4-bis-O-trimethylsilyl-5-ethyluracil (11; 0.31 mole) are dissolved in 3900 ml of anhydrous acetonitrile, then 300 g of molecular sieves (Merck, 4 A). 1 04.6 g of 2-deoxy-3,5-di-O-pchlorobenzoyl-alpha-beta-D-ribofuranosyl chloride (III; 0.243 mole) and 41.8 g dry HgBr2 are quickly added. Stirring is started and in a few minutes the mixture becomes clear, then crystallization begins.
The reaction mixture is slowly stirred for 5 hours then is left at room temperature overnight. The crystallized material is pure beta isomer of 3',5t-di-0-p-chlorobenzoyl-4-0-trimethylsilyl-5-ethyl-2'- deoxyuridine.
c/l. Isolation of pure beta-isomer of the compound of formula IV
Precipitated material is filtered out. (Filtrate contains a mixture of alpha and beta isomers). The precipitate is washed four times with chloroform, so that only molecular sieves remain on the filter. The combined chloroform filtrate are extracted with 50 ml of 30% KI solution. The organic layer is separated, dried over MgSO4 and, after filtration, evaporated in vacuo. To the residue of solid foam, 4 litres of 96% ethanol are added and the mixture is boiled for half an hour. The solution is cooled to room temperature and solid product is filtered out. This is the pure beta-isomer of the compound of general formula IV. Recrystallised from ethanol, yield is 42.5 g (32.6% based on halogenose of formula
III), melting point is 1 96--7 OC.
c/ll. Isolation of the alpha-beta isomeric mixture of the compound of formula IV
After standing overnight, mixture of the condensation reaction is filtered on glass filter, the precipitate remaining on the filter is dissolved in 1 50 ml of chloroform, the molecular sieve is washed three times with 1 50 ml of chloroform (beta-isomer). The acetonitrile filtrate containing the isomeric mixture is evaporated to dryness and 1 litre of chloroform is added. The precipitated material is filtered out. The combined chloroform solutions are extracted with 1 50 ml of 30% KI solution, separated, dried over MgSO4, and finally evaporated. The material obtained is refluxed in six liters of 96% ethanol for half an hour, and is left to cool down to room temperature. The precipitate is filtered off.Yield-96 g (73.8% total yield). Isomer ratio in compound of formula lV-1 :3 (alpha to beta).
Example 1
Preparation of (E)-5-(2-bromovinyl)-2'-deoxyuridine of formula Vl, where R=H, from the isomeric mixture of formula IV
26.7 g (0.05 mole) of 3',5'-di-0-p-chlorobenzoyl-5-ethyl-2'-deoxyuridine (isomeric mixture of formula IV, where ratio of beta to alpha is 3:1) are dissolved by warming in 350 ml of anhydrous dichloroethane. The flask is illuminated and nitrogen gas is bubbled through the mixture. 6.8 ml of bromine in 60 ml of anhydrous dichloroethane is added by dropping over 20-25 minutes.
Illumination is stopped, the mixture is refluxed for 15 minutes with strong nitrogen gas flux. The solvent is removed by evaporation in vacuo, evaporation is repeated twice with 20 ml of anhydrous dichloroethane. The foamy residue is dissolved in 140 ml of anhydrous dichloroethane, and 10.4 ml of triethylamine is added drop by drop to the mixture over 15 minutes. The precipitated material which is a mixture of beta-isomer of the compound of formula VI and triethylammonium hydrobromide is filtered out from the solution, washed with dichloroethane and 80% ethanol. The remaining solid material is pure beta-isomer of the compound of formula Vl, yield 14.8 g (0.024 mole, 48%).
Yield based on halogenose of formula Ill for the compound of formula VI obtained through alphabeta isomeric mixture of formula IV is 35.4%, whereas through the pure beta-isomer of formula IV (see next paragraph) is only 22.5%.
The compound of formula VI is deacylated, as described in Example 2, in 130 ml of 0.5 molar sodium methylate. The mixture is stirred for 3 hours, the pH adjusted to 5-6 with Dowex 50 H+ cation exchanger, the resin filtered out and washed with methanol. The combined methanol solution is evaporated and residue is recrystallized from water. Yield for the compound of formula VI, where R=H-7.4 g (92.6%), melting point--l 75--60C.
Example 2
Preparation of (E)-5-(2-bromovinyl)-2'-deoxyuridine of formula VI where R --H from pure betaisomer of compound of formula IV
27.6 g (0.05 mole) of pure beta-isomer of 3',5'-di-O-p-chlorobenzoyl-5-ethyl-2'-deoxyuridine of formula IV are dissolved by warming in 350 ml of anhydrous dichloroethane. Flask is illuminated, nitrogen gas is bubbled through the mixture and 6.8 ml (20 g; 0.125 mole) of bromine in 60 ml of anhydrous dichloroethane are dropped in the mixture according to the reaction rate (the mixture discolours). This takes about 20-25 minutes. Illumination is stopped, and the mixture is refluxed for 1 5 min under strong nitrogen gas flux. Solvent is removed in vacuo, and evaporation is repeated with 20 ml of anhydrous dichloroethane. The solid foam residue of pale yellow colour is dissolved in 140 ml of anhydrous dichloroethane, and 10.4 ml (7.59 g; 0.075 mole) of triethylamine are added dropwise over 1 5 minutes. Precipitated material, which is a mixture of the compound of formula VI and triethylammonium hydrobromide, is filtered out from the mixture and washed with dichloroethane. It is further washed with 80% ethanol in which triethylammonium hydrobromide dissolves.
The remaining solid residue of formula VI (21 g; 0.0345 mole; 69%) is deacylated at room temperature over three hours by adding 1 30 ml of 0.5 molar sodium methylate. Following this, the pH of the solution is adjusted to 5-6 with Dowex 50 H+ cation exchanger, the resin is removed by filtration and is washed twice with 100 ml of methanol. The combined methanol solution evaporated in vacuo. The residue is recrystallized from water, giving 10.6 g of compound of formula VI where R=H.
Yield based on starting compound of formula IV is 63.7% and based on intermediate of formula VI is 92.3%. Melting point is 1 75-60C.
Example 3 3',5'-Di-O-p-chlorobenzoyl-5-(E)-(2-bromovinyl)-2'-beta-deoxyurid ine
1.07 g (2 moles) of 3',5t-di-0-p-chlorobenzoyl-2'-beta-deoxyuridine is dissolved in 25 ml of anhydrous chloroform. The flask is illuminated with a 500 Watt bulb. A solution of 0.11 ml of bromine and 5 ml of anhydrous chloroform is added by dropping, and HBr formed is removed by nitrogen. The product is dehydrohalogenated with 0.6 ml of triethylamine by warming the mixture for 10 minutes.
Triethylammonium hydrobromide formed is removed by extraction with water. The organic layer is separated, evaporated, and the residue is recrystallized from ethanol. Yield#).8 g (66%). Melting point-2350C.
Example 4 (E)-5-(2-bromovinyl)-2'-deoxyuridine
340 mg (1 mmole) of 3',5'-di-0-acetyl-5-ethyl-2'-deoxyuridine is dissolved in 100 ml of anhydrous chloroform, and the mixture is refluxed. The flask is illuminated and 350 mg of bromine are added and reacted for 1-2 hours. The solvent is removed in vacuo and the residue is dissolved in 20 ml of diisopropyl-ethylamine. The mixture is refluxed for 1 5 minutes.
(E)-5-(2-bromovinyl)-3',5'-di-0-acetyl-2'-beta-deoxyuridine is isolated (melting point 1 460C) or is directly deacylated by adding to the mixture 50 ml of methanol saturated with ammonia. After removal of the solvent residue is purified with chromatography. Product is 206 mg (62%), melting point 1 62-30C.
Example 5 (E)-5-(2-bromovinyl)-2'-deoxyuridine 3.4 g (10 mmoles) of 3',5'-di-0-acetyl-5-ethyl-2'-deoxyuridin are dissolved in 600 ml of carbontetrachloride and reacted for 2-4 hours with 1.1 ml of bromine at reflux with stirring and illumination of the mixture, and with nitrogen gas influx. 1 0 ml of triethylamine are added and the mixture is warmed for 1 5 minutes. After cooling, and filtering, the filtrate is evaporated in vacuo to dryness, the residue deacylated with 100 ml of methanol saturated with ammonia. The product is purified on a silica gel (Merck) column with a mixture of chloroform-methanol (9:1) yielding 1.3 g (39%) of compound of formula VI where R=H, melting point: 1 690C.
Claims (13)
1. Process for the synthesis of (E)-5-(2-bromovinyl)-2'-deoxyuridine of general formula VI
(wherein
R is a hydrogen atom or an alkanoyl group of 1-8 carbon atoms, or benzoyl or a benzoyl group substituted in para position by an alkyl group of 1-4 carbon atoms or a halogen atom) wherein a 3',5' di-O-acyl-5-ethyl-2'-deoxyuridine of general formula IV
(where R is as defined above, other than hydrogen) is reacted with bromine, and the dibromo derivative of general formula V formed,
is dehydrohalogenated and (when the compound of formula VI in which R is a hydrogen atom is required) deacylated.
2. A process as claimed in claim 1, wherein said diacyl compound of general formula IV is an alpha-beta isomeric mixture of 3 ',5'-di-O-p-chlorobenzoyl-5-ethyl-2'-deoxyuridine.
3. A process as claimed in claim 1 or claim 2, wherein the bromination reaction is carried out photolytically and the dibromo derivative of general formula V formed is dehydrohalogenated (either directly in the reaction mixture or after isolation) with a tertiary amine base.
4. A process as claimed in claim 3 wherein the solvent for the bromination and/or dehydrohalogenation steps is a halogenated hydrocarbon.
5. A process as claimed in claim 3 or claim 4 wherein the base is triethylamine.
6. A process as claimed in any one of the preceding claims wherein deacylation is effected with a C14 alkali metal alcoholate.
7. A process as claimed in any one of the preceding claims, wherein R is an acetyl or pchlorobenzoyl group.
8. A process as claimed in claim 1 substantially as described herein in any one of the Examples.
9. Compounds of general formula VI as defined in claim 1 in which R is an acyl group.
10. A compound as claimed in claim 1 wherein R is a -COCH3 group.
11. A compound as claimed in claim 9 wherein R is a p-chlorobenzoyl group.
12. A pharmaceutical composition comprising a compound as claimed in any one of claims 9 to 11 and one or more pharmaceutical carriers.
13. Compounds of general formula VI is defined in claim 1 wherein the -OR group at the 5'position is an acyloxy group and the -OR at the 3'-position is a hydroxy group.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU822506A HU187736B (en) | 1982-08-04 | 1982-08-04 | Process for producing /e/ -5-/2-bromovinyl/-2-comma above-deoxyuridine and o-acyl derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8321081D0 GB8321081D0 (en) | 1983-09-07 |
| GB2125399A true GB2125399A (en) | 1984-03-07 |
| GB2125399B GB2125399B (en) | 1987-04-01 |
Family
ID=10959738
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08321081A Expired GB2125399B (en) | 1982-08-04 | 1983-08-04 | Process for the preparation of (e)-5-(2-bromovinyl)-2'-deoxyuridine and new derivatives thereof |
Country Status (12)
| Country | Link |
|---|---|
| AT (1) | AT380688B (en) |
| BE (1) | BE897434A (en) |
| CH (1) | CH660486A5 (en) |
| CS (1) | CS251078B2 (en) |
| DE (1) | DE3328238A1 (en) |
| FI (1) | FI74289C (en) |
| FR (1) | FR2531437B1 (en) |
| GB (1) | GB2125399B (en) |
| HU (1) | HU187736B (en) |
| IT (1) | IT1185759B (en) |
| PL (1) | PL143289B1 (en) |
| YU (1) | YU162683A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA005497B1 (en) * | 2001-01-03 | 2005-02-24 | Берлин Хеми Аг | One-day pharmaceutical composition containing brivudine |
| US6864366B2 (en) * | 2001-02-28 | 2005-03-08 | Menarini Richerche S.P.A. | Process for the preparation of (e)-5-(2-bromovinyl)-2′-deoxyuridine |
| CN102432655A (en) * | 2011-10-28 | 2012-05-02 | 河南师范大学 | Method for synthesizing 5-((E)-2-bromovinyl)-2'-deoxyuridine (brivudine) |
| EP3792271A1 (en) | 2019-09-13 | 2021-03-17 | Aurobindo Pharma Limited | A process for the preparation of brivudine |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115043894A (en) * | 2022-06-22 | 2022-09-13 | 华润双鹤药业股份有限公司 | Brivudine starting material isomer single crystal and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2106107A (en) * | 1981-09-07 | 1983-04-07 | Egyt Gyogyszervegyeszeti Gyar | (e)-5-(2-bromovinyl)-uridine, its derivatives and a process for the preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2721466A1 (en) * | 1977-05-12 | 1978-11-16 | Robugen Gmbh | PROCESS FOR THE PREPARATION OF 2'-DESOXYRIBOFURANOSYL NUCLEOSIDES |
| GB1601020A (en) * | 1978-04-24 | 1981-10-21 | Stichting Grega Vzw | 2'-deoxy-5 (2-halogenovinyl)-uridines |
| DE3002197A1 (en) * | 1980-01-22 | 1981-07-23 | Robugen Gmbh Pharmazeutische Fabrik Esslingen A.N., 7300 Esslingen | 5-Alkyl- and 5-alkenyl-uracil and -cytidine nucleoside derivs. - prepd. e.g. by reaction of 5'-chloro-5'-deoxy cpds. with ammonia |
| NZ199764A (en) * | 1981-03-20 | 1984-08-24 | Beecham Group Plc | 5-(2-halogenovinyl)-2'-deoxyuridine derivatives and pharmaceutical compositions |
| EP0082668A1 (en) * | 1981-12-18 | 1983-06-29 | Beecham Group Plc | 5-(2-Halogenovinyl)-2'-deoxyuridine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in treating viral infections |
| EP0095294A1 (en) * | 1982-05-22 | 1983-11-30 | Beecham Group Plc | Deoxyuridine compounds, methods for preparing them and their use in medicine |
| EP0097039A1 (en) * | 1982-06-16 | 1983-12-28 | Beecham Group Plc | 5-(E-2-halovinyl)-2'-deoxyuridine derivatives, processes for their preparation, pharmaceutical compositions containing them, and their use in treating viral infections |
-
1982
- 1982-08-04 HU HU822506A patent/HU187736B/en unknown
-
1983
- 1983-07-22 CH CH4019/83A patent/CH660486A5/en not_active IP Right Cessation
- 1983-08-01 BE BE1/10845A patent/BE897434A/en not_active IP Right Cessation
- 1983-08-03 FI FI832809A patent/FI74289C/en not_active IP Right Cessation
- 1983-08-03 CS CS835756A patent/CS251078B2/en unknown
- 1983-08-03 FR FR8312777A patent/FR2531437B1/en not_active Expired
- 1983-08-03 IT IT22401/83A patent/IT1185759B/en active
- 1983-08-04 PL PL1983243307A patent/PL143289B1/en unknown
- 1983-08-04 GB GB08321081A patent/GB2125399B/en not_active Expired
- 1983-08-04 YU YU01626/83A patent/YU162683A/en unknown
- 1983-08-04 DE DE3328238A patent/DE3328238A1/en not_active Withdrawn
- 1983-08-04 AT AT0282583A patent/AT380688B/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2106107A (en) * | 1981-09-07 | 1983-04-07 | Egyt Gyogyszervegyeszeti Gyar | (e)-5-(2-bromovinyl)-uridine, its derivatives and a process for the preparation thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA005497B1 (en) * | 2001-01-03 | 2005-02-24 | Берлин Хеми Аг | One-day pharmaceutical composition containing brivudine |
| US6864366B2 (en) * | 2001-02-28 | 2005-03-08 | Menarini Richerche S.P.A. | Process for the preparation of (e)-5-(2-bromovinyl)-2′-deoxyuridine |
| CZ299318B6 (en) * | 2001-02-28 | 2008-06-18 | Menarini Ricerche S. P. A. | Process for preparing (E)-5-(2-bromovinyl)-2?-deoxyuridine |
| CN102432655A (en) * | 2011-10-28 | 2012-05-02 | 河南师范大学 | Method for synthesizing 5-((E)-2-bromovinyl)-2'-deoxyuridine (brivudine) |
| EP3792271A1 (en) | 2019-09-13 | 2021-03-17 | Aurobindo Pharma Limited | A process for the preparation of brivudine |
Also Published As
| Publication number | Publication date |
|---|---|
| IT1185759B (en) | 1987-11-18 |
| GB8321081D0 (en) | 1983-09-07 |
| PL243307A1 (en) | 1984-11-08 |
| PL143289B1 (en) | 1988-01-30 |
| ATA282583A (en) | 1985-11-15 |
| IT8322401A0 (en) | 1983-08-03 |
| HU187736B (en) | 1986-02-28 |
| BE897434A (en) | 1984-02-01 |
| FR2531437B1 (en) | 1985-10-25 |
| FI832809A (en) | 1984-02-05 |
| CH660486A5 (en) | 1987-04-30 |
| GB2125399B (en) | 1987-04-01 |
| AT380688B (en) | 1986-06-25 |
| FR2531437A1 (en) | 1984-02-10 |
| CS251078B2 (en) | 1987-06-11 |
| DE3328238A1 (en) | 1984-02-23 |
| FI74289B (en) | 1987-09-30 |
| FI74289C (en) | 1988-01-11 |
| YU162683A (en) | 1986-02-28 |
| FI832809A0 (en) | 1983-08-03 |
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| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19930804 |