EP1105402A1 - Verfahren zur industriellen herstellung von diosmin durch die reaktion von hesperidin mit jod und pyridin - Google Patents
Verfahren zur industriellen herstellung von diosmin durch die reaktion von hesperidin mit jod und pyridinInfo
- Publication number
- EP1105402A1 EP1105402A1 EP99936746A EP99936746A EP1105402A1 EP 1105402 A1 EP1105402 A1 EP 1105402A1 EP 99936746 A EP99936746 A EP 99936746A EP 99936746 A EP99936746 A EP 99936746A EP 1105402 A1 EP1105402 A1 EP 1105402A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pyridine
- iodine
- hesperidin
- reaction
- diosmin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 50
- VUYDGVRIQRPHFX-UHFFFAOYSA-N hesperidin Natural products COc1cc(ccc1O)C2CC(=O)c3c(O)cc(OC4OC(COC5OC(O)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 VUYDGVRIQRPHFX-UHFFFAOYSA-N 0.000 title claims abstract description 49
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 239000001100 (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one Substances 0.000 title claims abstract description 25
- QUQPHWDTPGMPEX-UHFFFAOYSA-N Hesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(COC4C(C(O)C(O)C(C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-UHFFFAOYSA-N 0.000 title claims abstract description 25
- QUQPHWDTPGMPEX-UTWYECKDSA-N aurantiamarin Natural products COc1ccc(cc1O)[C@H]1CC(=O)c2c(O)cc(O[C@@H]3O[C@H](CO[C@@H]4O[C@@H](C)[C@H](O)[C@@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)cc2O1 QUQPHWDTPGMPEX-UTWYECKDSA-N 0.000 title claims abstract description 25
- APSNPMVGBGZYAJ-GLOOOPAXSA-N clematine Natural products COc1cc(ccc1O)[C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO[C@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@@H](O)[C@H](O)[C@H]4O)cc3O2 APSNPMVGBGZYAJ-GLOOOPAXSA-N 0.000 title claims abstract description 25
- 229940025878 hesperidin Drugs 0.000 title claims abstract description 25
- 239000011630 iodine Substances 0.000 title claims abstract description 25
- 229910052740 iodine Inorganic materials 0.000 title claims abstract description 25
- ARGKVCXINMKCAZ-UHFFFAOYSA-N neohesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(CO)O3)OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UHFFFAOYSA-N 0.000 title claims abstract description 25
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims abstract description 25
- GZSOSUNBTXMUFQ-NJGQXECBSA-N 5,7,3'-Trihydroxy-4'-methoxyflavone 7-O-rutinoside Natural products O(C[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](Oc2cc(O)c3C(=O)C=C(c4cc(O)c(OC)cc4)Oc3c2)O1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1 GZSOSUNBTXMUFQ-NJGQXECBSA-N 0.000 title claims abstract description 24
- GZSOSUNBTXMUFQ-YFAPSIMESA-N diosmin Chemical compound C1=C(O)C(OC)=CC=C1C(OC1=C2)=CC(=O)C1=C(O)C=C2O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)O1 GZSOSUNBTXMUFQ-YFAPSIMESA-N 0.000 title claims abstract description 24
- IGBKNLGEMMEWKD-UHFFFAOYSA-N diosmin Natural products COc1ccc(cc1)C2=C(O)C(=O)c3c(O)cc(OC4OC(COC5OC(C)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 IGBKNLGEMMEWKD-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960004352 diosmin Drugs 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 22
- QUQPHWDTPGMPEX-QJBIFVCTSA-N hesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]4[C@@H]([C@H](O)[C@@H](O)[C@H](C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-QJBIFVCTSA-N 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 title claims description 11
- 238000009776 industrial production Methods 0.000 title description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 21
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims abstract description 15
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000012429 reaction media Substances 0.000 claims abstract description 14
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 13
- 239000011707 mineral Substances 0.000 claims abstract description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 9
- 150000001342 alkaline earth metals Chemical class 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims abstract description 6
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000003335 secondary amines Chemical class 0.000 claims abstract description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 239000007787 solid Substances 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 239000002585 base Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 238000000746 purification Methods 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- 230000008030 elimination Effects 0.000 claims description 8
- 238000003379 elimination reaction Methods 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 3
- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 229930003949 flavanone Natural products 0.000 description 3
- 150000002208 flavanones Chemical class 0.000 description 3
- 235000011981 flavanones Nutrition 0.000 description 3
- 229930003944 flavone Natural products 0.000 description 3
- 150000002213 flavones Chemical class 0.000 description 3
- 235000011949 flavones Nutrition 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical class C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229920000075 poly(4-vinylpyridine) Polymers 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- IKGXIBQEEMLURG-NVPNHPEKSA-N rutin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-NVPNHPEKSA-N 0.000 description 1
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001643 venotonic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/06—Benzopyran radicals
- C07H17/065—Benzo[b]pyrans
- C07H17/07—Benzo[b]pyran-4-ones
Definitions
- the present invention relates to a process for the industrial manufacture of diosmin from hesperidin.
- Diosmin is a bioflavonoid known in its natural state and is found for example in the peel of citrus fruits and is used for its venotonic and protective application of the liver. On an industrial level, the hemisynthesis of diosmin is carried out using the natural product hesperidin.
- the manufacturing processes known to date consist of reacting:
- the invention relates more precisely, among these methods, those in which hesperidin is reacted as main reagents with iodine and pyridine, in the presence of a mineral base.
- FR-A-2411 845 and FR-A-2402655 describe such processes, in which the starting reaction mixture is additionally added with an aqueous sodium hydroxide solution.
- the process of the invention which aims at the industrial manufacture of diosmin from hesperidin by reaction with iodine and pyridine, is a process of the general type taught by FR-A-2 411 845 and FR-A-2402 655 mentioned above, that is to say comprising the steps of: a) preparation of a reaction medium by mixing hesperidin, iodine, pyridine and an inorganic alkali metal base or alkaline earth; b) heating this reaction medium, to obtain a reaction product containing diosmin, and c) purifying the reaction product by elimination of the pyridine and iodine residues.
- the reaction medium prepared in step a) is essentially devoid of water, the mineral base being provided in solid form.
- the mineral base of an alkali or alkaline earth metal is in particular a base chosen from the group comprising sodium hydroxide, potassium hydroxide and calcium carbonate.
- the incorporation without addition of water of this mineral base of an alkali or alkaline-earth metal into the reaction medium for the formation of diosmin makes it possible, by its catalytic effect, to obtain the latter with very high purity in terms of residual iodine traces.
- the purification step can be improved by providing in step c) of purification a sub-step for the elimination of iodized residues by dissolving in a solvent comprising a secondary amine, in particular morpholine.
- the residual iodine content at the end of the operation is in a range much greater than 200 ppm, while in the conditions of the invention the residual iodine content is less than 200 ppm, typically of the order of 80 to 100 ppm.
- the Applicant has found that one could advantageously provide, in the purification step, a sub-step for the elimination of pyridine by addition of water and azeotropic water-pyridine distillation. Evaporation in situ of all of the pyridine by such distillation makes it possible to obtain a residual pyridine level of less than 50 ppm, which is not the case. not possible to obtain by conventional means of purification.
- the proportion of the mineral base of alkali or alkaline-earth metal relative to hesperidin is between 1 and 2, preferably approximately 1, 8, molar equivalents
- the heating of the reaction medium in step b) is operated at a temperature between 70 and 110 ° C, preferably about 90 ° C, for a period between 5 to 7 hours, preferably about 6 hours.
- the applicant has found that, by providing, according to the invention, the incorporation into a reaction medium of a mineral base of alkali or alkaline-earth metal, it was possible, owing to the catalytic effect obtained, substantially reduce the reaction time compared to conventional pyridine-iodine processes, typically a reduction of around 40%.
- Elimination of morpholine the product isolated on the filter is dissolved again in a 5% sodium hydroxide solution. The medium is neutralized with sulfuric acid. The suspension is filtered and washed with hot water at 60 ° C. After drying, the diosmin is obtained with a yield of 80% and a purity meeting the standards of the pharmacopoeia, in particular a residual iodine content of less than 200 ppm and a residual pyridine content of less than 50 ppm. The residual iodine level can even be less than 100 ppm.
Landscapes
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9810544A FR2782518A1 (fr) | 1998-08-19 | 1998-08-19 | Procede de fabrication industrielle de diosmine a partir de l'hesperidine par reaction avec de l'iode et de la pyridine |
| FR9810544 | 1998-08-19 | ||
| PCT/FR1999/002001 WO2000011009A2 (fr) | 1998-08-19 | 1999-08-17 | Procede de fabrication industrielle de diosmine a partir de l'hesperidine par reaction avec de l'iode et de la pyridine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1105402A1 true EP1105402A1 (de) | 2001-06-13 |
Family
ID=9529773
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP99936746A Withdrawn EP1105402A1 (de) | 1998-08-19 | 1999-08-17 | Verfahren zur industriellen herstellung von diosmin durch die reaktion von hesperidin mit jod und pyridin |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1105402A1 (de) |
| FR (1) | FR2782518A1 (de) |
| WO (1) | WO2000011009A2 (de) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010092592A2 (en) * | 2009-02-11 | 2010-08-19 | Elder Pharmaceuticals Ltd. | Process for the preparation of diosmin |
| CN103012524B (zh) * | 2012-12-31 | 2015-02-25 | 浙江大学 | 一种半合成制备漆叶苷的方法 |
| CN103435666B (zh) * | 2013-07-30 | 2016-03-16 | 李玉山 | 一种香叶木苷的生产新技术 |
| EP3053930A1 (de) | 2015-02-03 | 2016-08-10 | Interquim, S.A. | Verfahren zur Herstellung von Diosmin |
| AR122887A1 (es) * | 2020-07-09 | 2022-10-12 | Servier Lab | Procedimiento de preparación de la diosmina |
| CN112979603A (zh) * | 2021-03-08 | 2021-06-18 | 宜宾西华大学研究院 | 黄酮类化合物的连续流微通道合成工艺 |
| AR126366A1 (es) | 2021-07-06 | 2023-10-11 | Servier Lab | Procedimiento para la preparación de diosmina y de fracción flavonoica |
| CN114306363B (zh) * | 2022-01-05 | 2022-11-08 | 成都亚中生物制药有限责任公司 | 一种工业化制备柑橘黄酮原料药的方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2740950A1 (de) * | 1977-09-10 | 1979-03-22 | Merck Patent Gmbh | Verfahren zur herstellung von flavonen |
| ES465156A1 (es) * | 1977-12-16 | 1978-10-01 | Merck Quimica S A | Procedimiento para preparar glicosidos con un aglicon insa- turado. |
| IT1191620B (it) * | 1985-05-30 | 1988-03-23 | Edmond Pharma Srl | Procedimento per la preparazione della diosmina |
-
1998
- 1998-08-19 FR FR9810544A patent/FR2782518A1/fr active Pending
-
1999
- 1999-08-17 EP EP99936746A patent/EP1105402A1/de not_active Withdrawn
- 1999-08-17 WO PCT/FR1999/002001 patent/WO2000011009A2/fr not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO0011009A3 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2000011009A3 (fr) | 2000-06-29 |
| FR2782518A1 (fr) | 2000-02-25 |
| WO2000011009A2 (fr) | 2000-03-02 |
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