RU2201917C2 - Method of synthesis of 3-nitrodiphenylamine - Google Patents
Method of synthesis of 3-nitrodiphenylamine Download PDFInfo
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- RU2201917C2 RU2201917C2 RU2001111401A RU2001111401A RU2201917C2 RU 2201917 C2 RU2201917 C2 RU 2201917C2 RU 2001111401 A RU2001111401 A RU 2001111401A RU 2001111401 A RU2001111401 A RU 2001111401A RU 2201917 C2 RU2201917 C2 RU 2201917C2
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- Prior art keywords
- synthesis
- bromobenzene
- nitrodiphenylamine
- nitroacetanilide
- hydrolysis
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 21
- VNRHTFXMONFRSL-UHFFFAOYSA-N 3-nitro-n-phenylaniline Chemical compound [O-][N+](=O)C1=CC=CC(NC=2C=CC=CC=2)=C1 VNRHTFXMONFRSL-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 title abstract description 7
- 230000015572 biosynthetic process Effects 0.000 title abstract description 5
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims abstract description 28
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- KFTYNYHJHKCRKU-UHFFFAOYSA-N n-(3-nitrophenyl)acetamide Chemical compound CC(=O)NC1=CC=CC([N+]([O-])=O)=C1 KFTYNYHJHKCRKU-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000007062 hydrolysis Effects 0.000 claims abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- 238000005887 phenylation reaction Methods 0.000 claims abstract description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 4
- 239000004094 surface-active agent Substances 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims abstract 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 238000010533 azeotropic distillation Methods 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 150000005323 carbonate salts Chemical class 0.000 claims 1
- 230000006793 arrhythmia Effects 0.000 abstract description 2
- 206010003119 arrhythmia Diseases 0.000 abstract description 2
- PQXGNJKJMFUPPM-UHFFFAOYSA-N ethacizine Chemical compound C1=CC=C2N(C(=O)CCN(CC)CC)C3=CC(NC(=O)OCC)=CC=C3SC2=C1 PQXGNJKJMFUPPM-UHFFFAOYSA-N 0.000 abstract description 2
- 206010061216 Infarction Diseases 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 abstract 1
- 230000007574 infarction Effects 0.000 abstract 1
- 239000013067 intermediate product Substances 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 229910052751 metal Inorganic materials 0.000 abstract 1
- 229960002608 moracizine Drugs 0.000 abstract 1
- GAQAKFHSULJNAK-UHFFFAOYSA-N moricizine hydrochloride Chemical compound [Cl-].C12=CC(NC(=O)OCC)=CC=C2SC2=CC=CC=C2N1C(=O)CC[NH+]1CCOCC1 GAQAKFHSULJNAK-UHFFFAOYSA-N 0.000 abstract 1
- 210000004165 myocardium Anatomy 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 5
- 229940072033 potash Drugs 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000006887 Ullmann reaction Methods 0.000 description 1
- VEFXTGTZJOWDOF-UHFFFAOYSA-N benzene;hydrate Chemical compound O.C1=CC=CC=C1 VEFXTGTZJOWDOF-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001944 continuous distillation Methods 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Изобретение относится к органическому синтезу, а именно к способу получения 3-нитродифениламина - полупродукта, используемого в синтезе лекарственных препаратов этмозина и этацизина, применяемых для лечения инфаркта миокарда и аритмии. The invention relates to organic synthesis, and in particular to a method for producing 3-nitrodiphenylamine, an intermediate used in the synthesis of drugs ethmosin and ethacyzin, used to treat myocardial infarction and arrhythmia.
Известные методы получения 3-нитродифениламина основаны на взаимодействии 3-нитроацетанилида с бромбензолом в условиях реакции Ульмана. Known methods for producing 3-nitrodiphenylamine are based on the interaction of 3-nitroacetanilide with bromobenzene under the conditions of the Ullmann reaction.
Впервые этот продукт получен Гольдбергом конденсацией 3-нитроацетанилида с бромбензолом в присутствии поташа, каталитических количеств йодистого калия и медного порошка в нитробензоле при температуре 180-210oС с последующим гидролизом N-ацетил-3-нитродифениламина спиртовым раствором соляной кислоты. Выход технического продукта 80%, Тпл. 100-105oС; после перекристаллизации из спирта Тпл. 112oС [Goldberg Y. Вег., 1907, 40, 4541-4543].This product was first obtained by Goldberg by condensation of 3-nitroacetanilide with bromobenzene in the presence of potash, catalytic amounts of potassium iodide and copper powder in nitrobenzene at a temperature of 180-210 o With the subsequent hydrolysis of N-acetyl-3-nitrodiphenylamine with an alcohol solution of hydrochloric acid. The yield of technical product 80%, T pl. 100-105 o C; after recrystallization from alcohol T pl. 112 o C [Goldberg Y. Veg., 1907, 40, 4541-4543].
Недостатком описанного метода является использование растворителя - нитробензола. Известен способ, в котором 3-нитродифениламин получен без растворителя - нитробензола с промежуточной очисткой N-ацетил-3-нитродифениламина хроматографированием на колонке с окисью алюминия, выход 86,9%, Тпл. 108-109oС [Светлаева В.М., Журавлев С.В., Ж.П.Х. 1962, 8, 1857-59]. Способ применяем только в лабораторных условиях.The disadvantage of this method is the use of a solvent - nitrobenzene. A known method in which 3-nitrodiphenylamine is obtained without a solvent nitrobenzene with intermediate purification of N-acetyl-3-nitrodiphenylamine by chromatography on a column of aluminum oxide, 86.9% yield, T pl. 108-109 o With [Svetlaeva V.M., Zhuravlev S.V., J.P.Kh. 1962, 8, 1857-59]. The method is used only in laboratory conditions.
Наиболее близким по технической сущности является способ получения 3-нитродифениламина реакцией 3-нитроацетанилида с бромбензолом в присутствии поташа и катализе смесью однобромистой меди и медного порошка при температуре 185-210oС с непрерывной отгонкой воды и бромбензола (бромбензол периодически возвращается) в течение 24 часов; с последующей отгонкой избыточного бромбензола с водяным паром, отделением неорганических солей от органической фазы путем разбавления ее горячей водой, отстаивания и разделения слоев (прием двухкратный), растворением органического слоя - технический N-ацетил-3-нитродифениламин - в этиловом спирте, фильтрацией полученного раствора от медного порошка, разбавлением фильтрата 8%-ным водным раствором гидроксида натра и гидролизом при кипячении, кристаллизацией, фильтрацией, промывкой на фильтре и сушкой продукта. Выход 75% [Л.Н.Яхонтов, Р.Г.Глушков "Синтетические лекарственные средства". М.: Медицина, 1983 г., с.224].The closest in technical essence is a method for producing 3-nitrodiphenylamine by reaction of 3-nitroacetanilide with bromobenzene in the presence of potash and catalysis with a mixture of monobromide copper and copper powder at a temperature of 185-210 o With continuous distillation of water and bromobenzene (bromobenzene periodically returns) for 24 hours ; followed by distillation of excess bromobenzene with water vapor, separation of inorganic salts from the organic phase by dilution with hot water, sedimentation and separation of the layers (twice), dissolving the organic layer - technical N-acetyl-3-nitrodiphenylamine - in ethyl alcohol, filtering the resulting solution from copper powder, diluting the filtrate with an 8% aqueous solution of sodium hydroxide and hydrolysis by boiling, crystallization, filtration, washing on a filter and drying the product. Yield 75% [L.N. Yakhontov, R.G. Glushkov "Synthetic Medicines". M .: Medicine, 1983, p.224].
Основными недостатками известного способа являются:
- большое количество операций;
- длительность процесса;
- применение в процессе безводного поташа, работа с которым в промышленных условиях представляет технические трудности;
- способ удаления неорганических солей из органической фазы, увеличивающий длительность процесса (операции разбавления, отстаивания и разделения фаз - двухкратные);
- недостаточно высокий выход продукта.The main disadvantages of this method are:
- a large number of operations;
- the duration of the process;
- application in the process of anhydrous potash, work with which in an industrial environment presents technical difficulties;
- a method of removing inorganic salts from the organic phase, increasing the duration of the process (dilution, sedimentation and phase separation operations are double);
- insufficiently high product yield.
Задача предлагаемого изобретения - повышение выхода продукта, упрощение и сокращение длительности технологического процесса,
Поставленная задача решается тем, что в предлагаемом способе фенилирования 3-нитроацетанилида бромбензолом осуществляется в присутствии безводного углекислого натрия и катализаторов - однойодистой меди и поверхностно-активного препарата (ПАВ) Твин-80, стадию гидролиза ведут в изопропиловом спирте.The objective of the invention is to increase product yield, simplify and reduce the duration of the process,
The problem is solved in that in the proposed method for the phenylation of 3-nitroacetanilide with bromobenzene is carried out in the presence of anhydrous sodium carbonate and catalysts - single-copper and surface-active drug (surfactant) Tween-80, the hydrolysis stage is carried out in isopropyl alcohol.
Пример 1. Example 1
1,08 кг 3-нитроацетанилида, 1,88 кг бромбензола, 0,827 кг углекислого натрия, 0,03 кг однойодистой меди и 0,1 кг Твин-80 кипятят 20 час. с непрерывной азеотропной отгонкой воды и непрерывным рециклом бромбензола, реакционную массу фильтруют. 1.08 kg of 3-nitroacetanilide, 1.88 kg of bromobenzene, 0.827 kg of sodium carbonate, 0.03 kg of monodist copper and 0.1 kg of Tween-80 are boiled for 20 hours. with continuous azeotropic distillation of water and continuous recycling of bromobenzene, the reaction mass is filtered.
К фильтрату прибавляют 4 л воды, нагревают до кипения и отгоняют весь бромбензол в виде азеотропа с водой. 4 L of water was added to the filtrate, heated to a boil, and all bromobenzene was distilled off as an azeotrope with water.
К остатку прибавляют 3,2 л 85%-го изопропилового спирта, 2 л 14%-го водного раствора гидроксида натрия, кипятят 4 часа и оставляют кристаллизоваться. Осадок фильтруют, промывают водой, сушат. Получают 1,18 кг 3-нитродифениламина Тпл. 110-112oС, выход 91,5% от теоретического в расчете на 3-нитроацетанилид (лит. Т.пл. 110-112oС).3.2 L of 85% isopropyl alcohol, 2 L of a 14% aqueous sodium hydroxide solution are added to the residue, boiled for 4 hours and allowed to crystallize. The precipitate was filtered, washed with water, and dried. Obtain 1.18 kg of 3-nitrodiphenylamine T pl. 110-112 o C, yield 91.5% of theoretical based on 3-nitroacetanilide (lit. T. pl. 110-112 o C).
Пример.2. Example 2.
Процесс проводят по примеру 1, но гидролиз осуществляют в присутствии водного раствора гидроксида калия. Выход 3-нитродифениламина - 92% от теоретического (в расчете на 3-нитроацетанилид), Тпл. 110-112oС.The process is carried out as in example 1, but the hydrolysis is carried out in the presence of an aqueous solution of potassium hydroxide. The yield of 3-nitrodiphenylamine is 92% of theoretical (calculated as 3-nitroacetanilide), T pl. 110-112 o C.
Предлагаемый способ позволяет повысить выход целевого продукта с 75% до 92% по сравнению с прототипом, а также существенно упростить технологию, исключив использование в процессе безводного поташа и длительные стадии отстаивания (как правило, образуется трудно разделяющаяся эмульсия и промежуточный слой) и разделения органической и водно-солевой фаз при удалении неорганических солей из реакционной массы путем отмывки водой, и значительно сократить длительность процесса. The proposed method allows to increase the yield of the target product from 75% to 92% compared with the prototype, as well as to significantly simplify the technology by eliminating the use of anhydrous potash in the process and long settling stages (as a rule, a hard-to-separate emulsion and an intermediate layer are formed) and organic and water-salt phases when removing inorganic salts from the reaction mixture by washing with water, and significantly reduce the duration of the process.
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Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| RU2001111401A RU2201917C2 (en) | 2001-04-27 | 2001-04-27 | Method of synthesis of 3-nitrodiphenylamine |
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| Application Number | Priority Date | Filing Date | Title |
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| RU2001111401A RU2201917C2 (en) | 2001-04-27 | 2001-04-27 | Method of synthesis of 3-nitrodiphenylamine |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB855719A (en) * | 1959-02-17 | 1960-12-07 | Bayer Ag | Process for the production of 4-nitro-diarylamines |
| US4102924A (en) * | 1973-10-25 | 1978-07-25 | Bayer Aktiengesellschaft | Process for the preparation of diaryl compounds |
| US4196146A (en) * | 1978-03-13 | 1980-04-01 | Monsanto Company | Making nitrodiarylamines from formyl derivatives of aromatic amines and nitrohaloarenes by admixing with certain aqueous salt solutions |
| US4900325A (en) * | 1987-08-28 | 1990-02-13 | Henkel Kommanditgesellschaft Auf Aktien | Hair-dyeing preparations |
-
2001
- 2001-04-27 RU RU2001111401A patent/RU2201917C2/en not_active IP Right Cessation
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB855719A (en) * | 1959-02-17 | 1960-12-07 | Bayer Ag | Process for the production of 4-nitro-diarylamines |
| US4102924A (en) * | 1973-10-25 | 1978-07-25 | Bayer Aktiengesellschaft | Process for the preparation of diaryl compounds |
| US4196146A (en) * | 1978-03-13 | 1980-04-01 | Monsanto Company | Making nitrodiarylamines from formyl derivatives of aromatic amines and nitrohaloarenes by admixing with certain aqueous salt solutions |
| US4900325A (en) * | 1987-08-28 | 1990-02-13 | Henkel Kommanditgesellschaft Auf Aktien | Hair-dyeing preparations |
Non-Patent Citations (2)
| Title |
|---|
| ВОРОЖЦОВ Н.Н. Основы синтеза промежуточных продуктов и красителей. - М.: Госхимиздат, 1955, с.327. * |
| ЯХОНТОВ Л.Н., ГЛУШКОВ Р.Г. Синтетические лекарственные средства. - М.: Медицина, 1983, с.224. * |
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