IE59681B1 - New process for the synthesis of N-amino-3-azabicyclo[3.30]octane - Google Patents
New process for the synthesis of N-amino-3-azabicyclo[3.30]octaneInfo
- Publication number
- IE59681B1 IE59681B1 IE148887A IE148887A IE59681B1 IE 59681 B1 IE59681 B1 IE 59681B1 IE 148887 A IE148887 A IE 148887A IE 148887 A IE148887 A IE 148887A IE 59681 B1 IE59681 B1 IE 59681B1
- Authority
- IE
- Ireland
- Prior art keywords
- azabicyclo
- octane
- amino
- monochloroamine
- medium
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 230000008569 process Effects 0.000 title claims abstract description 26
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 17
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 15
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 title description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000000243 solution Substances 0.000 claims abstract description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 22
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 claims abstract description 20
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 11
- 239000005708 Sodium hypochlorite Substances 0.000 claims abstract description 10
- 239000012429 reaction media Substances 0.000 claims abstract description 10
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000007864 aqueous solution Substances 0.000 claims abstract description 9
- 235000019270 ammonium chloride Nutrition 0.000 claims abstract description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000000908 ammonium hydroxide Substances 0.000 claims abstract description 7
- 238000004821 distillation Methods 0.000 claims description 7
- 230000002051 biphasic effect Effects 0.000 claims description 5
- UZHVXJZEHGSWQV-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole Chemical compound C1NCC2CCCC21 UZHVXJZEHGSWQV-UHFFFAOYSA-N 0.000 abstract description 15
- FJYWNYLUZBMVKI-UHFFFAOYSA-N 3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-amine Chemical compound C1CCC2CN(N)CC21 FJYWNYLUZBMVKI-UHFFFAOYSA-N 0.000 abstract description 5
- 238000004064 recycling Methods 0.000 abstract description 3
- 150000001412 amines Chemical class 0.000 description 8
- 239000002609 medium Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- 150000002429 hydrazines Chemical class 0.000 description 2
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- -1 bicyclic amine Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000009935 nitrosation Effects 0.000 description 1
- 238000007034 nitrosation reaction Methods 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001577 simple distillation Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
1. A process for continuous synthesis of N-amino-3-aza-bicyclo[3,3,0]octane characterized by reacting a solution of ammonium hydroxide and ammonium chloride with an aqueous solution of sodium hypochlorite at a temperature between -15 degrees C and -7 degrees C in an alkaline medium, - then reacting the thus formed monochloroamine with 3-aza-bicyclo[3,3,0]octane in a two-phase medium in a suitable reaction vessel equipped with a blade agitator at a temperature between 30 degrees C and 90 degrees C in an alkaline medium, - then separating by destillation the ammonia and subsequent the non-reacted 3-aza-bicyclo[3,3,0]octane from the reaction medium for recycling, - then isolating under demixing a concentrated solution of N-amino-3-aza-bicyclo[3,3,0]octane by addition of sodium hydroxide to the reaction medium and, if desired, purifying the thus formed hydrazine by destillation.
Description
The present invention relates to a novel process for the synthesis of N-amino-3-azabicyclo[3.3.0joctane.
N-amino - 3-azabicyclo[3.3 . 0 ] octane or N-aminooctahydrocyclopent[c]pyrrole is a compound very often used as an intermediate in the synthesis of medicaments (GB Patent No. 1,153,982).
At present, the only method described in the literature for the preparation of that compound is the process of Wright J.B. and Willette R.E. (J.Med. and Pharm. Chem. 1962, 5, 819) which consists in a nitrosation of 3-azabicyclo[3.3.0Joctane and then a reduction of the N~nitrosated derivative obtained. That synthesis results in fairly good yields but it requires two separate stages and the product resulting from the first stage has to be handled with great care owing to its potential toxicity, and that presents operational problems from the industrial standpoint.
Moreover, it is recognised that, for the preparation of the various hydrazines, recourse is often had to the reaction known as the Raschig reaction which consists in synthesising monochloroamine by the reaction of ammonia with a sodium hypochlorite solution and then reacting the monochloroamine formed with an amine to obtain the corresponding hydrazine. That process is quite difficult to put into practice because it requires two separate stages, the first carried out at reduced temperature for the synthesis of the monochloroamine and the second carried out at elevated temperature, during which the actual synthesis of the hydrazine is effected. In addition, the monochloroamine has to be in the presence of a sufficient excess of amine in the intermediate solutions in order to avoid secondary degradation reactions, and consequently the process always requires very large quantities of solutions to be treated.
French Patent Application No. 76.34692 describes a process for the synthesis of Ν,Μ-dimethylhydrazine which is carried out continuously starting from ammonia, sodium hypochlorite and dimethylamine in an aqueous medium.
That process, however, cannot be used for the preparation of 10 all alkylhydrazines and especially not for the preparation of M~amino-3-azabicyclo[3.3.0]octane, taking into account the fact that the starting material necessary for its synthesis, 3-azabicyclo[3.3.0]octane, has special physico-chemical properties which are very different from those of dimethylamine. On the one hand this bicyclic amine is soluble in aqueous alkaline solutions at average concentrations and especially at reduced temperature. On the other hand, it can react with the monochloroamine only at elevated temperatures at which mixtures of water and 3-azabicyclo[3.3.0]octane undergo demixing.
The applicants have now discovered a novel process for the synthesis of N-amino-3-azabicyclo[3.3.0joctane. That process, which is operated continuously, resides partly in a modification of the Raschig process, which consists in preparing chloroamine by the action of sodium hypochlorite on ammonia at low temperature, and then, and herein lies its great originality, causing the resulting chloroamine to act on 3-azabicyclo[3.3.Ojoctane in a biphasic medium, then extracting the hydrazine formed and recovering and recycling the starting amine in the form of an aqueous solution directly without any additional stage.
The present invention relates more especially to a process for the continuous synthesis of N-amino~3~azabicyclo[3.3.0]octane, characterised in that a solution of ammonium hydroxide and ammonium chloride is reacted with an aqueous solution of sodium hypochlorite at a temperature of between -15°C and -7°C in an alkaline medium,. - and then the resulting monochloroamine is reacted with 3azabicyclof3.3.Ojoctane in a biphasic medium in a suitable reactor equipped with a coaxial paddle stirrer at a temperature of between 30°C and 90°C and in an alkaline medium, the ammonia is then separated from the reaction medium and afterwards the 3-azabicyclo[3.3.0]octane that has not reacted is separated from the reaction medium by distillation in order to be recycled, then a concentrated solution of N-amino-3-azabicyclo[3.3.0)octane is isolated by demixing by the addition of sodium hydroxide to the reaction medium, and the resulting hydrazine is purified, if desired, by distillation.
In order to form the monochloroamine, an aqueous solution of sodium hypochlorite is mixed, with stirring, with a solution of ammonium hydroxide and ammonium chloride. The reaction is effected in an alkaline medium having a pH of from 9.2 to 10 in the presence of an excess of ammonium hydroxide and ammonium chloride.
The ratio of the molar concentrations of ammonium hydroxide and ammonium chloride to sodium hypochlorite is approximately from 2.5 to 3 and the ratio of the molar concentrations of ammonium chloride to ammonium hydroxide is approximately from 0.50 to 0.80.
The reaction of the monochloroamine with 3-azabicyclo[3.3.0Joctane is effected in the presence of an aqueous sodium hydroxide solution at elevated temperature. The ratio of the molar concentrations of 3-azabicyclo[3.3.0joctane to monochloroamine is to be greater than 4 and less than 8. The reaction time is variable and depends on the temperature at which the reaction is carried out and on the ratio of the concentrations of the reagents and is of the order of from 20 to 40 seconds.
After the formation of N-amino=3--azabicyclo[ 3.3.0 joctane and cooling, the reaction solution undergoes degassing in order to eliminate the ammonia, and the 3-azabicyclo[3.3.0Joctane that has not reacted is separated from the reaction medium by simple distillation under atmospheric pressure and at a temperature of approximately from 90° to 100°C. Under those conditions, the amine is obtained in the form of an aqueous solution having a 30 % concentration of 3-azabicyclo[3.3.0Joctane. That solution is recycled immediately.
The reaction solution containing the hydrazine is then treated with sodium hydroxide. That operation, which is carried out in two stages, permits the separation of the N-amino-3azabicyclof3.3.0Joctane in an organic phase having a 92 % concentration of hydrazine. The resulting concentrated solution can be used directly or distilled under reduced pressure.
The process of the present invention accordingly permits not only the continuous synthesis of N-amino-3-azabicyclo[3.3.0Joctane, without the formation of toxic intermediates, but also the inexpensive obtainment of hydrazine.
The conventional Raschig synthesis generally requires a large excess of amine, which is a considerable disadvantage when the amines used as starting material for the preparation of the corresponding hydrazines are very expensive. That is the case for 3-azabicyclo[3.3.0]octane .
The process of the present invention (reaction in a biphasic medium, geometry of the reactors) enables that excess of 3azabicyclo[3.3.0]octane to be limited to less than 5-fold relative to the quantity of monochloroamine. Furthermore, owing to the recovery and recycling of 3-azabicyclo~ [3.3.0]octane that has not reacted, it enables N-amino-3azabicyclo[3.3.0]octane to be obtained very inexpensively compared with the other known processes. The isolation of 3azabicyclo[3.3.0]octane in the form of an aqueous solution at a relatively low temperature is also another very original feature as well as a considerable economic advantage of the process of the invention. It is known that 3-azabicyclo[3.3.0]octane is a thermodegradable product which boils at atmospheric pressure at only 184°C. The process of the present invention permits the isolation of 3-azabicyclo[3.3.0]octane in the form of a heteroazeotrope at a lower temperature.
Another advantage of the process results from the easy demixing of N~amino-3-azabicyclo[3.3.0]octane in the form of a concentrated solution (92 % N-amino-3-azabicyclo[3.3.0]octane) simply by adding sodium hydroxide to the reaction medium, from which ammonia and 3-azabicyclo[3.3.0]octane have previously been removed.
A detailed, non-limiting description of the implementation of the process of the invention is given hereinafter, the basis scheme of which process is shown in Figure 1.
EXAMPLE 1; Preparation of W-aminO"3-azabicyclo[3.3.0]octane Ail the quantities indicated correspond to one operating unit and are relative to one litre of injected hypochlorite.
One litre of sodium hypochlorite solution assaying at 4 8°C by chlorometry and one litre of a solution having an ammonia concentration of 3.50 mole I1 and an ammonium chloride concentration of 2.37 mole Γ1 are introduced in continuous fashion into a stirred reactor (R,) at the rate of 3.1 ml min'1.
The temperature inside the reactor is maintained at between 8° and ~10°C, and the pH of the reaction is approximately 10. At the outlet of R,, a solution of monochloroamine is obtained having a titre greater than 1 nol.r’, which corresponds to a yield of approximately 100 % relative to the sodium hypochlorite, The synthesis of M-amino*-3-azabicyclo[ 3.3.0 ]octane is effected in a biphasic medium in a cylindrical reactor (R2) which is stirred vigorously by means of a coaxial paddle stirrer in such a manner as to keep the mixture emulsified. The height of the reactor is approximately 25 cm and its volume is 31.6 ml.
The chloroamine solution obtained above (2 litres), the aqueous solution of 3-azabicyclo[3.3.0]octane (3.8 litres, 30 %) and the sodium hydroxide (0.5 litre at 6 mol. I1) are introduced simultaneously and continuously into the reactor R2 at a rate suitable for obtaining a molar ratio of 3a2abicyclo[3.3.0]octane to monochloroamine of approximately .2 and a pH fixed at 13.4. The reaction temperature is maintained at approximately 50°C. After 30 seconds' reaction, the reaction mixture is cooled again in an exchanger to 16°C and becomes raonophasic again. A mixture is obtained having a concentration of approximately 0.26 mol.l'1 of hydrazine. The reaction mixture then undergoes a degassing operation to eliminate the ammonia contained in the solution. solution, from which the ammonia has been distilled at 98.4°C under atmospheric pressure column DC,) in order to eliminate the 3-azabicyclo[3.3.0joctane that has not reacted. The amine is obtained after distillation in the form of an aqueous solution having a composition of approximately 30 % amine. That solution is then recycled and used immediately.
The reaction removed, is (distillation After separating 3-azabicyclo[3.3.0]octane, the reaction solution containing the hydrazine is treated by the addition of solid sodium hydroxide in order to separate the N-amino-3~ azabicyclo[3.3.0joctane in an organic phase having a titre of approximately 92 % hydrazine. Depending on the specifications for use, the concentrated hydrazine solution can then be used directly or distilled under reduced pressure (distillation column DC2) .
The yield of hydrazine relative to the 3-azabicyclo[3.3.0]octane consumed is between 88 and 92 %.
Claims (6)
1. Process for the continuous synthesis of N-amino-3azabicyclo[3.3.0Joctane, characterised in that a solution of ammonium hydroxide and ammonium chloride is reacted with an aqueous solution of sodium hypochlorite at a temperature of between -15°C and -7°C in an alkaline medium, and then the resulting monochloroamine is reacted with 3-azabicyclo[3.3.0joctane in a biphasic medium in a suitable reactor equipped with a coaxial paddle stirrer at a temperature of between 30°C and 90°C and in an alkaline medium, the ammonia is then separated from the reaction medium and afterwards the 3-azabicyclo[3.3.0joctane that has not reacted is separated from the reaction medium by distillation in order to be recycled, then a concentrated solution of N-amino-3~ azabicyclo[3.3.0joctane is isolated by demixing by the addition of sodium hydroxide to the reaction medium, and the resulting hydrazine is purified, if desired, by distillation.
2. Process according to claim 1, characterised in that the molar ratio of 3~azabicyclo[3.3.0joctane/monochloroamine is greater than 4 and less than 8.
3. Process according to claim 1, characterised in that the reaction of the monochloroamine with the 3-azabicyclo[3.3.0joctane is effected at a pH of between 13 and 14.
4. Process according to claim 1, characterised in that the excess of 3~azabicyclo[3.3.0joctane which has not reacted with the monochloroamine is distilled at a temperature of between 9 0°C and 100°C under atmospheric pressure, before being recycled.
5. A process substantially as hereinbefore described with 5 reference to the example and drawings.
6. N-amino-3-azabicyclo[3.3.0Joctane whenever prepared by a process as claimed in any preceding claim. Dated this 5th day of June, 1987.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8701334A FR2610321B1 (en) | 1987-02-04 | 1987-02-04 | NEW PROCESS FOR THE SYNTHESIS OF N-AMINO AZA-3 BICYCLO (3, 3, 0) OCTANE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE871488L IE871488L (en) | 1988-08-04 |
| IE59681B1 true IE59681B1 (en) | 1994-03-23 |
Family
ID=9347573
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE148887A IE59681B1 (en) | 1987-02-04 | 1987-06-05 | New process for the synthesis of N-amino-3-azabicyclo[3.30]octane |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0277267B1 (en) |
| JP (1) | JPS63196565A (en) |
| AR (1) | AR243160A1 (en) |
| AT (1) | ATE57914T1 (en) |
| AU (1) | AU591784B2 (en) |
| CA (1) | CA1283420C (en) |
| DE (1) | DE3765925D1 (en) |
| DK (1) | DK169669B1 (en) |
| ES (1) | ES2005012A6 (en) |
| FR (1) | FR2610321B1 (en) |
| IE (1) | IE59681B1 (en) |
| PT (1) | PT85211B (en) |
| ZA (1) | ZA874526B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2769016B1 (en) * | 1997-09-30 | 1999-10-29 | Adir | HIGH-CONTENT CHLORAMINE SYNTHESIS PROCESS |
| FR2864078B1 (en) | 2003-12-17 | 2006-02-10 | Isochem Sa | PROCESS FOR THE CONTINUOUS SYNTHESIS OF MONOALKYL HYDRAZINES WITH FUNCTIONALIZED ALKYL GROUP |
| FR2864081B1 (en) * | 2003-12-17 | 2006-04-28 | Isochem Sa | PROCESS FOR THE SYNTHESIS OF EXOCYCLIC CYCLOALKYL HYDRAZINE DERIVATIVES AND EXOCYCLIC HETEROCYCLOALKYL HYDRAZINE DERIVATIVES |
| US20080156740A1 (en) * | 2006-12-29 | 2008-07-03 | Amit Gupta | Method for producing a stable oxidizing biocide |
| CN101307019B (en) * | 2008-04-28 | 2010-10-27 | 宁波九胜创新医药科技有限公司 | Method for preparing N-amino-3-azabicyclo[3,3,0]octane hydrochloride |
| CN118772145B (en) * | 2023-04-04 | 2025-10-10 | 上海医药工业研究院有限公司 | A preparation method of diazabicyclooctene compound |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1449404A (en) * | 1973-03-30 | 1976-09-15 | Science Union & Cie | N-arylsulphonyl urea derivatives |
| YU40105B (en) * | 1973-07-04 | 1985-08-31 | Science Union & Cie | Process for the manufacture of n-arylsulfonyl-n'-(aza-3-bicycloalyl)-carbamides |
| FR2540110B1 (en) * | 1983-02-02 | 1985-07-05 | Adir | NEW INDUSTRIAL MANUFACTURING PROCESS OF N-NITROSO AZABICYCLOALCANES |
-
1987
- 1987-02-04 FR FR8701334A patent/FR2610321B1/en not_active Expired
- 1987-06-05 IE IE148887A patent/IE59681B1/en not_active IP Right Cessation
- 1987-06-12 DE DE8787108477T patent/DE3765925D1/en not_active Expired - Lifetime
- 1987-06-12 EP EP87108477A patent/EP0277267B1/en not_active Expired - Lifetime
- 1987-06-12 AT AT87108477T patent/ATE57914T1/en not_active IP Right Cessation
- 1987-06-15 CA CA000539646A patent/CA1283420C/en not_active Expired - Lifetime
- 1987-06-15 AR AR87307860A patent/AR243160A1/en active
- 1987-06-15 DK DK303987A patent/DK169669B1/en not_active IP Right Cessation
- 1987-06-16 AU AU74260/87A patent/AU591784B2/en not_active Expired
- 1987-06-23 ZA ZA874526A patent/ZA874526B/en unknown
- 1987-06-30 PT PT85211A patent/PT85211B/en unknown
- 1987-07-06 JP JP62167147A patent/JPS63196565A/en active Granted
- 1987-09-14 ES ES8702644A patent/ES2005012A6/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| PT85211A (en) | 1987-07-01 |
| AR243160A1 (en) | 1993-07-30 |
| CA1283420C (en) | 1991-04-23 |
| FR2610321A1 (en) | 1988-08-05 |
| AU591784B2 (en) | 1989-12-14 |
| JPS63196565A (en) | 1988-08-15 |
| ATE57914T1 (en) | 1990-11-15 |
| PT85211B (en) | 1990-11-20 |
| AU7426087A (en) | 1988-08-11 |
| EP0277267A1 (en) | 1988-08-10 |
| DE3765925D1 (en) | 1990-12-06 |
| DK169669B1 (en) | 1995-01-09 |
| IE871488L (en) | 1988-08-04 |
| DK303987A (en) | 1988-08-05 |
| FR2610321B1 (en) | 1989-04-07 |
| ES2005012A6 (en) | 1989-02-16 |
| ZA874526B (en) | 1987-12-29 |
| DK303987D0 (en) | 1987-06-15 |
| JPH0427233B2 (en) | 1992-05-11 |
| EP0277267B1 (en) | 1990-10-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |