GB2132608A - Production of thiophene compounds - Google Patents
Production of thiophene compounds Download PDFInfo
- Publication number
- GB2132608A GB2132608A GB08312702A GB8312702A GB2132608A GB 2132608 A GB2132608 A GB 2132608A GB 08312702 A GB08312702 A GB 08312702A GB 8312702 A GB8312702 A GB 8312702A GB 2132608 A GB2132608 A GB 2132608A
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- GB
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- Prior art keywords
- formula
- thiophene
- acetic acid
- process according
- thiophene acetic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/12—Radicals substituted by halogen atoms or nitro or nitroso radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
A 2-thiophene acetic acid compound of formula (I): <IMAGE> in which: R represents an alkyl radical of 1 to 4 carbon atoms; and R1, R2 and R3 are the same or different and each represents a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a halogen atom; is prepared by reacting a haloalkylthiophene of formula (III): <IMAGE> in which R, R1, R2 and R3 are as defined above and Hal represents a halogen atom, with a cyanide of formula A-CN in which A represents an alkali metal atom, an alkaline-earth metal equivalent or a hydrogen atom to produce a cyanoalkylthiophene of formula (IV): <IMAGE> in which R, R1, R2 and R3 are as defined above, and hydrolysing the cyanoalkylthiophene of formula (IV) to the 2-thiophene acetic acid compound of formula (I). The compound of formula (I) is an intermediate in the production of pharmaceuticals.
Description
SPECIFICATION
Productior. of thiophene compounds
This invention relates to the production of 2-thiophene acetic acid compounds of formula (I):
in which R represents an alkyl radical of 1 to 4 carbon atoms and R1, R2 and R3 are the same or different and each represents a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a halogen atom.
These compounds are intermediates which can be used in the preparation of pharmaceutical products, in particular anti-inflammatory products. End products which can be prepared from the compounds are described in particular in French Patent 2 068 425.
Several processes for the preparation of the compounds are already known.
The following process is described in M. Bercotvatteroni et al., Bull, Soc. Chim. France 1961 p.
1820:
The following process is described in F. Clemence et al., Eur. J. Med. Chem. 1 974 (9) 390:
The following process is described in French Patent Application 2 398 068 in the name of
Sagami:
R'=H or lower alkyl Hal=halogen
R'2=H, hydrocarbon radical or halogen
These processes involve at least 4 stages starting from thiophene or in the case of the last mentioned process an optionally substituted thiophene of formula
A new process for the preparation of the compounds of formula (I) has now been discovered.
Accordingly, the invention provides a process for the preparation of a 2-thiophene acetic acid compound of formula (I):
in which
R represents an alkyl radical of 1 to 4 carbon atoms; and R1, R2 and R3 are the same or different and each represents a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a halogen atom; which process comprises reacting a haloalkylthiophene of formuia (III):
in which R, R,, R2 and R3 are as defined above and Hal represents a halogen atom, with a cyanide of formula A-CN in which A represents an alkali metal atom, an alkaline-earth metal equivalent or a hydrogen atom to produce a cyanoalkylthiophene of formula (IV):
in which R, R,, R2 and R3 are as defined above, and hydrolysing the cyanoalkylthiophene of formula (IV) to the 2-thiophene acetic acid compound of formula (I).
The new process is better because it produces the compounds more readily. If one starts from an optionally substituted thiophene of formula (ill):
the present process can produce the compounds in only 3 stages. Moreover, the present process has proved better on an industrial scale.
The haloalkylthiophene of formula (III) is preferably prepared by haloa!kylating a thio compound of formula (II), and thus the compound of formula (I) can be prepared from it in 3 stages.
The haloalkylation can be conducted by reacting the thio compound of formula (II) with an aldehyde of formula BCHO in the presence of a hydrohalic acid of formula HHal. Alternatively, the haloalkylation can be conducted by reacting the thio compound of formula (II) with a derivative of the aldehyde of formula BCHO in the presence of a hydrohalic acid of formula HHal, the derivative being reactive so as to enable the reaction to proceed.
R represents a lower alkyl radical, i.e. an alkyl radical of 1 to 4 carbon atoms, namely methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tert-butyl. R1, R2 and R3 can independently represent one of these alkyl radicals or equally a halogen atom, namely fluorine, chlorine, bromine or iodine.
The aldehyde of formula BCHO is the aldehyde corresponding to the value of the desired R. When
R represents a methyl radical, paraldehyde which is the trimer of acetaldehyde is preferably used. Of the other aldehydes, propanal and butanal may be mentioned.
Hal preferably represents an atom of chlorine or bromine, especially chlorine. Thus, the hydrohalic acid is preferably hydrochloric or hydrobromic acid, especially hydrochloric acid.
The haloalkylation is preferably chloroalkylation, especially chloroethylation, and can be carried out with or without the addition of an organic solvent. The solvent is preferably a chlorinated solvent such as carbon tetrachloride, chloroform or especially methylene chloride. Alternatively, the solvent can be an ether such as isopropyl ether, cyclohexane, ethanol or methanol. As a matter of convenience, the further stages in the synthesis can be carried out starting from a haloalkylthiophene of formula (III) in solution. The solvent can thus be an extraction solvent which is the same as or different from the reaction solvent. A reaction solvent is preferably used. The preferred solvent is methylene chloride which can equally be used for the extraction.
In addition to the hydrohalic acid which participates directly in the reaction, another acid such as phosphoric acid or acetic acid can be admixed to modify the acidity of the medium. It is likewise possible to use a Lewis acid such as zinc or aluminium chloride.
Obviously the different reagents: thio compound, aldehyde and acid can be introduced in different orders depending on the operational conditions used. The reaction temperature likewise can vary. The preferred operating temperature is between1 00 C and ambient temperature. More particularly a temperature of about -50C is used. A particular example of such a reaction is described in Org. Synth.
Vol. 38 p. 86.
When a reactive derivative of the aldehyde of formula BCHO is employed, this reactive derivative is preferably of formula (V):
in which Hal represents a halogen atom and Alk represents an alkyl radical containing preferably 1 to 3 carbon atoms. This derivative of formula (V) can be prepared by reacting the aldehyde RCHO with the hydrohalic acid of formula HHal in an alcoholic solvent of formula AlkOH. Preferably the reactive derivative is of formula
and is obtained by reacting acetaldehyde CH3CHO with hydrochloric acid in an alcohol of formula AlkOH, preferably methanol or ethanol.
The conversion of the haloalkylthiophene of formula (III) to the cyanoalkylthiophene of formula (IV) is preferably carried out with an alkali metal or alkaline-earth cyanide such as sodium, potassium, lithium or calcium cyanide. Hydrocyanic acid could equally be used. Sodium cyanide is preferred. The operation can be carried out with or without the presence of a base. When operating in the presence of a base, sodium or potassium hydroxide is preferred, particularly sodium hydroxide. However it is preferred to operate without a base.
The conversion of the haloalkylthiophene of formula (lil) to the cyanoalkylthiophene of formula (IV) is preferably carried out by a phase transfer reaction. The operation is then carried out in the presence of a specific catalyst. This catalyst can be, for instance, an ammonium, phosphonium or arsonium tetraalkyl or aralkyl salt, or a sulphonium salt. Of the catalysts of this type there may be mentioned, for example, triethyl benzylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium bromide, tetrab utylammonium sulphate, tetrabutylammonium hydroxide, tetra-nbutylammonium chloride, tetramethylphosphonium iodide or tetra-n-butylphosphonium bromide.
These salts can be fixed on ion exchange resin.
It is equally possible to employ a macrocyclic polyether, generally called an ether-ring. Such polyethers are described for example in Tetrahedron Letters no. 1 8 (1 972) p. 1 793. Of the polyethers which can be employed there may be mentioned in particular 1, 4, 7, 10, 13, 1 6-hexaoxacyclooctadecane. In short, it is possible to employ surface active agents formed by reacting a higher alcohol or a fatty acid with for example ethylene oxide.
The catalyst is advantageously an ammonium halide, especially trialkyl benzylammonium or tetraalkylammonium bromide or chloride. The preferred catalyst is triethyl benzylammonium chloride.
In a preferred mode of operation, as mentioned above, the haloalkylthiophene of formula (III) is used in an organic solution, preferably a methylene chloride solution, or in dichloroethane. It is equally possible to use a polar solvent such as dimethyl formamide or dimethyl sulphoxide. Methylene chloride is used from preference.
The quantity of phase transfer catalyst can vary depending on the reactions used. For example it can vary from 0.2 to 0.5 parts by weight relative to the haloalkylthiophene of formula (III).
The temperature can vary for example between OOC and the reflux temperature of the solvent. It is preferred to operate at a low temperature of the order of O to +50C.
The hydrolysis of the cyanoalkylthiophene of formula (IV) to the acid compound of formula (I) can first convert the nitrile into a salt, preferably the sodium or potassium salt, of the desired acid, which salt is then acidified to the desired acid. When the nitrile has thus been converted into a salt of the desired acid. The aqueous phase can be purified by an organic solvent. The aqueous phase can then be acidified and the desired compound extracted.
The first phase can be carried out in water or in a mixture of water and a water-miscible solvent.
The solvent preferably employed is a lower alcohol such as ethanol or isopropanol. The alkaline agent is preferably sodium or potassium hydroxide and the reaction preferably occurs at a temperature between 500C and the reflux temperature. The operation is preferably carried out at reflux in pure water. The reaction time is usually between 2 hours and 1 5 hours.
The organic solvent used to purify the aqueous solution of the salt obtained is preferably toluene, dichloroethane or methylene chloride, preferably methylene chloride.
The final acidification is preferably carried out with concentrated hydrochloric acid. The reaction is preferably conducted after the addition of a solvent chosen from the preceding group. The operation is usually conducted at a temperature between the ambient temperature and the reflux temperature of the solvent.
The hydrolysis of the cyanoalkylthiophene of formula (IV) to a compound of formula (I) can equally be carried out in an acid medium. The acid is preferably a mineral acid such as hydrochloric, sulphuric or phosphoric acid.
Bt, R2 and R3 preferably each represents a hydrogen atom, so that the acid compound is of formula (I'):
In that event, the corresponding thio compound of formula (II) is thiophene.
R preferably represents a methyl radical.
In a preferred embodiment, lx-methyl 2-thiophene acetic acid is prepared as described above, starting from thiophene and acetaldehyde.
As mentioned above, the reaction of the cyanide of formula A-CN with the haloalkylthiophene of formula (III) is carried out preferably by a phase transfer reaction. This reaction is preferably carried out in the presence as catalyst of triethyl benzylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium sulphate or tetrabutylammonium hydroxide.
In a particularly advantageous way of carrying out this reaction, the haloalkylthiophene of formula (III) in methylene chloride solution is poured into an aqueous solution of sodium cyanide and a phase transfer catalyst. The phase transfer catalyst is as indicated previously preferably triethyl benzylammonium chloride.
Especially preferred is carrying out the present process in the following way to produce methyl 2-thiophene acetic acid: Hydrochloric acid and paraldehyde are reacted with thiophene to produce 2 (1 -chloroethyl)thiophene, which is reacted with sodium cyanide by phase transfer reaction in the presence of triethyl benzylammonium chloride to produce methyl 2-thiophene acetonitrile, which is reacted with sodium hydroxide and then hydrochloric acid to obtain the desired compound.
The invention also provides a process for preparing a pharmaceutical using as an intermediate a 2-thiophene acetic acid compound as defined above, in which process the compound is prepared in the present way.
The invention is illustrated by the following Examples.
Example 1 methyl 2-thiophene acetic acid
Stage A: 2-(1 -chloroethyl)thiophene A mixture of 336 cc of methylene chloride and 75 cc of aqueous hydrochloric acid were cooled with stirring to -50C and then on the one hand a mixture of 84 g of thiophene and 44 g of paraldehyde and on the other hand 36.5 g of gaseous hydrochloric acid were introduced at this temperature over 5 hours. The mixture was stirred and 3.5 g of hydrochloric acid were added over thirty minutes. After three hours stirring at -50C, the mixture was brought to OOC and 50 g of ice were introduced.The resultant mixture was stirred at O to +50C for 1 5 minutes, the organic phase was decanted, the aqueous phase was extracted at O to +50C by 42 cc of methylene chloride and the two organic phases were combined.
Stage B: methyl 2-thiophene acetonitrile
8.4 g of triethyl benzylammonium chloride were added to a solution cooled to O to +50C of 88.5 g of sodium cyanide in 1 68 cc of demineralised water. The methylene chloride solution of 2-( 1 - chloroethyl)thiophene obtained in Stage A was poured over one minute into the medium which was stirred constantly. Vigorous stirring continued for 18 hours at O to +50C, and then 252 cc of demineralised water were added. After stirring for 1 0 minutes, the organic phase was decanted and the aqueous phase was extracted with 84 cc of methylene chloride and then with two batches of 42 cc of the same solvent.The organic phases were combined, and then washed by demineralised water, then by water containing 1% pure hydrochloric acid and again by demineralised water.
The organic phase was concentrated under reduced pressure for 2 hours. 105 g of the expected product were obtained.
Stage C; a-methyl 2-thiophene acetic acid
A mixture of 105 g of the product obtained in Stage B, 500 cc of demineralised water and 63.2 g of sodium hydroxide were brought to reflux for two hours thirty minutes. It was cooled to 200C and 1 68 cc of methylene chloride were added. After ten minutes stirring, the methylene chloride phase was decanted. The same operation was repeated twice. 168 cc of toluene and then 168 cc of 220Be hydrochloric acid were added to the aqueous phase. The mixture was brought to reflux for one hour, cooled to 200 C, and stirred for 1 5 minutes, and then the aqueous phase was decanted and then washed four times, each time with 42 cc of demineralised water.The organic phase was concentrated under reduced pressure. 71 to 74 g of the expected product were obtained.
Example 2
Stages A to C above can be modified in the following manner:
Stage A1: 2-(l-chloroethyl )thiophene Gaseous hydrochloric acid was bubbled to saturation for 25 minutes into a mixture of 84 g of thiophene, 44 g of paraldehyde and 75 cc of 220Be hydrochloric acid while maintaining the temperature at 10-1 30C.
The resultant mixture was poured into 75 cc of iced water, and after decanting, the aqueous phase was extracted with 1 68 cc of methylene chloride and the organic phase was washed three times with 50 cc of iced water.
Stage A2:
Gaseous hydrochloric acid was introduced at +1 00C to saturation into a mixture of 46 g of ethanol and 44 g of paraldehyde. This reagent was added over 10 minutes at + 1 00C with stirring to 84 g of thiophene. The procedure was then the same as described above for Stage A.
Stage A3:
A mixture of 84 g of thiophene, 44 g of paraldehyde, 1 68 cc of methylene chloride and 75 cc of 220 Be hydrochloric acid was stirred at 10-1 30C. This was saturated by 40 g of gaseous hydrochloric acid and then cooled to OOC. 50 g of ice were added, and after decanting, the aqueous phase was extracted with 42 cc of methylene chloride and the combined organic phases were washed twice by 63 cc of iced water.
Stage B':
The triethyl benzylammonium chloride was replaced by each of the following reagents:
-tetrapropylammonium bromide --tetrabutylammonium bromide --tetrabutylammonium sulphate --tetrabutylammonium hydroxide.
Stage C':
The methylene chloride was replaced by dichloroethane as the extraction solvent.
Claims (14)
1. Process for the preparation of a 2-thiophene acetic acid compound of formula (I):
in which
R represents an alkyl radical of 1 to 4 carbon atoms; and R1, R2 and R3 are the same or different and each represents a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a halogen atom; which process comprises reacting a haloalkylthiophene of formula (III):
in which R, R,, R2 and R3 are as defined above and Hal represents a halogen atom, with a cyanide of formula A-CN in which A represents an alkali metal atom, an alkaline-earth metal equivalent or a hydrogen atom to produce a cyanoalkylthiophene of formula (IV):
in which R, R,, R2 and R3 are as defined above, and hydrolysing the cyanoalkylthiophene of formula (IV) to the 2-thiophene acetic acid compound of formula (I).
2. Process according to claim 1 wherein the haloalkylthiophene of formula (III) is prepared by haloalkyiating a thio compound of formula (ill):
in which Rr, R2 and R3 are as defined in claim 1.
3. Process according to claim 2 wherein the haloalkylation is conducted by reacting the thio compound of formula (II) with an aldehyde of formula RCHO in which R is as defined in claim 1, in the presence of a hydrohalic acid of formula HHal in which Hal is as defined in claim 1.
4. Process according to claim 2 wherein the haloalkylation is conducted by reacting the thiophene of formula (II) with a reactive derivative of an aldehyde of formula RCH0 in which R is as defined in claim 1, which derivative contains the halogen atom Hal as defined in claim 1.
5. Process according to any one of the preceding claims wherein R1, R2 and R3 each represents a hydrogen atom.
6. Process according to claim 5 wherein R represents a methyl radical.
7. Process according to claim 3 wherein R represents a methyl radical and the aldehyde RCH0 is in the form of paraldehyde.
8. Process according to any one of the preceding claims wherein the reaction of the cyanide of formula A-CN with the haloalkylthiophene of formula (III) is carried out as a phase transfer reaction.
9. Process according to claim 8 wherein the phase transfer reaction is conducted in the presence as catalyst of triethyl benzylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium sulphate or tetrabutylammonium hydroxide.
10. Process according to claim 8 or 9 wherein in the phase transfer reaction the haloalkylthiophene of formula (III) in methylene chloride solution is poured into an aqueous solution of sodium cyanide and a phase transfer catalyst.
11. Process for the preparation of a-methyl 2-thiophene acetic acid, which process comprises reacting hydrochloric acid and paraldehyde with thiophene to produce 2-(1 -chloroethyl)thiophene, which is reacted with sodium cyanide in a phase transfer reaction in the presence of triethyl benzylammonium chloride to produce a-methyl 2-thiophene acetonitrile, which is reacted with sodium hydroxide and then hydrochloric acid to produce the methyl 2-thiophene acetic acid.
12. Process according to claim 1 performed substantially as described herein.
13. Process for preparing a 2-thiophene acetic acid compound of formula (I) as defined in claim 1, which process is performed substantially as described herein in any one of the Examples.
14. A 2-thiophene acetic acid compound of formula (I) as defined in claim 1, when prepared by a process claimed in any one of the preceding claims.
1 5. Process for preparing a pharmaceutical using as an intermediate a 2-thiophene acetic acid compound of formula (I) as defined in claim 1, in which process the 2-thiophene acetic acid compound is as claimed in claim 14.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8220272A FR2537138A1 (en) | 1982-12-03 | 1982-12-03 | PROCESS FOR THE PREPARATION OF ACETIC 2-THIOPHENE ACID DERIVATIVES |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8312702D0 GB8312702D0 (en) | 1983-06-15 |
| GB2132608A true GB2132608A (en) | 1984-07-11 |
| GB2132608B GB2132608B (en) | 1986-06-04 |
Family
ID=9279758
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08312702A Expired GB2132608B (en) | 1982-12-03 | 1983-05-09 | Production of thiophene compounds |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS59106483A (en) |
| KR (1) | KR900003281B1 (en) |
| AT (1) | AT392785B (en) |
| AU (1) | AU557065B2 (en) |
| BE (1) | BE896440A (en) |
| CA (1) | CA1201442A (en) |
| CH (1) | CH653681A5 (en) |
| DE (1) | DE3314028C2 (en) |
| DK (1) | DK157492C (en) |
| ES (1) | ES8401958A1 (en) |
| FI (1) | FI80882C (en) |
| FR (1) | FR2537138A1 (en) |
| GB (1) | GB2132608B (en) |
| HU (1) | HU191831B (en) |
| IE (1) | IE55097B1 (en) |
| IT (1) | IT1174758B (en) |
| LU (1) | LU84749A1 (en) |
| NL (1) | NL8301693A (en) |
| NZ (1) | NZ204510A (en) |
| PT (1) | PT76535B (en) |
| SE (1) | SE453918B (en) |
| ZA (1) | ZA832697B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1276738B1 (en) * | 1995-06-16 | 1997-11-03 | Erregierre Spa | PROCESS FOR THE PREPARATION OF DERIVATIVES OF -METHYL-2- THIOPHENEACETIC ACID |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE33054B1 (en) * | 1968-04-16 | 1974-03-06 | Ici Ltd | Heterocyclic compounds |
| GB2003570B (en) * | 1977-06-08 | 1982-01-20 | Imi Opella Ltd | Stop valve |
-
1982
- 1982-12-03 FR FR8220272A patent/FR2537138A1/en active Granted
-
1983
- 1983-03-28 DK DK140083A patent/DK157492C/en not_active IP Right Cessation
- 1983-03-30 SE SE8301786A patent/SE453918B/en not_active IP Right Cessation
- 1983-03-31 FI FI831116A patent/FI80882C/en not_active IP Right Cessation
- 1983-04-05 ES ES521231A patent/ES8401958A1/en not_active Expired
- 1983-04-11 PT PT76535A patent/PT76535B/en not_active IP Right Cessation
- 1983-04-12 CH CH1966/83A patent/CH653681A5/en not_active IP Right Cessation
- 1983-04-12 BE BE0/210537A patent/BE896440A/en unknown
- 1983-04-14 HU HU831307A patent/HU191831B/en unknown
- 1983-04-14 LU LU84749A patent/LU84749A1/en unknown
- 1983-04-15 AU AU13573/83A patent/AU557065B2/en not_active Ceased
- 1983-04-18 DE DE3314028A patent/DE3314028C2/en not_active Expired - Lifetime
- 1983-04-18 ZA ZA832697A patent/ZA832697B/en unknown
- 1983-04-23 KR KR1019830001730A patent/KR900003281B1/en not_active IP Right Cessation
- 1983-05-04 IT IT48216/83A patent/IT1174758B/en active Protection Beyond IP Right Term
- 1983-05-09 GB GB08312702A patent/GB2132608B/en not_active Expired
- 1983-05-10 IE IE1074/83A patent/IE55097B1/en not_active IP Right Cessation
- 1983-05-11 NL NL8301693A patent/NL8301693A/en active Search and Examination
- 1983-05-20 JP JP58087836A patent/JPS59106483A/en active Granted
- 1983-06-09 NZ NZ204510A patent/NZ204510A/en unknown
- 1983-07-28 CA CA000433422A patent/CA1201442A/en not_active Expired
- 1983-08-08 AT AT2867/83A patent/AT392785B/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 732E | Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977) | ||
| 732E | Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977) | ||
| PE20 | Patent expired after termination of 20 years |
Effective date: 20030508 |