CA1128038A - Bromination process of ergot alkaloids - Google Patents
Bromination process of ergot alkaloidsInfo
- Publication number
- CA1128038A CA1128038A CA336,448A CA336448A CA1128038A CA 1128038 A CA1128038 A CA 1128038A CA 336448 A CA336448 A CA 336448A CA 1128038 A CA1128038 A CA 1128038A
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- bromo
- methyl
- chloro
- amido
- 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.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
Abstract
BROMINATION PROCESS OF ERGOT ALKALOIDS
Abstract of the Disclosure The present invention provides a process for the production of a compound of formula I
I
wherein R1 is carboxyl, alkoxy(C1-5) carbonyl, amido, alkyl(C1-5)amido, di(alkyl(C1-5))amido or an amido radical of formula II
II
wherein Ra is alkyl(C1-4), Rb is alkyl(C1-4) or benzyl, and R2 is hydrogen or alkyl(C1-4), and either R3 is hydrogen and R4 is hydrogen or alkoxy(C1-4) or R3 and R4 together are a single bond, characterised in that a compound of formula III
III
wherein R1 to R4 are as defined above, is brominated with a bromine complex of 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine.
Abstract of the Disclosure The present invention provides a process for the production of a compound of formula I
I
wherein R1 is carboxyl, alkoxy(C1-5) carbonyl, amido, alkyl(C1-5)amido, di(alkyl(C1-5))amido or an amido radical of formula II
II
wherein Ra is alkyl(C1-4), Rb is alkyl(C1-4) or benzyl, and R2 is hydrogen or alkyl(C1-4), and either R3 is hydrogen and R4 is hydrogen or alkoxy(C1-4) or R3 and R4 together are a single bond, characterised in that a compound of formula III
III
wherein R1 to R4 are as defined above, is brominated with a bromine complex of 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine.
Description
28Q3~3 The present invention relates to brominating processes, especially for selectively brominating sensi-tive compounds such as ergot alkaloids, e.g. ~-ergocryp-tine.
It is known to brominate ~-ergocryptine with a mild brominating agent, e.g. N-bromosuccinimide, N-bromo-caprolactam, N-bromophthalamide and bromine/dioxane [see Swiss Patent No 507249]. It has also been recently proposed to brominate ~-ergocryptine using pyrrolidone-(2)-hydrotribromide or N-bromosaccharin in the presence of a radical lnitiator (German Offenlegungs-schrift 2752532).
The present invention provides an novel and advan-tageous process for the production of a compound of formula R ~
N-C~I I
N - ~r t~2 ~2t~Q3~
It is known to brominate ~-ergocryptine with a mild brominating agent, e.g. N-bromosuccinimide, N-bromo-caprolactam, N-bromophthalamide and bromine/dioxane [see Swiss Patent No 507249]. It has also been recently proposed to brominate ~-ergocryptine using pyrrolidone-(2)-hydrotribromide or N-bromosaccharin in the presence of a radical lnitiator (German Offenlegungs-schrift 2752532).
The present invention provides an novel and advan-tageous process for the production of a compound of formula R ~
N-C~I I
N - ~r t~2 ~2t~Q3~
- 2 - 118-3377 wherein Rl is carboxyl, alkoxy(Cl 5)carbonyl, amido, alkyl(Cl 5)amido, di(alkyl(Cl 5))amido or an amido radical of formula II
R OH
-Co-NH - - ~ ~ J II
H
`~
wherein Ra is alkyl(Cl_4), ~ is alkyl(Cl 4) or benzyl, and ~2 is hydrogen or alkyl(Cl 4), and either ~3 is hydrogen and R4 is hydrogen or alkoxy~Cl 4) or R3 and R4 together are a single bond, characterised in that a compound of formula III
~-C H3 N
wherein Rl to R4 are as ~efin~fl ahove, is brominatecl with a bromine complex of 3-bromo-6-chloro-2-methyl-imiclazo[1,2-b]pyridazine.
.
:~
. .
, ~128~38 This brominating agent may for example be prepared by reacting 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyrida--zine or 6-chloro-2-methyl-imidazo~1,2-b]pyridazine with excess bromine. The product is believed to comprise 3-bromo-6-chloxo-2-methyl-imidazo[1,2-b]pyridazine dibromide of formula IV
~ C1 ~ ,~ ~ Br ~ 2 IV
The brominating agent possesses especialls~ advan-tageous properties. For example it is selective and does not lead to large amounts of side products; it is soluble in a wide range of organic solvents e.g. halogenated sol-vents and is stable in solution jt excess brominating agent may be easily destroyed and the brominated product can be easily separated from the reaction mixture. The brominating agent may be easily regenerated from 3-bromo-6-chloro-2-methyl-imidazo[l~2-b~pyridazine formed in the reaction.
In formulae I and III the side chain in the 8 posi-tion may have the ~ or preferably the ~ configuration. The brominating reaction proceeds stereospecifically in that epimerisation at the 8 position may be unexpec~edly minimal.
For the above mentioned ergot alkaloids, it is , .
r . : : .
_ 4 _ ~12`8~38 preferred to use a ratio of 1 mole of ergot alkaloid to 1.2 to 1.5 moles of brominating agent (based on structure IV). The brominating reaction is preferably effected using methylene chloride or another appropriate chlorinated alkane (Cl 3) as solvent. Suitable reaction temperatures are for example from about -10C to about 100C. At room temperature satisfactory yields may be surprisingly obtained, for example in a few minute 5 .
Any excess brominating agent in the reaction mix-ture may be deactivated by the addition, for example, ofacetone and ammonium hydroxide. The isolation of the bromi-nated product is then facilitated. Conventional isolation methods may be used, for examFle, liquid/liquid extraction and column chromatography, to obtaln the brominated pro-duct in pure form.
From the reaction mixture 3-bromo-6-chloro-2-methyl-imidazo[l,2-b3pyridazine may be isolated. This may be conver-ted back into the brominating agent by treatment with excess bromine in concentrated acetic acid.
The brominating ag~nt may be inltially produced by reacting 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine or 6-chloro-2-methyl-imidazo[1,2-b]pyridazine with excess bro~ine in concentrated acetic acid, and collecting the re-~ultant precipitate.
The bromination of 6-chloro-2-methyl-imidazo[1,2-b3 pyridazine has been described by Kohe et al Tetrahedron,2~, ~28~3~
239 (1968), but there is no indication therein that the bromine complex formed could be used as a brominating agent. 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine may be prepared as described in the above-mentioned Tetra-hedron article and may be brominated in analogous manner tothe bromination of 6-chloro-2-methyl-imidazo[1,2-b]pyri-dazine and the bromine complex purified in conventional manner. The yield of brominating agent may be conveniently increased by brominating any unreacted starting material in the bromine complex. The complex may be purified further by recrystallization from acetic acid, washing the crystals with ether and drying, e.g., at 30C in a vacuum.
The complex may contain further bromine over that represented by structure IV~ e.g., in the form of HBr.
In the following examples all temperatures are in degrees Centigrade and are uncorrected.
112~3~38 EXP~SPLE 1: ~
0.584 g (1 mMol) 9,10-dihydroergotamlne are dissol-ved in 20 ml methylene chloride. The solution is stlrred and 0.~12 g (l.S m Mol) 3-bromo-6-chloro-2-methyl-imida~o-5 [1,2-b]pyrldazine-dibromlde in 180 ml methylene chloride are added. After the mixture haR been stirred for 2 minutes at room temperature, 10 ml acetone and lOo ml 2% aqueous c~mmonlum hydroxide are added. The methylene chloride phase i8 separate~ off and the aqueous phase is extracted twlce with 200 ml portions ofmethylene chlorlde. ~he o~ned nethylene chloride extracts are cDncentrated to give a dry residue.
Thls resldue ls applied to a column contalning 50 g of slllcagel. Uslng an eluant of methylene chlorlde contalnlng 5% ethanol 0.23 g 3-bromo-6-chloro-2-methyl~lmidazo[l,2-b]pyrldazlne are eluted.
Further elutlon yield~ pure 2-bromo-9,10-dlhydro-ergotamlner 0.33 g,So% yleld. M.Pt. 198-200 and []D
-84 (c= 1, pyridlne).
Replacing the 9,10-dlhydroergotamine wlth an equl-2~ valent amount o~:a) a-ergosine;
b) 9,10-dihydro-a-ergoslne;
c) a-ergocryptine;
d) ~-ergoslnine;
e~ (5R, 8R) lysergic acld diethylc~mide; or f) l-methyl-9,lo-dlhydrolysergic acid methyl ester, r - , ;
~ '.'' ''' ~ , ': .
112~3~3~
there are obtained, respectively:~
a) 2-bromo-~-ergos~ne; 81% yield, M.pt. 183-185 (decomp) []D = ~ 91.6, (c = 1, chloroform);
b) 2-bromo-9,10-dihydroergosine; 69~ yield, M.pt. 186-188 (decomp) [a]20 = - 40 (c = 1, methanol~;
c) 2-bromo-~-ergocryptine; 75% yield, M.pt, 215-218 [~]20= _ 98; (c = 1, pyridine); [~]D = -195; (c = 1, methylene chloride~;
d) 2-bromo-a-ergosinine; 70% yield, M.pt. 188-190; [~]D
= + 403i (c = 1, chloroform);
e) (5R, 8R) 2-bromo-lysergic acid diethyl amide; 73.4~ yield after recrystallization from ether of the dry resid~le before chromatography, M.pt. 122-125; ~a)20 = + 17 (c - 1, pyri-dine);
15 f) 2-bromo-1-methyl-9,10-dihydrolysergic acid methyl ester;
65~ yield after recrystallization of the dry residue before chromatography from methanol/water (85:15 by volume), ~.pt.
166-168; ~]20 = _ 94 (c = 0,5, chloro~orm).
EXAMPLE 2: Reqeneration of 3-hromo-6-chloro-2-~eth~l-imi-.
_azo[1,2-b]pyrid~zlne dibromlde 0.23 g (0.93 mMol) 3-bromo-6-chloro-2-methyl-imidazo [1,2-b]pyridazine obtained from Example 1 is clissolved in 2 ml concentrated acetic acid and treated with 1.39 n~lol elemen-tal bromine. Fromtthe reaction mixture crystallizes out 25 after a little while 3-bromo-6-chloro-2-methyl-imidaæo[1,2-b~
pyridazine dibromide. Thls is filtered off and dried~ Yield - 0.38 g, (~9.4%), M.pt 217-220.
.
R OH
-Co-NH - - ~ ~ J II
H
`~
wherein Ra is alkyl(Cl_4), ~ is alkyl(Cl 4) or benzyl, and ~2 is hydrogen or alkyl(Cl 4), and either ~3 is hydrogen and R4 is hydrogen or alkoxy~Cl 4) or R3 and R4 together are a single bond, characterised in that a compound of formula III
~-C H3 N
wherein Rl to R4 are as ~efin~fl ahove, is brominatecl with a bromine complex of 3-bromo-6-chloro-2-methyl-imiclazo[1,2-b]pyridazine.
.
:~
. .
, ~128~38 This brominating agent may for example be prepared by reacting 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyrida--zine or 6-chloro-2-methyl-imidazo~1,2-b]pyridazine with excess bromine. The product is believed to comprise 3-bromo-6-chloxo-2-methyl-imidazo[1,2-b]pyridazine dibromide of formula IV
~ C1 ~ ,~ ~ Br ~ 2 IV
The brominating agent possesses especialls~ advan-tageous properties. For example it is selective and does not lead to large amounts of side products; it is soluble in a wide range of organic solvents e.g. halogenated sol-vents and is stable in solution jt excess brominating agent may be easily destroyed and the brominated product can be easily separated from the reaction mixture. The brominating agent may be easily regenerated from 3-bromo-6-chloro-2-methyl-imidazo[l~2-b~pyridazine formed in the reaction.
In formulae I and III the side chain in the 8 posi-tion may have the ~ or preferably the ~ configuration. The brominating reaction proceeds stereospecifically in that epimerisation at the 8 position may be unexpec~edly minimal.
For the above mentioned ergot alkaloids, it is , .
r . : : .
_ 4 _ ~12`8~38 preferred to use a ratio of 1 mole of ergot alkaloid to 1.2 to 1.5 moles of brominating agent (based on structure IV). The brominating reaction is preferably effected using methylene chloride or another appropriate chlorinated alkane (Cl 3) as solvent. Suitable reaction temperatures are for example from about -10C to about 100C. At room temperature satisfactory yields may be surprisingly obtained, for example in a few minute 5 .
Any excess brominating agent in the reaction mix-ture may be deactivated by the addition, for example, ofacetone and ammonium hydroxide. The isolation of the bromi-nated product is then facilitated. Conventional isolation methods may be used, for examFle, liquid/liquid extraction and column chromatography, to obtaln the brominated pro-duct in pure form.
From the reaction mixture 3-bromo-6-chloro-2-methyl-imidazo[l,2-b3pyridazine may be isolated. This may be conver-ted back into the brominating agent by treatment with excess bromine in concentrated acetic acid.
The brominating ag~nt may be inltially produced by reacting 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine or 6-chloro-2-methyl-imidazo[1,2-b]pyridazine with excess bro~ine in concentrated acetic acid, and collecting the re-~ultant precipitate.
The bromination of 6-chloro-2-methyl-imidazo[1,2-b3 pyridazine has been described by Kohe et al Tetrahedron,2~, ~28~3~
239 (1968), but there is no indication therein that the bromine complex formed could be used as a brominating agent. 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine may be prepared as described in the above-mentioned Tetra-hedron article and may be brominated in analogous manner tothe bromination of 6-chloro-2-methyl-imidazo[1,2-b]pyri-dazine and the bromine complex purified in conventional manner. The yield of brominating agent may be conveniently increased by brominating any unreacted starting material in the bromine complex. The complex may be purified further by recrystallization from acetic acid, washing the crystals with ether and drying, e.g., at 30C in a vacuum.
The complex may contain further bromine over that represented by structure IV~ e.g., in the form of HBr.
In the following examples all temperatures are in degrees Centigrade and are uncorrected.
112~3~38 EXP~SPLE 1: ~
0.584 g (1 mMol) 9,10-dihydroergotamlne are dissol-ved in 20 ml methylene chloride. The solution is stlrred and 0.~12 g (l.S m Mol) 3-bromo-6-chloro-2-methyl-imida~o-5 [1,2-b]pyrldazine-dibromlde in 180 ml methylene chloride are added. After the mixture haR been stirred for 2 minutes at room temperature, 10 ml acetone and lOo ml 2% aqueous c~mmonlum hydroxide are added. The methylene chloride phase i8 separate~ off and the aqueous phase is extracted twlce with 200 ml portions ofmethylene chlorlde. ~he o~ned nethylene chloride extracts are cDncentrated to give a dry residue.
Thls resldue ls applied to a column contalning 50 g of slllcagel. Uslng an eluant of methylene chlorlde contalnlng 5% ethanol 0.23 g 3-bromo-6-chloro-2-methyl~lmidazo[l,2-b]pyrldazlne are eluted.
Further elutlon yield~ pure 2-bromo-9,10-dlhydro-ergotamlner 0.33 g,So% yleld. M.Pt. 198-200 and []D
-84 (c= 1, pyridlne).
Replacing the 9,10-dlhydroergotamine wlth an equl-2~ valent amount o~:a) a-ergosine;
b) 9,10-dihydro-a-ergoslne;
c) a-ergocryptine;
d) ~-ergoslnine;
e~ (5R, 8R) lysergic acld diethylc~mide; or f) l-methyl-9,lo-dlhydrolysergic acid methyl ester, r - , ;
~ '.'' ''' ~ , ': .
112~3~3~
there are obtained, respectively:~
a) 2-bromo-~-ergos~ne; 81% yield, M.pt. 183-185 (decomp) []D = ~ 91.6, (c = 1, chloroform);
b) 2-bromo-9,10-dihydroergosine; 69~ yield, M.pt. 186-188 (decomp) [a]20 = - 40 (c = 1, methanol~;
c) 2-bromo-~-ergocryptine; 75% yield, M.pt, 215-218 [~]20= _ 98; (c = 1, pyridine); [~]D = -195; (c = 1, methylene chloride~;
d) 2-bromo-a-ergosinine; 70% yield, M.pt. 188-190; [~]D
= + 403i (c = 1, chloroform);
e) (5R, 8R) 2-bromo-lysergic acid diethyl amide; 73.4~ yield after recrystallization from ether of the dry resid~le before chromatography, M.pt. 122-125; ~a)20 = + 17 (c - 1, pyri-dine);
15 f) 2-bromo-1-methyl-9,10-dihydrolysergic acid methyl ester;
65~ yield after recrystallization of the dry residue before chromatography from methanol/water (85:15 by volume), ~.pt.
166-168; ~]20 = _ 94 (c = 0,5, chloro~orm).
EXAMPLE 2: Reqeneration of 3-hromo-6-chloro-2-~eth~l-imi-.
_azo[1,2-b]pyrid~zlne dibromlde 0.23 g (0.93 mMol) 3-bromo-6-chloro-2-methyl-imidazo [1,2-b]pyridazine obtained from Example 1 is clissolved in 2 ml concentrated acetic acid and treated with 1.39 n~lol elemen-tal bromine. Fromtthe reaction mixture crystallizes out 25 after a little while 3-bromo-6-chloro-2-methyl-imidaæo[1,2-b~
pyridazine dibromide. Thls is filtered off and dried~ Yield - 0.38 g, (~9.4%), M.pt 217-220.
.
Claims (3)
1. A process for the production of a compound of formula I
I
wherein R1 is carboxyl, alkoxy(C1-5)carbonyl, amido, alkyl(C1-5)amido, di(alkyl(C1-5))amido or an amido radlcal of formula II
II
wherein Ra is alkyl(C1-4), Rb is alkyl(C1-4) or benzyl, and R2 is hydrogen or alkyl(C1-4), and either R3 ls hydrogen and R4 ls hydrogen or alkoxy(C1-4) or R3 and R4 together are a single bond, characterised in that a compound of formula III
III
wherein R1 to R4 are as defined above, is brominated with a bromine complex of 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine.
I
wherein R1 is carboxyl, alkoxy(C1-5)carbonyl, amido, alkyl(C1-5)amido, di(alkyl(C1-5))amido or an amido radlcal of formula II
II
wherein Ra is alkyl(C1-4), Rb is alkyl(C1-4) or benzyl, and R2 is hydrogen or alkyl(C1-4), and either R3 ls hydrogen and R4 ls hydrogen or alkoxy(C1-4) or R3 and R4 together are a single bond, characterised in that a compound of formula III
III
wherein R1 to R4 are as defined above, is brominated with a bromine complex of 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine.
2. A process according to claim 1, wherein the product of formula I is 2-bromo-.alpha.-ergocryptine and the compound of formula III is .alpha.-ergocryptine.
3. A process according to claim 1 or 2, wherein the bromine complex of 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyri-dazine is prepared by reacting 3-bromo-6-chloro-2-methyl-lmidazo[1,2-b]pyridazine or 6-chloro-2-methyl-imidazo-[1,2-b]pyridazine with excess bromine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU2268/78A YU39849B (en) | 1978-09-26 | 1978-09-26 | Process for preparing 2-bromo-ergolene and 2-bromo-ergoline compounds |
| YUP2268/78 | 1978-09-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1128038A true CA1128038A (en) | 1982-07-20 |
Family
ID=25557457
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA336,448A Expired CA1128038A (en) | 1978-09-26 | 1979-09-26 | Bromination process of ergot alkaloids |
Country Status (45)
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU196394B (en) * | 1986-06-27 | 1988-11-28 | Richter Gedeon Vegyeszet | Process for preparing 2-halogenated ergoline derivatives |
| CN104016982A (en) * | 2014-06-26 | 2014-09-03 | 华东理工大学 | Method for preparing fumigaclavine C by using macroporous resin |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH507249A (en) * | 1968-05-31 | 1971-05-15 | Sandoz Ag | Process for the preparation of 2-bromo-a-ergocryptine |
| YU39786B (en) * | 1976-12-23 | 1985-04-30 | Lek Tovarna Farmacevtskih | Process for preparing 2-bromo-alfa-ergocriptine |
| YU216177A (en) * | 1977-09-09 | 1984-02-29 | Rudolf Rucman | Process for preparing 2-bromo ergosine |
-
1978
- 1978-09-26 YU YU2268/78A patent/YU39849B/en unknown
-
1979
- 1979-09-19 IT IT7950300A patent/IT1206988B/en active
- 1979-09-20 CH CH8492/79A patent/CH649769A5/en not_active IP Right Cessation
- 1979-09-21 DE DE19792938313 patent/DE2938313A1/en active Granted
- 1979-09-24 GR GR60103A patent/GR73015B/el unknown
- 1979-09-24 NZ NZ191643A patent/NZ191643A/en unknown
- 1979-09-24 AR AR278180A patent/AR223496A1/en active
- 1979-09-24 CY CY1240A patent/CY1240A/en unknown
- 1979-09-24 LU LU81714A patent/LU81714A1/en unknown
- 1979-09-24 HU HU79SA3200A patent/HU182576B/en unknown
- 1979-09-24 NO NO793058A patent/NO153852C/en unknown
- 1979-09-24 AT AT0624379A patent/AT376439B/en not_active IP Right Cessation
- 1979-09-24 DD DD79215747A patent/DD146048A5/en not_active IP Right Cessation
- 1979-09-24 FI FI792957A patent/FI66185C/en not_active IP Right Cessation
- 1979-09-24 GB GB7932989A patent/GB2031890B/en not_active Expired
- 1979-09-24 BE BE1/9540A patent/BE878953A/en not_active IP Right Cessation
- 1979-09-24 IS IS2512A patent/IS2512A7/en unknown
- 1979-09-24 PT PT70216A patent/PT70216A/en unknown
- 1979-09-24 MX MX798393U patent/MX5864E/en unknown
- 1979-09-25 NL NL7907122A patent/NL7907122A/en not_active Application Discontinuation
- 1979-09-25 PL PL1979218497A patent/PL120388B1/en unknown
- 1979-09-25 AU AU51172/79A patent/AU529462B2/en not_active Ceased
- 1979-09-25 PH PH23062A patent/PH14986A/en unknown
- 1979-09-25 BG BG7944956A patent/BG32716A3/en unknown
- 1979-09-25 CS CS796471A patent/CS215027B2/en unknown
- 1979-09-25 DK DK401979A patent/DK149956C/en not_active IP Right Cessation
- 1979-09-25 SE SE7907942A patent/SE433497B/en not_active IP Right Cessation
- 1979-09-25 FR FR7923816A patent/FR2437411A1/en active Granted
- 1979-09-25 MA MA18795A patent/MA18595A1/en unknown
- 1979-09-25 IL IL58318A patent/IL58318A/en unknown
- 1979-09-25 JP JP12373279A patent/JPS5545699A/en active Granted
- 1979-09-25 UA UA2818045A patent/UA7078A1/en unknown
- 1979-09-25 RO RO7998760A patent/RO78936A/en unknown
- 1979-09-25 SU SU792818045A patent/SU1178324A3/en active
- 1979-09-25 ES ES484445A patent/ES484445A1/en not_active Expired
- 1979-09-25 EG EG566/79A patent/EG14277A/en active
- 1979-09-26 CA CA336,448A patent/CA1128038A/en not_active Expired
- 1979-09-26 ZA ZA00795110A patent/ZA795110B/en unknown
- 1979-09-26 IE IE1832/79A patent/IE49076B1/en not_active IP Right Cessation
- 1979-09-26 BR BR7906175A patent/BR7906175A/en unknown
-
1980
- 1980-09-23 IN IN1077/CAL/80A patent/IN154914B/en unknown
-
1984
- 1984-03-05 SG SG204/84A patent/SG20484G/en unknown
- 1984-04-12 KE KE3392A patent/KE3392A/en unknown
- 1984-06-14 HK HK491/84A patent/HK49184A/en not_active IP Right Cessation
-
1985
- 1985-12-30 MY MY131/85A patent/MY8500131A/en unknown
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