GB2031890A - Process for the preparation of brominated ergot alkaloids - Google Patents
Process for the preparation of brominated ergot alkaloids Download PDFInfo
- Publication number
- GB2031890A GB2031890A GB7932989A GB7932989A GB2031890A GB 2031890 A GB2031890 A GB 2031890A GB 7932989 A GB7932989 A GB 7932989A GB 7932989 A GB7932989 A GB 7932989A GB 2031890 A GB2031890 A GB 2031890A
- Authority
- GB
- United Kingdom
- Prior art keywords
- alkyl
- bromo
- amido
- formula
- chloro
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 10
- 229960003133 ergot alkaloid Drugs 0.000 title description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 11
- 125000003368 amide group Chemical group 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 229950001817 alpha-ergocryptine Drugs 0.000 claims description 7
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- LHUSNTKCDGCCOB-UHFFFAOYSA-N 3-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine Chemical compound C1=CC(Cl)=NN2C(Br)=C(C)N=C21 LHUSNTKCDGCCOB-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229960004704 dihydroergotamine Drugs 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- GWHLOBFYCUGPGE-UHFFFAOYSA-N 6-chloro-2-methylimidazo[1,2-b]pyridazine Chemical compound N1=C(Cl)C=CC2=NC(C)=CN21 GWHLOBFYCUGPGE-UHFFFAOYSA-N 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- HESHRHUZIWVEAJ-JGRZULCMSA-N dihydroergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2[C@@H](C3=CC=CC4=NC=C([C]34)C2)C1)C)C1=CC=CC=C1 HESHRHUZIWVEAJ-JGRZULCMSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GJNCXCPHNRATIQ-UHFFFAOYSA-N 1-bromoazepan-2-one Chemical compound BrN1CCCCCC1=O GJNCXCPHNRATIQ-UHFFFAOYSA-N 0.000 description 1
- QRADPXNAURXMSB-UHFFFAOYSA-N 2-bromo-1,1-dioxo-1,2-benzothiazol-3-one Chemical compound C1=CC=C2S(=O)(=O)N(Br)C(=O)C2=C1 QRADPXNAURXMSB-UHFFFAOYSA-N 0.000 description 1
- VKRAXSZEDRWLAG-SJKOYZFVSA-N 2-bromo-lsd Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N(CC)CC)C2)=C3C2=C(Br)NC3=C1 VKRAXSZEDRWLAG-SJKOYZFVSA-N 0.000 description 1
- RWKSIKQHBHYHCA-UHFFFAOYSA-N 2-n-bromobenzene-1,2-dicarboxamide Chemical compound NC(=O)C1=CC=CC=C1C(=O)NBr RWKSIKQHBHYHCA-UHFFFAOYSA-N 0.000 description 1
- HLPWNGZWBGZKPV-UHFFFAOYSA-N 3-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine dihydrobromide Chemical compound Br.Br.C1=CC(Cl)=NN2C(Br)=C(C)N=C21 HLPWNGZWBGZKPV-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- VAYOSLLFUXYJDT-RDTXWAMCSA-N Lysergic acid diethylamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N(CC)CC)C2)=C3C2=CNC3=C1 VAYOSLLFUXYJDT-RDTXWAMCSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- -1 ergot alkaloids Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005406 washing Methods 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
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for the production of a compound of formula I <IMAGE> 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 <IMAGE> 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, is characterised in that a compound of formula III <IMAGE> 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]pyridine having the formula IV: <IMAGE>
Description
SPECIFICATION
Improvements in or relating to bromination processes
The present invention relates to brominating processes, especially for selectively brominating sensitive
Compounds such as ergot alkaloids, e.g. a-ergocryptine.
It is known to brominate a-ergocryptine with a mild brominating agent N-bromosuccinimide, N-bromocaprolactam, N-bromophthalamide and bromine/dioxane [see Swiss Patent No 507249]. It has also been recently proposed to brominate a-ergocryptine using pyrrolidone-(2)-hydrotribromide or N-bromosaccharin in the presence of a radical initiator (German Offenlegungsschrift 2752532).
The present invention provides an novel and advantageous process for the production of a compound of formula 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
wherein R0 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 Ill
wherein R1 to R4 are as defined above, is brominated with a bromine complex of 3-bromo-6-chloro-2-methylimidazo[1 ,2-b]pyridazine.
This brominating agent may for example be prepared 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 bromine. The product is believed to comprise 3-bromo-6-chloro-2-methyl-imidazo[l ,2-b]pyridazine dibromide of formula IV
The brominating agent possesses especially advantageous 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 solvents and is stable in solution; 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[1 ,2-b]pyridazine formed in the reaction.
In formulae I and Ill the side chain in the 8 position may have the a or preferably the p configuration. The brominating reaction proceeds stereospecifically in that epimerisation at the 8 position may be unexpectedly minimal.
For the above mentioned ergot alkaloids, it is 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(C13) as solvent. Suitable reaction temperatures are for example from about - 1 0 C to about 10000. At room temperature satisfactory yields may be surprisingly obtained, for example in a few minutes.
Any excess brominating agent in the reaction mixture may be deactivated by the addition, for example, of acetone and ammonium hydroxide. The isolation of the brominated product is then facilitated. Conventional isolation methods may be used, for example, liquid/liquid extraction and column chromatography, to obtain the brominated product in pure form.
From the reaction mixture 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine may be isolated. This may be converted back into the brominating agent by treatment with excess bromine in concentrated acetic acid.
The brominating agent may be initially 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 bromine in concentrated acetic acid, and collecting the resultant precipitate.
The bromination of 6-chloro-2-methyl-imidazo[1,2-bjpyridazine has been described by Kobe et al
Tetrahedron, 24,239(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 Tetrahedron article and may be brominated in analogous manner to the bromination of 6-chloro-2-methyl-imidazo[1 ,2-b]pyridazine 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 30 centigrade in a vacuum. The complex may contain further bromine over that represented by structure IV. e.g. in the form of H.B.R.
In the following examples all temperatures are in degrees Centigrade and are uncorrected.
Example 1: 2-bromo-9, 10-dihydroergotamine 0.584 g (1 mMol) 9,10-dihydroergotamine are dissolved in 20 ml methylene chloride. The solution is stirred and 0.612 g (1.5 m Mol) 3-bromo-6-chloro-2-methyl-imidazo[1 ,2-bjpyridazine-dibromide in 180 ml methylene chloride are added. After the mixture has been stirred for 2 minutes at room temperature, 10 ml acetone and 100 mi 2% aqueous ammonium hydroxide are added. The methylene chloride phase is separated off and the aqueous phase is extracted twice with 200 ml portions of methylene chloride. The combined methylene chloride extracts are concentrated to give a dry residue.
This residue is applied to a column containing 50 g of silicagel. Using an eluant of methylene chloride containing 5% ethanol 0.23 g 3-bromo-6-chloro-2-methyl-imidazo[1 ,2-b]pyridazine are eluted.
Further elution yields pure 2-bromo-9,10-dihydroergotamine; 0.33 g, 50% yield. M.Pt. 1 98-200" and [ID20 -84" (c= 1, pyridine).
Replacing the 9,10-dihydroergotamine with an equivalent amount of: a) a-ergosine; b) 9,10-dihydro-a-ergosine; c) a-ergocryptine; d) a-ergosinine; e) (5R,8R) lysergic acid diethylamide; or f) 1 -methyl-9,1 0-dihydrolysergic acid methyl ester.
there are obtained respectively:a) 2-bromo-a-ergosine; 81% yield, M.pt. 183-185" (decomp) [a]i) = - 91.6 , (c = 1, chloroform); b) 2-bromo-9,10-dihydroergosine; 69% yield, M.pt. 186-188" (decomp) [a]D = - 40 (c = 1, methanol); c) 2-bromo-a-ergocryptine; 75% yield, M.pt. 215-218" [a]D = -98 ; (c = 1, pyridine); [a]D = -195 ; (c = 1, methylene chloride); d) 2-bromo-a-ergosinine; 70% yield, M.pt. 188-190"; [a]20 = + 403 ; (c = 1,chloroform); e) (5R, 8R) 2-bromo-lysergic acid diethyl amide; 73.4% yield after recrystallization from ether of the dry residue before chromatography, M.pt. 122-125"; [a]j, = + 17 (c = 1, pyridine); f) 2-bromo-1 -methyl-9,1 0-dihydrolysergic acid methyl ester; 65% yield after recrystallization of the dry residue before chromatography from methanol/water (85:15 by volume), M.pt. 166-168"; [a]D = - 94" (c = 0.5, chloroform).
Example 2: Regeneration of 3-bromo-6-chloro-2-methyl-imidazojl,2-b]pyridazine dibromide
0.23 g (0.93 mMol) 3-bromo-6-chloro-2-methyl-imidazo [1,2-b]pyridazine obtained from Example 1 is dissolved in 2 ml concentrated acetic acid and treated with 1.39 mMol elemental bromine. From the reaction mixture crystallizes out after a little while 3-bromo-6-chloro-2-methyl-imidazo[1 ,2-b]pyridazine dibromide.
This is filtered off and dried. Yield 0.38 g, (89.4%), M.pt 217-220 .
Claims (5)
1. A process for the production of a compound of formula I
wherein R is carboxyl, alkoxy(C1.5)carbonyl, amido, alkyl(C1 5)amido, di(alkyl(C1.5))amido or an amido radical of formula 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(Cn 4) or R3 and R4 together are a single bond, characterised in that a compound of formula Ill
wherein R1 to R4 are as defined above, is brominated with a bromine complex of 3-bromo-6-chloro-2-methylimidazo[l,2-b]pyridazine.
2. A process according to claim 1 substantially as herein before described with reference to the Example 1.
3. A compound of formula I whenever produced according to the process of claim 1 or 2.
4. A process according to claim 1 wherein the compound of formula Ill is a-ergocryptine.
5. 2-bromo-a-ergocryptine whenever produced according to the process of claim 2 or 4.
Applications Claiming Priority (1)
| 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2031890A true GB2031890A (en) | 1980-04-30 |
| GB2031890B GB2031890B (en) | 1983-02-02 |
Family
ID=25557457
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7932989A Expired GB2031890B (en) | 1978-09-26 | 1979-09-24 | Process for the preparation of brominated 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 DD DD79215747A patent/DD146048A5/en not_active IP Right Cessation
- 1979-09-24 BE BE1/9540A patent/BE878953A/en not_active IP Right Cessation
- 1979-09-24 MX MX798393U patent/MX5864E/en unknown
- 1979-09-24 NO NO793058A patent/NO153852C/en unknown
- 1979-09-24 GB GB7932989A patent/GB2031890B/en not_active Expired
- 1979-09-24 HU HU79SA3200A patent/HU182576B/en unknown
- 1979-09-24 LU LU81714A patent/LU81714A1/en unknown
- 1979-09-24 AR AR278180A patent/AR223496A1/en active
- 1979-09-24 PT PT70216A patent/PT70216A/en unknown
- 1979-09-24 IS IS2512A patent/IS2512A7/en unknown
- 1979-09-24 AT AT0624379A patent/AT376439B/en not_active IP Right Cessation
- 1979-09-24 GR GR60103A patent/GR73015B/el unknown
- 1979-09-24 CY CY1240A patent/CY1240A/en unknown
- 1979-09-24 NZ NZ191643A patent/NZ191643A/en unknown
- 1979-09-24 FI FI792957A patent/FI66185C/en not_active IP Right Cessation
- 1979-09-25 DK DK401979A patent/DK149956C/en not_active IP Right Cessation
- 1979-09-25 MA MA18795A patent/MA18595A1/en unknown
- 1979-09-25 IL IL58318A patent/IL58318A/en unknown
- 1979-09-25 SE SE7907942A patent/SE433497B/en not_active IP Right Cessation
- 1979-09-25 NL NL7907122A patent/NL7907122A/en not_active Application Discontinuation
- 1979-09-25 AU AU51172/79A patent/AU529462B2/en not_active Ceased
- 1979-09-25 RO RO7998760A patent/RO78936A/en unknown
- 1979-09-25 SU SU792818045A patent/SU1178324A3/en active
- 1979-09-25 UA UA2818045A patent/UA7078A1/en unknown
- 1979-09-25 EG EG566/79A patent/EG14277A/en active
- 1979-09-25 PL PL1979218497A patent/PL120388B1/en unknown
- 1979-09-25 ES ES484445A patent/ES484445A1/en not_active Expired
- 1979-09-25 PH PH23062A patent/PH14986A/en unknown
- 1979-09-25 JP JP12373279A patent/JPS5545699A/en active Granted
- 1979-09-25 CS CS796471A patent/CS215027B2/en unknown
- 1979-09-25 FR FR7923816A patent/FR2437411A1/en active Granted
- 1979-09-25 BG BG044956A patent/BG32716A3/en unknown
- 1979-09-26 CA CA336,448A patent/CA1128038A/en not_active Expired
- 1979-09-26 ZA ZA00795110A patent/ZA795110B/en unknown
- 1979-09-26 BR BR7906175A patent/BR7906175A/en unknown
- 1979-09-26 IE IE1832/79A patent/IE49076B1/en not_active IP Right Cessation
-
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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Effective date: 19980924 |