CS262148B1 - 2-brom-13-nitroderivatives of ergoline and process for preparing them - Google Patents
2-brom-13-nitroderivatives of ergoline and process for preparing them Download PDFInfo
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- CS262148B1 CS262148B1 CS877733A CS773387A CS262148B1 CS 262148 B1 CS262148 B1 CS 262148B1 CS 877733 A CS877733 A CS 877733A CS 773387 A CS773387 A CS 773387A CS 262148 B1 CS262148 B1 CS 262148B1
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- nitroderivatives
- ergoline
- bromo
- formula
- configuration
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- AWFDCTXCTHGORH-HGHGUNKESA-N 6-[4-[(6ar,9r,10ar)-5-bromo-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carbonyl]piperazin-1-yl]-1-methylpyridin-2-one Chemical class O=C([C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC(Br)=C(C=34)C2)C1)C)N(CC1)CCN1C1=CC=CC(=O)N1C AWFDCTXCTHGORH-HGHGUNKESA-N 0.000 title claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 title description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000004202 carbamide Substances 0.000 claims abstract description 7
- 239000002243 precursor Substances 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000002823 nitrates Chemical class 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims 1
- 238000006396 nitration reaction Methods 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
2-brom-13-nitroderiváty ergolinu (Obecného vzorce I, ve kterém- R značí, diethylaminoureidovou skupinu s konfiguraci 8a, tj. '8S, nebo methoxyikarboinylovou skupinu s 'konfigurací 8β, tj. 8R, a způsob jejich přípravy nitrací soli 2-brom-13-H-pr.ekursoru vodnou kyselinou dusičnou za přítomnosti močoviny.2-bromo-13-nitroderivatives of ergoline of formula (I) wherein R is diethylaminoreide the 8a configuration group, i. Or an 8S, or methoxycarboinyl group the 8β configuration, ie 8R, and the method of their preparation by nitration of the salt of 2-bromo-13-H-precursor with aqueous nitric acid in the presence urea.
Description
Vynález se týká 2-brom-13-nitroderivátů ergoiinu obecného vzorce I,The invention relates to 2-bromo-13-nitroderivatives of ergoline of formula I,
ve kterémin which
R značí diethylaminoureidovou skupinu '(—NHC-ON/C2H5/2) s konfigurací 8« (tj. 8S ] inebo methoxykarbonylovou skupinu (COOCH3) s konfigurací (tj. 8Rj a způsobu jejich výroby.R denotes a diethylamino -reide group '(—NHC-ON / C2H5 / 2) with an 8' configuration (ie 8S) or a methoxycarbonyl group (COOCH3) having the configuration (ie 8Rj) and a process for their preparation.
Sloučeniny obecného vzorce I jsou potenciálními léčivy s účinky na sekreci proláklinu a na dopaminové receptory. Mimoto slouží jako cenné (meziprodukty k výrobě léčiv s takovýmito účinky.The compounds of formula (I) are potential drugs with effects on the secretion of the prodrug and on dopamine receptors. Furthermore, they serve as valuable (intermediates for the manufacture of medicaments with such effects.
2-brom-13-nitroderiváity ergoiinu obecného vzorce I mají v molekule tři chirální centra, asymetrické uhlíky v polohách 5, 8 a 10, přičemž vodíkový atom na C(5) má polohu β (konfigurace 5R), skupina, vázaná na C(8) má ve shodě s obecným vzorcem I polohu a či já a vodíkový atom na C(10) má polohu « (konfigurace 10R).The 2-bromo-13-nitroderivatives of ergoline of formula I have three chiral centers in the molecule, asymmetric carbons at positions 5, 8 and 10, the hydrogen atom on C (5) having the β position (5R configuration), a C bonded group ( 8) is in accordance with the general formula I in position A or I and the hydrogen atom on C (10) has the position "(10R configuration).
Podle vynálezu se 2-brom-13-nitroderivá»ty ergoiinu obecného vzorce I dají vyrábět tím způsobem, že se výchozí 2-brom-13-H prekursor obecného vzorce II, ve kterém :má R shora uvedený význam, ve formě vodného roztoku soli s vhodnou kyselinou nitruje vodnou kyselinou dusičnou za přídavku močoviny, odstraňující přítomnost volných toxidů dusíku. Výchozí 2-bromderiváty vzorce II jsou látky známé.According to the invention, the 2-bromo-13-nitroderivatives of ergoline of formula (I) may be prepared by starting the 2-bromo-13-H precursor of formula (II) in which : R is as defined above in the form of an aqueous salt solution with a suitable acid nitrates with aqueous nitric acid with the addition of urea, eliminating the presence of free nitrogen toxins. The starting 2-bromo derivatives of formula II are known.
Reakce se výhodně provádí tak, že se k roztoku prekursoru ve vodné kyselině, například octové, vinné či methansulfonové, tedy k in šitu vzniklé isoli prekursoru, za 'chlazení na teplotu 0 °C až 15 °C přidá za míchání močovina a potom koncentrovaná kyselina dusičná v takovém množství, aby její koncentrace ve výsledné směsi byla 15 až 50 °/o. Močoviny se přitom přidává 1 % ia-ž 20 °/o hmotnostních, počítáno na -užitou kyselinu dusičnou. Výsledná směs se 1 minutu až 30 minut míchá při teplotě dané použitým substrátem a koncentrací kyseliny 'v reakční směsi.The reaction is preferably carried out by adding urea and then concentrated acid with stirring to a solution of the precursor in an aqueous acid such as acetic, tartaric or methanesulfonic acid, i.e. the in situ formed precursor salt, while cooling to 0 ° C to 15 ° C. nitric acid in an amount such that its concentration in the resulting mixture was 15-50%. 1% to 20% by weight, calculated on the nitric acid used, is added to the urea. The resulting mixture was stirred for 1 minute to 30 minutes at the temperature given by the substrate used and the acid concentration in the reaction mixture.
• -Po uplynutí reakční doby se reakční směs -zpracuje postupy, obvyklými v chemii derivátů ergoiinu, např. alkalizací, vytřepáním produktu do vhodného s vodou se nenosícího rozpouštědla, odpařením roztoku a chro-matografií a/nebo krystalizací ze vhodného rozpouštědla.After the reaction time has elapsed, the reaction mixture is worked up by conventional methods in the chemistry of ergoline derivatives, for example by alkalization, shaking the product into a suitable non-carrying solvent, evaporating the solution and chromatographing and / or crystallizing from a suitable solvent.
Sloučeniny obecného vzorce I jsou žluté, krystalické látky, slabě bazického charakteru, tvořící adiční soli se silnými anorganickými a organickými kyselinami.The compounds of formula (I) are yellow, crystalline substances, of slightly basic character, forming addition salts with strong inorganic and organic acids.
' Způsob výroby 2-brom-13-nitroderiváitů oibecného vzorce I je blíže objasněn v následujících příkladech, které však rozsah vynálezu nijak neomezují. Teploty tání jsou 'stanoveny na Koflerově -bloku a jsou uvedeny ve °C.The following non-limiting Examples illustrate the preparation of 2-bromo-13-nitroderivatives of formula (I). Melting points are determined on a Kofler block and are reported in ° C.
Struktura látek byla potvrzena infračervenými a hmotovými spektry, složení elementární analýzou.Structure of substances was confirmed by infrared and mass spectra, composition by elemental analysis.
Příklad 1Example 1
Q6'3 mg (1 mmol) methyl 2-brom-9,10-di-hydrolysergátu se rozpustí ve směsi 18 ml mody a 0,071 ml (1,1 mmolů) kyseliny meithansulfo-nové, k roztoku se přidá 1 g -močoviny a za míchání a chlazení se přidá 15 mililitrů 68% kyseliny dusičné, ochlazené na 0 °C. Reakční směs se pak za chlazení na 15 °C -míchá 4,5 minuty a pak nalije do směisi 50 g ledu, 15 ml koncentrovaného vodného amoniaku a- 50 ml chloroformu. Organická fáze se oddělí, vodná extrahuje 2 X -X 50 ml chloroformu. Spojené organické fáze se vysuší bezv-. síranem sodným a odpaří. Odparek se krystalizuje z ethyla-cetátu a vyloučená látka se dočistí 2násobnou ehromatografií na silikagelu (eluen-t chloroform, obs. 0,2 % triethyla-minu). Kvalitativně shodné frakce se spojí, zfil-trují a odpaří a odparek se krystalizuje z ethylaceItátu. Získá se ttk 175 mig (43 °/o teorie) zlatožlutého methyl 2-broim-9,10-dihydro-13-,-nitrolysergátu, -t. -t. 255 až 258 QC.Q6-3 mg (1 mmol) of methyl 2-bromo-9,10-dihydrolysergate is dissolved in a mixture of 18 ml of moda and 0.071 ml (1.1 mmol) of meithansulfonic acid, 1 g of urea is added and 15 ml of 68% nitric acid, cooled to 0 ° C, are added with stirring and cooling. The reaction mixture is then stirred for 4.5 minutes while cooling to 15 DEG C. and then poured into a mixture of 50 g of ice, 15 ml of concentrated aqueous ammonia and 50 ml of chloroform. The organic phase is separated, the aqueous is extracted with 2 X -X 50 ml of chloroform. The combined organic phases are dried freely. sodium sulfate and evaporated. The residue was crystallized from ethyl acetate and the precipitated material was purified by 2 x silica gel chromatography (eluent: chloroform, containing 0.2% triethylamine). Qualitatively identical fractions were combined, filtered and evaporated and the residue was crystallized from ethyl acetate. Ttk of 175 mig (43% of theory) of golden yellow methyl 2-broim-9,10-dihydro-13,11-nitrolysergate, m.p. -t. 255-258 Q C.
Příklad 2Example 2
Do roztoku 690 mg (1,645 mmol-u) 2-bromterguridu a 250 mg (1,67 mmolů) kyseliny vinné v- 75 ml vody se přidá 1,0 g močoviny a směs se ochladí na 5 °C. Pak se za míchání a chlazení přidá 50 ml 68% kyseliny dusičné, ochlazené na 5 °C a vzniklá reakční -směs se míchá 4,5 minuty. Zpracováním re-akční směsi podle příkladu 1 se po 3násob-né chromatogra-fii a krystalizací z ethanolu -získá 250 mg (33 %) žlutého 2-brom-13-nitroterguridu,, t.1. 157 až 160 °C.To a solution of 690 mg (1.645 mmol) of 2-bromo-terburide and 250 mg (1.67 mmol) of tartaric acid in 75 ml of water was added 1.0 g of urea and the mixture was cooled to 5 ° C. 50 ml of 68% nitric acid, cooled to 5 DEG C., are then added with stirring and cooling, and the resulting reaction mixture is stirred for 4.5 minutes. Workup of the reaction mixture of Example 1 yielded 250 mg (33%) of yellow 2-bromo-13-nitroterguride after 3 fold chromatography and crystallization from ethanol. Mp 157-160 ° C.
Β 2 1 4 81 2 1 4 7
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS877733A CS262148B1 (en) | 1987-10-28 | 1987-10-28 | 2-brom-13-nitroderivatives of ergoline and process for preparing them |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS877733A CS262148B1 (en) | 1987-10-28 | 1987-10-28 | 2-brom-13-nitroderivatives of ergoline and process for preparing them |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS773387A1 CS773387A1 (en) | 1988-07-15 |
| CS262148B1 true CS262148B1 (en) | 1989-02-10 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS877733A CS262148B1 (en) | 1987-10-28 | 1987-10-28 | 2-brom-13-nitroderivatives of ergoline and process for preparing them |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS262148B1 (en) |
-
1987
- 1987-10-28 CS CS877733A patent/CS262148B1/en unknown
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| Publication number | Publication date |
|---|---|
| CS773387A1 (en) | 1988-07-15 |
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