CS263293B1 - Method of 1-amino-2,6-dimethylpiperidine's cleaning prepared by reduction of 1-nitroso-2-6-dimethylpiridine - Google Patents
Method of 1-amino-2,6-dimethylpiperidine's cleaning prepared by reduction of 1-nitroso-2-6-dimethylpiridine Download PDFInfo
- Publication number
- CS263293B1 CS263293B1 CS874735A CS473587A CS263293B1 CS 263293 B1 CS263293 B1 CS 263293B1 CS 874735 A CS874735 A CS 874735A CS 473587 A CS473587 A CS 473587A CS 263293 B1 CS263293 B1 CS 263293B1
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- CS
- Czechoslovakia
- Prior art keywords
- dimethylpiperidine
- amino
- reduction
- nitroso
- crude
- Prior art date
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- UAHWWAIVYPJROV-UHFFFAOYSA-N 2,6-dimethylpiperidin-1-amine Chemical compound CC1CCCC(C)N1N UAHWWAIVYPJROV-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims abstract description 7
- 238000004140 cleaning Methods 0.000 title 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000000746 purification Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 4
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000342 sodium bisulfate Inorganic materials 0.000 claims description 2
- 150000004682 monohydrates Chemical class 0.000 claims 1
- SDGKUVSVPIIUCF-UHFFFAOYSA-N 2,6-dimethylpiperidine Chemical compound CC1CCCC(C)N1 SDGKUVSVPIIUCF-UHFFFAOYSA-N 0.000 abstract description 9
- UAHWWAIVYPJROV-KNVOCYPGSA-N (2r,6s)-2,6-dimethylpiperidin-1-amine Chemical compound C[C@H]1CCC[C@@H](C)N1N UAHWWAIVYPJROV-KNVOCYPGSA-N 0.000 abstract description 3
- LBXHRAWDUMTPSE-UHFFFAOYSA-N 4-chloro-N-(2,6-dimethyl-1-piperidinyl)-3-sulfamoylbenzamide Chemical compound CC1CCCC(C)N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 LBXHRAWDUMTPSE-UHFFFAOYSA-N 0.000 abstract description 2
- LBXHRAWDUMTPSE-AOOOYVTPSA-N 4-chloro-N-[(2S,6R)-2,6-dimethyl-1-piperidinyl]-3-sulfamoylbenzamide Chemical compound C[C@H]1CCC[C@@H](C)N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 LBXHRAWDUMTPSE-AOOOYVTPSA-N 0.000 abstract description 2
- 229960004070 clopamide Drugs 0.000 abstract description 2
- 239000002934 diuretic Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract description 2
- JXHZRQHZVYDRGX-UHFFFAOYSA-M sodium;hydrogen sulfate;hydrate Chemical compound [OH-].[Na+].OS(O)(=O)=O JXHZRQHZVYDRGX-UHFFFAOYSA-M 0.000 abstract description 2
- 229940030606 diuretics Drugs 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- WVMOOXDUBUXKDW-DTORHVGOSA-N CC[C@H]1CCC[C@H](N1N)CC Chemical compound CC[C@H]1CCC[C@H](N1N)CC WVMOOXDUBUXKDW-DTORHVGOSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000020055 borovička Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- -1 lithium aluminum hydride Chemical compound 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- XODPQKCXGFBFHX-UHFFFAOYSA-M sodium;hydrogen sulfite;hydrate Chemical compound O.[Na+].OS([O-])=O XODPQKCXGFBFHX-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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- Hydrogenated Pyridines (AREA)
Abstract
l-amino-cis-2,6-dimethylpiperidin je klíčovým meziproduktem výroby diuretika Clopamidu (4-ohlor-N-(cis-2,6-dimethylpiperidino)-3-sulfamoylbenzamidu). Řešení se týká čistění surového l-amino-2,6- -dimethylpiperidinu po redukci 1-nitroso- . -2,6-dimethylpiperidinu znečištěného 2,6-dimethylpiperidinem. Působením ekvivalentu hydrogensíranu sodného monohydrátu nebo bezvodého (vztaženo na množství přítomného 2,6-dimethylpiperidinu) na bezvodý roztok surové směsi po redukci v diethyletheru se vytvoří adukt s 2,6- -dimethylpiperidinem, který se odstraní. Metoda je pro vysoké výtěžky, kvalitu produktu a jednoduchost provedení velmi vhodná pro provozní použití.1-amino-cis-2,6-dimethylpiperidine is a key intermediate in the production of diuretics Clopamide (4-chloro-N- (cis-2,6-dimethylpiperidino) -3-sulfamoylbenzamide). Solution relates to the purification of crude 1-amino-2,6- -dimethylpiperidine after reduction of 1-nitroso-. -2,6-dimethylpiperidine contaminated 2,6-dimethylpiperidine. Equivalent sodium bisulfate monohydrate or anhydrous (based on quantity 2,6-dimethylpiperidine) anhydrous crude mixture solution after reduction in diethyl ether, adduct with 2,6- -dimethylpiperidine, which is removed. The method is for high yields, quality product and simplicity of design very suitable for operational use.
Description
Vynález se týká l-amino-cis-2,6-dimethylpiperidinu, který je jednou z klíčových komponent přípravy 4-chlor-N-(cis-2,6-dimethylpiperidino)-3-sulfamoylbenzamidu. Tato látka se používá pod generickým názvem Clopamid ve farmacii jako diuretikum a je vyráběna také v ČSSR.The invention relates to 1-amino-cis-2,6-dimethylpiperidine which is one of the key components of the preparation of 4-chloro-N- (cis-2,6-dimethylpiperidino) -3-sulfamoylbenzamide. This substance is used under the generic name Clopamide in pharmacy as a diuretic and is also produced in Czechoslovakia.
V literatuře je popsáno několik způsobů přípravy l-amino-2,6-dimethylpiperidinu vždy redukčí příslužného 1-nitrosoderivátu. Základní údaje o přípravě uvedené látky popisují následující autoři.Several methods for preparing 1-amino-2,6-dimethylpiperidine have been described in the literature, each by reducing the corresponding 1-nitroso derivative. Basic data on the preparation of the substance are described by the following authors.
C. G. Overberger a kol. v J. Org. Chem. 22, 858 (1957) popisuji přípravu l-amino-2,6-dimethylpiperidinu redukcí dithioničitanem sodným (NajSjO^).C. G. Overberger et al. in J. Org. Chem. 22, 858 (1957) describes the preparation of 1-amino-2,6-dimethylpiperidine by reduction with sodium dithionite (Na 2 SO 4).
C. G. Overberger a kol. v J. Am. Chem. Soc. 77, 4 100, (1957) provádějí přípravu l-amino-2,6-dimethylpiperidinu redukcí tlihiumalumiňiumhydridem v etheru.C. G. Overberger et al. in J. Am. Chem. Soc. 77, 4 100, (1957) carry out the preparation of 1-amino-2,6-dimethylpiperidine by reduction with lithium aluminum hydride in ether.
E. Jucker a A. Lindenmann připravují l-amino-2,6-dimethylpiperidin redukcí zinkovým prachem ve zředěné kys. octové viz Helv. Chim. Acta 45 (7) 2 316 (1962) .E. Jucker and A. Lindenmann prepare 1-amino-2,6-dimethylpiperidine by reduction with zinc dust in dilute acetic acid, see Helv. Chim. Acta 45 (7) 2,316 (1962).
M. Londýn a M. Borovička v čs. AO 253 620 provádějí přípravu l-amino-2,6-dimethylpiperidinu rovněž redukcí zinkem ve zředěné kyselině octové a stejní autoři v čs. AO 253 243 připravují 1-amino-2,6-dimethylpiperidin redukci Synhydridem v toluenu.M. London and M. Borovička in MS. AO 253 620 performs the preparation of 1-amino-2,6-dimethylpiperidine also by reduction with zinc in dilute acetic acid and the same authors in Czechoslovakia. AO 253 243 prepare 1-amino-2,6-dimethylpiperidine by reduction with synhydride in toluene.
P. Taufmann, M. Londýn a M. Borovička v čs. AO 263 292 provádějí tutéž redukci kyselinou sírovou a zinkem.P. Taufmann, M. London and M. Borovička in MS. AO 263 292 perform the same reduction with sulfuric acid and zinc.
Izolovaný produkt všech těchto uvedených reakcí je čištěn, pokud je uvedeno, vždy rektifikaci, avšak parametry rektifikačnlch kolon pro tuto danou rektifikaci uvedeny nejsou.The isolated product of all of these reactions is purified, if indicated, by rectification, but the parameters of the rectification columns for that particular rectification are not listed.
Za pomoci GC-chromatografie bylo zjištěno, že v surovém produktu po redukci je přítomen vedle žádaného l-amino-cis-2,6-diwethylpiperidinu také 2,6-dimetylpiperidin, jehož množství podle použité metody redukce značně kolísá, avšak hraje při Čistění tohoto surového produktu rektifikaci klíčovou roli. Technologické zvládnutí této operace by si vyžádalo devizové investice při nákupu účinných provozních rektifikačnlch kolon, nehledě na jejich velkou energetickou spotřebu a nutnost kvalifikované obsluhy a údržby.By means of GC-chromatography, it was found that in the crude product after reduction, in addition to the desired 1-amino-cis-2,6-di-ethylpiperidine, 2,6-dimethylpiperidine is present in the crude product. raw product rectification key role. Technological mastery of this operation would require foreign exchange investment in the purchase of efficient operational rectification columns, despite their high energy consumption and the need for qualified operation and maintenance.
M. Londýn v čs. AO 253 898 popisuje čistění surového l-amino-2,6-dimethylpiperidinu znečistěného 2,6-dimethylpiperidinem na základě rozdílnosti hodnot disociačnlch konstant těchto látek. Tato medoha je velmi účinná a odstraňuje nežádoucí 2,6-dimethylpiperidin v dostatečné míře. Reakce je prováděna ve vodném prostředí látkami kyselé povahy. Nevýhodou tohoto postupu jsou relativně nízké výtěžky l-amino-2,6-dimethylpiperidinu a pak teké skutečnost, že se ve vodném prostředí, ve kterém je reakce prováděna, zvyšuje zastoupení trans-izomeru této látky, který je z hlediska další syntézy ve větší míře nežádoucí.M. London in MS. AO 253 898 describes the purification of crude 1-amino-2,6-dimethylpiperidine contaminated with 2,6-dimethylpiperidine on the basis of differences in the dissociation constants of these substances. This honey is very effective and removes undesirable 2,6-dimethylpiperidine to a sufficient degree. The reaction is carried out in an aqueous medium by substances of an acidic nature. The disadvantage of this process is the relatively low yields of 1-amino-2,6-dimethylpiperidine, and the fact that the trans-isomer of this compound is increased in the aqueous medium in which the reaction is carried out, which is to a greater extent for further synthesis. undesirable.
Tyto nevýhody řeší postup podle vynálezu, kdy se surový l-amino-2,6-dimethylpiperidin rozpustí v trojnásobném množství diethyletheru, přidá se hydrogensíran sodný monohydrát nebo bezvodý jemně rozmletý v množství ekvivalentním přítomnému 2,6-dimethylpiperidinu a za dobrého míchání se provádí reakce při teplotě 0 až 36 °C po dobu 0,5 až 5 hodin podle velikoeti násady. Pak se odfiltruje pevný nežádoucí adukt hydrogenslranu sodného s 2,6-dimethylpiperidinem a po zahuštění diethyletheru se získá žádaný l-amino-2,6-dimethylpiperidin velmi dobré kvality a výborném výtěžku.These disadvantages are solved by the process according to the invention, wherein the crude 1-amino-2,6-dimethylpiperidine is dissolved in a triple amount of diethyl ether, sodium bisulfate monohydrate or anhydrous finely divided in an amount equivalent to 2,6-dimethylpiperidine present is added and the reaction is carried out well. at 0 to 36 ° C for 0.5 to 5 hours depending on the size of the batch. The solid undesired adduct of sodium hydrogensulfate with 2,6-dimethylpiperidine is then filtered off, and after concentration of diethyl ether, the desired 1-amino-2,6-dimethylpiperidine of very good quality and excellent yield is obtained.
Tato metoda separace l-amino-2,6-dimethylpiperidinu je pro své vysoké výtěžky, kvalitu produktu a jednoduché provedení zvlášt vhodná pro provozní účely. Lze ji provádět v libovolných množstvích a neklade žádné nároky ha investice do zařízení.This method of separating 1-amino-2,6-dimethylpiperidine is particularly suitable for operational purposes due to its high yields, product quality and simple design. It can be made in any quantity and does not require any investment or investment in equipment.
Příklad «Example «
Ke směsi (50,0 g), obsahující 4,63 t 2,6-dimethylpiperidinu a 91,26 % l-amino-2,6-dimethyl piperidinu rozpuštěné v diethyletheru (150,0 ml) se přidá za míchání při 36 °C hydrogensiran sodný monohydrát (2,17 g) a míchá se po dobu 1 hodiny. Pak se susenze zfiltruje a filtrát zahustí ve vakuu. Produkt podle GC-chromatografie obsahuje 0,65 % nežádoucího 2,6-dimethylpiperidinu a 96,32 % l-amino-cis-2,6-dimethylpiperidinu. Výtěžek je 45 g.To a mixture (50.0 g) containing 4.63 t of 2,6-dimethylpiperidine and 91.26% of 1-amino-2,6-dimethyl piperidine dissolved in diethyl ether (150.0 mL) was added with stirring at 36 ° C sodium bisulfite monohydrate (2.17 g) and stir for 1 hour. The suspension is filtered and the filtrate is concentrated in vacuo. The product according to GC-chromatography contains 0.65% undesirable 2,6-dimethylpiperidine and 96.32% 1-amino-cis-2,6-dimethylpiperidine. Yield: 45 g.
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Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS874735A CS263293B1 (en) | 1987-06-25 | 1987-06-25 | Method of 1-amino-2,6-dimethylpiperidine's cleaning prepared by reduction of 1-nitroso-2-6-dimethylpiridine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS874735A CS263293B1 (en) | 1987-06-25 | 1987-06-25 | Method of 1-amino-2,6-dimethylpiperidine's cleaning prepared by reduction of 1-nitroso-2-6-dimethylpiridine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS473587A1 CS473587A1 (en) | 1988-06-15 |
| CS263293B1 true CS263293B1 (en) | 1989-04-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS874735A CS263293B1 (en) | 1987-06-25 | 1987-06-25 | Method of 1-amino-2,6-dimethylpiperidine's cleaning prepared by reduction of 1-nitroso-2-6-dimethylpiridine |
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| CS (1) | CS263293B1 (en) |
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1987
- 1987-06-25 CS CS874735A patent/CS263293B1/en unknown
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| Publication number | Publication date |
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| CS473587A1 (en) | 1988-06-15 |
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