CS248744B2 - Production method of the d(-)-alpha-aminobenzylphenicilin derivates - Google Patents
Production method of the d(-)-alpha-aminobenzylphenicilin derivates Download PDFInfo
- Publication number
- CS248744B2 CS248744B2 CS853802A CS380285A CS248744B2 CS 248744 B2 CS248744 B2 CS 248744B2 CS 853802 A CS853802 A CS 853802A CS 380285 A CS380285 A CS 380285A CS 248744 B2 CS248744 B2 CS 248744B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- formula
- molecule
- chloride
- water
- aminobenzylphenicilin
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 2
- UKXSKSHDVLQNKG-UHFFFAOYSA-N benzilic acid Chemical compound C=1C=CC=CC=1C(O)(C(=O)O)C1=CC=CC=C1 UKXSKSHDVLQNKG-UHFFFAOYSA-N 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- -1 alkali metal salt Chemical class 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Description
Způsob podíle vynálezu spočívá v tom, že se kandenzuje sůl D( — j-anamjmiDberazylpeinieiliinu obecného vzorce IIThe process according to the invention consists in the cande [not]
kdewhere
X znamená molekulu chlorovodíku nebo trieithyliaimiirat s chloridem vzorce IIIX represents a hydrogen chloride molecule or a triethylium imirate with a chloride of formula III
(III)(III)
V případě, že X znamená molekulu chlorovodíku, provádí se kondenzace v rozpouštědle, místtelném s Modlou, například dloixanu, teitnaihydrofuinainu nebo acetonu, s výhodou ve $měsi vody a acetonu při teplioitě —10 až 4-10 °C. V případě, že X znamená molekulu -triethylaimiinu, provádí se kondenzace, v rozpouštědle, nemísitelném s vodou, naipřfklad v methylenchloridu, chloroformu, toluenu nebo xylenu v teplotním rozimezí —10 až +10 °C.In the case where X is a hydrogen chloride molecule, condensation is carried out in a Model-stable solvent, for example dloixan, teitinhydrofuinain or acetone, preferably in a mixture of water and acetone at a temperature of -10 to 4-10 ° C. In the case where X is a triethylaimine molecule, the condensation is carried out in a water-immiscible solvent, for example in methylene chloride, chloroform, toluene or xylene, in the temperature range of -10 ° C to + 10 ° C.
Obě výchozí látky, D(—j-^aminobenzylpenicilin la 4-e.t!hyl-2,3-dioxoipiperazi'.nylkairboinylchloiřid jisou známé sloučeniny, které se běžně dodávají.;Both the starting materials, D (^ -J- aminobenzylpenicillin et la 4-! Hyl-2,3-oxytocic nylchloiřid dioxoipiperazi'.nylkairbo well known compounds which are commercially available .;
Podle známých způsobů se deriváty D(—)-cťJ-aiminioibenJzylpeniciliinu vzorce I připravovaly kondenzací soli D( — )-a-aminobenzylpeniciliinujampiiícilinu) s alkalickým kovem а 4-е,1Ьу1-2,3-diio^oplperaziinylkairboinylchloridu vzorce III ve vodném proistředí. V nevod ných prostředích· dochází ke kondenzaci’ mezi silylojvainou formou D[ —)-a-iaimiiniobeinzyípeiniciildinu vzorce II a 4-ethyl-2,3-dlox opípeirazinylkarbeiny Ichlioirid u vzore e III, jak bylo popsáno v publikaci Yakugaku Zasshíi 97 (9), 980—-986 (1977).According to known methods, the D (-) -? -? In non-aqueous environments, condensation occurs between the silyl form of the D [-] - α-α-β-aminobenzylpiperidine of formula II and the 4-ethyl-2,3-dlox opirazinylcarbines Ichlioirid in model III as described in Yakugaku Zasshi 97 (9) , 980-986 (1977).
Vynález se liší od známých způsobů tím, že v příjpadě reakce ve vodném prostředí se užije hydrochlorid Dj — )-c^-aminobenzy,l248744 a popřípadě se takto získaná sloučenina vzorce I převede na některou ze svých solí, přijiatelmou z fairmaceutického hlediska.The present invention differs from the known methods in that, in the case of an aqueous reaction, the N 1 -? -?
penicilinu ' místo soli této ílátky s alkalickým kovem.penicillin 'instead of the alkali metal salt of this substance.
V případě reakce v rozpouštědlech, nemísite-ných s vodou, tj. v případech, že · X znamená molekulu trieithyliam-inu, není zapotřebí užít silylovanou formu · D( — )-a-arnn-obenzylpeniclímu, postačí tuto látku pouze rozpustit v triethyiiarninu. Protože se vypouští silylační stupeň, je způsob podle vynálezu daleko hospodárnější a datoko přijatelnější z hlediska čistoty okolního prostředí, protože v odpadní vodě nedochází k výskytu sillaniolů.In the case of reaction in water-immiscible solvents, i.e., when X is a trieithyliamine molecule, it is not necessary to use the silylated form of D (-) -? - amine-obenzylpeniclim, it only needs to be dissolved in triethylamine . Since the silylation step is omitted, the process according to the invention is far more economical and datocompatible in terms of environmental purity, since sillaniols do not occur in the waste water.
Výtěžky jsou· velmi vyspké, surový produkt je· chromatoigiraficlky čistý, takže náklady na čištění jsou podstatně sníženy.The yields are very high, the crude product is chromatographically pure, so that the purification costs are substantially reduced.
Vynález bude osvětlen následujícími příklady.The invention will be illustrated by the following examples.
Příklad 1Example 1
Sodná sůl kyseliny 6-[D,(— )-a-4-ethy^^]^-^2,3-dlOιχOil-piperιaziιnylkmbbxamidoiíenylac· etamido ] pě nic · liánové g ampiciiintTlhydrátu v suspenzi ve 40 mililitrech vody se rozpustí v koncentrovaném roztoku chlorovodíku. Takto získaný roztok se zředí 250 ml acetonu, zchladí se na teplotu —10 °C a piaík se začnou přidávat 2 g 4-e^thyl-^2,,í^^d^^^c^Kio-:-p^-iípea^az2^i-^yllkíw^^^onylchtaridu v roztoku· v 50 ml acetonu po jednotlivých kapkách. · Směs se ještě hodinu míchá při teplotě —10 °C, načež, se· přidáSodium salt of 6- [D, (-) -? - 4-ethyl-4- [2,3-d] -piperazin-4-yl] -benzamido-phenylamino-ethanido] -pentanoic acid ampicillin hydrate in suspension in 40 ml of water is dissolved in a concentrated solution hydrogen chloride. The solution thus obtained is diluted with 250 ml of acetone, cooled to -10 DEG C. and 2 g of 4-ethyl-2,4-dihydrochloride are added. The solution was dissolved in 50 ml of acetone dropwise. The mixture was stirred for an additional hour at -10 ° C and then added
1,6 g ly^^d^i^geenl^flliiičtti^r^u «sodného v roztoku ve 40 ml vody. Pak se upraví pH zbývajjcííha roztoku po odpaření acetonu za· sníženého tlaku na hodnotu 7,5 přidáním· hydrogeinuhličitanu seodného Získaný roztok se promyje 40 ml methylenchloridu a pH vodné vrstvy se upraví na hodnotu 2· · přidáním 2N · roztoku chlorovodíku. Po 2-hodinovém si^.-íiní se vzniklá sraženina oddělí filtrací -a piromyje se vodou. Tímto, způsobem se ve ^výtěžku 66 % získá celkem 3,4 g volné · kyseliny, která se počíná rozkládat při teplotě 160· °C. Vznikne sraženina, která· se uvede· db suspenze ve· vodě· a piaík se rozpustí přidáním ekvivalentního množství hydrogenuihličltlanu sodného, načež se výsledný materiá- lyofilizuje Takto získaný produkt je · vhodný pro farmaceutické použití.1.6 g of sodium dihydrogen chloride in solution in 40 ml of water. Then the pH of the remaining solution is adjusted to 7.5 with acetone under reduced pressure by addition of sodium hydrogen carbonate. After 2 hours, the resulting precipitate was collected by filtration and treated with water. In this way, a total of 3.4 g of free acid is obtained in a yield of 66%, which begins to decompose at 160 ° C. A precipitate is formed which is suspended in water and dissolved by addition of an equivalent amount of sodium bicarbonate, and the resulting material is then freeze-dried.
Příklad 2Example 2
Sodná sůl kyseliny 6-[D( — )-«-(4-ethy)l-2,3-dioxo-1-piperaztoykkarooaamidoijf enylac etamddio ] peniic HaniovéSodium salt of 6- [D (-) - N - (4-ethyl) -1,3,3-dioxo-1-piperazto-cyclohexanediophenylacetamethyldio] peniic Haniic acid
3,5 g bezvodého· amwpicilinu se uvede· do suspenze ve 35 · ml methylenchloridu a pak se materiál· převede· do* roztoku přidáním 2,8 mililitrů triethylaminu. Získaný roztok se zchladí na teplotu —10 °C a pak se· po jednotlivých kapkách počnou přidávat 2 g 4-et^h^yl-^Z.S-idcox^-0l-^^ij^ι^^ea^il^]^l^l^йaгbonylchl^>ori' · du, rozpuštěného· ve 20 ml methylenchloridu. Reakční roztok se ještě hodinu míchá při teplotě —10 °C, načež se přidá · 100 ml vody a pH vodné vrstvy se upraví na hodnotu 7,5, vrstvy se· oddělí /a. pH· vodné vrstvy se upraví na hodnotu 2 přidáváním 2N roztoku chlorovodíku. Vznikne sraženina, která se oddělí filtrací a promyje· se· vodou. Tímto způsobem» se ve výtěžku 82: % získá3.5 g of anhydrous ampicillin are suspended in 35 ml of methylene chloride and then the material is brought into solution by the addition of 2.8 ml of triethylamine. The solution obtained is cooled to -10 DEG C. and then 2 g of 4-ethyl-4-ethyl-1H-idcox-4-ol are added dropwise thereto. l ^ l ^ ^ йaгbonylchl> ori '· du dissolved in 20 · ml of methylene chloride. The reaction solution was stirred at -10 ° C for an additional hour, then 100 ml of water was added and the pH of the aqueous layer was adjusted to 7.5, the layers were separated. The pH of the aqueous layer was adjusted to 2 by addition of 2N hydrogen chloride solution. A precipitate formed which was collected by filtration and washed with water. A yield of 82% was obtained
4,3 g chrornatograílcky volné kyseli- ny. Takto získaná látkia se převede na svou sodnou sůl stejným způsobem jako v příkladu 1.4.3 g of chromium-free acid. The material thus obtained is converted to its sodium salt in the same manner as in Example 1.
Claims (3)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU926/84A YU43570B (en) | 1984-05-30 | 1984-05-30 | Process for preparation of derivatives of d()alpha-amino-benzile-penicilyns |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS248744B2 true CS248744B2 (en) | 1987-02-12 |
Family
ID=25552027
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS853802A CS248744B2 (en) | 1984-05-30 | 1985-05-27 | Production method of the d(-)-alpha-aminobenzylphenicilin derivates |
Country Status (4)
| Country | Link |
|---|---|
| CS (1) | CS248744B2 (en) |
| DD (1) | DD237166A5 (en) |
| PL (1) | PL253585A1 (en) |
| YU (1) | YU43570B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BG46664A1 (en) * | 1985-08-16 | 1990-02-15 | Druzhestven N Izsledovatelski | Method for preparing of 6- /d (-)- alpha- (4- ethyl- 2, 3- dioxo- 1- piperazine carbonylamino)- phenylacetamido/- penicillanic acid |
| JP5173842B2 (en) * | 2007-01-31 | 2013-04-03 | 富山化学工業株式会社 | Novel crystals of piperacillin sodium |
-
1984
- 1984-05-30 YU YU926/84A patent/YU43570B/en unknown
-
1985
- 1985-05-24 PL PL25358585A patent/PL253585A1/en unknown
- 1985-05-27 CS CS853802A patent/CS248744B2/en unknown
- 1985-05-29 DD DD85276751A patent/DD237166A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| YU92684A (en) | 1986-10-31 |
| DD237166A5 (en) | 1986-07-02 |
| YU43570B (en) | 1989-08-31 |
| PL253585A1 (en) | 1986-02-25 |
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