CS265559B1 - Process for preparing 2-ethyl-3-/3,5-dibrom-4-hydroxybenzoyl/cumarone - Google Patents
Process for preparing 2-ethyl-3-/3,5-dibrom-4-hydroxybenzoyl/cumarone Download PDFInfo
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- CS265559B1 CS265559B1 CS873177A CS317787A CS265559B1 CS 265559 B1 CS265559 B1 CS 265559B1 CS 873177 A CS873177 A CS 873177A CS 317787 A CS317787 A CS 317787A CS 265559 B1 CS265559 B1 CS 265559B1
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- Czechoslovakia
- Prior art keywords
- ethyl
- hydroxybenzoyl
- coumarone
- dibromo
- stirred
- Prior art date
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- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000004519 manufacturing process Methods 0.000 title 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 10
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000031709 bromination Effects 0.000 claims abstract description 4
- 238000005893 bromination reaction Methods 0.000 claims abstract description 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000012429 reaction media Substances 0.000 claims description 4
- -1 hydroxybenzoyl Chemical group 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 239000003383 uricosuric agent Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 3
- WHQCHUCQKNIQEC-UHFFFAOYSA-N benzbromarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(Br)=C(O)C(Br)=C1 WHQCHUCQKNIQEC-UHFFFAOYSA-N 0.000 description 2
- 229960002529 benzbromarone Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- YUTFQTAITWWGFH-UHFFFAOYSA-N 1-(1-benzofuran-2-yl)ethanone Chemical compound C1=CC=C2OC(C(=O)C)=CC2=C1 YUTFQTAITWWGFH-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000003424 uricosuric effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Řešení se týká bromace 2-ethyl-3-(4'- -hydroxybenzoyl)kumaronu v přítomnosti alkalického činidla, zejména triethylaminu, ethanolaminu nebo práškovitého hydroxidu sodného, kdy vzniklý 2-ethyl-3-(3',5'-dibrom-4-hydroxybenzoyi)kumaronu je zcela čistý. Získaný produkt se používá jako urikosurikum.The solution relates to the bromination of 2-ethyl-3- (4'- -hydroxybenzoyl) coumarone in the presence an alkaline agent, especially triethylamine, ethanolamine or powdered hydroxide sodium when the 2-ethyl-3- (3 ', 5'-dibromo-4-hydroxybenzoylamino) coumarone formed is completely net. The product obtained is used as uricosuricum.
Description
Vynález se týká způsobu přípravy 2-ethyl-3-(3',5'-dibrom-4-hydroxybenzoyl)kumaronu (benzbromaronu), vzorec (I), který se používá jako léčivo s urikosurickým účinkem.The invention relates to a process for the preparation of 2-ethyl-3- (3 ', 5'-dibromo-4-hydroxybenzoyl) coumarone (benzbromarone), formula (I), which is used as a medicament with uricosuric action.
(I)(AND)
V literatuře (Belg. pat. 553 621, HU T 018 236, HU T 024 005) popsaná příprava preparátu spočívá v několikastupňové syntéze vycházející z 2-acetylkumaronu a salicylaldehydu. Největší úskalí všech uvedených způsobů přípravy benzbromaronu spočívá v posledním stupni syntézy a to v brcnaci 2-etliyl-3-(4-hydroxybenzoyl)kumaronu. V uvedené patentové literatuře je popsáno provedeni bromace v různém reakčním prostředí, avšak při reprodukci těchto postupů se vždy připraví produkt, který dle chromatografie na tenké vrstvě obsahuje nežádoucí 2-ethyl-3-(3'-brom-4-hydroxybenzoyl)kumaron, který ani několikanásobnou krystalizací prakticky nelze zcela odstranit.The preparation of the preparation described in the literature (Belg. Pat. 553 621, HU T 018 236, HU T 024 005) consists of a multi-step synthesis starting from 2-acetylcoumarone and salicylaldehyde. The greatest drawback of all the above-mentioned processes for the preparation of benzbromarone lies in the last stage of the synthesis, namely in the bramation of 2-ethyl-3- (4-hydroxybenzoyl) coumarone. In the patent literature, bromination in a different reaction medium is described, but in reproducing these processes, a product is always prepared which, according to thin-layer chromatography, contains the undesired 2-ethyl-3- (3'-bromo-4-hydroxybenzoyl) coumarone which even by multiple crystallizations it is practically impossible to remove completely.
Uvedenou nevýhodu odstraňuje způsob přípravy 2-ethyl-3-(3' , 5'-dibrom-4'-hydroxybenzoyl)kumaronu reakcí 2-ethyl-3-(4-hydroxybenzoyl)kumaronu s bromem podle vynálezu, jehož podstata spočívá v tom, že se bromace 2-ethyl-3-(4'-hydroxybenzoyl)kumaronu provádí za přítomností alkalického činidla při pH 6 až 7, načež se získaný 2-ethyl-3-(3',5'-dibrom-4'-hydroxybenzoyl)kumaron oddělí, promyje methanolem a vymichá s vodou. Znovu odstátý produkt se překrystaluje z toluenu.This disadvantage is overcome by the process for the preparation of 2-ethyl-3- (3 ', 5'-dibromo-4'-hydroxybenzoyl) coumarone by reacting 2-ethyl-3- (4-hydroxybenzoyl) coumarone with bromine according to the invention. by brominating 2-ethyl-3- (4'-hydroxybenzoyl) coumarone in the presence of an alkaline agent at pH 6-7, followed by 2-ethyl-3- (3 ', 5'-dibromo-4'-hydroxybenzoyl) obtained the coumarone is separated, washed with methanol and rinsed with water. The recovered product is recrystallized from toluene.
Způsob podle vynálezu se výhodně provádí tak, že bromace 2-ethyl-3-(4'-hydroxybenzoyl)kumaronu probíhá za přítomnosti alkalického činidla rozpustného v reakčním prostředí, zejména triethylaminu nebo ethanolaminu nebo práškového hydroxidu sodného.The process according to the invention is preferably carried out by brominating 2-ethyl-3- (4'-hydroxybenzoyl) coumarone in the presence of an alkaline reagent soluble in the reaction medium, in particular triethylamine or ethanolamine or powdered sodium hydroxide.
Hlavní předností způsobu podle vynálezu je snadné provedení reakce přidáním alkalického činidla rozpustného v reakčním prostředí a docílení posunutí reakční rovnováhy ve prospěch žádaného produktu. Při kontrole čistoty produktu chromatografií na tenké vrstvě v soustavě CHClg-CHgOH-25%NHg 4:1:0,05 byla vždy nalezena jednotná látka, což má zvláště velký význam při přípravě léčiv.The main advantage of the process according to the invention is that the reaction can be carried out easily by adding an alkaline reagent soluble in the reaction medium and achieving a shift of the reaction equilibrium in favor of the desired product. When checking the purity of the product by thin layer chromatography in a system of CHCl g g -CH-OH 25 g% NH 4: 1: 0.05 was always found in a uniform material, which is of particular importance in the preparation of medicaments.
Způsob podle vynálezu se provádí tak, že se k 2-pthyl-3-(4'-hydroxybenzoyl)kumaronu, rozpuštěnému v methanolu, přidá alkalické činidlo a při teplotě místnosti (20 až 25 °C) se přikape brom. Po následném ochlazení reakční směsi a jejím míchání se odsaje krystalická látka, která se promyje methanolem, vymichá s vodou a překrystaluje z toluenu. Získá se zcela čistý produkt.The process according to the invention is carried out by adding an alkaline reagent to 2-ethyl-3- (4'-hydroxybenzoyl) coumarone dissolved in methanol and adding bromine dropwise at room temperature (20-25 ° C). After cooling the reaction mixture and stirring, the crystalline substance is filtered off with suction, washed with methanol, washed with water and recrystallized from toluene. A completely pure product is obtained.
Příklad 1Example 1
62,0 g 2-ethy1-3-(4'-hydroxybenžoyl)kumaronu (obsah 100 % dle GLC) se rozpustí v 372 ml methanolu při laboratorní teplotě. K čirému roztoku se přidá 52,5 g triethylaminu a za intenzivního míchání se přikape 83 g bromu při teplotě do 30 °C a po přikapáni se reakční směs míchá ještě 2 h, pH reakční směsi je 6,5. Potom se reakční směs ochladí na 10 °C a při této teplotě se míchá ještě 1 h. Vyloučená krystalická látka se odsaje, promyje 30 ml vychlazeného methanolu. Krystalická látka se rozmíchá vil vody, míchá se 1 h a znovu se odsaje.62.0 g of 2-ethyl-3- (4'-hydroxybenzoyl) coumarone (content 100% by GLC) are dissolved in 372 ml of methanol at room temperature. 52.5 g of triethylamine are added to the clear solution and 83 g of bromine are added dropwise with vigorous stirring at a temperature of up to 30 [deg.] C. and after the dropwise addition the reaction mixture is stirred for a further 2 h. The reaction mixture was then cooled to 10 ° C and stirred at this temperature for 1 h. The precipitated crystalline solid was filtered off with suction, washed with 30 ml of cold methanol. The crystalline substance is stirred with 1 l of water, stirred for 1 h and sucked off again.
Po vysušeni se čistí krystalizací z toluenu (175 ml). Získá se 70,5 g produktu (85,5 % th. na kryst., 71,4 % th. na výchozí produkt^ o t.t. 151 až 152,5 °C.After drying, it was purified by crystallization from toluene (175 ml). 70.5 g of product are obtained (85.5% th. On crystals, 71.4% th. On starting product, m.p. 151-152.5 ° C).
Příklad2Example2
24,5 g 2-ethyl-3-(4'-hydroxybenzoyl)kumaronu (obsah 100 % dle GLC) se rozpustí ve 250 ml methanolu a přidá se za mícháni 8,1 g práškového hydroxidu sodného, přičemž teplota vystoupila na 40 °C. Po ochlazení na 20 °C se přikape 32,8 g bromu při reakční teplotě 30 °C a po přikapáni se ještě 2 h míchá, pH reakční směsi 7. Reakční směs se ochladí na 10 °C a při této teplotě se míchá ještě 1 h. Vyloučená krystalická látka se rozmíchá v 400 ml vody, míchá se 1 h a znovu se odsaje. Po krystalizaci z toluenu se získá 17,5 g produktu (70 % th.) o t.t. 151 až 152,5 °C.24.5 g of 2-ethyl-3- (4'-hydroxybenzoyl) coumarone (GLC content 100%) are dissolved in 250 ml of methanol and 8.1 g of powdered sodium hydroxide are added with stirring, the temperature rising to 40 ° C. . After cooling to 20 ° C, 32.8 g of bromine are added dropwise at a reaction temperature of 30 ° C and stirring is continued for 2 hours, the pH of the reaction mixture 7. The reaction mixture is cooled to 10 ° C and stirred at this temperature for 1 hour. The precipitated crystalline substance is stirred in 400 ml of water, stirred for 1 h and filtered off with suction again. After crystallization from toluene, 17.5 g (70%) of the product are obtained. 151-152.5 ° C.
Příklad 3Example 3
24,5 g 2-ethyl-3-(4'-hydroxybenzoyl)kumaronu (obsah 100 % dle GLC) se rozpustí ve 150 ml methanolu a přidá se za míchání 12,52 g ethanolaminu, přičemž teplota vystoupila na 30 °C.24.5 g of 2-ethyl-3- (4'-hydroxybenzoyl) coumarone (100% content by GLC) are dissolved in 150 ml of methanol and 12.52 g of ethanolamine are added with stirring, raising the temperature to 30 ° C.
Po ochlazení na 16 °C se přikape 32,8 g bromu při reakční teplotě 20 až 30 °C a po přikapání se míchá ještě 6 h, pH reakční směsi 6,5. Po ochlazení na 10 °C se míchá ještě 1 h. Vyloučená krystalická látka se rozmíchá v 400 ml vody, míchá se 1 h a znovu se odsaje. Po krystalizaci z toulenu se získá 19,1 g produktu (76,4 %) o t.t. 151 až 152,5 °C.After cooling to 16 ° C, 32.8 g of bromine are added dropwise at a reaction temperature of 20 to 30 ° C, and stirring is continued for 6 hours, the pH of the reaction mixture being 6.5. After cooling to 10 ° C, it is stirred for a further 1 h. The precipitated crystalline material is stirred in 400 ml of water, stirred for 1 h and suctioned off again. After crystallization from toluene, 19.1 g of product (76.4%) of m.p. 151-152.5 ° C.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS873177A CS265559B1 (en) | 1987-05-05 | 1987-05-05 | Process for preparing 2-ethyl-3-/3,5-dibrom-4-hydroxybenzoyl/cumarone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS873177A CS265559B1 (en) | 1987-05-05 | 1987-05-05 | Process for preparing 2-ethyl-3-/3,5-dibrom-4-hydroxybenzoyl/cumarone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS317787A1 CS317787A1 (en) | 1989-02-10 |
| CS265559B1 true CS265559B1 (en) | 1989-10-13 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS873177A CS265559B1 (en) | 1987-05-05 | 1987-05-05 | Process for preparing 2-ethyl-3-/3,5-dibrom-4-hydroxybenzoyl/cumarone |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS265559B1 (en) |
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1987
- 1987-05-05 CS CS873177A patent/CS265559B1/en unknown
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| Publication number | Publication date |
|---|---|
| CS317787A1 (en) | 1989-02-10 |
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