CS256431B1 - Method of 1,2-bis-(3,5-dioxo-1-piperazinyl)-ethane production - Google Patents
Method of 1,2-bis-(3,5-dioxo-1-piperazinyl)-ethane production Download PDFInfo
- Publication number
- CS256431B1 CS256431B1 CS855245A CS524585A CS256431B1 CS 256431 B1 CS256431 B1 CS 256431B1 CS 855245 A CS855245 A CS 855245A CS 524585 A CS524585 A CS 524585A CS 256431 B1 CS256431 B1 CS 256431B1
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- dioxo
- piperazinyl
- bis
- formula
- urea
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 title abstract description 6
- GBLIGNUYGOFIKS-UHFFFAOYSA-N 4-[2-(3,5-dioxopiperazin-1-yl)ethyl]piperazine-2,6-dione Chemical compound C1C(=O)NC(=O)CN1CCN1CC(=O)NC(=O)C1 GBLIGNUYGOFIKS-UHFFFAOYSA-N 0.000 title abstract description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000004202 carbamide Substances 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 7
- 238000009835 boiling Methods 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical group ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000000079 pharmacotherapeutic effect Effects 0.000 description 1
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 1
- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical compound O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Řešení se týká způsobu výroby 1,2-bis- -/3,5-dioxo-l-piperazinyl/-ethanu. Podstata vynálezu spočívá v tom, že se titulární látka vyrábí působením močoviny na kyselinu ethylendiaminotetraootovou v prostředí, tvořeném látkou s relativní permitivitou 30 až 109 a teplotou varu 100 až 200 °C.The solution relates to a process for the production of 1,2-bis- - [3,5-dioxo-1-piperazinyl] -ethane. Essence of the invention is that it is titular the substance is produced by the action of urea on acid ethylenediaminotetraoot in the environment constituted by a substance with relative permittivity 30 to 109 and boiling at 100 to 200 ° C.
Description
Vynález se týká nového způsobu výroby l,2-bis-/3,5-dioxo-l-piperazinyl/-ethanu vzorce I xco-ch2 x ch2-co x The invention relates to a novel process for the preparation of 1,2-bis- (3,5-dioxo-1-piperazinyl) -ethane of the formula I x co-ch 2 x ch 2 -co x
HN N-CH2-CH2-N NH /1/.HN N-CH 2 -CH 2 -N NH / 1 /.
CO-CH2 Z CH2-COCO-CH 2 from CH 2 -CO
Látka vzorce I je svými kanceroterapeutickými účinky farmakologicky velmi zajímavou.The compound of formula I is pharmacologically very interesting in its pharmacotherapeutic effects.
Známé výrobní postupy vycházejí z kyseliny ethylendiaminotetraoctové. Na tuto látku se působí formamidem, močovinou nebo karbamátem ethylnatým. Reakce se provádí při teplotě 160 až 170 °C. Uvedené postupy mají řadu nevýhod. Základní nevýhoda syntézy z formamidu spočívá v tom, že formamidu se používá znač ný nadbytek a tím rostou výrobní náklady. Dalším nedostatkem je poměrně velká rozpustnost produktu vzorce I ve formamidu, čímž se snižuje výtěžek. Výroba z močoviny sice tyto problémy řeší, ale na druhé straně tato reakce neposkytuje produkt požadované čistoty. Syntéza se provádí v tavenině. Výroba z karbamátu je z hlediska hygieny a bezpečnosti práce velmi náročná, nebol výchozí látkou pro syntézu karbamátu je fosgen.Known manufacturing processes are based on ethylenediaminotetraacetic acid. This substance is treated with formamide, urea or ethyl carbamate. The reaction is carried out at a temperature of 160-170 ° C. These processes have a number of disadvantages. The basic disadvantage of the synthesis from formamide is that formamide is used in a considerable excess and thus increases production costs. Another drawback is the relatively high solubility of the product of formula I in formamide, thereby reducing the yield. Urea production solves these problems, but on the other hand, this reaction does not provide the product of the desired purity. The synthesis is carried out in the melt. The manufacture of carbamate is very demanding in terms of hygiene and safety at work, since the starting material for the synthesis of carbamate is phosgene.
Uvedené nedostatky odstraňuje postup podle předkládaného vynálezu. Podle vynálezu se diketopiperazin vzorce I připravuje z močoviny a kyseliny ethylendiaminotetraoctové v prostředí látky, mající relativní permitivitu 30-109, s teplotou varu 100 až 200 °G, jako je například 1,2-propylenglykol, 1,3-propylenglykol, gl.ycerol, nebo směsi uvedených rozpouštědel s vodou, při teplotě 80 až 200 °G. Tímto postupem se připraví látka vzorce I v čistém stavu a izoluje se filtrací. Další výhodou výroby lát258 431 ky vzorce I podle vynálezu je nízká technické náročnost na zařízení a poměrně malá pracnost.These drawbacks are overcome by the process of the present invention. According to the invention, diketopiperazine of formula I is prepared from urea and ethylenediaminotetraacetic acid in a medium of a substance having a relative permittivity of 30-109, with a boiling point of 100 to 200 ° C, such as 1,2-propylene glycol, 1,3-propylene glycol, glycerol. or a mixture of said solvents with water at a temperature of 80 to 200 ° C. In this way, the compound of formula I is prepared in pure form and isolated by filtration. A further advantage of the preparation of the compounds of formula (I) according to the invention is the low technical complexity of the apparatus and the relatively low labor intensity.
Vynález je blíže osvětlen na následujících příkladech.The invention is illustrated by the following examples.
Příklad 1Example 1
Do 2 000 ml trojhrdlé baňky, opatřené míchadlem, teploměrem, chladičem a topným hnízdem, bylo naváženo 100 g kyseliny ethylendiaminotetraoctové a 150 mg močoviny a 5 ml vody. Směs byla 30 min. míchána s 500 ml 1,3-propylenglykolu a poté zahřívána k varu 3 hodiny. Po ochlazení na 80 °C byla reakční směs zředěna 1 000 ml vody. Po tříhodinovém míchání byl vyloučený di ketopiperazin vzorce I odfiltrován. Bylo získáno 50 g látky vzorce I, t.t. 285 °C /57,5 %/·100 g of ethylenediaminotetraacetic acid and 150 mg of urea and 5 ml of water were weighed into a 2,000 ml three-necked flask equipped with a stirrer, thermometer, condenser and heating nest. The mixture was 30 min. stirred with 500 ml of 1,3-propylene glycol and then heated to boiling for 3 hours. After cooling to 80 ° C, the reaction mixture was diluted with 1000 mL of water. After stirring for 3 hours, the precipitated di ketopiperazine of formula I was filtered off. 50 g of the compound of formula I were obtained, m.p. 285 ° C / 57.5% / ·
Příklad 2Example 2
Do téže aparatury jako v předchozím příkladu bylo vneseno 100 g kyseliny ethylendiaminotetraoctové, 150 mg močoviny, reakční směs byla po zředění 30 ml vody 30 min. míchána a poté by lo přidáno 500 ml 1,2-propylenglykolu a potom zahříváno 3 hodiny k varu. Po ochlazení a zředění 1 000 ml vody bylo získáno 64 g látky vzorce I /73 %/ t.t. 280 až 285 °C.100 g of ethylenediaminotetraacetic acid, 150 mg of urea were added to the same apparatus as in the previous example, and the reaction mixture was diluted with 30 ml of water for 30 min. and then 500 ml of 1,2-propylene glycol was added and then heated to boiling for 3 hours. After cooling and diluting with 1000 ml of water, 64 g of the compound of formula I (73%) was obtained. Mp 280-285 ° C.
Příklad 3Example 3
Do dříve popsané aparatury bylo naváženo 100 g kyseliny ethylendiaminotetraoctové, 200 g močoviny. Po přidání 500 ml di bromethanu a 10 ml vody byla reakční směs míchána 30 min. a potom zahřívána 6 hodin k varu. Po ochlazení na 20 °G bylo filtra cí získáno 20 g látky vzorce I /23 %/ t.t. 279 až 285 °C.100 g of ethylenediaminotetraacetic acid, 200 g of urea were weighed into the previously described apparatus. After addition of 500 mL of di bromoethane and 10 mL of water, the reaction mixture was stirred for 30 min. and then heated to boiling for 6 hours. After cooling to 20 ° C, 20 g of the compound of formula I (23%) was obtained by filtration. Mp 279-285 ° C.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS855245A CS256431B1 (en) | 1985-07-15 | 1985-07-15 | Method of 1,2-bis-(3,5-dioxo-1-piperazinyl)-ethane production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS855245A CS256431B1 (en) | 1985-07-15 | 1985-07-15 | Method of 1,2-bis-(3,5-dioxo-1-piperazinyl)-ethane production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS524585A1 CS524585A1 (en) | 1987-09-17 |
| CS256431B1 true CS256431B1 (en) | 1988-04-15 |
Family
ID=5396968
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS855245A CS256431B1 (en) | 1985-07-15 | 1985-07-15 | Method of 1,2-bis-(3,5-dioxo-1-piperazinyl)-ethane production |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS256431B1 (en) |
-
1985
- 1985-07-15 CS CS855245A patent/CS256431B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS524585A1 (en) | 1987-09-17 |
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