CS271893B1 - Method of 4(5)-formamido-imidazole-5(4)-carboxamide hydrochloride production - Google Patents
Method of 4(5)-formamido-imidazole-5(4)-carboxamide hydrochloride production Download PDFInfo
- Publication number
- CS271893B1 CS271893B1 CS886267A CS626788A CS271893B1 CS 271893 B1 CS271893 B1 CS 271893B1 CS 886267 A CS886267 A CS 886267A CS 626788 A CS626788 A CS 626788A CS 271893 B1 CS271893 B1 CS 271893B1
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- hydrochloride
- hydrogen
- formula
- formic acid
- carboxamide hydrochloride
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 6
- 238000004519 manufacturing process Methods 0.000 title abstract description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 26
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 13
- 235000019253 formic acid Nutrition 0.000 claims abstract description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 241001436679 Adama Species 0.000 claims 1
- 241000282994 Cervidae Species 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 abstract description 8
- 238000009835 boiling Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- 239000013067 intermediate product Substances 0.000 abstract 1
- 231100000590 oncogenic Toxicity 0.000 abstract 1
- 230000002246 oncogenic effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- DYDNPESBYVVLBO-UHFFFAOYSA-N formanilide Chemical compound O=CNC1=CC=CC=C1 DYDNPESBYVVLBO-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical group CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
4(5)-Formamidoimidazol-5(4)-karboxamid hydrochlorid vzorce (I)4 (5) -Formamidoimidazole-5 (4) -carboxamide hydrochloride of formula (I)
conh2 conh 2
NH CHO (I) je důležitým meziproduktem pro syntézu imidazolových derivátů, které mají význam například jako léčivé látky. Typickým příkladem je dacarbazin (5-(3,3-dimethyl-l-triazeno)imidazol-4-karboxamid), látka používaná k terapii nádorových onemocnění.NH CHO (I) is an important intermediate for the synthesis of imidazole derivatives, which are important, for example, as active substances. A typical example is dacarbazine (5- (3,3-dimethyl-1-triazeno) imidazole-4-carboxamide), a substance used to treat cancer.
Dosavadní způaob přípravy 4(5)-formamidoimidazol-5(4)-karboxamid hydrochloridu popsaný v literatuře (Montgomery 0. A. et al.: J. Org. Chem. 24, 256 /1959/) spočívá v katalytické hydrogenolýze 2-fenylazomalonamidamidin hydrochloridu vzorce (II) vodíkem v prostředí kyseliny mravenčí za vzniku 2-formamidomalonamidamidin hydrochloridu vzorce (III), ktec /The present process for the preparation of 4 (5) -formamidoimidazole-5 (4) -carboxamide hydrochloride described in the literature (Montgomery, A.A. et al .: J. Org. Chem. 24, 256 (1959)) consists in catalytic hydrogenolysis of 2-phenylazomalonamidamidine of the hydrochloride of formula (II) with hydrogen in the formic acid medium to give 2-formamidomalonamidamidine of the hydrochloride of formula (III),
H2NH 2 N
NHNH
CH I \CH I \
N NH2 . HCI (II)N NH 2 . HCI (II)
O rý bez izolace varem v kyselině mravenčí cyklizuje na žádaný 4(5)-formamidoimidazol-5(4)0 % - CH / i H2N Oils without isolation by boiling in formic acid cyclize to the desired 4 (5) -formamidoimidazole-5 (4) 0% - CH / 1 H 2 N
NHNH
NHNH
(III)(III)
CHOCHO
-karboxamid hydrochlorid. Anilin, odštěpený při hydrogenolýze 2-fenylazomalonamidamidin hydrochloridu, přitom kondenzuje s kyselinou mravenčí za vzniku formanilidu.-carboxamide hydrochloride. The aniline cleaved by hydrogenolysis of 2-phenylazomalonamidamidine hydrochloride is condensed with formic acid to form formanilide.
Nedostatky této metody spočívají především v tom, že pro výrobu 2-fenylazomalonamidamidin hydrochloridu je nutno pracovat s toxickým anilinem, který po reakci odchází ve formě formanilidu do odpadních vod bez možnosti regenerace nebo dalšího využití a dála je nedostatkem této metody i skutečnost, že pro hydrogenolýzu 2-fenylazomalonamidamidin hydrochloridu jsou nutné poměrně vysoké teploty a tlaky.The disadvantages of this method are mainly that for the production of 2-phenylazomalonamidamidine hydrochloride it is necessary to work with toxic aniline, which after the reaction in the form of formanilide goes to wastewater without the possibility of regeneration or further utilization. 2-Phenylazomalonamidamidine hydrochloride requires relatively high temperatures and pressures.
Nyní bylo zjištěno, že uvedené nedostatky odstraňuje způsob výroby 4(5)-formamidoimidazol-5(4)-karboxamid hydrochloridu vzorce (I) vycházející z 2-oximinomalonamidamidin hydrochloridu vzorce (IV) podle vynálezu,It has now been found that these deficiencies are overcome by a process for preparing 4 (5) -formamidoimidazole-5 (4) -carboxamide hydrochloride of formula (I) starting from 2-oximinomalonamidamidine hydrochloride of formula (IV) according to the invention,
ÍIH . HCL (IV) nh2 ÍIH. HCL (IV) n 2
N - OHN-OH
CS 271893 Bl který je vyznačen tím, že se na 2-oximinomalonamidamidin hydrochlorid vzorce (IV) působí vodíkem v prostředí kyseliny mravenčí, s výhodou za použití katalyzátoru, např. paladia na inertním nosiči nebo Adamsova katalyzátoru, při teplotě od 10 °C do bodu varu reakční směsi a po skončení působení vodíku se dále reakční směs zahřívá po dobu 0,5 až 10 hodin při teplotě 30 až 150 °C, načež se 4(5)-formamidoimidazol-5(4)-karboxamid hydrochlorid vzorce (I) izoluje z reakční směsi.CS 271893 B1 which is characterized in that the 2-oximinomalonamidamidine hydrochloride of formula (IV) is treated with hydrogen in a formic acid medium, preferably using a catalyst such as palladium on an inert support or an Adams catalyst at a temperature of from 10 ° C to point boiling the reaction mixture and, after the end of hydrogen treatment, the reaction mixture is further heated for 0.5 to 10 hours at 30 to 150 ° C, whereupon 4 (S) -formamidoimidazole-5 (4) -carboxamide hydrochloride of formula (I) is isolated from the reaction mixture.
Pokud se k hydrogenolýze použije plynný vodík, je nutno, podobně jako při způsobu popsaném v literatuře, pracovat za zvýšeného tlaku a za použiti katalyzátoru, přičemž reakční rychlost při výrobě podle vynálezu je za stejných podmínek asi lOkrát vyšší. Cyklizační reakci je možno provést přímo v autoklávu, kde byla prováděna hydrogenolýza bez nutnosti odstranit použitý katalyzátor. Ten se odfiltruje až po skončení oyklizaoe. Dále je možno využít i vodíku in státu nascendi, připraveného reakcí kyseliny mravenčí se zinkem nebo cínem přímo v reakční směsi, takže není nutno pracovat v uzavřené nádobě za zvýšeného tlaku. Látka se izoluje po odpaření veškeré kyseliny mravenčí, a to rozmícháním ve vodě a odsátím, přičemž odpadní vody neobsahují formanilid. Způsob výroby podle vynále zu poskytuje oproti známým způsobům 4(5)-formamidoimidazol-5(4)-karboxamid hydrochlorid \e výtěžku vyšším o 10 % a v čistší formě.When hydrogen gas is used for hydrogenolysis, it is necessary, as in the literature, to operate at elevated pressure and using a catalyst, the reaction rate of the production according to the invention being about 10 times higher under the same conditions. The cyclization reaction can be carried out directly in an autoclave where hydrogenolysis was performed without the need to remove the catalyst used. It is filtered off only after the end of the cyclization. It is also possible to use hydrogen in the state of nascendi, prepared by reacting formic acid with zinc or tin directly in the reaction mixture, so that it is not necessary to work in a closed vessel under elevated pressure. The substance is isolated after evaporation of all formic acid by stirring in water and suction, the effluents being free of formanilide. The process according to the invention provides 4% (5) -formamidoimidazole-5 (4) -carboxamide hydrochloride yields higher by 10% and in a more pure form.
Způsob podle vynálezu blíže objasňují následující příklady.The following examples illustrate the process according to the invention.
Příklad 1Example 1
Do nerezového 1 000 ml autoklávu se předloží roztok 71,3 g 2-oximinomalonamidamidin hydrochloridu v 600 ml 85% kyseliny mravenčí a přidá se 10 g 5% paladia na aktivním uhlí. Autokláv se uzavře a na reakční směs se působí vodíkem za tlaku 2 MPa a při teplotě 40 °C po dobu 3 hodin až do ukončení spotřeby vodíku. Potom se sníží přetlak vodíku na 0,2 MPa a směs se zahřívá 5,5 hodiny na teplotu 110 °C za míchání. Potom se ochladí na 20 °C, vypustí z autoklávu, katalyzátor se odfiltruje, promyje 50 ml kyseliny mravenčí a veškerá kyselina mravenčí se odpaří na vakuové odparce při 70 °C. K odparku se přidá 500 ml vody, rozmíchá na homogenní suspenzi a pevná látka se odsaje. Promyje se 100 ml a 100 ml ethanolu. Po vysušení se získá 50 g 4(5)-formamldoimidazol-5(4)-karboxamid hydrochloridu identického s komerčním preparátem (3H NMR, IR, UV spektra).A solution of 71.3 g of 2-oximinomalonamidamidine hydrochloride in 600 ml of 85% formic acid was charged to a 1000 ml autoclave and 10 g of 5% palladium on charcoal was added. The autoclave was sealed and the reaction mixture was treated with hydrogen at 40 psi at 40 ° C for 3 hours until hydrogen uptake ceased. The hydrogen pressure was then reduced to 200 psig and the mixture was heated at 110 ° C for 5.5 hours with stirring. It is then cooled to 20 ° C, discharged from the autoclave, the catalyst is filtered off, washed with 50 ml of formic acid and all the formic acid is evaporated in a vacuum evaporator at 70 ° C. 500 ml of water are added to the residue, mixed to a homogeneous suspension and the solid is filtered off with suction. Wash with 100 ml and 100 ml ethanol. After drying, 50 g of 4 (S) -formamido-imidazole-5 (4) -carboxamide hydrochloride identical to the commercial preparation ( 3 H NMR, IR, UV spectra) are obtained.
P ř í k 1 a d 2Example 1 a d 2
V 500 ml tříhrdlé skleněné baňce se rozpustí 16,7 g 2-oximinomalonamidamidin hydrochloridu ve 350 ml kyseliny mravenčí, vyhřeje se na 80 °C a po částech se za míchání vnáší během 1 hodiny celkem 50 g zinku. Exotermni reakcí se směs samovolně vyhřeje až k refluxu. Po skončení přidávání zinku še směs zahřívá pod zpětným chladičem k varu po dobuDissolve 16.7 g of 2-oximinomalonamidamidine hydrochloride in 350 ml of formic acid in a 500 ml three-necked glass flask, heat to 80 ° C and add in portions a total of 50 g of zinc over 1 hour with stirring. By exothermic reaction, the mixture is spontaneously heated to reflux. Upon completion of the addition of zinc, the mixture was heated to reflux for a period of time
4,5 hodiny. Nerozpustná látka se za horka odfiltruje a promyje 100 ml horké kyseliny mravenčí. Filtrát se ochladí na 20 °C a vyloučená sraženina se opět odsaje. Čirý filtrát se na vakuové odparce odpaří do sucha při 70 °C. Zbytek se rozmíchá se 150 ml vody na homogenní suspenzi. Nerozpustná látka se odsaje a promyje 50 ml vody a 50 ml ethanolu. Po vysušení se získá 10,0 g 4(5)-formamidoimidazol-5(4)-karboxamid hydrochloridu identického s komerčním preparátem.4.5 hours. The insoluble material is filtered while hot and washed with 100 ml of hot formic acid. The filtrate is cooled to 20 ° C and the precipitate formed is filtered off with suction. The clear filtrate was evaporated to dryness on a vacuum evaporator at 70 ° C. The residue is stirred with 150 ml of water to give a homogeneous suspension. The insoluble material is filtered off with suction and washed with 50 ml of water and 50 ml of ethanol. After drying, 10.0 g of 4 (S) -formamidoimidazole-5 (4) -carboxamide hydrochloride identical to the commercial preparation are obtained.
CS 271893 BlCS 271893 Bl
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS886267A CS271893B1 (en) | 1988-09-21 | 1988-09-21 | Method of 4(5)-formamido-imidazole-5(4)-carboxamide hydrochloride production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS886267A CS271893B1 (en) | 1988-09-21 | 1988-09-21 | Method of 4(5)-formamido-imidazole-5(4)-carboxamide hydrochloride production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS626788A1 CS626788A1 (en) | 1990-03-14 |
| CS271893B1 true CS271893B1 (en) | 1990-12-13 |
Family
ID=5409334
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS886267A CS271893B1 (en) | 1988-09-21 | 1988-09-21 | Method of 4(5)-formamido-imidazole-5(4)-carboxamide hydrochloride production |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS271893B1 (en) |
-
1988
- 1988-09-21 CS CS886267A patent/CS271893B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS626788A1 (en) | 1990-03-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPS62205058A (en) | Novel aryl-substituted (n-piperidinyl)methyl- and (n-piperazinyl)methylazole compound, drug and manufacture | |
| CZ289931B6 (en) | Aminoacyl pyrrolidines, their use and pharmaceutical preparation in which they are comprised | |
| CA2936871A1 (en) | Dihydropteridinone derivatives and uses thereof | |
| US20060009510A1 (en) | Method of synthesizing indolinone compounds | |
| CA2932051A1 (en) | Piperazine derivatives having multimodal activity against pain | |
| TWI659044B (en) | Cyclopeptide, composition comprising the same and method for preparing the same | |
| Santos et al. | 1, 2, 3-Triazoles: general and key synthetic strategies | |
| WO2019114258A1 (en) | Method for preparing baricitinib | |
| NO873945L (en) | SUBSTITUTED KINOXALINES. | |
| RS61317B1 (en) | Novel amino-imidazopyridine derivatives as janus kinase inhibitors and pharmaceutical use thereof | |
| RU2163604C2 (en) | Derivatives of n-substituted 3-azabicyclo-[3,2,0]-heptane and their salts with physiologically acceptable acids and pharmaceutical composition with antipsychotic activity | |
| GB2198128A (en) | Dihydroxy benzene derivatives | |
| O'Sullivan et al. | Antiviral benzimidazoles. Direct 1-substitution of 2-(. alpha.-hydroxybenzyl) benzimidazole and related compounds | |
| Ramasamy et al. | Synergistic Effect of Copper and Ruthenium on Regioselectivity in the Alkyne–Azide Click Reaction of Internal Alkynes | |
| RU2256660C2 (en) | Method for preparing (r)-5-(2-benzenesulfonylethyl)-3-n-methylpyrrolidine-2-ylmethyl)-1h- indole | |
| CS271893B1 (en) | Method of 4(5)-formamido-imidazole-5(4)-carboxamide hydrochloride production | |
| CN110028436B (en) | Preparation method of Vonoprazan key intermediate | |
| CN103910734B (en) | A kind of DPP-4 inhibitor with piperazine structure | |
| JP2000500464A (en) | Blood regulatory compounds | |
| Elderfield et al. | Synthesis of Potential Anticancer Agents. XV. Nitrogen Mustards from Indole Derivatives1, 2 | |
| Lazny et al. | New simple polymeric supports with hydrazone linkers for solid-phase synthesis of ketones and primary amines | |
| CN1159807A (en) | Novel imidazoquinoxalinones with heterocyclic substituents and their preparation methods and applications | |
| Kumar et al. | Synthesis and cytotoxicity evaluation of novel C7–C7, C7–N3 and N3–N3 dimers of 1-chloromethyl-5-hydroxy-1, 2-dihydro-3 H-benzo [e] indole (seco-CBI) with pyrrole and imidazole polyamide conjugates | |
| KR102467444B1 (en) | Iso-exiguamine A derivatives, preparation method thereof and pharmaceutical composition for use in preventing or treating IDO-1 related disease containing the same as an active ingredient | |
| JP3088561B2 (en) | Method for producing 2,3-diaminopyridines |