WO1998041520A1 - A process for the preparation of furazidin - Google Patents
A process for the preparation of furazidin Download PDFInfo
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- WO1998041520A1 WO1998041520A1 PCT/PL1998/000011 PL9800011W WO9841520A1 WO 1998041520 A1 WO1998041520 A1 WO 1998041520A1 PL 9800011 W PL9800011 W PL 9800011W WO 9841520 A1 WO9841520 A1 WO 9841520A1
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- aminohydantoin
- furyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to the novel process for the preparation of l-[[3-(5-nitro-2 -fury l)-2-propenylidene]amino] -2,4 -imidazo- lidinedione (furazidin).
- Furazidin also known under generic name furagin and chemical names l-[3-[2-(5-nitrofuryl)prop-2-enylidene]amino]imidazolidin-2,4- dione and l-[3-(5-nitro-2-furyl)allylideneamino]hydantoin, shown by the formula I, is the biologically active substance with a wide spectrum of antibacterial activity against Gram-positive and Gram-negative bacteria as well as against bacteria resistant to sulphonamides and some antibiotics.
- Furazidin is commonly used in the treatment of acute and chronic urinary tract infections (among others in prostatitis and cystitis) and in long-term prevention the recurrence of these infections. It is more potent antibacterial agent than nitrofurantoin, another medicinal substance from nitrofurane derivatives group, and is devoid of side effects typical for nitrofurantoin, such as gastro-intestinal disturbances (vomiting, nausea, abdominal pains, diarrhoea).
- the aim of the invention is to provide a simplified process for the preparation of furazidin, giving increased overall process yield and improved final product purity
- This aim has been achieved by using another starting materials and, optionally, by carrying the synthesis in such a manner so as to move the reaction equilib rium towards the formation of furazidin by removal of carbonyl compound formed as a by-product from the reaction medium .
- the reaction equilibrium is moved towards the formation of the furazidin because the latter precip itates from the reaction medium during the course of the reaction .
- the process for the preparation of 1 - [[3 -(5 -nitro-2-furyl-2-propenylidene]amino] -2 ,4-imidazolidinodione (furazidin) of the formula I is based on the reaction of 3 -( 5 -nitro-2 - furyl )p ropenal with aminohydantoin derivative of general formu la II ,
- R is phenyl, tolyl, 5 -nitro-2 -furyl, furyl or C i -C ⁇ alkyl
- Ri is hydrogen atom
- R and Rj are both methyl groups or R and R] together with carbon atom to which they are attached, form cyclic system of 5 or 6 carbon atoms .
- the reaction is carried out in the presence of mineral acid or sulphonic acid of the formula R 3 S O 3 H, where R 3 is methyl, trifluoromethyl or tolyl, in aqueous solution or in a mixture of water with a water-miscible organic solvent, at reflux temperature of the reaction medium, optionally while removing the formed carbonyl byproduct by distillation. Then, after cooling the reaction mixture, the precipitate of the final product is separated from the solution, washed and dried.
- the process according to the invention is performed to a high degree of conversion, usually over 80%.
- the insoluble in water reaction product is collected by filtration, washed to a neutral filtrate and then boiled several times with alcohol to remove residual organic starting materials.
- Good results can be obtained by the crystallisation of the raw product from dimethylformamide.
- Both main starting materials are used in stoichiometric amounts or in a small excess (up to 10%) of the cheaper one.
- an intensive stirring is usually required.
- heating of the reaction mixture at reflux temperature is carried out for a period of 1 to 6 hours.
- the content of the carbonyl by-product in the distillate is determined; this is easy due to the separation of the organic and water phase in the distillate. If new portions of the distillate do not contain carbonyl compound, the reaction can be regarded as terminated .
- the progress of the reaction can also be estimated by determination of the reaction mixture composition by Thin Layer Chromatography (TLC ) or High Performance Liquid Chromatography (HPLC ) .
- the preferred aminohydantoin derivative is benzylidene- 1 - aminohydantoin or isopropylidene- 1 -aminohydantoin, and especially preferred is 5 -nitro-2 -furfurylidene- 1 -aminohydantoin (nitrofurantoin) .
- a mineral acid sulphuric acid or hydrochloric acid is preferably u sed, in the concentration range from 0. 1 N to 1 . 5 N, preferably 0.5N to 1 .2N .
- a sulphonic acid of the formula R 3 S O 3 H where R 3 is methyl, trifluoromethyl, phenyl or tolyl can be used successfully.
- a water-miscible organic solvent a C 1 -C4 alcohol, such as methanol, ethanol, iso-propanol, etc. , or glycol is preferably used.
- l - [ [3 -(5 -nitro-2-furyl) -2 -propenylidene]amino ⁇ -2,4-imidazolidi- nedione (furazidin) obtained by the process according to the invention is of high purity and doesn 't contain impurities typical for known meth- ods.
- Example 1 The process according to the invention is illustrated by the following examples.
- Example 1 The process according to the invention is illustrated by the following examples.
- Example 1 The process according to the invention is illustrated by the following examples.
- Example 1 Example 1 .
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- Chemical & Material Sciences (AREA)
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- Plural Heterocyclic Compounds (AREA)
Abstract
There is disclosed a new process for the preparation of furazidin 1-[[3-(5-nitro-2-furyl)-2-propenylidene]amino]-2,4-imidazolidinedione), wherein 3-(5-nitro-2-furyl)propenal is reacted with aminohydantoin derivative of general formula (II), where R is phenyl, tolyl, 5-nitro-2-furyl or C1-C6, and R1 is hydrogen atom, or R and R1 are both methyl groups or R and R1 together with carbon atom to which they are attached, form cyclic system of 5 or 6 carbon atoms; in an aqueous solution or in a mixture of water and water-miscible organic solvent in presence of a mineral acid or sulphonic acid of the formula R3SO3H, at reflux temperature, and optionally while removing carbonyl by-product from the reaction medium by distillation. Furazidin is a valuable antibacterial agent.
Description
A process for the preparation of furazidin
The present invention relates to the novel process for the preparation of l-[[3-(5-nitro-2 -fury l)-2-propenylidene]amino] -2,4 -imidazo- lidinedione (furazidin).
Furazidin, also known under generic name furagin and chemical names l-[3-[2-(5-nitrofuryl)prop-2-enylidene]amino]imidazolidin-2,4- dione and l-[3-(5-nitro-2-furyl)allylideneamino]hydantoin, shown by the formula I, is the biologically active substance with a wide spectrum of antibacterial activity against Gram-positive and Gram-negative bacteria as well as against bacteria resistant to sulphonamides and some antibiotics.
I
Furazidin is commonly used in the treatment of acute and chronic urinary tract infections (among others in prostatitis and cystitis) and in long-term prevention the recurrence of these infections. It is more potent antibacterial agent than nitrofurantoin, another medicinal substance from nitrofurane derivatives group, and is devoid of side effects typical for nitrofurantoin, such as gastro-intestinal disturbances (vomiting, nausea, abdominal pains, diarrhoea).
The process for the preparation of furazidin, disclosed in J.Pharm. Soc. Japan 75, 117 (1955) involves a reaction between 3-(5- nitro-2-furyl)acrolein and 1-aminohydantoin or a reaction between 3-(5- nitro-2-furyl)acrolein and semicarbazideacetic acid derivative followed by the formation of hydantoin ring.
Main problems in the first of the said known processes are connected with the preparation of starting material, namely 1- aminohydantoin. It is usually obtained in a multistep synthesis process.
In the first step of the known method of 1 -aminohydantoin preparation the reaction between hydrazine and chloroacetic acid is carried out The resulting acid is esteπficated and transformed into hydrochloπde, which is treated with potassium cyanate to form aminocarbonylhydrazinacetic acid ester, the latter subsequently undergoing cychsation to aminohydantoin The disadvantage of this method is low yield, usually not exceeding 20 - 30% (Ber 3 1 , 1 64 ( 1 898 )) Different subsequent modifications of this method, described for example in the Acta Polonia Pharmaceutica 16, 1 , ( 1959) and Przemysl Chemiczny 1 1 , 306 , ( 1955 ) do not give rise to significant yield increase
Another process for the preparation of 1 -amιnohydantoιn, disclosed in J Pharm Pharmacol 1 1 , 108 , ( 1959) consists in a reaction between benzaldehyde and semicarbazide The resulting semicarbazone is reacted with ethyl chloroacetate in the presence of sodium ethanolate in ethanol to form benzylideneaminohydantoin After heating of the latter in a mineral acid solution, 1 -amιnohydantoιn and initial benzal dehyde are obtained Overall yield of this process is about 70% Although this process is more effective than the first one, its disadvantage is the low purity of the product obtained, especially on a large-scale This product can not be purified by crystallisation When such 1 - aminohydantoin is used in the synthesis of furazidin, particularly on a large scale process, a low purity product containing high amounts of unremovable impurities is obtained
The second of the mentioned above processes for the preparation of furazidin, consisting in the reaction between 3 -(5 -nιtro-2 -furyl)- acrolein (nitrofurylacrolein) with semicarbazideacetic acid derivative involves similar difficulties as in case of 1 -amιnohydrazιne preparation from hydrazine and chloroacetic acid, I e the reactions for preparing starting semicarbazideacetic acid are non-selective and give poor yields This increases process costs and decreases the final product quality
Known processes for the preparation of furazidin, described above, are multistep processes, frequently of low overall yield and/or give a product of unsatisfactory purity
The aim of the invention is to provide a simplified process for the preparation of furazidin, giving increased overall process yield and improved final product purity
This aim has been achieved by using another starting materials and, optionally, by carrying the synthesis in such a manner so as to move the reaction equilib rium towards the formation of furazidin by removal of carbonyl compound formed as a by-product from the reaction medium . Furthermore, the reaction equilibrium is moved towards the formation of the furazidin because the latter precip itates from the reaction medium during the course of the reaction .
According to the invention, the process for the preparation of 1 - [[3 -(5 -nitro-2-furyl-2-propenylidene]amino] -2 ,4-imidazolidinodione (furazidin) of the formula I is based on the reaction of 3 -( 5 -nitro-2 - furyl )p ropenal with aminohydantoin derivative of general formu la II ,
II where R is phenyl, tolyl, 5 -nitro-2 -furyl, furyl or C i -C^ alkyl, and Ri is hydrogen atom, or R and Rj are both methyl groups or R and R] together with carbon atom to which they are attached, form cyclic system of 5 or 6 carbon atoms . The reaction is carried out in the presence of mineral acid or sulphonic acid of the formula R3 S O3H, where R3 is methyl, trifluoromethyl or tolyl, in aqueous solution or in a mixture of water with a water-miscible organic solvent, at reflux temperature of the reaction medium, optionally while removing the formed carbonyl byproduct by distillation. Then, after cooling the reaction mixture, the precipitate of the final product is separated from the solution, washed and dried.
The process according to the invention is performed to a high degree of conversion, usually over 80%. The insoluble in water reaction product is collected by filtration, washed to a neutral filtrate and then boiled several times with alcohol to remove residual organic starting materials. Good results can be obtained by the crystallisation of the raw product from dimethylformamide. Both main starting materials are used in stoichiometric amounts or in a small excess (up to 10%) of the
cheaper one. As the starting materials have limited solubility in reaction medium, an intensive stirring is usually required. Depending on the aminohydantoin derivative used, heating of the reaction mixture at reflux temperature is carried out for a period of 1 to 6 hours. To estimate the reaction progress, the content of the carbonyl by-product in the distillate is determined; this is easy due to the separation of the organic and water phase in the distillate. If new portions of the distillate do not contain carbonyl compound, the reaction can be regarded as terminated . The progress of the reaction can also be estimated by determination of the reaction mixture composition by Thin Layer Chromatography (TLC ) or High Performance Liquid Chromatography (HPLC ) .
The preferred aminohydantoin derivative is benzylidene- 1 - aminohydantoin or isopropylidene- 1 -aminohydantoin, and especially preferred is 5 -nitro-2 -furfurylidene- 1 -aminohydantoin (nitrofurantoin) . As a mineral acid sulphuric acid or hydrochloric acid is preferably u sed, in the concentration range from 0. 1 N to 1 . 5 N, preferably 0.5N to 1 .2N . Instead of a mineral acid a sulphonic acid of the formula R3 S O3H where R3 is methyl, trifluoromethyl, phenyl or tolyl can be used successfully. As a water-miscible organic solvent a C 1 -C4 alcohol, such as methanol, ethanol, iso-propanol, etc. , or glycol is preferably used. l - [ [3 -(5 -nitro-2-furyl) -2 -propenylidene]amino } -2,4-imidazolidi- nedione (furazidin) obtained by the process according to the invention is of high purity and doesn 't contain impurities typical for known meth- ods.
The process according to the invention is illustrated by the following examples. Example 1 .
A mixture of 20 g (0. 12 mol) of 3 -(5 -nitro-2-furyl)propenal and 22.5 g (0. 1 mol) of 5-nitro-2-furfurylidene- l -aminohydantoin
(nitrofurantoin) in 500 ml of water containing 10 ml of concentrated sulphuric acid was heated at reflux temperature with vigorous stirring. After 30 minutes the distillation of 5 -nitrofurfural formed in the reaction together with water was started. The reaction was carried out until disappearance of 5 -nitrofurfural in the new portions of the distillate. The reaction mixture was cooled, the obtained yellow precipitate fil-
tered off, washed with water until obtaining neutral filtrate. Then the precipitate was boiled with 100 ml of ethanol, filtered and filtrates discarded. The precipitate was dried on air. 19.75 g of the compound of the formula I were obtained (yield 79%). Melting point 267°C (decomposition).
Results of the elemental analysis:
C = 45.55%; H = 3.02%; N = 21.26%
Example 2.
A mixture of 10 g (0.06 mol) of 3-(5-nitro-2-furyl)propenal and 10 g (0.05 mol) of benzylidene-1-aminohydantoin in 200 ml of water containing 20 ml of concentrated hydrochloric acid was heated with stirring and the formed benzaldehyde was distilled off together with water. The process was carried out for about 60 minutes. After cooling the mixture the obtained product was filtered off, washed with water to a neutral reaction and dried. The precipitate was heated to a temperature of 70°C together with 50 ml of dimethylformamide, cooled, the precipitate obtained was collected by filtration and washed with ethanol. 10.5 g of the compound of the formula I were obtained after drying. Yield 84%o, melting point 265°C (decomposition). Example 3.
Starting from 10 g of 3-(5-nitro-2-furyl)propenal and 9.7 g of cyclohexylideneaminohydantoin and proceeding in the same manner as in Example 1 and using 4 g of toluenesulphonic acid instead of sulphuric acid 10.4 g of the compound of the formula I were obtained. Yield 83%, melting point 262°C (decomposition). Example 4.
A mixture of 10 g of 3-(5-nitro-2-furyl)propenal and 7.8 g of iso- propylidene-1-aminohydantoin in 200 ml of water containing 5 ml of concentrated sulphuric acid was kept at reflux temperature for 35 min- utes, then cooled and proceeding in the same way as in Example 1, 10.4 g of the compound of the formula I were obtained. Yield 84%. Example 5.
A mixture of 10 g of 3-(5-nitro-2-furyl)propenal and 9.7 g of 2- furfurylidene-1-aminohydantoin in 200 ml of water containing 2.5 ml of concentrated sulphuric acid was heated at reflux temperature with stirring and distilling off furfural formed till to its disappearance in new
portions of the distillate. Proceeding in the same way as in Example 1, the compound of the formula I was obtained with 72% yield. Example 6.
A mixture of 20 g of 3-(5-nitro-2-furyl)propenal and 22.5 g of 5- nitro-2-furfurylidene-l-aminohydantoin (nitrofurantoin) in 500 ml of water containing 120 ml of propanol and 10 ml of concentrated sulphuric acid was maintained at reflux temperature for 30 minutes and, proceeding in the same way as in Example 1, the compound of the formula I was obtained with 88% yield. Melting point 262°C (decomposition).
Claims
Claims
1 A process for the preparation of furazidin l-[[3-(5-nιtro-2- furyl)-2-propenylιdene]amιno]-2,4-ιmιdazohdιnedιone), characterised in that 3-(5-nιtro-2-furyl)propenal is reacted with aminohydantoin derivative of the general formula II,
II where R is phenyl, tolyl, 5-nιtro-2-furyl or Cj-Cg alkyl, and R\ is hy- drogen atom, or R and Rj are both methyl groups or R and Ri together with carbon atom to which they are attached, form cyclic system of 5 or 6 carbon atoms, in an aqueous solution or in a mixture of water and water-miscible or- game solvent in presence of a mineral acid or sulphonic acid of the formula R3SO3H, where R3 is methyl, trifluoromethyl or tolyl, at reflux temperature of the reaction medium, and optionalh while removing carbonyl by-product from the reaction medium by distillation, and then, after cooling the reaction mixture obtained precipitate is separated from the solution, washed and dried
2 The process of claim 1, wherein
dantoin derivative is 5 -nit ro - 2 -furfuryhdene- 1 -aminohydantoin
3 The process of claim 1. wherein amιnoh\ dantoin derivative is benzylιdene-1 -aminohydantoin 4 The process of claim 1, wherein aminohydantoin derivative is ιsopropylιdene-1 -aminohydantoin
5 The process of claim 1. wherein as water-miscible organic sol-
vent a C1-C4 alcohol is used,
6. The process of claim 1, wherein as water-miscible organic solvent glycol is used.
7. The process of claim 1, wherein a mineral acid concentration in a reaction mixture is 0.1N to 1.5N, preferably 0.5N to 1.2N.
8. The process of claim 1, wherein as a mineral acid hydrochloric acid is used.
9. The process of claim 1, wherein as a mineral acid sulphuric acid is used.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PLP.319007 | 1997-03-17 | ||
| PL97319007A PL185120B1 (en) | 1997-03-17 | 1997-03-17 | Method of obtaining 1-{[3-(5-nitro-2-furyl)-2-propenyliden]-amino}imidazolydin-2,4-dione |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998041520A1 true WO1998041520A1 (en) | 1998-09-24 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/PL1998/000011 Ceased WO1998041520A1 (en) | 1997-03-17 | 1998-03-13 | A process for the preparation of furazidin |
Country Status (2)
| Country | Link |
|---|---|
| PL (1) | PL185120B1 (en) |
| WO (1) | WO1998041520A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101792433B (en) * | 2009-12-10 | 2011-11-30 | 浙江科技学院 | Method for synthesizing 1-((3-(5-nitro-2-furyl)allylidene)amino)-hydantoin |
| WO2015181741A1 (en) | 2014-05-29 | 2015-12-03 | Akciju Sabiedriba "Olainfarm" | Polymorphic forms of furazidin |
| CN108715588A (en) * | 2018-06-12 | 2018-10-30 | 黄石法姆药业股份有限公司 | A kind of 1-（（3-（5- nitro-2-furyls）Allylidene）Amino）The synthetic method of glycolylurea |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2990402A (en) * | 1958-10-07 | 1961-06-27 | Smith Kline French Lab | Preparation of 1-aminohydantoin derivatives |
| FR1272714A (en) * | 1958-10-01 | 1961-09-29 | Norwich Pharma Co | New derivative of 3-amino-2-imidazolidinethione and its preparation process |
| GB1173212A (en) * | 1966-05-09 | 1969-12-03 | Clin Byla Ets | Hydantoins and processes for the preparation thereof |
| JPS6424966A (en) * | 1987-07-21 | 1989-01-26 | Kajima Corp | Method of designing building by sun shadow diffusion |
| WO1997019930A1 (en) * | 1995-11-27 | 1997-06-05 | Lonza Ag | Process for producing 1-aminohydantoin |
-
1997
- 1997-03-17 PL PL97319007A patent/PL185120B1/en not_active IP Right Cessation
-
1998
- 1998-03-13 WO PCT/PL1998/000011 patent/WO1998041520A1/en not_active Ceased
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1272714A (en) * | 1958-10-01 | 1961-09-29 | Norwich Pharma Co | New derivative of 3-amino-2-imidazolidinethione and its preparation process |
| US2990402A (en) * | 1958-10-07 | 1961-06-27 | Smith Kline French Lab | Preparation of 1-aminohydantoin derivatives |
| GB1173212A (en) * | 1966-05-09 | 1969-12-03 | Clin Byla Ets | Hydantoins and processes for the preparation thereof |
| JPS6424966A (en) * | 1987-07-21 | 1989-01-26 | Kajima Corp | Method of designing building by sun shadow diffusion |
| WO1997019930A1 (en) * | 1995-11-27 | 1997-06-05 | Lonza Ag | Process for producing 1-aminohydantoin |
Non-Patent Citations (3)
| Title |
|---|
| CHEMICAL ABSTRACTS, vol. 50, no. 3, 10 February 1956, Columbus, Ohio, US; abstract no. 1782f, H. UOTA ET AL.: "Aminohydantoin derivatives and related compounds. Furan compounds" XP002068484 * |
| CHEMICAL ABSTRACTS, vol. 62, no. 9, 26 April 1965, Columbus, Ohio, US; abstract no. 10442f, H. UOTA ET AL.: "Furan derivatives" XP002068485 * |
| J. PHARM. SOC. JAPAN, vol. 75, 1955, pages 117-120 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101792433B (en) * | 2009-12-10 | 2011-11-30 | 浙江科技学院 | Method for synthesizing 1-((3-(5-nitro-2-furyl)allylidene)amino)-hydantoin |
| WO2015181741A1 (en) | 2014-05-29 | 2015-12-03 | Akciju Sabiedriba "Olainfarm" | Polymorphic forms of furazidin |
| CN108715588A (en) * | 2018-06-12 | 2018-10-30 | 黄石法姆药业股份有限公司 | A kind of 1-（（3-（5- nitro-2-furyls）Allylidene）Amino）The synthetic method of glycolylurea |
Also Published As
| Publication number | Publication date |
|---|---|
| PL185120B1 (en) | 2003-02-28 |
| PL319007A1 (en) | 1998-09-28 |
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