GB2064522A - Phenylbutazone Salt - Google Patents
Phenylbutazone Salt Download PDFInfo
- Publication number
- GB2064522A GB2064522A GB8036306A GB8036306A GB2064522A GB 2064522 A GB2064522 A GB 2064522A GB 8036306 A GB8036306 A GB 8036306A GB 8036306 A GB8036306 A GB 8036306A GB 2064522 A GB2064522 A GB 2064522A
- Authority
- GB
- United Kingdom
- Prior art keywords
- molecular compound
- diketo
- diphenylpyrazolidine
- butyl
- chlorophenoxyacetic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/28—Two oxygen or sulfur atoms
- C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
- C07D231/32—Oxygen atoms
- C07D231/34—Oxygen atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
By reacting together p- chlorophenoxyacetic acid, beta - diethylaminoethylamine and 4-n- butyl-3,5-diketo-1,2-diphenyl- pyrazolidine in the medium of a non- polar solvent at the temperature of 107 to 148 DEG C, the molecular compound of these three reactants is obtained in a single reaction, the said compound having the Formula 1 <IMAGE> The molecular compound is isolated from the reaction medium and purified by crystallisation from an organic water-miscible polar solvent containing not less than two moles of water per mole of the molecular compound. The molecular compound produced by the process according to the invention has antiphlogistic and antirheumatic properties.
Description
SPECIFICATION
Process for Preparation of the Molecular Compound of ,B-diethylaminoethylamide of pchlorophenoxyacetic Acid With 4-n-butyl-3,5-diketo-I .2-diphenylpyrazolidine This invention relates to a process for the preparation of a molecular compound of p- diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n-butyl-3,5-di keto- 1 2- diphenylpyrazolidine having the Formula 1.
There is known, and employed in therapeutics, p-diethyí-aminoethylamide of pchlorophenoxyacetic acid, having the Formula 2,
Also known is 4-n-butyl-3,5-diketo-1 ,2-diphenyl-pyrazolidine having the Formula 3.
The compounds of Formulae 2 and 3, are employed in therapeutics as antiphlogistics and antirheumatics.
There is known from the Polish Patent Specification No. 60 210 a process of preparation of a molecular compound of P-diethylaminoethylamide ofp-chlorophenoxyacetic acid with 4-n-butyl-3,5- diketo-1 ,2-diphenylpyrazolidine in which 4-n-butyl-3,Sdiketo-1 2-diphenylpyrazolidine is reacted with pdiethylaminoethylamide of p-chlorophenoxyacetic acid in equimolecular ratio. In the course of reaction and/or separation of the product there must be present water in at least equimolecular amount with respect to the obtained product. /3-diethylaminoethylamide of p-chlorophenoxyacetic acid, having the
Formula 2, used for preparation of molecular compound with 4-n-butyl-3,5-diketo-1 2- diphenylpyrazolidine can be obtained by one of the conventional methods described in the literature.
The p-chlorophenoxyacetic acid may be chlorinated with thionyl chloride or other suitable chlorinating agent, and then the acid chloride condensed with ss-diethylaminoethylamine, as in British Patent
Specification 942,761, or with ,B-hydroxyethylamine, as in East German Patent Specification 92 727.
According to the method of British Patent Specification No. 942,761 the required 5- diethylaminoethylamide of p-chlorophenoxyacetic acid is obtained after condensation of the acid chloride with p-diethylaminoethylamine, whereas by the method of East German Patent Specification
No. 92 727 the ss-hydroxyethylamide of p-chlorophenoxyacetic acid is obtained, wherein the hydroxyl group is chlorinated by means of thionyl chloride, and then the ss-chloroethylamide of pchlorophenoxyacetic acid is condensed with diethylamine. As a result of the reaction the desired ,B- diethylaminoethylamide of p-chlorophenoxyacetic acid is obtained.
During the action of diethylamine with ss-chloroethylamide of p-chlorophenoxyacetic acid 2-(pchlorophenoxymethyl)-oxazoline 2 is formed as a contaminating by-product.
The separation of the desired ss-diethylaminoethylamide of p-chlorophenoxyacetic acid from the contamination occurs by binding the ,B-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4 n-butyl-3,5-diketol ,2-diphenylpyrazolidine.
Referring to the accompanying drawing, Reaction Scheme I depicts the process of preparation of the molecular compound of ,B-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n-butyl3,5-diketo-1 ,2-diphenylpyrazolidine, having the Formula 1, according to the prior art.
The inconveniences of known processes of preparation of p-diethylaminoethylamide of pchlorophenoxyacetic acid as well as of its molecular compound with 4-n-butyl-3,5-diketo-1 ,2- diphenylpyrazolidine, are, the need for several stages, the laboriousness of the synthesis, the necessity to use thionyl chloride as chlorinating agent which is troublesome on an industrial scale.
In the literature there has been found no information about obtaining of pdiethylaminoethylamide of p-chlorophenoxyacetic acid through direct action of p- diethylaminoethylamine and p-chlorophenoxyacetic acid, although there are known processes of obtaining other amides in this way.
There exists a possibility of obtaining the p-diethylaminoethylamide of p-chlorophenoxyacetic acid by heatingp-chlorophenoxyacetic acid with an excess of p-diethylaminoethylamine in a medium of a non-polar solvent, for example, toluene. The p-diethylaminoethylamide of p-chlorophenoxyacetic acid obtained in this way is, however, strongly coloured. Also the molecular compound with 4-n-butyl3,5-diketo-1 ,2-diphenylpyrazolidine, obtained thereof in the process as described in the Polish Patent
Specification 60210 has a yellow-tawny colour which cannot be removed by normal methods of purification, for example, by crystallization.Such an unfavourable result is obtained because of the instability of the amide formed which at the temperature of amidation undergoes to tar-formation and decomposition.
According to the present invention there is provided a process for preparation of a molecular compound of the p-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n-butyl-3 ,5-diketo
1 ,2-diphenylpyrazolidine, having the Formula 1
comprising reacting p-chlorophenoxyacetic acid with p-diethylaminoethylamine in presence of 4-n butyl-3,5-diketo-1 ,2-diphenylpyrazolidine in a non-polar solvent medium at a temperature of from 107 to 1480C.
Preferably the reactants are present in stoichiometric proportions or with slight excess of the p- diethylaminoethylamine.
Unexpectedly it has been found that 4-n-butyl-3,5-diketo 1 ,2-diphenylpyrazolidine binding with nascent p-diethylaminoethylamide of p-chlorophenoxyacetic acid in the reaction of amidation, at a temperature of from 107 to 1480 C, secures p-diethylaminoethylamide of p-chlorophenoxyacetic acid against thermal decomposition and tar-formation. While the free amide undergoes such reaction very easily, in molecular combination its resistance to elevated temperature increases considerably.
The essence of the invention is that the molecular compound of the p-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n-butyl-3,5-diketo-1 ,2-diphenylpyrazolidine is obtained in a process of direct amidation of p-chlorophenoxyacetic acid with p-diethylaminoethylamine in the presence of 4-n-butyl-3,5-diketo-1 ,2-diphenylpyrazolidine in a medium of an organic non-polar solvent at the temperature of 107 to 1 480C, and is illustrated in Reaction Scheme ll shown in the accompanying drawings.
The amidation of p-chlorophenoxyacetic acid, according to the invention may be carried out with stoichiometric quantities of p-chlorophenoxyacetic acid and 4-n-butyl-3,5-diketo-1 ,2diphenylpyrazolidine, whereas p-diethylaminoethylamine may be used in stoichiometric quantity or in slight excess.
The reaction medium is a non-polar organic solvent, preferably toluene or xylene.
Water evolved in the amidation reaction is bound by the molecular compound of the amide with 4-n-butyl-3,5-diketo-1 ,2-diphenylpyrazolidine. On cooling the reaction mixture to the temperature of from 10 to 200C, the molecular compound with one molecule of water of crystallisation, crystallises from the reaction medium. If, instead, the water evolved is distilled off from the reaction mixture together with the solvent vapours then after cooling a product in form of an oily liquid is formed which is also obtainable by complete distilling off of the solvent.
The crude product, obtained in form of hydrated crystals or of an oil, only contains a slight amount of contaminating tarry substances. Its crystallisation from a water-miscible organic polar solvent containing an adequate quantity of water, gives crystals of a dihydrated molecular compound with high purity, suitable for application in therapeutics.
As polar water-miscible organic solvent there is preferably used acetone or ethanol containing water in a quantity not less than 2 moles per 1 mole of the molecular compounds to be crystallised.
The molecular compound of p-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n butyl-3,5-diketo-l ,2-diphenylpyrazolidine is able to bind one or two water molecules strongly enough that complete dehydration is possible only at the boiling point of xylene. Thus, the forming molecular compound removed the water evolved in course of the amidation process and hence enhances the rate of reaction.
The protective effect of 4-n-butyl-3,5-diketo- 1 ,2-diphenylpyrazolidine against decomposition of the p-diethylaminoethylamide of p-chlorophenoxyacetic acid at elevated temperature can be illustrated by heating a sample of p-diethylaminoethylamide of p-chlorophenoxyacetic acid and a sample of the same amide in form of a compound with 4-n-butyl-3,5-diketo-1 ,2-diphenylpyrazolidine for 3 hours at the temperature of 1200 C. Ethanol solutions with equal molar concentrations prepared from the heattreated specimens show very different absorptions of visible radiation, demonstrating different degrees of decomposition of the samples and different degrees of contamination with coloured tarry substances.The contamination is high for the amide itself, and only slight for its compound with 4-n butyl-3,5-diketo- 1 ,2-diphenylpyrazolidine.
An advantage of the process of the invention is the possibility of obtaining the molecular compound of p-diethyla minoethylamide of p-chlorophenoxyacetic acid with 4-n-butyl-3,5-diketo-1 2- diphenylpyrazolidine in a single-stage by direct reaction of p-chlorophenoxyacetic acid, pdiethylaminoethylamine and 4-n-butyl-3,5-diketo-1 ,2-diphenylpyrazolidine. After crystallisation from aqueous acetone or similar solvent a product is obtained of high purity, being suitable for application in the therapeutics.
The molecular compound of p-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n butyl-3,5-diketo-1 ,2-diphenylpyrazolidine has lower acute toxicity compared with the more widely used 4-n-butyl-3,5-diketo-1 ,2-diphenylpyrazolidine.
The invention will now be described, by way of illustration, in the following Examples:- Example 1
To 200 ml of toluene 77 g of 4-n-butyl-3,5-diketo-1 ,2-diphenylpyrazolidine, 46.5 g of pchlorophenoxyacetic acid and 29 g of p-diethylaminoethylamine were added, whereafter the mixture was heated to boiling in a flask provided with a reflux condenser. The mixture was maintained at boiling for 8 hours. The content of the flask was then cooled to the temperature of 200 C. From the post-reaction mixture there precipitated crystals of monohydrated compound of the p- diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n-butyl-3,5-diketo- 1,2diphenylpyrazolidine.
After filtering and washing with toluene, the crystals were treated, at the temperature of 600 C, with an 80% aqueous solution of acetone in a quantity of 252 g. After cooling, the molecular compound of the p-diethylaminoethyla mide of p-chlorophenoxyacetic acid with 4-n-butyl-3,5-diketo1 ,2-diphenylpyrazolidine, crystallised with two molecules of water and was filtered off, washed with aqueous solution of acetone and dried at the temperature of 600C.
102 g of the molecular compound were obtained, corresponding to a yield of 65%.
The molecular compound of p-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n butyl-3,5-diketo-1 2-diphenylpyrazolidine is a white powder readily soluble in methanol, dimethylformamide, dioxane, acetone and ethanol. Its solubility in chloroform is 0.5 g/1 0 cm3. It is insoluble in water, ether, benzene, and toluene. The melting point of the molecular compound is 89 to 900C.
A 0.002% solution of the molecular compound in methyl alcohol exhibits ultraviolet absorption maxima at wave-lengths of about 225 and 270 ym and the minima at a wave-length of about 239,tom.
Example 2
In 200 ml of toluene 77 g of 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine,46.5 g of pchlorophenoxyacetic acid, and 30.5 g of p-diethylaminoethylamine were dissolved, whereafter the mixture was heated to boiling in a flask provided with a reflux condenser and an adaptor for draining water. The mixture was maintained at boiling for 8 hours. Within this time about 2.5 ml of water collected in the adaptor. The toluene was then completely distilled off, and the oily residue was treated at 600C with an 80% solution of acetone in water in amount of 252 g.After cooling the molecular compound of p-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n-butyl-3,5-diketo-1 2- diphenylpyrazolidine crystallised with two molecules of water and was filtered off, washed with an aqueous solution of acetone, and dried at a temperature of 600 C, 108.5 g of molecular compound were obtained, having the characteristics specified in Example 1, corresponding to a yield of 69%.
Example 3
In 220 ml of xylene 77 g of 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine, 46.5 g of pchlorophenoxyacetic acid, and 29 g of p-diethylaminoethylamine were dissolved, whereafter the mixture was heated to boiling in a flask provided with a reflux condenser, and maintained at boiling for 4 hours.
The flask contents were then cooled to a temperature of 200C. From the post-reaction mixture there precipitated crystals of the monohydrate of the compound of p-diethylaminoethylamide of pchlorophenoxyacetic acid with 4-n-butyl-3,5-diketo-1 ,2-diphenylpyrazolidine.
After filtering and washing with xylene, the crystals were treated at a temperature of 600C with 80% aqueous solution of acetone in a quantity of 252 g. After cooling, the molecular compound crystallised with two molecules of water and was filtered off, washed with aqueous solution of acetone, and dried at a temperature of 600C.
104 g of the molecular compound were obtained, having the characteristics specified in Example 1, corresponding to a yield of 66%.
Example 4
In 220 ml of xylene 77 g of 4-n-butyl-3,5-diketo-1 ,2-diphenylpyrazolidine, 46.5 g of pchlorophenoxyacetic acid, and 31 g of p-diethylaminoethylamine were dissolved, whereafter the mixture was heated to boiling in a flask provided with a reflux condenser and an adaptor for draining water. The mixture was maintained at boiling for 4 hours. Over this period about 3.8 ml of water accumulated in the adaptor and the boiling point of the liquid increased to 1 480C.
After cooling the contents of the flask to the temperature of 200C the product was isolated in the form of an oily liquid, which after separation from the xylene layer was treated with 80% aqueous solution of acetone in a quantity of 265 g, and heated to a temperature of 600C.
The molecular compound of p-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n butyl-3,5-diketo-1 ,2-diphenylpyrazolidine, containing two molecules of water crystallised out and was filtered off, washed with an aqueous solution of acetone, and dried at a temperature of 600C.
114 g of the molecular compound were obtained, having the characteristics specified in Example 1 and corresponding to a yield of 72%.
Claims (5)
1. A process for preparation of a molecular compound of the p-diethylaminoethylamide of pchlorophenoxyacetic acid with 4-n-butyl-3,5-diketo-1 ,2-diphenylpyrazolidine, having the Formula 1,
comprising reacting p-chlorophenoxyacetic acid with p-diethylaminoethylamine in presence of 4-nbutyl-3,5-diketo-1,2-diphenylpyrazolidine in a non-polar solvent medium art a temperature of from 107 to 14800.
2. A process according to claim 1, in which the reactants are present in stoichiometric proportions or with slight excess of the p-diethylaminoethylamine.
3. A process according to claim 1 or claim 2, in which the molecular compound is isolated from the reaction medium and purified by crystallisation from an organic water-miscible polar solvent containing not less than 2 moles of water per 1 mole of molecular compound.
4. A process as claimed in claim 1, according to any one of Examples 1 to 4 hereinbefore.
5. The molecular compound of the p-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n-butyl-3,5-diketo-1 ,2-diphenylpyrazolidine, having the Formula 1 defined in claim 1, whenever prepared by the process claimed in any of the preceding claims.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PL1979219874A PL122256B1 (en) | 1979-11-26 | 1979-11-26 | Process for preparing molecular compound of beta-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidin |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2064522A true GB2064522A (en) | 1981-06-17 |
GB2064522B GB2064522B (en) | 1983-05-11 |
Family
ID=19999619
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8036306A Expired GB2064522B (en) | 1979-11-26 | 1980-11-12 | Phenylbutazone salt |
Country Status (8)
Country | Link |
---|---|
JP (1) | JPS5687567A (en) |
CS (1) | CS212286B2 (en) |
DD (1) | DD154817A5 (en) |
GB (1) | GB2064522B (en) |
HU (1) | HU185287B (en) |
PL (1) | PL122256B1 (en) |
RO (1) | RO81174B (en) |
SU (1) | SU1034605A3 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2628422A1 (en) * | 1988-03-10 | 1989-09-15 | Richter Gedeon Vegyeszet | SALT OF SODIUM MONOHYDRATE OF 1,2-DIPHENYL-3,5-DIOXO-4-N-BUTYLPYRAZOLIDINE ("PHENYLBUTAZONE") AND ITS PREPARATION |
WO2018231795A1 (en) * | 2017-06-13 | 2018-12-20 | Afecta Pharmaceuticals, Inc. | Ccl2 inhibitors |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1282693B1 (en) * | 1996-02-27 | 1998-03-31 | Dompe Spa | GEMINAL CARBOXYLIC ACIDS AND THEIR ESTERS; PHARMACEUTICAL PREPARATIONS THAT CONTAIN THEM USEFUL IN THE TREATMENT OF BONE DYSMETABOLISM |
-
1979
- 1979-11-26 PL PL1979219874A patent/PL122256B1/en unknown
-
1980
- 1980-11-12 SU SU803003653A patent/SU1034605A3/en active
- 1980-11-12 GB GB8036306A patent/GB2064522B/en not_active Expired
- 1980-11-14 CS CS807738A patent/CS212286B2/en unknown
- 1980-11-21 RO RO102656A patent/RO81174B/en unknown
- 1980-11-25 JP JP16577880A patent/JPS5687567A/en active Pending
- 1980-11-26 DD DD80225497A patent/DD154817A5/en unknown
- 1980-11-26 HU HU802826A patent/HU185287B/en unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2628422A1 (en) * | 1988-03-10 | 1989-09-15 | Richter Gedeon Vegyeszet | SALT OF SODIUM MONOHYDRATE OF 1,2-DIPHENYL-3,5-DIOXO-4-N-BUTYLPYRAZOLIDINE ("PHENYLBUTAZONE") AND ITS PREPARATION |
WO2018231795A1 (en) * | 2017-06-13 | 2018-12-20 | Afecta Pharmaceuticals, Inc. | Ccl2 inhibitors |
Also Published As
Publication number | Publication date |
---|---|
DD154817A5 (en) | 1982-04-21 |
HU185287B (en) | 1984-12-28 |
GB2064522B (en) | 1983-05-11 |
SU1034605A3 (en) | 1983-08-07 |
RO81174A (en) | 1983-04-29 |
PL122256B1 (en) | 1982-07-31 |
CS212286B2 (en) | 1982-03-26 |
PL219874A1 (en) | 1981-06-05 |
RO81174B (en) | 1983-04-30 |
JPS5687567A (en) | 1981-07-16 |
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PCNP | Patent ceased through non-payment of renewal fee |