Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

• the present invention relates to a new process for the preparation of 4- (acetylamino) phenyl nitrooxyalkanoates, in particular of 4- (acetylamino) phenyl 4-nitrooxybutanoa-te .
• 4- (Acetylamino) henyl 4-nitrooxybutanoate is a nitric oxide donating analgesic with significantly reduced li-ver toxicity in comparison with 4- (acetylamino) phenol (paracetamol or acetaminophen) .
• the principal drawbacks of the above reported synthesis are the use of the silver salts in an amount more than stoichiometric and the fact that 4-bromobutanoic acid is not commercially available.
• the use of the silver nitrate in a large amount makes the method expensive and not useful under the point of view of the industrial application.
• Furthermore the use of a transition metal in the last step of the process makes difficult the complete removal of the same from the active pharmaceutical product, unless techniques of chromatographic purification are applied. Said techniques are not industrially applicable for the amount of drug necessary to satisfy the market demand of an analgesic drug.
• the present application provides a new method of synthesis which overcomes the drawbacks of the previous method.
• the present invention relates to a process for preparing a compound of the following formula (I) :
• Y is OH, CI, OCOOR, 0C0-X-0N0 2 .
• R is a C ⁇ -C e alkyl and X is as defined above.
• X is preferably a straight or branched Ci-C ⁇ alkylene chain, more preferably X is an ethylene, propylene or butylene chain, most preferably it is propylene.
• Y is preferably OH or CI.
• M is preferably a hydrogen atom, or a cation of Na or of K or tetralkylamonium or tetraalkylphosphonium. When M is H and Y is OH, the reaction is carried out in the presence of a dehydrating agent in aprotic dipolar solvents such as THF, DMF, N-Methyl-pyrrolidone .
• the dehydrating agent is preferably dicyclohexylcarbodiimide (DCC) ; or DCC and an aminopyridine; Amberlyst-15; diethtyl azodicarboxylate and triphenylphosphine (Mitsunobu esterification reaction) .
• Other dehydrating agents include chlorosilanes; methanesolsonyl chloride and triethylamine; and N,N-carbonyldiimidazole .
• the molar ratio between the compound of formula (II) and the acid of formula (III) is from 0.5 to 2.0.
• the reaction is carried out at a temperature ranging from 0°C to 100°C.
• M is a cation of Na or K and Y is CI
• the reaction may be carried out in dipolar aprotic solvents such as tetrahydrofuran, dioxane, tert-butyl methylether, pyridine.
• M is tetralkylamonium or tetralkylphosphonium and Y is CI
• the reaction is carried out in aprotic solvents such as toluene, chlorobenzene, tetrahydrofuran, tert-butyl methyl ether.
• the reaction may be carried out under phase transfer conditions.
• the reaction may be carried out at a temperature ranging from 0°C to 100°C.
• the molar ratio between the compound of formula (II) and the acid chloride of formula (III) is from 0.5 to 2.0.
• compounds of formula (I) are obtained by a synthesis which does not involve chemical transformation of intermediates structurally related to the active principle. Therefore the formation of impurities structurally related to the end compounds of formula (I) , which could make problematic the purification, is avoided. This is a further advantage in comparison with the process described in the prior art.
• the compound of formula (II) wherein M is H is paracetamol, a commercially available compound.
• the compounds of formula (II) wherein M is a cation of an alkaline metal or of an alkaline earth metals may be prepared by reacting 4-acetylaminophenol in a suitable organic solvent, for example tetrahydrofuran, dimethylformarrd.de etc., with a base such as NaH, NaOH, KOtBu.
• the compounds of formula (II) wherein M is a onium cation may be prepared by reacting 4-acetylaminophenol with tetralkylamonium or tetralkylphosphonium hydroxide or by reacting an alkaline salt of 4-acetylaminophenol with a tetralkylamonium or tetralkylphosphonium salt generally in a two phases system consisting of inorganic solvents such as toluene, chlorobenzene and water.
• the compounds of formula (III), wherein Y is CI can be obtained from the corresponding compounds of formula (III) wherein Y is OH by procedures known to a person skilled in the art such as for example by treatment with S0C1 2 /DMF
• the compounds of formula (III) wherein Y is 0C00R can be obtained from the corresponding compounds of formula (III) wherein Y is OH by procedures known to a person skilled in the art such as for example by treating an alkaline metal salt of III with the C1C00R of choice.
• the compounds of formula (III) wherein Y is 0C0-X-ON02 can be obtained from the corresponding compounds of formula (III) wherein Y is OH by procedures known to a person skilled in the art such as for example by treatment with dehydrating agents .
• the compound of formula (III) wherein Y is OH can be prepared transforming an acid of formula (IV)
• the preparation of the 4-nitrooxybutirric acid and the reaction with PCI5 to give its corresponding acyl chloride is described in the patent US 4 801 596 of January 31, 1989.
• the nitration method consists in the addition of the sodium or potassium salt of the 4-hydroxybutirric acid, obtained by opening the ⁇ -butyrolactone with KOH, to a sulfonitric mixture according to the following Scheme 2 :
• the product was obtained as a yellowish solid (3.25 g) .
• Nitric acid (100% HN0 3 , 0.6 ml) was added dropwise to stirred sulphuric acid (96% H 2 S0 4 , 0.6 ml) kept at 0°C by external cooling.
• CH 2 C1 2 (10 ml) was added to the HN03/H2S04 mixture, and the resulting solution was stirred for 15 minutes.
• Potassium 4- (hydroxy) butanoate 500 mg, 3.52 mmol

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Pain & Pain Management (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Engineering & Computer Science (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (5)

Applications Claiming Priority (2)

Publications (2)

Family

ID=34639350

Family Applications (1)

Country Status (8)

Cited By (3)

Families Citing this family (3)

Family Cites Families (6)

• 2004
  • 2004-11-04 US US10/579,904 patent/US7442826B2/en not_active Expired - Fee Related
  • 2004-11-04 CA CA002546807A patent/CA2546807A1/en not_active Abandoned
  • 2004-11-04 EP EP04798162A patent/EP1727787B1/en not_active Expired - Lifetime
  • 2004-11-04 WO PCT/EP2004/052806 patent/WO2005054175A2/en not_active Ceased
  • 2004-11-04 JP JP2006540430A patent/JP2007511581A/ja active Pending
  • 2004-11-04 ES ES04798162T patent/ES2309579T3/es not_active Expired - Lifetime
  • 2004-11-04 AT AT04798162T patent/ATE399757T1/de not_active IP Right Cessation
  • 2004-11-04 DE DE602004014822T patent/DE602004014822D1/de not_active Expired - Lifetime

Also Published As

Similar Documents

Legal Events