Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
  • C07D307/83—Oxygen atoms
• • 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
  • A61P25/24—Antidepressants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
  • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3

Definitions

• the present invention concerns a process for the preparation of an isobenzofuran derivative. More particularly, the invention refers to a process for the preparation of 1-oxo-l, 3-dihydro-5- 5 isobenzofurancarboxylic acid.
• 5- 15 carboxyphthalide is an intermediate useful in the synthesis of citalopram, a well-known antidepressant drug, whose preparation using said intermediate is described in the International Patent Application WO 00023431 and in the corresponding Italian Patent Application IT1999 MI 0001724, whose contents must be considered 20 as integral part of the present description.
• 5-carboxyphthalide may be prepared by reduction of one of the carbonyl groups of trimellitic anhydride, which can occur by hydrogenation or, according to DE-2630927, by electrochemical reduction.
• This method has the drawback of giving 25 a 5-carboxyphthalide containing, as a by-product, the 6 isomer in an amount which can reach 10%.
• An impurity which is present in such a percent cannot be accepted if 5-carboxyphthalide must be used as an intermediate in the preparation of drugs and, in such a case, it must be removed or strongly reduced to a value not higher 30 than 0.1%. The removal of the 6 isomer occurs by several crystallizations which lower the yield in final product considerably .
• 5-carboxyphthalide may be prepared according to another method, described in US 3,607,884, which
• the present invention provides, according to a method of simple execution, a process for the preparation of 5- carboxyphthalide of formula A, which comprises adding terephthalic acid of formula I
• formaldehyde is used in one of its solid forms, currently in form of its precursor 1, 3 , 5-trioxane of formula II
• the fuming sulfuric acid which represents the reaction medium, also is the dehydrating agent which allows the direct transformation, in situ, of the 2-hydroxymethylterephthalic acid thus obtained of formula III
• terephthalic acid is added to fuming sulfuric acid, currently containing at least by weight 20%, advantageously 22 ⁇ 33%, preferably 25 ⁇ 30% by weight of S ⁇ 3 , then the mixture thus obtained is treated with 1, 3 , 5-trioxane at a temperature of 30 ⁇ 35°C and subsequently heated at a temperature of 120 ⁇ 145°C, preferably at 130 ⁇ 135°C.
• the temperature is brought to 130 ⁇ 145°C and, after a 2 ⁇ 5-hour heating at this temperature, there is formed compound III which concurrently dehydrates to give 5-carboxyphthalide.
• the preferably used amount of fuming sulfuric acid containing 25 ⁇ 30% by weight in S0 3 is 2 ⁇ 8 1/Kg of terephthalic acid, advantageously 2 ⁇ 6 1/Kg, preferably 3 ⁇ 6 1/Kg, particularly about 3 1/kg.
• the mixture when the reaction is over, the mixture may be poured into ice, by anyhow controlling the exothermia of this operation, and the strong acidity of the medium may be neutralized with a base, preferably sodium, hydroxide, carbonate or bicarbonate .
• a base preferably sodium, hydroxide, carbonate or bicarbonate .
• the mixture in sulfuric acid may also at first be diluted with glacial acetic acid and then treated with water.
• the mixture is diluted with glacial acetic acid in an amount of 200 ml per 100 g of terephthalic acid, by letting the temperature to rise to 20 ⁇ 25°C at the end of the addition. Successively the water is added and, under external cooling, the temperature may rise to 45 °C. Finally, the mixture is neutralized with a base, as set forth above.
• the isolation steps during the addition of the base, it may be suitable to reach a pH ⁇ 8, whereby the 5-carboxyphthalide is present in the solution as a salt, advantageously of an alkali metal, preferably of sodium, and to filter off the insoluble products whilst the 5-carboxyphthalide salt remains dissolved in the medium.
• a neutral filter aid for example Celite" or Dicalite ® .
• the 5- carboxyphthalide free acid may be easily recovered in good yields from the solution containing its salt by neutralization with an acid, for example with hydrochloric acid, and isolated in sufficiently pure form for its use as intermediate for the preparation of drugs.
• the 5-carboxyphthalide precipitates at acid pH at a value of about 3, preferably in the range of 1.8 ⁇ 3.0, and is isolated by simple filtration.
• the isolation steps through the salt preferably with an alkaline metal, it is suitable to maintain the pH value not higher than 8 in order to avoid the formation of by-products.
• the alkaline agent it is suitable to control the pH changes when a value of about 5 is reached, because around this value it is possible that small additions of base involve considerable pH variations .
• the mixture may be treated by dropping water thereinto, so that said water initially destroys any possible residual S0 3 and then dilutes sulfuric acid progressively thus rendering the isolation of 5-carboxyphthalide easier.
• the addition of water, which produces exothermia, is preferably made at a temperature of 0 ⁇ 5°C.
• the control of the temperature may be limited to the initial period of the addition of 10 ⁇ 15% of water (in respect of the used fuming sulfuric acid); afterwards, particular care are not necessary because the temperature of the mixture remains at about 20 ⁇ 25°C and, hence, it may be easily controlled.
• the 5-carboxy phthalide may be isolated by simple filtration, by washing with water, if necessary by triturating the obtained product in water.
• the mixture is heated to 120°C and it is noted that, already at
• the solid is removed by filtration on Dicalite in a buchner and washed with water.
• the solid is filtered, washed 3 times with 500 ml of deionized water at 40°C and suspended in 1000 ml of deionized water.
• the suspension is heated under stirring at 50 ⁇ 55°C and kept 1 hour under these conditions, then it is hot filtered.
• the solid is washed with deionized water and dried in vacuo at 50 °C to constant weight.
• 180 g of light-brown coloured 5- carboxyphthalide with a purity (HPLC) > 95% are obtained.
• the mixture is nevertheless heated to 130 ⁇ 135°C and kept 4 hours under these conditions.
• the cooled mixture is poured, in about 1 hour and without exceeding the temperature of 25 ⁇ 35°C, into 3000 g of crushed ice.
• 300 ml of 5% w/w solution of sodium hydroxide are added to the mixture to a pH __ 8.
• the solid is
• the mixture is let to stand 60 minutes under stirring at 20 ⁇ 25°C and filtered.
• the wet product is suspended in 1900 ml of water.
• the suspension is heated up to 25 ⁇ 30°C under stirring, its pH is adjusted to about 8 by gradual addition of 175 g of sodium bicarbonate.
• the solid is filtered off
• the mass is cooled to -5 ⁇ 0°C and 1800 ml of cold deionized water are added thereto. During this operation the temperature rises to 43 ⁇ 45°C. At the end of the addition, the mixture is kept 1 hour under stirring at 23 ⁇ 25°C, then it is filtered, the solid is washed with deionized water abundantly and suspended, still wet, in 1200 ml of deionized water at room temperature. To the suspension thus obtained, about 1550 g of a 7% solution of NaHC0 3 are added to a constant pH of 7,6 ⁇ 7,8.
• the mixture is kept 1 hour under stirring at 20 ⁇ 25°C, the product thus obtained is filtered, still moist triturated in 300 ml of water repeatedly until the reddish colour of the mother liquors disappears. After the third trituration, the pH of the mother liquors stabilizes at values ranging from 5 to 6.
• the product is dried in vacuo at 45 ⁇ 50°C until constant weight to give 47.5 g of 5-carboxyphthalide with a titer and a purity (HPLC) > 95%.
• EXAMPLE 6 In a 3000-1 glass lined reactor, 550 Kg of oleum containing 25% of S0 3 are charged under vacuum and good aspiration, then, consecutively, under stirring, 56 Kg of terephthalic acid at 20 ⁇ 23°C and 26 Kg of 1 , 3 , 5-trioxane at 15 ⁇ 20°C are added thereinto. The reactor is heated at 130 ⁇ 133°C for 4 hours, then the mixture is cooled to 20 ⁇ 23°C and 118 Kg of glacial acetic acid are couled portionwise thereinto at a temperature not higher than 25 °C. At the end of this operation, 1000 Kg of water are added portionwise, whereby the temperature is maintained not higher than 43 ⁇ 45°C by circulation of water in the jacket.
• the mixture is stirred for about 1 hour at 20 ⁇ 23°C, then the product is centrifugated, squeezed and abundantly washed with water in order to remove the larger amount of sulfuric acid from the mother liquors and to obtain 100 ⁇ 105 Kg of 5-carboxyphthalide as a well squeezed, wet raw-product.
• the product thus obtained is suspended in 680 Kg of deionized water and a solution of 60 Kg of sodium bicarbonate in 540 Kg of deionized water is then slowly added to said suspension to a pH of

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• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pain & Pain Management (AREA)
• Life Sciences & Earth Sciences (AREA)
• Psychiatry (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Furan Compounds (AREA)
• Cephalosporin Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Seasonings (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

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• 2000
  • 2000-01-18 IT IT2000MI000050A patent/IT1317729B1/it active
  • 2000-10-17 DK DK00203602.8T patent/DK1118614T4/da active
  • 2000-10-17 US US09/690,301 patent/US6458973B1/en not_active Expired - Fee Related
  • 2000-10-17 ES ES00203602T patent/ES2178626T5/es not_active Expired - Lifetime
  • 2000-10-17 DE DE60000226T patent/DE60000226T3/de not_active Expired - Lifetime
  • 2000-10-17 EP EP00203602A patent/EP1118614B2/en not_active Expired - Lifetime
  • 2000-10-17 AT AT00203602T patent/ATE219489T1/de not_active IP Right Cessation
  • 2000-10-17 PT PT00203602T patent/PT1118614E/pt unknown
  • 2000-12-07 JP JP2000372224A patent/JP4558182B2/ja not_active Expired - Lifetime
• 2001
  • 2001-01-17 CN CNB018038484A patent/CN1184220C/zh not_active Expired - Lifetime
  • 2001-01-17 CA CA2397497A patent/CA2397497C/en not_active Expired - Fee Related
  • 2001-01-17 HU HU0204187A patent/HUP0204187A3/hu unknown
  • 2001-01-17 RO ROA200200989A patent/RO121737B1/ro unknown
  • 2001-01-17 AU AU26798/01A patent/AU779581B2/en not_active Revoked
  • 2001-01-17 PL PL01356563A patent/PL356563A1/xx not_active IP Right Cessation
  • 2001-01-17 BR BR0107853-4A patent/BR0107853A/pt not_active Application Discontinuation
  • 2001-01-17 WO PCT/EP2001/000617 patent/WO2001053284A1/en not_active Ceased
  • 2001-01-17 MX MXPA02007031A patent/MXPA02007031A/es active IP Right Grant
  • 2001-01-17 EP EP01901181A patent/EP1187822A1/en not_active Withdrawn
• 2002
  • 2002-01-25 HK HK02100631.3A patent/HK1042290B/en not_active IP Right Cessation
  • 2002-07-09 ZA ZA200205475A patent/ZA200205475B/xx unknown
  • 2002-07-16 BG BG106925A patent/BG65763B1/bg unknown
  • 2002-08-23 US US10/227,038 patent/US6703516B2/en not_active Expired - Fee Related
• 2004
  • 2004-03-08 US US10/796,336 patent/US20040171851A1/en not_active Abandoned
• 2007
  • 2007-10-22 US US11/975,842 patent/US20080249319A1/en not_active Abandoned

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