WO2005066185A1 - Procede de preparation de 1-(4-fluorophenyle) -1,3-dihydroisobenzofuranes substitues en 5 - Google Patents

Procede de preparation de 1-(4-fluorophenyle) -1,3-dihydroisobenzofuranes substitues en 5 Download PDF

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Publication number
WO2005066185A1
WO2005066185A1 PCT/IN2004/000007 IN2004000007W WO2005066185A1 WO 2005066185 A1 WO2005066185 A1 WO 2005066185A1 IN 2004000007 W IN2004000007 W IN 2004000007W WO 2005066185 A1 WO2005066185 A1 WO 2005066185A1
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formula
substituted
solvent
boron complex
solution
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PCT/IN2004/000007
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English (en)
Inventor
Ambati Narahari Babu
Vuddamari Srinivas Goud
Santosh Laxman Gaonkar
Sulur G. Manjunatha
Ashok Krishna Kulkarni
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Jubilant Organosys Limited
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Priority to PCT/IN2004/000007 priority Critical patent/WO2005066185A1/fr
Publication of WO2005066185A1 publication Critical patent/WO2005066185A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids

Definitions

  • the present invention relates a method for preparation and isolation of hitherto unknown solid boron complex of formula (V) which are useful in the preparation of 5- substituted phthalens, which are key staring materials for manufacturing citalopram and pharmaceutically acceptable acid addition salts.
  • the hydroxymethylketone of the Formula (4A) is then reduced with lithium aluminium hydride in ether medium to provide 4-bromo-2-hydroxymethylphenyl-(4- fluorophenyl)methanol (diol of Formula 5A).
  • the diol of the Formula (5A) is then cyclized with aqueous phosphoric acid to produce crude 5-bromophthalane (5-bromo- 1-(4-fluorophenyl)-1 ,3-dihydroisobenzofuran of the Formula (2A) having an HPLC purity around 75-80%.
  • the crude 5-bromophthalane is purified by high vacuum distillation at 170-175°C /1 mm Hg to get substantially pure 5-bromophthalane, which is then converted to 5-cyanophthalane (5-cyano-1-(4-fluorophenyl)-
  • reaction mass is diluted with alcoholic solvents like methanol, ethanol and isopropyl alcohol followed by addition of sodium borohydride at 10°C. After completion of the reduction, reaction mass is diluting with aq. hydrochloric acid. The resulting solution is extracted into toluene. The toluene layer is removed under reduced pressure to get oily crude diol compound (5A). The diol compound is subjected to cyclization in the presence of para-toluene sulphonic acid in toluene medium to get 5-bromo-1-(4-fluorophenyl)-1,3 -dihydroisobenzofuran (2A) .
  • alcoholic solvents like methanol, ethanol and isopropyl alcohol followed by addition of sodium borohydride at 10°C.
  • reaction mass is diluting with aq. hydrochloric acid.
  • the resulting solution is extracted into toluene.
  • the toluene layer is removed under reduced pressure
  • the crude5-bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (2A) is subjected to cyanation reaction with copper (I) cyanide in dimethylformamide at 150- 160°C, followed by work up to get crude 5-cyano-1-(4-fluorophenyl)-1 ,3- dihydroisobenzofuran (2B) with HPLC purity of around 80-85%, which is purified in different solvents and mixture of solvents to get pure 5-cyanophthalane (2B).
  • the major drawbacks of this process are that: i) repeated purification steps are required to get desired quality of 5-cyano-1-( 4- fluorophenyl)-1,3-dihydroisobenzofuran from crude 5-cyano-1-(4-fluorophenyl)-1 ,3 dihydroisobenzofuran thus rendering the process uneconomical.
  • the present invention provides a simple procedure for the preparation and isolation of free flowing solid of boron complex of Formula (V) which as it is subjected to cyclization reaction with aqueous hydrochloric acid to produce corresponding 5- substituted phthalanes of Formula (2) with high purity. Summary of the Invention According to the present invention it has now been surprisingly found that solid boran complex of Formula (V)
  • Formula (V) wherein R is selected from Br; CN; CI; I; NH2 and CO2; can be prepared in good yields, by a process comprising: a) subjecting 5-substitued phthalide of Formula (3) in a solvent to Grignard reaction with a solution containing a 4-fluorophenylmagnesium halides followed by quenching to obtain hydroxymethylketone a compound of Formula (4) in a solvent medium.
  • R is selected from Br; CN; CI; I; NH2 and CO2
  • the 5-bromo 1-(4-fluorophenyl)-1 ,3-dihydro- isobenzofuran is 5-bromophthalane(2A)
  • the corresponding 5-substituted phthalide is 5-bromophthalide(3A).
  • the 5-cyano 1-(4-fluorophenyl)-1 ,3-dihydro-isobenzofuran is 5-cyanophthalane(2B)
  • the corresponding 5-substituted phthalide is 5- cyanophthalide(3B).
  • the boron complex of Formula (V) can be prepared in good yields by a Grignard reaction with substituted phthalides (3) in which the molar ratio of 4-fluorophenyl magnesium halide to the 5-substituted phthalide is preferably is 1:1 to 1.4 :1.
  • the solvent is selected from the group of 1 ,4-dioxane, diethylether or dimethoxyethane. and tetrahydrofuran (THF) for generating 4-fluorophenyl magnesiumhalides.
  • the most preferred ether solvent is tetrahydrofuran ( THF).
  • 5-substituted phthalides of the Formula (3) is taken in a solvent selected from the group consisting of aliphatic or aromatic chlorinated solvents or aromatic hydrocarbons.
  • a solvent selected from the group consisting of aliphatic or aromatic chlorinated solvents or aromatic hydrocarbons.
  • the solvent is selected from the group consisting of methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform, chlorobenzene, dichlorobenzene, and mixtures thereof. Methylene dichloride and especially chloroform are particularly preferred.
  • aromatic hydrocarbon co-solvents toluene, benzene or xylene, or mixtures thereof, are preferred. Toluene is particularly preferred.
  • the ether solvent and a solvent medium for 5-substituted phthlides are both dry and suitably, the volumetric ratio of ether solvent to a solvent medium for 5-substituted phthlides is between 3 : 10 and 6 : 7.
  • the lowest proportion of the ether solvent to the solvent medium for 5-substituted phthlides is restricted by the tendency of the Grignard reagent to precipitate out of solution.
  • the Grignard reaction is suitably carried out at a temperature below 10°C, preferably at a temperature from -6°C to +6°C, and most preferably, at a temperature from -6°C to - 2°C.
  • the process comprises boron complex formation, a ketone reduction and step following the Grignard reaction.
  • the reducing agent for the reduction and complex formation is sodium borohydride.
  • about 0.25 to about 1.0 molar equivalents of sodium borohydride are used.
  • Particularly, preferably, only about 0.5 molar equivalents of sodium borohydride are used.
  • sodium borohydride is used for reducing ketone and also formation of boron complex of formula (V).
  • the two reactions (reduction, complex formation) are carried out in situ in a single stage.
  • the structurally similar impurities and the starting materials of formula (3) can be removed by filtration to get pure boron complex of Formula (V) which is characterised by NMR spectrum and elemental analysis.
  • the NMR spectrum shows the following peaks at ( ⁇ ppm).
  • Solvent is CD3OD; 4.48 -4.73 dd 2H ; 6.07 s 1 H ; 7.04-7.87 m 7H aromatic, and the same compound analysed by elemental analysis shows 3-4% of boron content.
  • Structurally similar impurities are formed during the Grignard reaction of 5- substituted phthalides with 4-fluorophenylmagnesium halide in a solvent medium followed by reduction in the presence of sodiumborohydride. These impurities have high boiling points.
  • the process further comprises carrying out a cyclisation reaction of the boron complex.
  • the cyclization reaction is carried out in presence of an inorganic acid or organic acid.
  • Inorganic acids that may be used include aqueous phosphoric acid and aqueous sulphuric acid, but preferably, aqueous hydrochloric acid, more preferably concentrated hydrochloric acid, is used.
  • Organic acids that may be used include methanesulfonic acid, benzenesulfonic acid and para-toluene sulfonic acid (PTSA).
  • PTSA para-toluene sulfonic acid
  • the amount of acid used is suitably a limited amount and preferably is a catalytic amount.
  • a solution of 4-fluorophenyl magnesium bromide is prepared from 4-bromofluorobenzene, magnesium turnings and catalytic amount of iodine in dry tetrahydrofuran (THF), and is added drop-wise to a suspension of 5-bromophthalide of Formula (3A) in a dry dichloromethane under nitrogen atmosphere at a temperature below 10°C, preferably -6°C to + ⁇ °C, and most preferably -6°C to -2°C, over a period of 4-6 hours.
  • THF dry tetrahydrofuran
  • reaction mixture is quenched with 20% aqueous ammonium chloride solution, and the organic layer is separated and diluted with methanol. Then, sodium borohydride (0.5-1.0 molar equivalents, preferably 0.5 molar equivalents) is added lot-wise to the reaction mixture at a temperature of below 25°C and the reaction mixture is further stirred for an additional 2 hours at the same temperature.
  • solvent is distilled off completely under reduced pressure to obtain a residue, which is treated with non polar solvents like n-hexane, n-heptane and pentane, (the most preferred non polar solvent being n-hexane) and stirred for 2-3 hours at 0-5°C.
  • the precipitated solid is filtered and washed with n-hexane to obtain pure boron complex of Formula (VA).
  • the above isolated boron complex of formula (VA) is then as such subjected to cyclization reaction in the presence of an inorganic acid or organic acid.
  • a particularly preferred organic acid is para-toluene sulfonic acid (PTSA), and this is suitably used in catalytic amounts.
  • PTSA para-toluene sulfonic acid
  • solid boron complex and aqueous hydrochloric acid mixture is heated to 60-70°C for 2-3 hours. After the completion of the reaction, the reaction mass is cooled to room temperature and extracted with an aliphatic or aromatic hydrocarbon, such as n-hexane, cyclohexane, benzene and toluene.
  • the organic layer is washed with dilute sodium hydroxide solution and water.
  • the organic layer is treated with activated charcoal, and concentrated under reduced pressure to provide 5- bromophthalane of the Formula (2A) having a purity of greater than 98%
  • solid boron complex is suspended in an organic solvent, for example, in toluene, and a catalytic amount of p-toluene sulfonic acid (5- 10% w/w) is added.
  • the resulting mixture is heated to 85-90°C.
  • the reaction mixture is washed with dilute sodium hydroxide solution, water and finally the solvent is removed under reduced pressure to produce 5-bromophthalane of the Formula (IIA).
  • 5-Bromophthalane of the Formua (2A) can be converted to 5-cyanophthalane (2 B) using known procedures, without any further purification to get pure 5-cyanophthale HPLC having a purity of more than 98%.
  • a solution of 4-fluorophenyl magnesium bromide in tetrahydrofuran is added drop-wise over a period of 4-6 hours to a suspension of 5-cyanophthalide of Formula (3B) in a dry dichloromethane under nitrogen atmosphere below 10°C (preferably, -6°C to +6°C, and most preferably, -6°C to -2°C).
  • reaction mixture is quenched with 20% aqueous ammonium chloride solution.
  • organic layer is separated and diluted with methanol.
  • sodiumborohydride 0.5 molar equivalents
  • the reaction mixture is stirred for additional 4-6 hours.
  • the reaction mixture is cooled to below 10°C and the precipitated solid is filtered to produce pure crystalline boron complex with more than 98% purity by HPLC.
  • the crystalline boron complex of Formula (VB) is taken in an organic solvent such as toluene or methanol, preferably toluene, followed by cyclisation in 30% aqueous hydrochloric acid at 65-70°C. After the completion of the reaction, the reaction mass is cooled to 25-30°C and extracted into water immiscible organic solvents such as benzene, toluene, dichloromethane, dichloroethane and ethylacetate. The preferred organic solvent is dichloromethane. The organic layer is treated with activated carbon and concentrated under reduced pressure to get residue.
  • organic solvent such as toluene or methanol, preferably toluene
  • Isopropanol is added to the residue to provide white crystalline 5-cyanophthalane of the Formula (2B) having a purity of more than 99% by HPLC.
  • the cyclisation may also be carried out in toluene using a catalytic amount of p-toluenesulfonic acid (5- 10% w/w with respect to 5-cyanophthalide) to produce 5-cyanophthalane of the Formula (2B).
  • p-toluenesulfonic acid 5- 10% w/w with respect to 5-cyanophthalide
  • Such solid boron complex can be filtered to remove structurally similar impurities, which are formed during the Grignard reaction of 5- substituted phthalides with a solution of 4-fluorophenyl magnesium halides followed by reduction, In other words, these structurally similar impurities are removed by simple filtration, without applying any high vacuum distillation at higher temperature and repeated crystallizations of intermediate stages. Furthermore, using the method of the present invention, 0.50 molar equivalents of sodium borohydride is sufficient to reduce the hydroxyketone of the Formula (4) into boron complex of Formula (V),
  • the present invention will now be described in greater detail with reference to the following examples, which are merely intended to further illustrate the present invention and not to limit the scope thereof:
  • Example 1 Process for preparation of 5-cyano phthalane (2B).
  • the organic layer was separated and diluted with 100ml of methanol. Slowly, 12g of sodium borohydride (0.324moles) was added over a period of one hour at below 25°C, and the same temperature was maintained for 4-6 hours. The mixture was then cooled to 5-10°C, maintained for 2 hours and then the precipitated boron complex VB solid was filtered. The solid was washed with chilled dichloromethane and dried under vacuum below 40°C to provide pure boron complex.
  • Example 2 Process for Preparation of 5-bromophthalane (2A) a) Isolation of boran complex (VA) from 5-bromo phthalide (2A) A solution of 4-fluorophenyl magnesium bromides prepared from 116g 4-fluoro bromobenzene (0.662 moles), 18.81g magnesium turnings (0.78 moles) and 0.05g iodine in dry 300ml tetrahydrofuran was added to a suspension of 100g 5-bromophthalide (0.469 moles) in 1000ml of dichloromethane at -6 to -2°C.
  • VA boran complex
  • reaction mass was quenched with 100ml 20% aqueous ammonium chloride solution.
  • organic layer was separated and diluted with 100ml of methanol.
  • 12g of sodium borohydride (0.324moles) was added in lots over a period of one hour at below 25°C and the temperature was maintained for additional one hour.
  • the solvent was removed under reduced pressure to get residue.
  • the residue was treated with n-Hexane 500 ml to precipitate boron complex of Formula -

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Abstract

L'invention concerne un procédé pour préparer et isoler un complexe de bore solide inconnu jusqu'alors de formule (v), que l'on obtient en faisant réagir des phtalides substitués en 5 avec une solution de bromure de magnésium 4-fluorophényle, puis en réalisant une réduction in situ et en formant un complexe en présence de borohydrure de sodium. Des complexes de bore de ce type sont aisés à filtrer pour ôter les impuretés structurellement similaires, avant d'être soumis à une réaction de cyclisation dans un milieu acide pour former des phtalènes de haute pureté substitués en 5, qui sont des matières de base clés pour la production de citaloprame et de sels d'addition acide pharmaceutiquement acceptables.
PCT/IN2004/000007 2004-01-12 2004-01-12 Procede de preparation de 1-(4-fluorophenyle) -1,3-dihydroisobenzofuranes substitues en 5 WO2005066185A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8288569B2 (en) 2006-01-23 2012-10-16 Sandoz Ag Carbonyl asymmetric alkylation
CN105801539A (zh) * 2016-03-31 2016-07-27 常州大学 一种1-（4-碘苯基）-5-氯异苯并呋喃的合成方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KUZNETSOV ET AL., CHEM. HETEROCYCL. COMPD., vol. 37, no. 1, 2001, pages 129 - 130, XP009036689, ISSN: 0022-328X *
WITTIG, CHEM. BER., vol. 64, 1931, pages 2395 - 2403, XP009036688, ISSN: 0168-583X *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8288569B2 (en) 2006-01-23 2012-10-16 Sandoz Ag Carbonyl asymmetric alkylation
CN105801539A (zh) * 2016-03-31 2016-07-27 常州大学 一种1-（4-碘苯基）-5-氯异苯并呋喃的合成方法

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