WO2011044990A1 - Process for preparing 1,2,6,7-tetrahydro-8h-indeno[5,4-b]furan-8-one - Google Patents

Process for preparing 1,2,6,7-tetrahydro-8h-indeno[5,4-b]furan-8-one Download PDF

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WO2011044990A1
WO2011044990A1 PCT/EP2010/005941 EP2010005941W WO2011044990A1 WO 2011044990 A1 WO2011044990 A1 WO 2011044990A1 EP 2010005941 W EP2010005941 W EP 2010005941W WO 2011044990 A1 WO2011044990 A1 WO 2011044990A1
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formula
furan
indeno
tetrahydro
iii
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PCT/EP2010/005941
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French (fr)
Inventor
Yunwei Zhu
Jingjun Wei
Liang Chen
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Lonza Ltd
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Priority to EP10763319A priority patent/EP2483258A1/en
Publication of WO2011044990A1 publication Critical patent/WO2011044990A1/en

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    • 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
    • C07D307/93—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 condensed with a ring other than six-membered

Definitions

  • the present invention relates to a process for preparing 1 ,2,6,7-tetrahydro-8H- indeno[5,4-b]furan-8-one.
  • EP-A-0 885 210, EP-A- 1 792 899 and Uchikawa et al. describe methods for the preparation of 1 ,2,6,7-tetrahydro-8/- -indeno[5,4-?]furan- 8-one as an intermediate in the preparation of indenofurannitrile starting from 2,3-dihydrobenzofuran. This route involves numerous and complex reaction steps and the overall yield is low.
  • the object of the present invention was to provide a simple and cost efficient process for preparing 1 ,2,6,7-tetrahydro-8H-indeno[5,4-fo]furan-8-one having a reduced number of steps and resulting in good yields.
  • step (ii) reducing the ozonide formed in step (i) in the presence of methanol to form 2- methoxy-I ⁇ J-tetrahydro-SH-indeno ⁇ -bJfuran-S-one of the formula (III)
  • Ozonolysis of compound (II) in step (i) of the process of the invention is typically carried out in an organic solvent inert under the reaction conditions.
  • suitable organic solvents include alcohols, ethers and halogenated hydrocarbons.
  • Preferred alcohols are methanol, ethanol and isopropanol.
  • Preferred ethers are isopropyl ether, diethyl ether and tetrahydrofuran (THF).
  • Preferred halogenated hydrocarbons are dichloromethane, chloroform and 1 ,2-dichloroethane. Solvents may be used alone or as mixtures of 2 or more.
  • a mixture of methanol and dichloromethane is preferred, wherein the methanol/dichlormethane ratio (v/v) is typically of from 1 :100 to 100:1 , for example 1 :10.
  • reaction of compound (II) with ozone (O3) is carried out by bubbling ozone through a solution of the starting compound (II).
  • the required ozone may be generated, for example, by an ozone generator using oxygen or compressed air as gas source.
  • Ozonolysis is conventionally carried out at temperatures below 0 °C, typically at temperatures in a range of from -100 °C to 0 °C.
  • the reaction is usually carried out at -78 °C in a cooling bath of dry ice/acetone.
  • Reaction time is typically in a range of from 0.5 hrs to 48 hrs, preferably of from 5 hrs to 15 hrs.
  • excess ozone is advantageously removed from the reaction mixture, preferably by purging the reaction mixture with an inert gas, such as nitrogen.
  • the ozonide formed as an intermediate in ozonolysis is reduced in the presence of a reducing agent to allow ring closure so as to form the compound of the formula (III), advantageously in the presence of a reducing agent that does not reduce aldehydes.
  • the reducing agent is added to the reaction mixture typically after completion of ozonolysis and removal of excess ozone.
  • suitable reducing agents to be added include triphenylphosphine (PPh 3 ) and dimethyl sulfide ((CH 3 ) 2 S).
  • the reducing agent is preferably used in at least equimolar amounts relative to the starting material, in particular in a molar ratio of from 1 :1 to 2:1. It is believed that the reducing agent reduces the ozonide to the aldehyde which together with methanol forms the cyclic acetal of formula (III).
  • Reduction temperature is not critical and reduction is typically carried out at a temperature in the range of from 0 °C to 45 °C, for example at ambient temperature.
  • Reaction time is typically in a range of from 0.5 hrs to 48 hrs, preferably of from 5 to 15 hrs.
  • the 2-methoxy-1 > 2,6,7-tetrahydro-8/-/-indeno[5,4-/)]furan-8-one of the formula (III) obtained in step (i) is a novel compound and thus is also subject of the present invention. This compound may be used in step (iii) of the present process with or without purification.
  • Elimination of methanol in step (iii) of the process of the invention to form compound (IV) is typically performed in an organic solvent.
  • suitable organic solvents include aromatic hydrocarbons, ethers and alkyl cyanides.
  • aromatic hydrocarbons are toluene and benzene.
  • Preferred ethers are diisopropyl ether, diethyl ether and tetrahydrofuran.
  • Preferred alkyl cyanide is acetonitrile.
  • the solvents may be used alone or as mixtures of 2 or more.
  • Preferred solvent is toluene.
  • Elimination in step (iii) is typically carried out in the presence of inorganic and organic acids or bases as a catalyst.
  • Acids and bases are typically used in catalytic amounts, for example in a molar ratio of from 0.001 :1 to 1 :1 with respect to the compound of the formula (III).
  • inorganic bases include alkali and earth alkali carbonates and hydrogen carbonates, such as potassium carbonate and potassium hydrogen carbonate, alkali hydrides, such as sodium hydride and potassium hydride, and alkali and earth alkali hydroxides, such as sodium hydroxide and potassium hydroxide.
  • Preferred organic bases include alkali alkoholates such as sodium methanolate, sodium ethanolate, sodium tert-butylate and potassium tert-butylate, and tertiary amines such as triethylamine, triethylenediamine, tri(n-butyl)amine, diisopropylethylamine, N,N-dimethyl- aniline and pyridine.
  • suitable acids are protic acids and Lewis acids.
  • Preferred protic acids are toluenesulfonic acid (TsOH), methanesulfonic acid and sulfuric acid with TsOH being preferred.
  • Preferred Lewis acid is boron trifluoride (BF 3 ) which is usually provided in the form of a BF 3 adduct.
  • Typical adducts include ether adducts such as BF 3 (CH 3 ) 2 0, BF 3 (C 2 H 5 ) 2 0, BF 3 (C 4 H 9 ) 2 O and BF 3 THF with BF 3 (CH 3 ) 2 0 being preferred.
  • Elimination is typically carried out at a temperature of from 20 °C to 150 °C, preferably of from 80 °C to 130 °C, for example at 110 °C.
  • Reaction time is typically in a range of from 10 min to 24 hrs, preferably of from 0.5 hrs to 5 hrs.
  • Hydrogenation of 6,7-dihydro-8H-indeno-[5,4-£>]furan-8-one of the formula (IV) in step (iv) of the process of the invention is typically performed in an organic solvent.
  • suitable organic solvents include organic acids, organic esters, alcohols, ethers and tertiary amines.
  • organic acids include formic acid, acetic acid and propionic acid.
  • An example of an organic ester is ethyl acetate.
  • examples of alcohols include methanol, ethanol and isopropanol.
  • examples of ethers include diisopropyl ether, diethyl ether and tetrahydrofuran.
  • An example of a tertiary amine is triethylamine.
  • the solvents may be used alone or as mixtures of 2 or more.
  • a mixture of ethanol and tetrahydrofuran is preferred.
  • the ethanol/tetrahydrofuran ratio (v/v) is typically in a range of from 1 :20 to 20:1 , for example 2:1.
  • a tertiary amine is added to the reaction mixture to reduce the catalytic activity of the hydrogenation catalyst, typically in an amount of from 1 :100 to 1 :1000 (v/v) relative to the total volume of the reaction mixture.
  • Hydrogenation typically is a catalytic hydrogenation using hydrogen in the presence of a hydrogenation catalyst.
  • hydrogenation catalysts typically the elements of group 10 of the periodic table, i.e., Ni, Pd and Pt, are used. Further useful hydrogenation catalysts include Rh, Ru, Fe and Co. Examples of catalysts include Pd(OH) 2 -C, Pd on carbon, Raney-Ni and Lindlar Pd.
  • the amount of added catalyst in the present invention is typically of from 2.5 % to 50 % (w/w) relative to the starting material.
  • the catalyst is added in an amount of from 10 % to 40 % (w/w), such as 25 % (w/w), relative to the starting material.
  • Preferred catalyst is Pd on carbon, such as 5 % Pd/C (w/w).
  • the hydrogen pressure in the hydrogenation reaction is typically of from 0.05 MPa to 5.0 MPa, preferably of from 0.2 to 3.0 MPa, more preferably of from 0.5 to 0.7 MPa.
  • hydrogenation is carried out at a reaction temperature of from 0 °C to 60 °C, preferably of from 15 °C to 45 °C, more preferred of from 30 °C to 35 °C.
  • Reaction time is typically in a range of from 5 hrs to 80 hrs, preferably of from 20 hrs to 60 hrs, more preferably of from 30 hrs to 50 hrs.
  • step (iv) of the process of the invention may be further subjected to a condensation reaction to form indenofurannitrile following general procedures described in the literature (see, e.g., Uchikawa, O. et al., J. Med. Chem, 2002, 45, 4222-4239).
  • 6-hydroxy-7-allyl-indan- 1-one of the formula (II) may be obtained by a two step process starting from commercially available 6-hydroxy-1-indanone of the formula (V) according to known methods (see, e.g., Rodrigues, D.C. et al., Magn. Reson. Chem. 2000, 38, 970-974, and Gering H.L. et al., J. Am. Chem. Soc. 1958, 3277-3285).
  • 6-hydroxy-1-indanone of the formula (V) may be subjected to allylation using an allyl halogenide, such as allyl chloride or allyl bromide in acetone to give 6-allyloxy-indan-1-one of the formula (VI).
  • 6-Allyloxy-indan- 1-one of the formula (VI) may be further subjected to a thermal rearrangement reaction (Claisen rearrangement) to give 6-hydroxy-7-allyl-indan-1-one of the formula (II).
  • Ion source APCI in Positive Module
  • Ion source El in Positive Module
  • Ion source temp 250 °C
  • Electron energy 70 eV; Scan mode: full scan;
  • 6-Hydroxy-7-allyl-indan-1-one of the formula (II) (16 g, 99 %, 84.2 mmol) was dissolved in methanol/dichloromethane (32 ml/320 ml) at ambient temperature. The solution was cooled to -78 °C in a dry ice-acetone bath. A stream of O3 was bubbled through the stirred solution. The ozone was produced by an ozone generator using compressed air as gas source (flow rate, 2 l/min). The progress of the reaction was monitored by thin layer chromatography (TLC) until absence of starting material. After the reaction was completed (ca. 10 hrs), excess ozone was removed by purging the reaction mixture with nitrogen for 1 hr.
  • TLC thin layer chromatography
  • 6-Hydroxy-1-indanone of the formula (V) (74.1 g, 0.50 mol), K 2 C0 3 (166.0 g, 1.2 mol), acetone (750 ml) and allyl bromide (52 ml, 0.6 mol) were charged into a 1000 ml flask.
  • 6-Allyloxy-indan-1-one of the formula (VI) (112 g, 0.6 mol) and A/,A/-dimethylaniline (110 ml) were charged into a 500 ml flask. The mixture was heated to reflux under N2 and stirred for 12-13 hrs. The reaction was monitored by HPLC. After the reaction was finished, the solution was cooled quickly to 25 °C in a water-bath. Aqueous HCI (6 N, 250 ml) and ice-water (200 ml) were added subsequently. The mixture was stirred for further 5 minutes and then extracted with ethyl acetate (500 ml ⁇ 2, and 300 ml). The combined organic phases were washed with saturated brine (400 ml).

Abstract

The invention provides a process for preparing 1,2,6,7-tetrahydro-8H-indeno-[5,4-b]furan-8-one (I), said process comprising the steps: (i) subjecting 6-hydroxy-7-allyl-indan-1-one to ozonolysis followed by reduction in the presence of methanol to form 2-methoxy-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one; (ii) subjecting 6-hydroxy-7-allyl-indan-1-one to alcohol elimination to form 6,7-dihydro-8H-indeno-[5,4-b]furan-8-one; and (iii) subjecting 6,7-dihydro-8H-indeno-[5,4-b]furan-8-one to hydrogenation to obtain 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one.

Description

- -
Process for preparing 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one
The present invention relates to a process for preparing 1 ,2,6,7-tetrahydro-8H- indeno[5,4-b]furan-8-one.
1 ,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one is an important intermediate in the preparation of indenofurannitrile (2-(1 ,2,6,7-tetrahydro-8 - -indeno[5,4-/9]furan-8-ylidene)- acetonitrile). Indenofurannitrile itself is a key building block for the preparation of ramelteon [(S)-/S/-[1 ,6,7,8-tetrahydro-2H-indeno[5,4-£>]furan-8-yl)ethyl]-propionamide]I which acts as a selective melatonin receptor agonist.
EP-A-0 885 210, EP-A- 1 792 899 and Uchikawa et al. (J. Med. Chem, 2002, 45, 4222- 4239) describe methods for the preparation of 1 ,2,6,7-tetrahydro-8/- -indeno[5,4-?]furan- 8-one as an intermediate in the preparation of indenofurannitrile starting from 2,3-dihydrobenzofuran. This route involves numerous and complex reaction steps and the overall yield is low. The object of the present invention, therefore, was to provide a simple and cost efficient process for preparing 1 ,2,6,7-tetrahydro-8H-indeno[5,4-fo]furan-8-one having a reduced number of steps and resulting in good yields.
This object has been achieved by the present invention which provides a process for preparing ,2,6,7-tetrahydro-8H-indeno[5,4-ib]furan-8-one of the formula (I),
Figure imgf000002_0001
(I) said process comprising the steps of:
(i) subjecting 6-hydroxy-7-allyl-indan-1-one of the formula (II)
Figure imgf000003_0001
(II)
to ozonolysis,
(ii) reducing the ozonide formed in step (i) in the presence of methanol to form 2- methoxy-I ^^J-tetrahydro-SH-indeno^^-bJfuran-S-one of the formula (III)
Figure imgf000003_0002
(III)
(iii) subjecting the compound of the formula (III) to alcohol elimination to form 6,7-dihydro-8H-indeno-[5,4-b]furan-8-one of the formula (IV), and
Figure imgf000003_0003
(iv) subjecting the compound of the formula (IV) to hydrogenation to obtain the compound of the formula (I).
Ozonolysis of compound (II) in step (i) of the process of the invention is typically carried out in an organic solvent inert under the reaction conditions. Examples of suitable organic solvents include alcohols, ethers and halogenated hydrocarbons. Preferred alcohols are methanol, ethanol and isopropanol. Preferred ethers are isopropyl ether, diethyl ether and tetrahydrofuran (THF). Preferred halogenated hydrocarbons are dichloromethane, chloroform and 1 ,2-dichloroethane. Solvents may be used alone or as mixtures of 2 or more. A mixture of methanol and dichloromethane is preferred, wherein the methanol/dichlormethane ratio (v/v) is typically of from 1 :100 to 100:1 , for example 1 :10.
Typically, reaction of compound (II) with ozone (O3) is carried out by bubbling ozone through a solution of the starting compound (II). The required ozone may be generated, for example, by an ozone generator using oxygen or compressed air as gas source.
Ozonolysis is conventionally carried out at temperatures below 0 °C, typically at temperatures in a range of from -100 °C to 0 °C. For practical purposes, the reaction is usually carried out at -78 °C in a cooling bath of dry ice/acetone. Reaction time is typically in a range of from 0.5 hrs to 48 hrs, preferably of from 5 hrs to 15 hrs. Following completion of the reaction, excess ozone is advantageously removed from the reaction mixture, preferably by purging the reaction mixture with an inert gas, such as nitrogen. Following ozonolysis, the ozonide formed as an intermediate in ozonolysis is reduced in the presence of a reducing agent to allow ring closure so as to form the compound of the formula (III), advantageously in the presence of a reducing agent that does not reduce aldehydes. The reducing agent is added to the reaction mixture typically after completion of ozonolysis and removal of excess ozone. Examples of suitable reducing agents to be added include triphenylphosphine (PPh3) and dimethyl sulfide ((CH3)2S). The reducing agent is preferably used in at least equimolar amounts relative to the starting material, in particular in a molar ratio of from 1 :1 to 2:1. It is believed that the reducing agent reduces the ozonide to the aldehyde which together with methanol forms the cyclic acetal of formula (III).
Reduction temperature is not critical and reduction is typically carried out at a temperature in the range of from 0 °C to 45 °C, for example at ambient temperature. Reaction time is typically in a range of from 0.5 hrs to 48 hrs, preferably of from 5 to 15 hrs. The 2-methoxy-1 >2,6,7-tetrahydro-8/-/-indeno[5,4-/)]furan-8-one of the formula (III) obtained in step (i) is a novel compound and thus is also subject of the present invention. This compound may be used in step (iii) of the present process with or without purification.
Elimination of methanol in step (iii) of the process of the invention to form compound (IV) is typically performed in an organic solvent. Examples of suitable organic solvents include aromatic hydrocarbons, ethers and alkyl cyanides. Preferred aromatic hydrocarbons are toluene and benzene. Preferred ethers are diisopropyl ether, diethyl ether and tetrahydrofuran. Preferred alkyl cyanide is acetonitrile. The solvents may be used alone or as mixtures of 2 or more. Preferred solvent is toluene.
Elimination in step (iii) is typically carried out in the presence of inorganic and organic acids or bases as a catalyst. Acids and bases are typically used in catalytic amounts, for example in a molar ratio of from 0.001 :1 to 1 :1 with respect to the compound of the formula (III).
Examples of inorganic bases include alkali and earth alkali carbonates and hydrogen carbonates, such as potassium carbonate and potassium hydrogen carbonate, alkali hydrides, such as sodium hydride and potassium hydride, and alkali and earth alkali hydroxides, such as sodium hydroxide and potassium hydroxide. Preferred organic bases include alkali alkoholates such as sodium methanolate, sodium ethanolate, sodium tert-butylate and potassium tert-butylate, and tertiary amines such as triethylamine, triethylenediamine, tri(n-butyl)amine, diisopropylethylamine, N,N-dimethyl- aniline and pyridine.
Examples of suitable acids are protic acids and Lewis acids. Preferred protic acids are toluenesulfonic acid (TsOH), methanesulfonic acid and sulfuric acid with TsOH being preferred. Preferred Lewis acid is boron trifluoride (BF3) which is usually provided in the form of a BF3 adduct. Typical adducts include ether adducts such as BF3 (CH3)20, BF3 (C2H5)20, BF3 (C4H9)2O and BF3 THF with BF3 (CH3)20 being preferred.
Elimination is typically carried out at a temperature of from 20 °C to 150 °C, preferably of from 80 °C to 130 °C, for example at 110 °C. Reaction time is typically in a range of from 10 min to 24 hrs, preferably of from 0.5 hrs to 5 hrs. Hydrogenation of 6,7-dihydro-8H-indeno-[5,4-£>]furan-8-one of the formula (IV) in step (iv) of the process of the invention is typically performed in an organic solvent. Examples of suitable organic solvents include organic acids, organic esters, alcohols, ethers and tertiary amines. Examples of organic acids include formic acid, acetic acid and propionic acid. An example of an organic ester is ethyl acetate. Examples of alcohols include methanol, ethanol and isopropanol. Examples of ethers include diisopropyl ether, diethyl ether and tetrahydrofuran. An example of a tertiary amine is triethylamine. The solvents may be used alone or as mixtures of 2 or more. A mixture of ethanol and tetrahydrofuran is preferred. The ethanol/tetrahydrofuran ratio (v/v) is typically in a range of from 1 :20 to 20:1 , for example 2:1.
Preferably, a tertiary amine is added to the reaction mixture to reduce the catalytic activity of the hydrogenation catalyst, typically in an amount of from 1 :100 to 1 :1000 (v/v) relative to the total volume of the reaction mixture.
Hydrogenation typically is a catalytic hydrogenation using hydrogen in the presence of a hydrogenation catalyst. As hydrogenation catalysts, typically the elements of group 10 of the periodic table, i.e., Ni, Pd and Pt, are used. Further useful hydrogenation catalysts include Rh, Ru, Fe and Co. Examples of catalysts include Pd(OH)2-C, Pd on carbon, Raney-Ni and Lindlar Pd. The amount of added catalyst in the present invention is typically of from 2.5 % to 50 % (w/w) relative to the starting material. Preferably, the catalyst is added in an amount of from 10 % to 40 % (w/w), such as 25 % (w/w), relative to the starting material. Preferred catalyst is Pd on carbon, such as 5 % Pd/C (w/w).
The hydrogen pressure in the hydrogenation reaction is typically of from 0.05 MPa to 5.0 MPa, preferably of from 0.2 to 3.0 MPa, more preferably of from 0.5 to 0.7 MPa. Typically, hydrogenation is carried out at a reaction temperature of from 0 °C to 60 °C, preferably of from 15 °C to 45 °C, more preferred of from 30 °C to 35 °C. Reaction time is typically in a range of from 5 hrs to 80 hrs, preferably of from 20 hrs to 60 hrs, more preferably of from 30 hrs to 50 hrs.
The 1 ,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one of the formula (I) obtained in step (iv) of the process of the invention may be further subjected to a condensation reaction to form indenofurannitrile following general procedures described in the literature (see, e.g., Uchikawa, O. et al., J. Med. Chem, 2002, 45, 4222-4239). Typically, 1 ,2,6,7-tetra- hydro-8H-indeno[5,4-b]furan-8-one of the formula (I) is reacted in a Horner-Woodward- Emmons reaction in the presence of NaH and diethylcyanomethylphosphonate in THF to give indenofurannitrile.
The starting compound of the process of the present invention, 6-hydroxy-7-allyl-indan- 1-one of the formula (II), may be obtained by a two step process starting from commercially available 6-hydroxy-1-indanone of the formula (V) according to known methods (see, e.g., Rodrigues, D.C. et al., Magn. Reson. Chem. 2000, 38, 970-974, and Gering H.L. et al., J. Am. Chem. Soc. 1958, 3277-3285). As shown in Scheme 1 below, wherein Hal represents halogen, 6-hydroxy-1-indanone of the formula (V) may be subjected to allylation using an allyl halogenide, such as allyl chloride or allyl bromide in acetone to give 6-allyloxy-indan-1-one of the formula (VI). 6-Allyloxy-indan- 1-one of the formula (VI) may be further subjected to a thermal rearrangement reaction (Claisen rearrangement) to give 6-hydroxy-7-allyl-indan-1-one of the formula (II).
Figure imgf000007_0001
(V) (VI) (II) Scheme 1 By the process of the present invention, 1 ,2,6,7-tetrahydro-8 -/-indeno[5,4-b]furan-8-one of the formula (I) may be obtained in a simple manner starting from commercially available 6-hydroxy-1-indanone.
The present invention is illustrated in more detail by the following non-limiting examples. Examples
General:
HPLC (High Pressure Liquid Chromatography) conditions:
Column: Phenomenex Gemini Ci8 5 μητι; 4.6*150 mm; P.N. 00F-4435-E0;
L.N. 306930-6
Mobile Phase: A: H20
B: Acetonitrile (Merck)
Injection Volume: 5 μΙ
Wavelength: 248 nm (for compounds (II), (V) and (VI))
220 nm (for compounds (I), (III), (IV) and indenofurannitrile)
Oven temperature: 35 °C
Flow rate: 0.6 ml/min
Gradient:
Figure imgf000008_0001
LC-MS (Liquid Chromatography Mass Spectrometry) conditions:
Ion source: APCI in Positive Module
Split (after LC): 1/3.5 MS (Mass Spectrometry) conditions
Ion source: El in Positive Module; Ion source temp: 250 °C;
Electron energy: 70 eV; Scan mode: full scan;
NMR (Nuclear Magnetic Resonance) conditions:
Instrument: Bruker Avance 400
1H and 13C NMR spectra were recorded at room temperature. Chemical shifts are reported in parts per million (ppm) from tetramethylsilane with the solvent resonance as the internal standard (CDCI3: δΗ 7.240 for 1H and δ0 77.7 for 13C respectively; d<rDMSO: 5H 2.500 for 1H and δο 39.95 for 13C respectively) and coupling constants in Hertz (Hz). Example 1 (2-Methoxy-1.2.6.7-tetrahvdro-8/-/-indenof5.4-felfuran-8-one of the formula mm
6-Hydroxy-7-allyl-indan-1-one of the formula (II) (16 g, 99 %, 84.2 mmol) was dissolved in methanol/dichloromethane (32 ml/320 ml) at ambient temperature. The solution was cooled to -78 °C in a dry ice-acetone bath. A stream of O3 was bubbled through the stirred solution. The ozone was produced by an ozone generator using compressed air as gas source (flow rate, 2 l/min). The progress of the reaction was monitored by thin layer chromatography (TLC) until absence of starting material. After the reaction was completed (ca. 10 hrs), excess ozone was removed by purging the reaction mixture with nitrogen for 1 hr. Then (CH3)2S (7.4 ml, 100.9 mmol, 1.2 eq) was added, the reaction mixture was heated gradually up to ambient temperature and stirred overnight. The solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate (400 ml), washed with water (80 ml * 3), followed by saturated brine (100 ml). Evaporation afforded a white yellow solid (yield 90 %, 90 % HPLC purity). The crude 2-methoxy-1 ,2,6,7-tetrahydro-8H-indeno[5,4-/9]furan-8-one obtained could be used in the next step without further purification.
1H NMR (CDCI3, 400 MHz), δ: 7.25 ( d, J = 8.4 Hz, 1 H), 7.08 ( d, J = 8.4 Hz, 1 H), 5.73 (dd, J = 6.4 Hz, 2 Hz, 1 H), 3.52 (s, 3H), 3.51-3.46 (m, 1 H), 3.38 (d, J = 18 Hz, 1 H), 3.08 (t, J = 6 Hz, 2H), 2.68 (t, J = 6 Hz, 2H)
13C NMR (CDCI3, 100 MHz), δ: 207.82, 158.77, 148.31 , 134.32, 126.43, 122.92, 116.71 , 109.16, 56.56, 37.77, 36.03, 26.15
Retention time (LC/MS), min: 13.35; MS (MH+), m/z: 205; Molecular weight, g/mol: 204.
Example 2 (6,7-Dihvdro-8H-indeno-r5,4-fo1furan-8-one of the formula (IV))
2-Methoxy-1 ,2,6,7-tetrahydro-8H-indeno[5,4-fe]furan-8-one of the formula (III) (17 g, 83.2 mmol) was dissolved in toluene (300 ml). TsOH H2O (8.4 g, 44.2 mmol) was added, and the mixture was refluxed for 0.75 hrs. The solution was cooled to ambient temperature and H20 (100 ml) was added. After separation of the phases, the aqueous phase was extracted with ethyl acetate (250 ml χ 3). The organic phase was washed subsequently with aqueous sodium bicarbonate solution (200 ml), followed by saturated brine (200 ml). The solvent was evaporated under vacuum to give 6,7-dihydro-8/-/- indeno-[5,4-i ]furan-8-one of the formula (IV) as a yellow solid (yield 79 %, 73 % HPLC purity).
1H NMR (CDCI3, 400 MHz), δ: 7.77 (s, 1 H), 7.70 (d, J = 8.4 Hz, 1 H), 7.34 (s, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 3.20 (t, J = 6.0 Hz, 2H), 2.75 (t, J = 6.0 Hz, 2H)
13C NMR (CDCI3, 100 MHz), δ: 206.56, 154.71 , 151.86, 147.74, 130.04, 123.43, 121.58, 117.56, 105.78, 36.87, 26.16
Retention time (LC/MS), min: 12.26; MS (MH+), m/z: 173; Molecular weight, g/mol: 172.
Example 3 (1 ,2,6,7-Tetrahydro-8/-/-indeno[5,4-/3lfuran-8-one of the formula (I))
6,7-dihydro-8H-indeno-[5,4-b]furan-8-one of the formula (IV) (2.0 g, 11.6 mmol) was dissolved in a solvent mixture (40 ml ethanol, 20 ml tetrahydrofuran and 12 drops of triethylamine). The stirred solution was hydrogenated for 24 hours at 35 °C/0.6-0.7 MPa over Pd-C (500 mg, 5 % Pd-C (w/w)). The progress of reaction was monitored with HPLC. After the reaction was completed, the hydrogen gas was released, Pd-C was filtered off and the product was washed with 20 ml THF. After removal of the solvent under vacuum, recrystallization from ethanol afforded 1 ,2,6,7-tetrahydro-8 - -indeno- [5,4-b]furan-8-one of the formula (I) as light yellow solid (yield 62 %, 99.6 HPLC purity). 1H NMR (CDCI3, 400 MHz), δ: 7.22 (d, J = 8.4 Hz, H), 7.03 (d, J = 8.4 Hz, 1 H), 4.67 (t, J = 8.8 Hz, 2H), 3.49 (t, J = 8.8 Hz, 2H,), 3.10 (t, J = 5.2 Hz, 2H), 2.70 (t, J = 5.2 Hz, 2H) 13C NMR (CDCI3, 100 MHz), δ: 207.42, 160.25, 147.11 , 133.68, 125.62, 123.93, 115.63, 72.34, 37.16, 28.41 , 25.40
Retention time (LC/MS), min: 8.38; MS (MH+), m/z: 173; Molecular weight, g/mol: 174.
Example 4 (2-(1 ,2,6,7-tetrahvdro-8 -/-indenof5,4- 3lfuran-8-ylidene)acetonitrile
Sodium methoxide (7.8 g, 144 mmol) was added to a solution of diethyl cyanomethyl- phosphonate (22 g, 126 mmol) in THF (60 ml) at ambient temperature. The mixture was stirred for an hour. The resulting solution was added dropwise to a solution of I ^^J-tetrahydro-SH-indenotS^-felfuran-e-one of the formula (I) (15.7 g, 90 mmol) in THF (60 ml) over 15 min at room temperature. This reaction mixture was stirred for 2.0 hours and subsequently quenched with water (150 ml). THF was evaporated and the product was extracted with ethyl acetate. The combined organic phase was evaporated under vacuum to afford a yellow solid (22 g). Recrystallization from a solvent mixture (ethyl acetate/hexane = 2/1 (v/v)) gave 10,1 g 2-(1 ,2,6,7-tetrahydro-8 - -indeno- [5,4-/}]furan-8-ylidene)acetonitrile as light yellow solid. The mother liquor was concentrated, and was recharged to retry the above reaction. In the following, additional 4.5 g 2-(1 ,2,6,7-tetrahydro-8H-indeno[5,4-i ]furan-8-ylidene)acetonitrile was obtained (yield 80 %, 96.5 HPLC purity).
1H NMR (CDCI3, 400 MHz), δ: 7.09 (d, J = 8.4Hz, 1 H), 6.84 (d, J = 8.4 Hz, 1 H), 5.44 (t, J = 2.4 Hz, 1 H), 4.65 (t, J = 8.8 Hz, 2H), 3.29 (t, J = 8.8 Hz, 2H), 3.12-3.09 (m, 2H), 3.03 (t, J = 5.2 Hz, 2H)
13C NMR (CDCI3, 100 MHz), δ: 167.76, 160.16, 142.25, 134.97, 124.84, 121.91 , 118.14, 112.98, 87.93, 71.43, 32.41 , 29.31 , 29.11
Retention time (LC/MS), min: 9.94; MS (MH+), m/z: 197; Molecular weight, g/mol: 197.
Example 5 (6-Allyloxy-indan-1-one of the formula (VI))
6-Hydroxy-1-indanone of the formula (V) (74.1 g, 0.50 mol), K2C03 (166.0 g, 1.2 mol), acetone (750 ml) and allyl bromide (52 ml, 0.6 mol) were charged into a 1000 ml flask.
The mixture was heated to reflux and stirred for 5 hours. The reaction was monitored by HPLC. After the reaction was finished, the solution was quickly cooled to room temperature in a water-bath. The solids were filtered and washed with acetone (300 ml).
Evaporation under vacuum at 45 °C afforded the crude product as yellow solid (yield
95 %, 95 % HPLC purity). Crude 6-allyloxy-indan-1-one of the formula (VI) could be used in the next step without further purification.
1H NMR (CDCI3, 400 MHz), δ: 7.37 (d, J = 8.0 Hz, 1 H), 7.23-7.19 (m, 2H), 6.09-6.01
(m, 1 H), 5.43 (dd, J = 17.2 Hz, 1.2 Hz, 1 H), 5.30 (dd, J = 10.4 Hz, 1.2 Hz, 1 H), 4.57 (d,
J = 5.2 Hz, 2H), 3.07 (t, J = 5.2 Hz, 2H), 2.71 ( t, J = 5.2 Hz, 2H)
13C NMR (CDCI3, 100 MHz), δ: 207.46, 158.93, 148.66, 138.83, 133.39, 128.02, 125.05, 118.54, 106.72, 69.68, 37.60, 25.72
Retention time (LC/MS), min: 12.98; MS (MH+), m/z: 189; Molecular weight, g/mol: 188. Example 6 (6-Hydroxy-7-allyl-indan-1 -one of the formula (II))
6-Allyloxy-indan-1-one of the formula (VI) (112 g, 0.6 mol) and A/,A/-dimethylaniline (110 ml) were charged into a 500 ml flask. The mixture was heated to reflux under N2 and stirred for 12-13 hrs. The reaction was monitored by HPLC. After the reaction was finished, the solution was cooled quickly to 25 °C in a water-bath. Aqueous HCI (6 N, 250 ml) and ice-water (200 ml) were added subsequently. The mixture was stirred for further 5 minutes and then extracted with ethyl acetate (500 ml χ 2, and 300 ml). The combined organic phases were washed with saturated brine (400 ml). Evaporation under vacuum at 40 °C afforded an orange solid (115 g). The solid was dissolved in a solvent mixture (petrol ether/ethyl acetate = 2/3 (v/v), 300 ml) at 70°C, followed by cooling and crystallization to get 6-hydroxy-7-allyl-indan-1-one of the formula (II) (65 g, 97.5 % HPLC purity). Further 6-hydroxy-7-allyl-indan-1-one of the formula (II) was obtained from the mother liquid (17 g, 98 % HPLC purity). The final yield was 75 %. H NMR (CDCI3, 400 MHz), δ: 7.22 ( d, J = 8.0 Hz, 1 H), 7.11 ( d, J = 8.0 Hz, 1 H), 6.04- 5.97 ( m, 1 H), 5.70 ( s, 1 H), 5.16 (d, J = 1.6 Hz, 1 H), 5.11 (dd, J = 8.8 Hz, 1.6 Hz, 1 H), 4.00 (d, J = 6.0 Hz, 2H), 3.00 (t, J = 6.0 Hz, 2H), 2.70 (t, J = 6.0 Hz, 2H)
13C NMR (CDCI3, 100 MHz), δ: 208.82, 154.07, 148.69, 135.92, 134.68, 125.21 , 124.43, 123.08, 115.87, 37.73, 28.10, 24.44
Retention time (LC/MS), min: 10.69; MS (MH+), m/z: 207; Molecular weight, g/mol: 206

Claims

Claims
Process for preparing 1 )2,6,7-tetrahydro-8/-/-indeno[5,4-d]furan-8-one of the formula (I),
Figure imgf000013_0001
(I)
said process comprising the steps of:
(i) subjecting 6-hydroxy-7-allyl-indan-1-one of the formula (II)
Figure imgf000013_0002
(II) to ozonolysis,
reducing the ozonide formed in step (i) in the presence of methanol to form 2-methoxy-1 ,2,6,7-tetrahydro-8H-indeno[5,4-jb]furan-8-one of the formula (III)
Figure imgf000013_0003
(III) subjecting the compound of the formula (III) to alcohol elimination to form 6,7-dihydro-8 - -indeno-[5,4- )]furan-8-one of the formula (IV), and
Figure imgf000014_0001
(iv) subjecting the compound of the formula (IV) to hydrogenation to obtain the compound of the formula (I).
The process of claim 1 , wherein ozonolysis in step (i) is carried out in a solvent, preferably selected from the group consisting of methanol, tetrahydrofuran, dichloromethane, chloroform, 1 ,2-dichloroethane and mixtures thereof.
The process of claim 1 or 2, wherein the reduction in step (ii) is carried out in the presence of a reducing agent selected from triphenylphosphine and dimethyl sulfide.
The process of any of claims 1 to 3, wherein alcohol elimination in step (iii) is carried out in a solvent, preferably selected from the group consisting of toluene, tetrahydrofuran and mixtures thereof.
The process of any of claims 1 to 4, wherein the alcohol elimination in step (iii) is earned out in the presence of an acid, preferably selected from toluenesulfonic acid and boron trifluoride.
The process of any of claims 1 to 5, wherein hydrogenation in step (iv) is carried out in the presence of a hydrogenation catalyst, preferably selected from an element of group 10 of the periodic table.
RECTIFIED SHEET (RULE 91)
ISA/EP The process of any of claims 1 to 6, wherein the hydrogenation in step (iv) is carried out in a solvent, preferably selected from the group consisting of ethanol, ethyl acetate, tetrahydrofuran and mixtures thereof.
Process according to any one of claims 1 to 7, further comprising the step of:
(v) subjecting 1 ,2,6,7-tetrahydro-8 - -indeno[5,4-6]furan-8-one of the formula (I) to a condensation reaction in the presence of diethyl cyanomethylphosphonate to form 2-(1 ,2,6,7-tetrahydro-8H-indenol5,4- D]furan-8-ylidene)acetonitrile.
2-Methoxy-1 ,2,6,7-tetrahydro-8H-indeno[5,4-ft]furan-8-one of the formula (III):
Figure imgf000015_0001
RECTIFIED SHEET (RULE 91)
ISA/EP
PCT/EP2010/005941 2009-09-29 2010-09-29 Process for preparing 1,2,6,7-tetrahydro-8h-indeno[5,4-b]furan-8-one WO2011044990A1 (en)

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