WO1997042194A1 - Process for the preparation of an indacene compound - Google Patents

Process for the preparation of an indacene compound Download PDF

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Publication number
WO1997042194A1
WO1997042194A1 PCT/EP1997/002284 EP9702284W WO9742194A1 WO 1997042194 A1 WO1997042194 A1 WO 1997042194A1 EP 9702284 W EP9702284 W EP 9702284W WO 9742194 A1 WO9742194 A1 WO 9742194A1
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Prior art keywords
compound
formula
methyl
solution
salts
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PCT/EP1997/002284
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French (fr)
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Jose Maria Bueno Calderon
Jesus Chicharro Gonzalo
Jose Fiandor Roman
Sophie Huss
Richard Anthony Ward
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Glaxo Wellcome S.A.
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Priority to AU28915/97A priority Critical patent/AU2891597A/en
Publication of WO1997042194A1 publication Critical patent/WO1997042194A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
    • C07D309/10—Oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • This invention relates to a process for preparing an antifungal agent and to novel Intermediates for use in the synthesis.
  • the present invention provides a process for the preparation of compound of formula (I) which comprises cyclisation of a compound of formula (II)
  • R is a carboxyl protecting group, followed where necessary or desired by one or more of the following steps, (I) removal of the carboxyl protecting group R;
  • the cyclisation reaction may be carried in the presence of a radical chain carrier.
  • Suitable radical chain carriers include tin radicals and a convenient source of tin radicals is a trialkyltin hydride e.g. tributyltin hydride.
  • a radical initiator such as azoisobutyronitrile may also be present in the reaction.
  • the process is carried out in a suitable aprotic solvent such as hydrocarbon eg. toluene or an ether such as dioxan, and with heating eg at reflux.
  • the cyclisation may be carried out by reaction with hypophosphorous acid in the presence of an organic base such as triethylamine and a radical initiator such as azoisobutyronitrile.
  • suitable carboxyl protecting groups include acid or base labile ester groups, such as a substituted methyl esters eg pivaloyloxymethyl, or trimethylsilylethyloxymethyl.
  • the carboxyl protecting groups may be removed by conventional procedures well known to those skilled in the art.
  • pivaloyloxymethyl may be cleaved by reaction with a suitable base such as an alkali metal alkoxide e.g. sodium methoxide in a suitable solvent such as methanol or an ether e.g. tetrahydrofuran.
  • the trimethylsilylethyloxymethyl ester may be cleaved by reaction with fluoride ions e.g. tetrabutylammonium fluoride in a suitable aprotic solvent such as an ether e.g. tetrahydrofuran.
  • fluoride ions e.g. tetrabutylammonium fluoride
  • a suitable aprotic solvent such as an ether e.g. tetrahydrofuran.
  • Suitable pharmaceutically acceptable salts of the compounds of formula (I) include inorganic base salts such as alkali metal salts (for example sodium and potassium salts) and ammonium salts and organic base salts.
  • Suitable organic base salts include amine salts such as trialkylamine (e.g. triethylamine), dialkylamine (e.g. dicyclohexylamine), optionally substituted benzylamine (e.g. phenylbenzylamine or p-bromobenzylamine), procaine, ethanolamine, diethanolamine, N-methylglucosamine and tri(hydroxymethyl)methylamine salts and amino acid salts (e.g. lysine and arginine salts).
  • trialkylamine e.g. triethylamine
  • dialkylamine e.g. dicyclohexylamine
  • optionally substituted benzylamine e.g. phenylbenzylamine or p-bromobenzy
  • Salts of compounds of formula (I) may be conveniently formed by treating a compound of formula (I) with an appropriate salt or base.
  • salts may conveniently be prepared by treating a compound of formula (I) with a salt or a base selected from sodium or potassium hydroxide, hydrogen carbonate, carbonate or acetate (e.g. potassium hydroxide, potassium hydrogen carbonate, sodium hydrogen carbonate or potassium acetate), ammonium acetate, calcium acetate or an organic amine e.g. L-lysine as appropriate.
  • the salt may, for example, be prepared by adding the appropriate salt or base (if necessary as an aqueous solution) to a solution or suspension of the compound of formula (I) in a suitable solvent such as an alcohol (e.g. methanol) or dioxane at temperatures of for example 0°C to 80°C and conveniently at about room temperature.
  • Pharmaceutically acceptable salts may also be prepared from other salts including other pharmaceutically acceptable salts of the compounds of formula (I), using conventional methods.
  • the compound of formula (II) may be prepared by reaction of compound (III) wherein R has the meaning defined above
  • iodine or iodoform or triiodoimidazole and imidazole in the presence of triphenylphosphine in a suitable solvent such as a hydrocarbon eg: toluene or an ether e.g. tetrahydrofuran.
  • a suitable solvent such as a hydrocarbon eg: toluene or an ether e.g. tetrahydrofuran.
  • the compound of formula (III) may be prepared be reaction of compound (IV) wherein R has the meaning defined above.
  • the diol of formula (IV) may be prepared from of a compound of formula (V)
  • the acetonide (V) may be prepared by reaction of the triol (VI);
  • the triol of formula (VI) wherein R is a carboxyl protecting group may be prepared by esterifying the corresponding compound of formula (VI) wherein R is hydrogen using conventional procedures for preparing such protected carboxylic acid derivatives.
  • R is a substituted methyl group
  • compounds wherein R is a substituted methyl group may be prepared by reaction with the corresponding substituted methyl halide e.g. chloride or bromide in the presence of a base such as a tertiary organic amine such as trialkylamine, or an alkali metal hydroxide, carbonate or bicarbonate.
  • the triol of formula (VI) wherein R is a hydrogen atom may be prepared by the procedures described in WO96/14326.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A process for the preparation of a compound of formula (I); and novel intermediates for use in the synthesis.

Description

PROCESS FOR THE PREPARATION OF AN INDACENE COMPOUND
This invention relates to a process for preparing an antifungal agent and to novel Intermediates for use in the synthesis.
The compound of formula (I)
Figure imgf000003_0001
and pharmaceutically acceptable salts or metabolically labile esters thereof exhibit a particularly desirable spectrum of antifungal activity.
The present invention provides a process for the preparation of compound of formula (I) which comprises cyclisation of a compound of formula (II)
Figure imgf000003_0002
wherein R is a carboxyl protecting group, followed where necessary or desired by one or more of the following steps, (I) removal of the carboxyl protecting group R;
(II) isolation of the compound of formula (I) in the form of a pharmaceutically acceptable salt thereof; (III) conversion of the compound of formula (I) into a metabolically labile ester thereof:
In one embodiment of the process the cyclisation reaction may be carried in the presence of a radical chain carrier. Suitable radical chain carriers include tin radicals and a convenient source of tin radicals is a trialkyltin hydride e.g. tributyltin hydride. Conveniently a radical initiator such as azoisobutyronitrile may also be present in the reaction. Desirably the process is carried out in a suitable aprotic solvent such as hydrocarbon eg. toluene or an ether such as dioxan, and with heating eg at reflux.
In a further embodiment of the process the cyclisation may be carried out by reaction with hypophosphorous acid in the presence of an organic base such as triethylamine and a radical initiator such as azoisobutyronitrile.
For compound (II) suitable carboxyl protecting groups include acid or base labile ester groups, such as a substituted methyl esters eg pivaloyloxymethyl, or trimethylsilylethyloxymethyl.
The carboxyl protecting groups may be removed by conventional procedures well known to those skilled in the art. For example pivaloyloxymethyl may be cleaved by reaction with a suitable base such as an alkali metal alkoxide e.g. sodium methoxide in a suitable solvent such as methanol or an ether e.g. tetrahydrofuran.
The trimethylsilylethyloxymethyl ester may be cleaved by reaction with fluoride ions e.g. tetrabutylammonium fluoride in a suitable aprotic solvent such as an ether e.g. tetrahydrofuran.
Suitable pharmaceutically acceptable salts of the compounds of formula (I) include inorganic base salts such as alkali metal salts (for example sodium and potassium salts) and ammonium salts and organic base salts. Suitable organic base salts include amine salts such as trialkylamine (e.g. triethylamine), dialkylamine (e.g. dicyclohexylamine), optionally substituted benzylamine (e.g. phenylbenzylamine or p-bromobenzylamine), procaine, ethanolamine, diethanolamine, N-methylglucosamine and tri(hydroxymethyl)methylamine salts and amino acid salts (e.g. lysine and arginine salts).
Salts of compounds of formula (I) may be conveniently formed by treating a compound of formula (I) with an appropriate salt or base. Thus, for example, salts may conveniently be prepared by treating a compound of formula (I) with a salt or a base selected from sodium or potassium hydroxide, hydrogen carbonate, carbonate or acetate (e.g. potassium hydroxide, potassium hydrogen carbonate, sodium hydrogen carbonate or potassium acetate), ammonium acetate, calcium acetate or an organic amine e.g. L-lysine as appropriate. The salt may, for example, be prepared by adding the appropriate salt or base (if necessary as an aqueous solution) to a solution or suspension of the compound of formula (I) in a suitable solvent such as an alcohol (e.g. methanol) or dioxane at temperatures of for example 0°C to 80°C and conveniently at about room temperature.
Pharmaceutically acceptable salts may also be prepared from other salts including other pharmaceutically acceptable salts of the compounds of formula (I), using conventional methods.
The compound of formula (II) may be prepared by reaction of compound (III) wherein R has the meaning defined above
Figure imgf000006_0001
with iodine or iodoform or triiodoimidazole and imidazole in the presence of triphenylphosphine in a suitable solvent such as a hydrocarbon eg: toluene or an ether e.g. tetrahydrofuran.
The compound of formula (III) may be prepared be reaction of compound (IV) wherein R has the meaning defined above.
OH
Figure imgf000006_0002
with propargyl bromide or iodide in the presence of dibutyltin oxide or dibutyltin dimethoxide and tetrabutylammonium fluoride, in a solvent such as toluene and with heating.
The diol of formula (IV) may be prepared from of a compound of formula (V)
Figure imgf000007_0001
(V)
by reaction with thiocarbonyl diimidazole in a solvent such as acetonitrile, treatment of the resultant thioester with tributyltin hydride and azoisobutyronitrile in a solvent such as toluene followed by removal of the acetonide protecting group e.g. by hydrolysis with aqueous acid e.g. hydrochloric acid.
The acetonide (V) may be prepared by reaction of the triol (VI);
OH
Figure imgf000007_0002
(VI)
with p-toluenesulphonic acid and 2,2 dimethyloxypropane in acetone as a solvent.
The triol of formula (VI) wherein R is a carboxyl protecting group may be prepared by esterifying the corresponding compound of formula (VI) wherein R is hydrogen using conventional procedures for preparing such protected carboxylic acid derivatives. Thus compounds wherein R is a substituted methyl group may be prepared by reaction with the corresponding substituted methyl halide e.g. chloride or bromide in the presence of a base such as a tertiary organic amine such as trialkylamine, or an alkali metal hydroxide, carbonate or bicarbonate. The triol of formula (VI) wherein R is a hydrogen atom may be prepared by the procedures described in WO96/14326.
The examples hereinafter illustrate aspects of the invention but are not intended to limit the invention in any way.
INTERMEDIATE 1
[1R-(1α. 3aβ.4β .4aβ.7β.7aα.8aβ^] 8a-[(6-Deoxy-β-D-altroDyranosyloxy)methyl]-
4-formyl-4.4a.5.6.7.7a.8.8a-octahydro-7-methyl-3-(1-methylethyn-1.4-methano- s-indacene-3a(1l-n-carboxylic acid, pivaloyloxymethyl ester
A mixture of [1 R-(1α, 3aβ,4β ,4aβ,7β,7aα,8aβ)] 8a-[(6-Deoxy-β-D- altropyranosyloxy)methyl]-4-formyl-4,4a,5,6,7,7a,8,8a-octahydro-7-methyl-3-(1 - methylethyl)-1 ,4-methano-s-indacene-3a(1 H)-carboxylic acid, (10.00g) and tetra n-butylammonium iodide (3.86g) in N,N- dimethylformamide (70ml) was stirred and treated with diisopropylethylamine (5.5ml) and chloromethyl pivalate (3.3ml). Then the resulting solution was heated at 50-55° under nitrogen. After 5.25h the reaction mixture was treated with water (40ml) and then after a further 0.25h more water (240ml) was added. After a further 1h the solid was collected by vacuum filtration, washed with water (3 x 20ml) and then dried to give the title compound (11.71g).
δ (1H, DMSO.d6): 0.77δ(3H) d, J=6.7Hz; 0.87δ(3H), J=6.7Hz; 0.94δ(1H) m;
0.98δ(3H) d, J=6.9Hz; 1.14δ(3H) d, J=6.2Hz; 1.16δ(1H) m; 1.19δ(9H) s; 1.55-
2.05δ(9H) m; 2.17δ(1H) m; 2.77δ(1H) t, J=3.8Hz; 3.29δ(1H) m; 3.49δ(1H) m;
3.55δ(1H) d, J=9.4Hz; 3.67δ(1H) m; 3.70δ(1 H) d, J=9.4Hz; 4.44δ(3H) m;
4.78δ(1H) d, J=3.7Hz; 5.81δ(1H) d, J=6.2Hz; 5.91δ(1H) d, J=6.2Hz; 6.13δ(1H) d, J=3.8Hz; 9.60δ(1H) s.
INTERMEDIATE 2
[1R-(1α. 3aβ. 4β. 4aβ. 7β. 7aα. 8aβ^ 8a-[(6-Deoxy-3.4-O-isopropylidene-β-D- altropyranosyloxy^methyl]-4-formyl-4.4a.5.6.7.7a.8.8a-octahydro-7-methyl-3-(1- methylethyO-d H)-1.4-methano-s-indacene-3a(1 H)-carboxylic acid. pivaloyloxymethyl ester
A stirred solution of Intermediate 1 (262.60g) in acetone (3.9I) was treated with 2,2-dimethoxypropane (205ml), p-toluene sulphonic acid (7.94g) and 3A molecular sieves (184.0g). After 1.75h the reaction mixture was treated with potassium hydrogen carbonate (17.0g). After a further 10min Harborlite J2 (25.0g) was added and then after 5min the mixture was filtered through a bed of Harborlite J2 washing through with acetone (3 x 130ml). The combined filtrate and washings were evaporated in vacuo to give a solid which was redissolved in acetone (1.251). The cloudy solution was stirred and treated with water (2.51) and then cooled to 10°. After 1 h the product was collected by vacuum filtration, washed with water (3 x 250ml) and then dried to give the title compound (243.95g).
INTERMEDIATE 3
f1 R-(1α. 3aβ. 4β. 4aβ. 7β. 7aα. 8aβ^ 8a-r(6-Deoxy-2-O-1 H-imidazol-1-yl- thioxomethyl-3.4-O-isopropylidene-β-D-altropyranosyloxy)methyl]-4-formyl- 4.4a.5.6.7.7a.8.8a-octahvdro-7-methyl-3-(1-methylethvn-(1H)-1.4-methano-s- indacene-3a(1 H)-carboxylic acid, pivaloyloxymethyl ester
A solution of Intermediate 2 (243.20g) in acetonitrile (1215ml) at 45° was stirred and treated with thiocarbonyldiimidazole (92.51 g) and then the mixture was heated at 50° under nitrogen. After 4h the reaction mixture was cooled and then concentrated in vacuo. The residue was dissolved in ethyl acetate (1.51) and the orange solution was washed with 1M-hydrochloric acid (2 x 500ml) and then 1% w/v sodium chloride (500ml) and then evaporated in vacuo to give the title compound (297.46g).
δ (1H, CDCI3): 0.79δ(3H) d, J=6.5Hz; 0.86δ(3H) d , J=6.6Hz; 0.93δ(1H) m; 0.97δ(3H) d, J=6.2Hz; 1.23δ(1H) m; 1.23δ(9H) s; 1.35δ(3H) d, J=6.0Hz; 1.39δ(3H) s; 1.50δ(3H) s; 1.45-2.31δ(10H) m; 2.53δ(1 H) t, J=3.9Hz; 3.56δ(1 H) d, J=9.0Hz; 3.68δ(1H) m; 3.82δ(1 H) d, J=9.0Hz; 4.00δ(1 H) dd, J=8.4Hz, 6.0Hz; 4.56δ(1 H) m; 4.87δ(1 H) d, J=2.0Hz; 5.67δ(1 H) d, J=5.1 Hz; 5.83δ(1 H) m; 5.89δ(1H) d, J=5.1Hz; 7.08δ(1 H) m; 7.69δ(1H) t, J=1.4Hz;8.38δ(1H) m; 9.64δ(1H) s.
INTERMEDIATE 4
[1R-(1α. 3aβ. 4β. 4aβ. 7β. 7aα. 8aβη 8a-[(2.6-Dideoxy-3.4-O-isoproDylidenβ-β- D-allopyranosvloxv^methvll-4-formvM.4a.5.6.7.7a.8.8a-octahvdro-7-methyl-3-(1- methylethyh-1 ^-methano-s-indacene-SaMHVcarboxylic acid, pivaloyloxymethyl ester
A solution of Intermediate 3 (7.88g) in toluene (80ml) was treated with azoisobutyronitrile (43mg) and tributyltin hydride (7.1ml) and the resulting mixture was stirred and heated at 80° under nitrogen. After 1.75h the mixture was diluted with ethyl acetate (50ml) and then washed with 1M-hydrochloric acid saturated with sodium chloride (2 x 25ml) and saturated sodium chloride (25ml). The organic phase was evaporated in vacuo to an oil. After chromatography (iso-hexane:ethyl acetate, v:v 49:1, 19:1 and 9:1) the title compound (2.14g) was obtained.
δ (1H, CDCI3): 0.79δ(3H) d, J=6.5Hz; 0.93δ(6H) m; 0.99δ(1H) m; 1.03δ(3H) d, J=7.2Hz; 1.24δ(1H) m; 1.23δ(9H) s; 1.27δ(3H) d, J=4.6Hz; 1.35δ(3H) s; 1.47δ(3H) s; 1.65-2.31δ(10H) m; 2.76δ(1H) t, J=3.9Hz; 3.42δ(1H) m; 3.62δ(1H) d, J=9.1Hz; 3.66δ(1H) m; 3.87δ(1H) d, J=9.1Hz; 4.12δ(2H) Abq, J=4.39δ(1H) m; 4.54δ(1H) dd, J=8.7Hz, 2.3HZ; 5.85δ(2H) ABq, J=5.0Hz; 6.07δ(1H) dd, J=3.6Hz, 1.2Hz; 9.70δ(1 H) s.
INTERMEDIATE 5
[1R-(1cx, 3j& 4ϋ 4a& Z& Zaα, 8ϋβ)] 8g-[(2,e-Pideoxy-β-P- allopyranosyloxy^methyl]-4-formyl-44a.56.7.7a.8.8a-octahvdro-7-methyl-3-(1- methylethylVI ^-methano-s-indacene-SadHVcarboxylic acid, pivaloyloxymethyl gster
A solution of Intermediate 4 (300.0g) in methanol (1.21) and tetrahydrofuran (1.21) was stirred and treated with 1M-hydrochloric acid (1.21) and then warmed to 30°. After 3.5h 2M-hydrochloric acid (25ml) was added. After 8h sodium hydrogen carbonate (100.0g) was added over 10min. The mixture was then concentrated in vacuo to ca half volume and then extracted with ethyl acetate (11, 2 x 500ml). The combined extracts were washed with water (500ml) and then evaporated in vacuo to a gum. After repeated chromatography (iso- hexane:ethyl acetate and chlorofornτacetone) and recycling of recovered starting material the title compound (72.53g) was obtained.
δ ( 'H, CDCI3): 0.79δ(3H) d, J=6.8Hz;0.92δ(3H) d, J=6.8Hz; 0.98δ(1H) m; 1.03δ(3H) d, J=6.8Hz; 1.2δ(1H) m; 1.23δ(9H) s; 1.30δ(3H) d, J=6.4Hz; 1.68-
2.09δ(9H) m; 2.27δ(1 H) m; 2.76δ(1 H) t, J=3.9Hz; 3.34δ(1 H) m; 3.62δ(1 H) d, J=9.3Hz; 3.69δ(1H) m; 3.87δ(1H) d, J=9.4Hz; 4.11δ(1H) m; 4.63δ(1H) dd, J=9.5Hz, 1.9HZ; 5.84δ(2H) ABq, J=5.4Hz; 6.07δ(1H) dd, J=3.5Hz, 1.2Hz; 9.70δ(1H) s.
INTERMEDIATE 6
f1 R-riα. 3aβ. 4β. 4aβ. 7β. 7aα. 8aβ)] 8a-f(2.6-Dideoxy-4-Q-proparαyl-β-D- allopyranosvloxv)methyl1-4-formyl-4.4a.5.6.7.7a.8.8a-octahvdro-7-methvl-3-ri- methylethyh-1 4-methano-s-indacene-3a(1 HVcarboxylic acid. pivaloxyloxymethyl ester.
A stirred solution of Intermediate 5 (214mg) in toluene (9ml) under nitrogen was treated with powdered 4A molecular sieves (514mg) and dibutyl tin methoxide (0.1ml) and the mixture was heated at reflux for 2h and then allowed to cool to 20° over 1h. The mixture was then treated with propargyl bromide (70μl) and a 1M solution of tetra butyl ammonium fluoride in tetrahydrofuran (0.44ml). After 22.5h at 20° the mixture was diluted with ethyl acetate (10ml) and filtered through a pad of Harborlite J2 washing through with ethyl acetate. The combined filtrate and washings were evaporated in vacuo to a gum. After chromatography (iso-hexane:ethyl acetate, v:v 4:1) the title compound (100mg) was obtained.
δ OH, CDCI3): 0.79δ(3H) d, J=6.7Hz; 0.92δ(3H), J=6.7Hz; 0.98δ(1 H) m; 1.03δ(3H) d, J=6.7Hz; 1.2δ(1H) m; 1.23δ(9H) s; 1.28δ(3H) d, J=6.3Hz; 1.67- 2.32δ(10H) m; 2.47δ(1H) t, J=2.4Hz; 2.76δ(1H) t, J=3.8Hz; 3.25δ(2H) dd, J=9.1Hz, 3.0Hz; 3.63δ(1H) d, J=9.3Hz; 3.74δ(1H) m; 3.87δ(1H) d, J=9.3Hz; 4.22δ(2H) m; 4.30δ(1H) m; 4.64δ(1H) dd, J=9.5Hz, 1.8Hz; 5.85δ(2H) Abq, J=5.4Hz; 6.07δ(1 H) m; 9.69δ(1 H) s.
INTERMEDIATE 7
[1R-(1α. 3aβ. 4β. 4aβ. 7β. 7aα. 8aβ^ 8a-f(4-O-propargyl-3-iodo-2.3.6-trideoxy-b- D-glucopyranosyloxy^ methyl]-4-formyl-4 ,4a .5.6.7.7a .8.8a-octahvdro-7-methyl-3- M-methylethyn-1.4-methano-s-indacene-3a(1HVcarboxylic acid, pivaloylmethyl esteL
A mixture of Intermediate 6 (95mg), triphenylphosphine (157mg), imidazole (41 mg) and iodine (76mg) in tetrahydrofuran (3ml) was stirred at 20° under nitrogen. After 3.25h the mixture was treated with water (0.5ml) and sodium metabisulphite (100mg) and then after a further 5min more water (10ml) was added and the mixture was extracted with ethyl acetate (3 x 7ml). The combined extracts were washed with water (7ml) and then evaporated in vacuo to a solid. After chromatography (iso-hexane:ethyl acetate, v:v 19:1) the title compound (70mg) was obtained.
δ (1H, CDCI3): 0.79δ(3H) d, J=6.3Hz; 0.91δ(3H), J=6.9Hz; 0.95δ(1 H) m; 1.02δ(3H) d, J=6.7Hz; 1.2δ(1H) m; 1.23δ(9H) s; 1.39δ(3H) d, J=5.9Hz; 1.67- 2.31δ(9H) m; 2.47 -2.60δ(2H) m; 2.74δ(1H) t, J=3.9Hz; 3.26δ(2H) m; 3.61- 3.82δ(2H) Abq, J=9.1Hz; 4.05δ(1H) m; 4.19δ(1H) dd, J=9.5Hz, 2.3Hz; 4.49δ(1H) dABq, J=9.5Hz, 2.3Hz; 5.84δ(2H) Abq, J=5.2Hz; 6.05δ(1H) dd, J=3.6Hz, 1.3Hz; 9.70δ(1H) s.
INTERMEDIATE 8
[1R-(1α. 3aβ. 4β. 4aβ. 7β. 7aα. 8aβ^ 8a-|[1S.7R.9R1-2.8-Dioxa-9-methyl-4- methylene-c/s-bicyclo[3.4.0]-non-7-yl-oxy-methyl]-4-formyl-4.4a.5.6.7.7a.8.8a- octahydro-7-methyl-3-(1-methylethyh-1.4-methano-s-indacene-3aMHV carboxylic acid, pivaloyloxymethyl ester. Method A
A solution of Intermediate 7 (3.7 g) in dry toluene (50 ml) was degassed with an argon stream for 1 hour and then heated to 100-105°C. Tributyltin hydride (2.5 ml) was added and heating continued for 1.5 hours. After cooling carbon tetrachloride (15 ml) was added and the solution stirred at room temperature for 1 hour. A dilute solution of iodine in ether was then added until a faint coloration persisted. The solvent was then removed in vacuo and the residue taken up in diethyl ether and washed several times with a saturated aqueous solution of potassium fluoride until no more precipitation of tributyltin fluoride was observed. The organic layer was dried and evaporated to give a residue which was flash chromatographed on silica gel eluting with hexane:ethyl acetate (9:1) to give the title compound (2.2 g).
δ (1H, CDCI3): 9.71 (s, 1 H, CHO), 6.06 (dd, 1H, H-2, J=1.5 and 3.6 Hz), 5.89 and 5.78 (2d, 2H, Mβ3CCO2Chl2θ, J=5.4 Hz), 5.07 and 5.02 (2dd, 2H, hl2C=C, J=2.7 and 5.1 Hz), 4.5-4.29 (m, 3H, H-7' and CH2-3'), 3.83-3.75 (m, 2H, 8a-CHa and H-1'), 3.61 (d, 1 H, 8a-CHb, J=9.3 Hz), 3.31-3.21 (dq, 1H, H-9\ Jq=6.3 Hz, Jd=9.6 Hz), 3.01 (bs, 1 H, H-5'), 2.76 (t, 1H, H-1 , J=3.9 Hz), 1.22 (s, 9H, (CH3)3COO).
Method B
Hypophosphorous acid (0.59mL) was added to a solution of Intermediate 7 (654mg), triethylamine (0.75mL) and azoisobutyronitrile (7.4mg) in 1 ,4-dioxan (6.5mL). The solution was degassed by placing the mixture briefly under vacuum before heating at 80°C under nitrogen for 1.5 hours. After cooling to room temperature the reaction mixture was diluted with water (30mL) and extracted with diethyl ether (2x30mL). The combined organic extracts were then dried (magnesium sulphate) and evaporated in vacuo to give a colourless oil. This was further purified by flash chromatography on Merck 9385 silica eluting with isohexane/ethyl acetate (10% ethyl acetate) to give the desired product (306mg) as a colourless oil. δ (1 H, CDCI3): 0.79δ(3H) d, J=6.8Hz; 0.91δ(1 H) m; 0.92δ(3H) d, J=6.9Hz; 1.04δ(3H) d, J=6.8Hz; 1.2δ(1H) m; 1.23δ(9H) s; 1.27δ(3H) d, J=6.4Hz; 1.68- 2.05δ(9H) m; 2.26δ(1H) m; 2.758(1 H) t, J=4.0Hz; 3.06δ(1 H) m; 3.33δ(1 H) m; 3.69δ(2H) ABq, J=9.3Hz; 3.98δ(1H) m; 4.31 δ(2H) m; 5.84δ(2H) ABq, J=5.7Hz; 6.05δ(1 H) m; 9.71δ(1 H) s.
EXAMPLE 1
[1 R-Mα. 3aβ. 4β. 4aβ. 7β. 7a«. 8aβ)] 8a-[[1S.7R.9Ry2.8-Dioxa-9-methyl-4- methylene-c/s-bicvclof3.4.0]-non-7-yl-oxymethyl]-4-formyl-4.4a.5.6.7.7a.8.8a- octahydro-7-methγl-3-M-methylethvh -1 ^-methano-s-indacene-SaM H)- carboxylic acid.
A solution of Intermediate 8 (80 mg) in dry methanol (1 ml) was treated with sodium methoxide (11 mg) and stirred at room temperature for 1 hour. The reaction mixture was partitioned between diethyl ether (50 ml) and 0.5 N aqueous hydrochloric acid (100 ml). The organic layer was washed with water (3x50 ml) and brine, then dried and evaporated to afford the title compound (60 mg) as a white foam.
δ (1H, CDCI3): 9.87 (s, 1H, CHO), 6.04 (dd, 1H, H2, J=1.2 and 3.3 Hz), 5.08 and 5.02 (2m, 2H, CH2=), 4.50-4.29 (m, 4H, H7'+2H3'+8aCH2(1H)), 3.76 (dd, 1 H, H1\ J=9.3 and 7.5 Hz), 3.32-3.22 (m, 2H, 8aCH2(1H)+H9'), 3.02 (bs, 1 H, H5'), 2.45 (t, 1H, H1, J=3.6 Hz).

Claims

Claims
A process for the preparation of a compound of formula (I);
Figure imgf000015_0001
and pharmaceutically acceptable salts or metabolically labile esters thereof which comprises cyclisation of a compound of formula (II);
Figure imgf000015_0002
wherein R is a carboxyl protecting group followed where necessary or desired by one or more of the following steps;
(I) removal of the carboxyl protecting group R;
(ii) isolation of the compound of formula (I) in the form of a pharmaceutically acceptable salt thereof; (iii) conversion of the compound of formula (I) into a metabolically labile ester thereof.
2. A process as claimed in claim 1 wherein R is a substituted methyl group.
3. A process as claimed in claim 1 or claim 2 wherein R is a pivalolyloxymethyl group.
4. A process as claimed in any of claims 1 to 3 wherein the cyclisation process is carried out in the presence of a radical chain carrier.
A process as claimed in claim 4 wherein the reaction is carried out in the presence of a radical initiator.
A process as claimed in any of claims 1 to 3 wherein the cyclisation is carried out using hypophosphorous acid in the presence of an organic base and a radical initiator.
7. A compound of formula (II);
Figure imgf000016_0001
wherein R is a carboxyl protecting group.
8. A compound as claimed in claim 7 wherein R is a pivaloyloxymethyl group.
PCT/EP1997/002284 1996-05-08 1997-05-06 Process for the preparation of an indacene compound WO1997042194A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0916664A1 (en) * 1997-11-13 1999-05-19 Glaxo Wellcome, S.A. Enynes used in the synthesis of antifungal agents
EP0987235A1 (en) * 1998-08-25 2000-03-22 MERCK PATENT GmbH Method for the conversion of arenes or alkenes with iodoalkenes, aryl iodides or arenediazonium salts

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6240292A (en) * 1985-08-14 1987-02-21 Sankyo Co Ltd Antibiotic substance zofimarin
EP0711784A1 (en) * 1994-11-08 1996-05-15 Glaxo, S.A. Antifungal Sordarin derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6240292A (en) * 1985-08-14 1987-02-21 Sankyo Co Ltd Antibiotic substance zofimarin
EP0711784A1 (en) * 1994-11-08 1996-05-15 Glaxo, S.A. Antifungal Sordarin derivatives

Non-Patent Citations (1)

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Title
CHEMICAL ABSTRACTS, vol. 107, no. 1, 1987, Columbus, Ohio, US; abstract no. 5745j, T. OGITA ET AL.: "Antibiotic zofimarin manufacture by Zofiela marina and its fungal activity" page 540; XP002015901 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0916664A1 (en) * 1997-11-13 1999-05-19 Glaxo Wellcome, S.A. Enynes used in the synthesis of antifungal agents
EP0987235A1 (en) * 1998-08-25 2000-03-22 MERCK PATENT GmbH Method for the conversion of arenes or alkenes with iodoalkenes, aryl iodides or arenediazonium salts

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