GB2287709A

GB2287709A - Silylated azetidinone intermediates

Info

Publication number: GB2287709A
Application number: GB9406073A
Authority: GB
Inventors: Angelo Pecunioso; Chiara Ghiron; Elisabetta Piga
Original assignee: Glaxo SpA
Current assignee: GlaxoSmithKline SpA
Priority date: 1994-03-26
Filing date: 1994-03-26
Publication date: 1995-09-27
Also published as: GB9406073D0

Abstract

A process for the preparation of a compound of formula (I) wherein R1 is a trialkylsilyl group and R2 is a hydrogen atom or a trialkylsilyl group <IMAGE> which comprises reacting the azetidinone (II) with the homochiral enol ester (III> <IMAGE> in an aprotic solvent in the presence of a slannic catalyst.n

Description

Chemical Process The present invention relates to an improved process for the preparation of an intermediate useful in the preparation of antibacterial agents.

European Patent Application, publication No. 041 6953A2 describes a novel class of tricyclic antibacterial agents. A particularly preferred compound described and claimed therein is the compound (A)

and salts thereof.

A key intermediate in the synthesis of compound (A) is the methoxy ketone (B).

wherein R1 is a hydroxyl protecting group such as trialkylsilyl group e.g. tbulydimethylsilyl. The present invention provides an improved process for preparing the intermediates of formula (B) with a high degree of enantiomeric purity.

Thus the present invention provides a process for the preparation of compounds of formula (I)

wherein R1 is a trialkylsilyl group and R2 is a hydrogen atom or a trialkysilyl group which comprises reaction of the azetidinone (II) wherein R1 is defined in formula (I) and R2 is a trialkysilyl group

with the homochiral enol ether (III)

wherein R3 is a trialkylsilyl group. The reaction is carried out in an aprotic solvent such as halohydrocarbon e.g. dichloromethane, chlorobenzene or fluorobenzene, acetonitrile or a hydrocarbon e.g. toluene in the presence of a suitable catalyst such as stannic chloride stannic chloride etherate or stannic chloride dimethylsulphide complex and preferably at a temperature within the range -15 to 300 e.g. -15 to 250 and when desired or necessary subsequent conversion of the compound of formula (I) wherein R2 is trialkylsilyl into the corresponding compound of formula (I) wherein R2 is hydrogen.

The trialkylsilyl groups R1, R2 and R3 are preferably tri(C1 4)alkyl groups.

Examples of suitable trialkylsilyl groups include trimethylsilyl and tbutyldimethylsilyl.

A preferred azetidinone (II) for use in the reaction is that wherein R1 is tbutyldimethysilyl and R2 is trimethylsilyl.

A preferred chiral enol ether (III) is that wherein R3 is trimethylsilyl.

The interconversion of a compound of formula (I) wherein R2 is trialkylsilyl into a compound of formula (I) wherein R2 is hydrogen may be carried using conventional methods known for carrying out such reactions. Thus compounds wherein R2 is hydrogen may be prepared from compounds wherein R2 is trimethylsilyl by reaction with acetic acid and tetrabutylammonium fluoride in an aprotic solvent such as tetrahydrofuran or by reaction with trifluoroacetic acid.

The homochiral enol ethers (III) are novel compounds and represent a further aspect of the present invention.

The homochiral enol ether (III) may conveniently be prepared from the homochiral cyclohexanone derivative (IV).

by reaction with an appropriate O-silylating agent. Examples of suitable 0silylating agents include ethyl trimethylsilylacetate or trimethylsilyl trifluoromethylsulphonate.

The reaction of the cyclohexanone derivative (IV) with ethyl trimethylsilylacetate is preferably carried out in the presence of tetrabutylammonium fluoride on silica gel and in a solvent such as an ether e.g. tetrahydrofuran and at a temperature within the range -78-00 e.g. -400.

The reaction of the cyclohexane derivative (IV) with trimethylsilyl trifluoromethylsulphonate is preferably carried out in the presence of a tertiary organic base such as triethylamine and in an aprotic solvent such as dichlormethane.

The cyclohexanone derivative (Ill) may be prepared by oxidation of the homochiral hydroxy ether (V)

using conventional procedures. Thus for example the oxidation may be carried out using oxalyl chloride and dimethylsulphoxide, pyridine/sulphur trioxide, sodium hyprochlorite/2,2,6,6-tetramethyl-1 -piperidinyloxy, N-bromacetamide 1 ,3-dibromo-5,5-dimethylhydantoin or Jones reagent (CrO3/H2SO4). The reaction is conveniently carried out in a solvent, the choice of which will depend upon the oxidants to be used. Thus oxidation using oxalylchloride and dimethylsulphoxide is conveniently carried out in a halohydrocarbon e.g.

dichloromethane and at a temperature within the range -780-500. Oxidation using pyridine and sulphur trioxide is conveniently carried out in a solvent such as an ether e.g. t-butylmethyl ether and in the presence of acetone and a base such as triethylamine or diisopyropylethylamine.

The homochiral hydroxyether (V) is a known compound and may be prepared using known procedures such as those described by . Honig H, Senfer Wassenthal P, Synthesis 1990, 1137-1140 Laumen K et al, J Chem. Soc., Chem. Commun., 1989, 148-150 or Peterson et al, Jorg. Chem, 1988, 53 19031907 or more preferably by the prodedure described herein below in Intermediate 1.

In order that the invention may be more fully understood the following examples are given by way of illustration only.

Intermediate 1 (1 S.2S)-2-methoxycyclohexanol Immobilised Candida antarctica lipase (Novozyme 435;10g) was added to a solution of (+) trans-2-methoxycyclohexanol (50g), vinyl acetate (42ml) and triethylamine (6ml) in cyclohexane (167ml). The mixture was stirred in a stoppered conical flask for 24h at room temperature and then filtered through a number 3 sinter funnel under vacuum. The filter cake was washed with cyclohexane (100ml). The filtrate (350ml) was taken and vigourously extracted with water (4 x 180ml). The combined water extracts (820ml) were back extracted with cyclohexane (200ml). The water layer was taken and sodium chloride (245g to give 5M) added. After dissolution, the salt solution (ca 900ml) was extracted with ethyl acetate (2 x 450ml) and the combined ethyl acetate extracts were reduced in vacuo to afford the title product as a pale yellow oil (17.5g ee > 99%).

Intermediate 2 (2S)-2-methoxycyclohexanone Concentrated sulphuric acid (6.1 ml) was added to a solution of chromium trioxide (7 g) in water (50ml) cooled to 00. An aliquot of this solution (30ml) was added dropwise over a few minutes to a solution of (1 S,2S)-1-methoxy cyclohexanol (1.95 g) in dichloromethane (15ml) cooled to 00. The solution was vigorously stirred at 0 for 1 h and then quenched by addition of of isopropyi alcohol (2.5 ml). The mixture was extracted with dichloromethane (3x50ml); the combined extracts were washed with a saturated solution sodium bicarbonate (30ml), then with brine (50ml) and dried. The mixture was then filtered over celite; the solution was evaporated under reduced pressure at room temperature to give the title compound as a pale yellow liquid ( yield=56%, e.e.=1 00%).

1 H-NMR(400 MHz; CDC13): 3.68(m,1 H);3.40(s,3H); 2.50(m,1 H);2.22 2.18(m,2H);2.0-1 .8(m,2H);1.6(m,3H).

Intermediate 3 (3S.4R)-1 -(tnmethvlsilvl)-4-acetoxy-3((R)-(t- butyldim ethylsilylxoy)ethyl]azetidine-2-one Triethylamine (5.4ml) and trimethylsilylchloride (4.3ml) were added to a solution of (3S,4R)-4-acetoxy-3((R)-(t-butyldimethylsilyloxy)ethyl]-2-azetidi none (7.5g) in dry tetrahydrofuran (60ml) and the mixture stirred at room temperature for 1 hr.

The reaction mixture was filtered twice on a sintered glass filter under nitrogen and the filtrate concentrated under reduced pressure to give the title compound in 99% yield.

Example 1 (3 S)-3-meth oxy-2-trim ethylsiloxycyclohex-1 -ene To a cooled (-300C) solution of triethylamine (8.4ml) in dry dichloromethane (60ml) under nitrogen, trimethylsilyl trifluoromethylsulphonate (10.2ml) was added. (2S)-2-Methoxycyclohexanone (6g) was added, the mixture was stirred at -300C for 2 hours, and hexane (ca. 3 volumes) was then added. The hexane phase was separated from the oil which precipitated out, concentrated under vacuum and the residue was filtered on a short alumina pad eluting with petroleum ether to give the title compound as a colourless oil (5.5g).

e.e + 86% (shift reagent: trisC3-(trifluoroacetyl-d-camphorate)l Eu(lll), CDCI3) [alD 74.60 (nm = 589, c=2.005, 1=10cm, CH2CI2) 1H-NMR (400 MHz; CDC13) 4.97(1H,dd); 3.49(1H,m); 3.40(3H,s); 2.141.84(3H,m); 1.70-1.44(3H,m); 0.20-0.11 (9H,s).

Example 2 (3S.4R)-3-[(R)-1 -(t-butyldimethylsilyloxy)ethyl]-4t(R)-2'-((S)-61m ethoxy-1 - oxocyclohexyl)azetidine-2-one To a solution of intermediate 3 (9.49) and the compound of Example 1 (139) in an hydros dichloromethane (50ml) was added dropwise a preformed solution of stannic chloride etherate (6.1 ml) in dry dichloromethane (80ml) (over 20 mins) keeping the reaction flask in a water bath at room temperature.The bright yellow solution was stirred for an additional 10 mins, poured into a stirred ice-cold saturated solution of sodium hydrogen carbonate (800ml) and diluted with diethyl ether (500ml). The mixture was filtered on a Celite pad and then extracted twice with diethyl ether (2x500ml). The combined organic extracts were washed with brine, then dried over sodium sulphate and evaporated under vacuum. The resulting yellow oil was dissolved in distilled tetrahydrofuran (150ml), then acetic acid (0.9eq.) and tetrabutylammonium fluoride (0.9eq. from 1.1 M soln. in tetrahydrofuran) were added and the reaction stirred under nitrogen for one hour. The reaction was then poured into a saturated solution of sodium hydrogen carbonate (150ml) and extracted with diethyl ether (2x100ml).

The organic layer was washed with ice cold hydrochloride acid (2% soln.), then with a saturated solution of sodium hydrogen carbonate, and finally brine. The organic phase washed and evaporation of the solvent afforded an oil (ca. 1 3g).

The residue was dissolved into acetonitrile (80ml). The white solid which precipitated was filtered off. Acetonitrile (15ml) and water (5ml) were added to the filtrate, which was extracted with cyclohexane (2x15ml). Evaporation of the acetonitrile afforded an oil which was filtered through a silica pad (50g) eluting with petroleum ether (2 1) and then diethyl ether/petroleum ether 1/1(2 1). The elutant was concentrated and the residue crystallised from petroleum ether to give the title compound (2.19). The mother liquors were filtrered on a silica pad, concentrated and the residue crystallized from petroleum ether to give additional 500mg of the title compound.

Example 3 (3S .4R)-3-f(R)-1 -(t-butyldimethylsilyloxy)ethyl]-4[(R )-2'-(S)-6'-methoxy-1 'oxocyclohexyl)azetidin-2-one Tin tetrachloride (0.86ml) was added to dry fluorobenzene (20ml), under a nitrogen atmosphere. The solution was cooled to -6 C, then a solution of intermediate 3 (1.2g) in dry fluorobenzene (14ml) was added over 15 minutes.The mixture was stirred for 5 min at 0 C, then a solution of (-)-3 methoxy-2-tri methylsilyloxycyclohex-1 -ene (1.4ml) in i n dry fluorobenzene (1 4ml) was added over 30 minutes. The reaction was stirred at 0 C for further 7 minutes and then poured into a mixture of Rochelle salt (100ml), saturated sodium hydrogen carbonate solution (100ml) and ethyl acetate (200ml). The mixture was stirred for 20 minutes, then the layers were separated. The aqueous layer was extracted with further ethyl acetate (100ml). The combined organic extracts were washed with brine (50ml), dried (Na2SO4) and concentrated in vacuo to give an oil (1.9g).

This material was dissolved in dichloromethane (24ml) and treated with potassium fluoride (0.29), tetrabutyl ammonium bromide (1.lg) and acetic acid (0.2ml). The suspension was stirred at 23"C for 30 minutes, then a satured sodium hydrogen carbonate solution (50my) was added and the mixture was stirred for 30 minutes. The layers were separated; the organic layer was washed with water (2x50ml), dried (Na2SO4) and concentrated in vacuo to give the crude title compound (1.859) as a white solid.

A portion (1.579) was crystallized from n-hexane to give the title compound as a white solid (0.729).

1H-NMR (CDC13): 5.76 (s, 1H); 4.18 (m, 1H); 3.99 (m,1H); 3.57 (t, 1H); 3.27 (s, 3H); 3.09 (m, 1 H); 2.88 (dd, 1 H); 2.23 (m, 1 H); 2.09(m, 1 H); 1.99 (m, 1 H); 1.771.5 (m, 3H); 1.24 (d, 3H); 0.87 (s, 9H); 0.07 (s, 3H); 0.06 (s, 3H).

Example 4 (3S .4R)-3-[(R)-I -(t-butyidimethylsilyloxy)ethyl]-4ttR)-2'-(S!-6'-methoXv^1 '- oxocyclohexyl)azetidin-2-one To a stirred solution of tin tetrachloride (6.5ml) in dry dichloromethane (80 ml) at 0 C under nitrogen was added dry dimethylsulphide (8.2 ml) over 5 minutes. The resulting solution was stirred for 5 minutes before being allowed to reach room temperature. To the reaction flask was introduced a solution of Intermediate 3 (10g) and Example 1 (16 ml) in dry dichloromethane (100 ml) dropwise over 1 h. The reaction mixture was then stirred for a further 1.5 h before pouring into a stirred mixture of saturated aqueous NaHCO3 (500 ml) and saturated aqueous Rochelle's salt (500 ml) and ethyl acetate (600 ml). After 20 min, the aqueous phase was washed with ethyl acetate (3 x 200 ml) and the combined organic phases were washed with saturated brine (400 ml), dried over an hydros sodium sulphate (2009), filtered and the solvents removed under reduced pressure. The resulting viscous oil was dissolved in ethanol (50 ml) and treated with vegetable charcoal (3.9 g) at reflux for 45 min. After filtration under reduced pressure, the solvent was evaporated to give a crude foam (11 g) which was dissolved in hot n-hexane (20ml), allowed to reach room temperature and seeded with a few crystals of the title compound before standing at 40C for 6 h. The resulting precipitate was filtered washed with cold hexane (3 x 20 ml) and dried under vacuum to afford the title compound (2.8 g) as an off-white solid.

The mother liquors were evaporated to give a foam (8 g) which was dissolved in nhexane (20 ml) and filtered through a pad of silica gel (16 g in a pad 9 cm high).

The pad was then washed with separate aliquots of n-hexane (10 x 50 ml) and then 50 : 1 n-hexane : ethyl acetate (3 x 200 ml). The filtrate fractions collected containing the desired product (TLC) were evaporated to dryness to give title compound as a colourless solid (1.4 g).

1H-NMR(400 MHZ);CDCl3) 5.75(1H sa);4.18(1H m), 3.99(1H m); 3.57(1H t); 3.28(3H s); 3.10(1H m); 2.88(1H dd); 2.24(1H m); 2.09(1H m); 1.99(1H m); 1.71.5(3H m); 1.24(3H d); 0.87(3H s); 0.08 (3H s); 0.06(3H s).

Claims

Claims

A process for the preparation of a compound of formula (I) wherein R, is a trialkylsilyl group and R2 is a hydrogen atom or a trialkylsilyl group

which comprises reacting the azetidinone (II) wherein R1 is as defined in formula (I) and R2 is a trialkylsilyl group

with the homochiral enol ester (III) wherein R3 is a trialkylsilyl group

in an aprotic solvent and in the presence of a catalyst selected from stannic chloride, stannic chloride etherate or a stannic chloride dimethylsulphide complex, followed when desired or necessary by the subsequent conversion of a compound of formula (I) wherein R2 is trialkylsilyl into the corresponding compound of formula (I) wherein R2 is hydrogen.
2. A process as claimed in claim 1 wherein the aprotic solvent is a halohydrocarbon.
3. A process as claimed in claim 1 or claim 2 wherein the reaction is carried out at a temperature within the range -15" to 300.
4. A process as claimed in any of claims 1 to 3 wherein R1 is a tbutyldimethylsilyl group and R2 and R3 each represent a trimethylsilyl group.
5. A compound of formula (I), as defined in claim 1 whenever prepared by a process as claimed in any of claims 1 to 4.