Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ WO 94/21637 PCT/EP94/00838
21S778~
PROCESS FOR THE PREPARATION OF CONDENSED CARBAPENEME DERIVATIVES
The present invention relates to an improved process for the synthesis of an
antibacterial agent.
European Patent Application publication No. 041 6953A2 describes a novel
class of tricyclic antibacterial agents and processes for their preparation. A
particùlar preferred compound described therein is the methoxy derivative (I)
C ~ OCH3 (I)
~N
O C02H
and salts thereof. EPA 0416953A2 also teaches that the compound of formula
(I) may be prepared by the process as outlined below:-
~?"' OCH ~ OCH3
I O COOR2
IC= Y (B)
COOR2"
(A)
OCH, CH3~ OCH,
N CO2H COOR2
(I) (C)
wherein R1 a is a hydroxyl protecting group;
R2a is a carboxyl protecting group and
WO 94/21637 PCT/EP94/00838 ~
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Y is oxygen or a phosphine group.
More specifically the specification teaches the preparation of compound (I)
using intermediates wherein R1a is t-butyldimethylsilyl group~ Y is oxygen and
5 R2a is allyl or R1a is t-butyldimethylsilyl, Y is PPh3 and R2a is benzyl.
J
It has unexpectedly been found that the conversion of the lactam (A), wherein
Y is a phosphine group into the required tricyclic antibacterial agent (I) can be
significantly improved if the hydroxyl protecting group R1a is removed prior to
10 the cyclisation step in the synthesis.
Thus the present invention provides a process for the preparation of the
compound of formula (I)
C~ OCH3 (I)
~N CO2H
15 and salts thereof which comprises the thermal cyclisation of the lactam (Il)
~ ~ OCH3
CH3 o
o~NI
IC=PPh3
CO2R
(Il)
wherein R is a carboxyl protecting group followed by removal of the carboxyl
protecting to give either the free carboxylic acid or a physiologically acceptable
salt thereof. Suitable carboxyl protecting groups R include allyl or arylmethyl
20 such as benzyl, t-butylbenzyl, diphenylmethyl or p-biphenylmethyl.
The thermal cyclisation process is preferably carried out by heating the
compound of formula (Il) in a solvent at a temperature within the range 40-
WO 94/21637 PCT/EP94/00838
~ 21~ 7787
200 . Examples of suitable solvents include hydrocarbons such as toluene or
' xylene, ethers such as tetrahydrofuran or 1 ,4-dioxan or an alkanol e.g. propanol
or isopropanol, or esters such as ethyl acetate or mixtures of two or more such
solvents.
The carboxyl protecting group R may be removed by standard processes such
as those described in Protective Groups in Organic Chemistry, pages 192-210,
Edited by J F W McOmie (Plenum Press 1983). For example when R represents
an arylmethyl group this may be removed by conventional procedures using
hydrogen and a metal catalyst e.g. palladium in a suitable solvent such as an
alkanol e.g. propanol and preferably in the presence of a tertiary amine such asa trialkylamine e.g. triethylamine.
When the group R represents an allyl group then this is preferably removed by
treatment with an allyl acceptor in the presence of tetrakis(triphenylphospine)
palladium and optionally in the presence of triphenylphospine. Suitable allyl
acceptors include sterically hindered amines such as t-butylamine, cyclic
secondary amines such as morpholine or thiomorpholine, tertiary amines such
as triethylamine, aliphatic or cycloaliphatic ,~-dicarbonyl compounds such as
acetylacetone, ethyl acetoacetate or dimedone, or alkanoic acids or alkali metalsalts thereof such as acetic acid, propionic acid or 2-ethyl hexanoic acid or the
potassium or sodium salt thereof. The reaction is preferably carried out in an
inert solvent such as an ether e.g. diethyl ether or tetrahydrofuran, an alkanole.g. ethanol, or propanol, an ester e.g. ethyl acetate or a halohydrocarbon e.g.methylene chloride, or mixtures thereof. The reaction is conveniently carried out
in the temperature range 0-40 more particularly at room temperature.
In a preferred aspect of the invention the thermal cyclisation is carried out using
a compound of formula (Ill) wherein R is an arylmethyl group such as benzyl or
p-t-butylbenzyl and at a temperature within the range 40-120 and in a solvent
such as a hydrocarbon e.g. toluene, an ether e.g. 1,4-dioxan or an alkanol e.g.
propanol or isopropanol or an ester e.g. ethylacetate or a mixture thereof with
an alkanol.
WO 94121637 PCT/EP94/00838 ~
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The arylmethyl carboxyl protecting group R is preferably removed by
hydrogenolysis using hydrogen and a metal catalyst such as palladium and in a
solvent such as an alkanol e.g. ethanol, isopropanol, esters e.g. ethyl acetate or
ketone e.g. acetone and in the presence of a base. Suitable bases for use in the5 reaction include tertiary organic bases such as trialkylarnines e.g. triethylamine.
The carboxylic acid (I) or a salt thereof may conveniently be converted into a
physiologically acceptable salt thereof without isolation of the product of the
hydrogenolysis. Thus for example the sodium salt thereof may be obtained by
the addition of acetone and sodium ethylhexanoate to the reaction solution,
10 followed by addition of a non solvent such as an ether e.g. diisopropyl ether. In
this process it may be advantageous to add seed crystals of the required
sodium salt.
Salts of the compound of formula (I) include physiologically acceptable salts
15 thereof and non physiologically acceptable salts thereof.
Suitable physiologically acceptable salts of compound of formula (I) include
salts formed with alkali metals e.g. sodium or potassium, alkaline earth metals
e.g. calcium, amino acids (e.g. Iysine and arginine) and organic bases (e.g.
20 procaine, phenylbenzylamine, ethanolamine, diethanolamine and N-methyl
glucosamine). Non physiologically acceptable salts of the compound of formula
(I) may be useful as intermediates for the preparation and/or isolation of the
compound of formula (I) or a physiologically acceptable salt thereof.
25 The hydroxy compounds of formula (Il) which are novel and represent another
aspect of the invention may be prepared from the corrresponding ether (Ill)
WO 94/21637 PCT/EP94100838
~ 21~7787
, R,~ OCH3
CH3 o
O
C=PPh3
CO2R
(III)
wherein R1 is a trialkylsilyl group and R is as defined in formula (Il) by
conventional procedures. Thus if R1 is a t-butyldimethysilyl group this may be
5 removed by treatment with tetrabutylammonium fluoride and acetic acid in a
solvent such as tetrahydrofuran or by hydrolysis with a mineral acid such as
hydrochloric acid in a suitable organic solvent, for example acetonitrile and
acetic acid.
10 The silylethers of formula (Ill) are either known compounds or may be prepared
by the procedures described in EPA No. 0416953A2 and or the examples given
below.
In order that the invention may be more fully understood the following examples
15 are given by way of illustration only.
In the intermediates and examples all temperatures refer to OC; solutions were
dreid refers to solutions dried over anhydrous sodium sulphate.
.
Intermediate 1
Benzyl 2-[3S.4R)-3[(R)-1-(t-butyldimethylsilyloxy)ethyll-4-[(2'S.6'R)-2-methoxy-1"-oxocyclohexy-6"-yl]azetidin-2-on-1-yl]-2-triphenylphosphoranyl acetate
To a solution of (3S,4R)-3[(R)-1-(t-Butyldimethylsilyloxyethyl]-4[(R)-2'-(S)-6-
methoxy-1'-oxocyclohexyl)]azetindin-2-one (4.59) in dry tetrahydroduran (15ml)
under nitorgen, benzyl glyoxylate (2.49) triethylamine (0.5ml) and 3A molecular
WO 94/21637 PCT/EP94/00838
2ls7~ ~ 6
sieves were added.The reaction mixture was stirred at 22 for 24hrs then dilutedwith ethyl acetate (100ml), washed with saturated aq. ammonium chloride
(2x100m!), brine (2x200ml), dried and concentrated under vacuum. The oily
residue (6.4g) was dissolved in dry tetrahydrofuran (100ml1 urider nitrogen at 0,
and thionyl chloride (1.84ml) and 2,6-lutidine (3.20ml) wete added. The reactionmixture was stirred at 22 for 4 hrs, diluted with ethyl acetate (100ml), washedwith saturated aq. ammomium chloride (2x150ml), 5% aq. sodium hydrogen
carbonate (2x150ml), brine (2x150ml), dried and concentrated under vacuum.
The oily residue (6.2g) was dissolved in 1,4-dioxane (50ml) and 2,6-lutidine
(2.2ml) sodium bromide (2.69) and triphenylphospine (6.649) were added.The
reaction mixture was stirred at 22 for 15hrs, then poured into saturated aq.
ammonium chloride (200ml) and extracted with ethyl acetate (200ml). The
organic layer was washed with saturated aq. ammonium chloride (200ml) and
brine (2x200ml), dried and concentrated under reduced pressure. The oily
resiude was chromatographed on silica gel using light petroleum/diethyl ether
1/1 as eluant, to give the title compound as a white solid (5.04g) m.p. =128;
t.l.c. ethyl acetate.cyclohexane 1/1 Rf = 0.6).
Example 1
Benzyl (4S.8S.9R.1 OS.12R)-4-methoxy-10-(-1 -hydroxyethyl)-11 -oxo-1 -
azatricyclo~7.2Ø03 8]undec-?-ene-2-carboxylate
To a solution of the intermediate 1 (3.7g) in acetonitrile (100ml), acetic acid
(4.8ml) and 37% hydrochloric acid (3.73ml) were added with ice cooling.The
reaction mixture was stirred at -15 for 1hr. poured into cold 5% aq. sodium
hydrogen carbonate (200ml) and extracted with ethyl acetate (200ml). The
organic layer was washed with brine (2x200ml), dried and concentrated under
reduced pressure to give enzyl 2-[3S,4R)-3[(R)-1-(hydroxyethyl)-4-[(2'S,6'R)-2-
methoxy-1 "-oxocyclohexy-6"-yl~azetidin-2-on-1 -yl]-2-triphenylphosphoranyl
acetate as a white foam which was dissolved in 1,4-dioxan (30ml) and heated at
reflux for 7hrs. The solution was diluted with ethyl acetate (100ml) and washed
with saturared aq. ammonium chloride (2x100ml) and brine (2x100ml) and
washed with saturated aq. ammonium chloride (2x100ml) and brine (2x100ml),
dried and concentrated under vacuum. The oily residue was chromatographed
~ WO 94/21637 PCT/EP94/00838
2157787
on silica gel, using ethyl acetate/cyclohexane 1/1 as eluant, to afford the title
compound as a foam (0.599; t.l.c. ethyl acetate/cyclohexane 1/1 Rf=0.3).
IR (CDCI3) V maXcm-1 3600 (O-H), 1772(C=0 ~ lactam), 1718(C=O ester),
1632(C=C);
1H-NMR (300MHz, CDCI3): 7.47-7.30(m), 5.29(dd), 4.94(t), 4.24(m), 4.19(dd),
3.3-3.2(m), 3.20(s), 2.05(m),1.9-1.2(m),1.61 (d),1.32(d).
Exam~le 2
4-t-Butylbenzyl (4S.8S.9R.1 OS.12R)-4-methoxy-10-(-1 -hydroxyethyl)-11 -oxo-1 -
azatricyclo[7.2Ø03 8]undec-2-ene-2-carboxylate
(i) 4-t-Butylbenzyl-2(3S.4S)-3[(R)-1-(hydroxyethyl)-4-[(2'S.6'R)-2-methoxy-
1"oxocyclohexy-6"-yl]azetidin-2-on-1-yl]-2- triphenylphosphoranyl acetate
2,6-Lutidine (3.95 9) was added to a solution of (3S,4R)-3[(R)-1-
(tbutyldimethylsilyloxyethyl]-4(R)-2'(S)-6-methoxy-1 '-oxocyclohexyl)]azetidin-2-
one (5.0 g) and 4-t-butylbenzylglyoxylate (4.51 9) in ethyl acetate (50 ml) and
the resultant solution was heated to reflux. Ethyl acetate (10 ml) was removed
by distillation and the resultant solution was heated at reflux for 6 hours. Thereaction was cooled to 0-5, thionyl chloride (2.05 ml) in ethyl acetate (10 ml)was added over 30 min. and the reaction mixture was stirred at 0-5 for 45 min.
The reaction was quenched by dropwise addition of an 8% solution of sodium
bicarbonate (70 ml), the resultant mixture was stirred at 5 for 30 min and thenthe phases were separated. The aqueous layer was re-extracted with ethyl
acetate (15 ml) and the combined organic phases were washed with lM a
solution of citric acid (40 ml), water (20 ml) and brine (20 ml). The organic
solution was treated with 2,6-lutidine (2.5 ml), sodium bromide (2.25 g) and
triphenylphosphine (5.7 9). The resultant mixture was stirred at 25 C for 20
hours after that was washed with 1 M solution of citric acid (25 ml), water (25 ml)
- and brine (3x50 ml). The organic phase was evaporated under vacuum to give a
light brown foam (13.8 9) of 4-t-butylbenzyl-2(3S,4S)-3[(R)-1 -(t-
butyldimethylsilyloxy)ethyl]-4-~(2'S,6'R)-2-methoxy-1"oxocyclohexy-6"-
yl]azetidin-2-on-1-yl]-2- triphenylphosphoranyl acetate ,which was dissolved in a
mixture of cyclohexane (138 ml), ethyl acetate (27 ml) and tetrahydrofuran (91
ml) and the resultant solution cooled at 0-5 with stirring. Cold 4M hydrochloric
WO 9~/21637 PCT/EP94/00838
21577~7
acid (262 ml) was added over 15 min whilst maintaining a temperature of 0-5
and the biphasic mixture was stirred for 1 hour at 2-5. The phases were
separated, the aqueous layer was washed with a mixture of cyclohexane (138
ml) and ethyl acetate (27 ml), and then basified at ~5j,by addition of a 4M
5 solution of potassium carbonate (215 ml). The aqueou~s layer was extracted with
ethyl acetate (2x165 ml), dried and evaporated under vacuum to give a foam
(3.27 g) which foam was dissolved in methyl ethyl ketone (60 ml). To the cooled
(0) solution was added dropwise, over 30 min., n-hexane (275 ml) with
vigorous stirring and under nitrogen atmosphere. The mixture was stirred at 0-510 for 1 hour and then filtered. The solid was washed with a n-hexane/methyl ethyl
ketone (55 ml / 11.7 ml) mixture and then dried to give the title com~ound as
solid(4.35 g).
(t.l.c. ethyl acetate; Rf = 0.35)
IR ( film ) VmaX (cm~1) 3468 (O-H) 1745 (C=O b lactam) 1651-1618 (C=O,
15 C=C)
1H -NMR (300MHz, CDCI3): 7.20-7.28 (m), 7.10-7.00 (m), 6.70-6.56 (m), 5.10
(m), 4.96-4.56 (m), 4.07 (m), 4.00-3.66 (m), 3.47 (m), 3.26 (s), 3.12 (s), 3.08 (s),
3.00-2.84 (m), 2.71 (m), 2.52-1.80 (m), 1.70-1.50 (m), 1.44-1.20 (m), 1.25 (d),
1.02 (d)
(ii) 4-t-E3utylbenzyl(4S.8S.9R.1 OS.1 ~R)-4-methoxy-10-(1 -hydroxyethyl)-11 --oxo-
1-azatricyclo~7.?Ø03 8]undec-2-ene-2-carboxylate
A solution of the compound of Example 2(i) (1.3 g) in toluene (52 ml) was
25 heated at reflux for 13 hours and then concentrated under reduced pressure.
The oil was dissolved in tertbutylmethylether (25 ml) and the organic solution
was washed three times with 1/1 DMF/water mixture (25 ml). The organic layer
was diluted with tertbutylmethylether (10 ml), washed with water (3x25 ml), dried
and evaporated to give the title compound (0.7g) as a yellow foam.
30 (t.l.c. diethylether; Rf = 0.32)
1H -NMR (300MHz, CDCI3): 7.38 (s), 5.34 (d), 5.19 (d), 4.95 (t), 4.21 (m), 4.17
(dd), 3.25 (dd), 3.23 (m), 3.21 (s), 2.06 (m), 1.86 (m), 1.77 (d), 1.60 (m), 1.40
(m),1.32 (d),1.31 (s).
~ WO 94/21637 PCT/EP94/00838
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Example 3
'' Sodium(4S.8S.9R.1 OS.12R)-4-methoxy-10(1 -hydroxyethyl~-11 -oxo-1 -
~7~tricyclo[7.2.003-3]undec-~-ene-~-carboxy!ate
10% palladium on carbon (0.86 g) was added to a solution of
Benzyl(4S,8S,9R,1 OS,12R)-4-methoxy-10-(1 -hydroxyethyl)-11 -oxo-1 -
azatricyclo~7.2Ø0-3-8 ]undec-2-ene-carboxylate (300 mg) in tetrahydrofuran (10ml), under nitrogen. The mixture was then hydrogenated at 25-26 C and 1 atm
for 20 min. and after that, the catalyst filtered off and washed with diethyl ether
(10 ml). Sodium 2-ethylhexanoate (0.134 g) was added to the filtrate followed
by diethyl ether (100 ml). The white suspension was stirred at O under nitrogen
for 1 hr. The solid was filtered off, washed with diethyl ether (5 ml) and driedunder vacuum to give the title compound (0.115 9) as a white solid.
1H-NMR (300MHz) (D20): 4.74 (m), 4.10 (m), 4.03 (dd), 3.31 (dd), 3.11 (s),
3.03 (m),1.90(m),1.75 (m),1.6-1.2 (m),1.13 (m).
Fxample 4
Sodium(4S.8S.9R.10S.12R)-4-methoxy!-10(1 -hydroxyethyl)-11 -oxo-1 -
~7~tricyclo[7.2 003-8]undec-~-ene-?-carboxylate
10% Palladium on carbon (0.2g) and triethylamine (0.23ml) were added to a
solution of t-butylbenzyl(4S,8S,9R,1 OS,12R)-4-methoxy-10-(1 hydroxyethyl)-11 -
oxo-1-azatricyclo[7.2Ø0 3 3 lundec-2-ene-carboxylate (0.5 9) in n-propanol
(5ml) under nitrogen. The mixture was then hydrogenated at room
temperature and 1 atm for approximately 40 min. The catalyst was filtered off
washed with acetone (2 ml). Sodium 2-ethylhexanoate (0.29 g) was added to
the combined filtrates and, after few minutes, diisopropylether (20 ml) was
added dropwise and the mixture seeded. The white suspension was stirred at
room temperature under nitrogen for approximately 2 hrs, the solid was filtered
off, washed with a 1012.5/1 mixture of diisopropylether/n-propanol/acetone (1 ml)
and dried under vacuum, the to give title compound (0.115 g) as a white solid.
Fx~mple 5
Sodium(4S.8S.9R.1 OS.12R!-4-methoxy-10(1 -hydroxyethyl)-11 -oxo-1 -
azatricyclo~7.2.003 8]undec-2-ene-2-carboxylate
A solution of benzyl 2-(3S,4R)-3[(R)-1-(hydroxyethyl)-4-[(2'S,6'S)-2-methoxy-1"-oxoocyclohexy-6"-yl~azetidin-2-on-1^yl]-2-triphenylphosphoranyl acetate (20 9)
WO 94/21637 PCT/EP94/00838
2157787 ~
in 1-propanol (300 ml) was heated at reflux for 3 hrs. After cooling the solventwas evaporated under vacuum, 2-propanol (120 ml) was added and the solution
was concentrated to give crude benzyl(4S,8S,9R,10S,12R)-4-methoxy-10-(1 -
hydroxyethyl9-11-oxo-1-azatricyclo[7.2Ø0-3 8 ]undec-2-ene-carboxylate as an
oil (209). 10% Palladium on carbon (4.8 9) and triethylamine (4.6 ml) were
added to a solution of the oil in 2-propanol (3~00 ml), under nitrogen. The
obtained mixture was then hydrogenated at 25-26 C and 1 atm for 35 min. The
catalyst was filtered off washed with acetone (100 ml) and the combined filtrateconcentrated to 100 ml. A solution of sodium 2-ethylhexanoate (5.8 9) in
acetone (40 ml) was added to the concentrate followed by the dropwise addition
of diisopropylether (400 ml) over approximately 30min. The white suspension
was stirred at room temperature under nitrogen for 1.5 hrs, the solid is filtered
off, washed with diisopropylether (2x25 ml) and dried under vacuum to give the
title compound (5.35 9) as a white solid.
IR (nujol) Vmax (cm~1): 3387 (OH),1776-1726 (C=O),1616-1587 (C=C)
