CA2157787A1 - Process for the preparation of condensed carbapeneme derivatives - Google Patents
Process for the preparation of condensed carbapeneme derivativesInfo
- Publication number
- CA2157787A1 CA2157787A1 CA002157787A CA2157787A CA2157787A1 CA 2157787 A1 CA2157787 A1 CA 2157787A1 CA 002157787 A CA002157787 A CA 002157787A CA 2157787 A CA2157787 A CA 2157787A CA 2157787 A1 CA2157787 A1 CA 2157787A1
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- Prior art keywords
- compound
- formula
- protecting group
- carboxyl protecting
- salt
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
-
- 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Cephalosporin Compounds (AREA)
Abstract
A process for the preparation of the antibacterial compound of formula (I) or a salt thereof which comprises the thermal cyclisation of a compound of formula (II), wherein R is a carboxyl protecting group, followed by removal of the said carboxyl protecting group R and if necessary or desired conversion of the resultant carboxylic acid into a salt thereof.
Description
~ 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
and salts thereof. EPA 0416953A2 also teaches that the compound of formula (I) may be prepared by the process as outlined below:-~?"' OCH ~ OCH3 IC= Y (B) COOR2"
(A) OCH, CH3~ OCH, (I) (C) wherein R1 a is a hydroxyl protecting group;
R2a is a carboxyl protecting group and WO 94/21637 PCT/EP94/00838 ~
2l57~8~
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 (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-~ 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 ~
2l5~787 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) ~ 21~7787 , R,~ OCH3 CH3 o O
C=PPh3 (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 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 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 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) 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)
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
and salts thereof. EPA 0416953A2 also teaches that the compound of formula (I) may be prepared by the process as outlined below:-~?"' OCH ~ OCH3 IC= Y (B) COOR2"
(A) OCH, CH3~ OCH, (I) (C) wherein R1 a is a hydroxyl protecting group;
R2a is a carboxyl protecting group and WO 94/21637 PCT/EP94/00838 ~
2l57~8~
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 (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-~ 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 ~
2l5~787 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) ~ 21~7787 , R,~ OCH3 CH3 o O
C=PPh3 (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 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 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 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) 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)
Claims (10)
1. A process for the preparation of the compound of formula (I) (I) or a salt thereof which comprises the thermal cyclisation of a compound of formula (II) (II) wherein R is a carboxyl protecting group, followed by removal of the said carboxyl protecting group R and if necessary or desired converting the resultantcarboxylic acid into a salt thereof.
2. A process as claimed in Claim 1 wherein the thermal cyclisation is carried out in a solvent.
3. A process as claimed in Claims 1 or 2 wherein the solvent is selected from a hydrocarbon, ether, alkanol or ester or a mixture of 2 or more such solvents.
4. A process as claimed in any of claims 1 to 3 wherein the cyclisation is carried out at a temperature within the range 40-200°C.
5. A process as claimed in any of Claims 1 to 4 wherein the carboxyl protecting group R is an arylmethyl group.
6. A process as claimed in Claim 5 wherein the carboxyl protecting group is removed by hydrogenolysis.
7. A process as claimed in any of Claims 1 to 6 wherein the compound of formula (I) is isolated in the form of a physiologically acceptable salt thereof.
8. The compound of formula (I) or a salt thereof whenever prepared by a process as claimed in any of Claims 1 to 7.
9. Sodium (4S, 8S, 9R, 10S, 12R)-4-methoxy-10-(1-hydroxyethyl)-11-oxo-1-azatricyclo [7.2Ø0.3,8]undec-2-ene-2-carboxylate whenever prepared by a process as claimed in any of Claims 1 to 7.
10. The benzyl or 4-t-butylbenzyl ester of the compound of formula (I) whenever prepared by the thermal cyclisation of a compound of formula (II) wherein R is a benzyl or 4-t-butylbenzyl group.
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|---|---|---|---|
| GB939305813A GB9305813D0 (en) | 1993-03-20 | 1993-03-20 | Chemical process |
| GB9305813.9 | 1993-03-20 |
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| EP (1) | EP0689542A1 (en) |
| JP (1) | JPH08507776A (en) |
| CN (1) | CN1119864A (en) |
| AU (1) | AU6427294A (en) |
| CA (1) | CA2157787A1 (en) |
| FI (1) | FI954399A (en) |
| GB (1) | GB9305813D0 (en) |
| HU (1) | HUT73486A (en) |
| NO (1) | NO953697L (en) |
| PL (1) | PL310620A1 (en) |
| WO (1) | WO1994021637A1 (en) |
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| EP2085084A1 (en) | 2008-01-29 | 2009-08-05 | LEK Pharmaceuticals D.D. | Use of inhibitor of beta-lactamases and its combination with beta-lactam antibiotics |
| AU2018265192B2 (en) | 2017-05-08 | 2021-06-17 | Glaxosmithkline Intellectual Property Development Limited | Sanfetrinem or a salt or ester thereof for use in treating mycobacterial infection |
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| KR900006449B1 (en) * | 1982-08-24 | 1990-08-31 | 상꾜 가부시끼가이샤 | Process for the preparation of azetidinone derivatives |
| CZ435990A3 (en) * | 1989-09-08 | 1999-11-17 | Glaxo S.P.A. | 10-(1-hydroxyethyl)-11-oxo-1-azatricyclo/7,2,0,03,8/-undec-2ene-2- carboxylic acid and derivatives thereof, process of their preparation, use for preparing pharmaceutical preparations and pharmaceutical compositions containing thereof |
| EP0507313A1 (en) * | 1991-04-05 | 1992-10-07 | Takeda Chemical Industries, Ltd. | Polycyclic carbapenem compounds, their production and use |
-
1993
- 1993-03-20 GB GB939305813A patent/GB9305813D0/en active Pending
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1994
- 1994-03-17 HU HU9502738A patent/HUT73486A/en unknown
- 1994-03-17 CA CA002157787A patent/CA2157787A1/en not_active Abandoned
- 1994-03-17 CN CN94191532A patent/CN1119864A/en active Pending
- 1994-03-17 JP JP6520645A patent/JPH08507776A/en active Pending
- 1994-03-17 EP EP94911906A patent/EP0689542A1/en not_active Withdrawn
- 1994-03-17 AU AU64272/94A patent/AU6427294A/en not_active Abandoned
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| PL310620A1 (en) | 1995-12-27 |
| WO1994021637A1 (en) | 1994-09-29 |
| EP0689542A1 (en) | 1996-01-03 |
| FI954399A0 (en) | 1995-09-18 |
| HUT73486A (en) | 1996-08-28 |
| JPH08507776A (en) | 1996-08-20 |
| NO953697D0 (en) | 1995-09-19 |
| FI954399A (en) | 1995-09-18 |
| HU9502738D0 (en) | 1995-11-28 |
| NO953697L (en) | 1995-09-19 |
| GB9305813D0 (en) | 1993-05-05 |
| AU6427294A (en) | 1994-10-11 |
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