CA1251455A - Process for the manufacture of optically uniform azetidinones - Google Patents
Process for the manufacture of optically uniform azetidinonesInfo
- Publication number
- CA1251455A CA1251455A CA000462331A CA462331A CA1251455A CA 1251455 A CA1251455 A CA 1251455A CA 000462331 A CA000462331 A CA 000462331A CA 462331 A CA462331 A CA 462331A CA 1251455 A CA1251455 A CA 1251455A
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- Prior art keywords
- signifies
- lower alkyl
- general formula
- process according
- phenyl
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
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- 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)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Saccharide Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Abstract The optically uniform azetidinones of the general formula wherein R signifies benzyl, .beta.-(trimethyl-silyl)-lower alkyl or .beta.-halo-lower alkyl, R1 signifies a readily cleavable protecting group, R2 signifies a lower. optionally oxy-gen-containing, hydrocarbon group linked via a carbon, atom and R3 signifies a lower hydrocarbon group linked via a carbon atom, whereby R2 and R3 can also be linked with one another to form a ring, are valuable intermediates for the production of anti-microbially active .beta.-lactam antibiotics and can be manu-factured by reacting an alkali metal salt of a carboxylic acid of the general formula wherein R has the above significance, with an optically uniform compound of the general formula III
wherein R1, R2 and R have the above significance, in the presence of a base and a sulphonic acid chloride of the general formula wherein R4 signifies phenyl, lower alkyl-phenyl, halophenyl, lower alkyl or halo-lower alkyl.
wherein R1, R2 and R have the above significance, in the presence of a base and a sulphonic acid chloride of the general formula wherein R4 signifies phenyl, lower alkyl-phenyl, halophenyl, lower alkyl or halo-lower alkyl.
Description
~5~5 RAN 44~0/1?9 The known 3,4-cis-3-acylamino-azetidinones are valuable intermediates for the production of antimicro-bially active ~-lactam antibio~ics. Thleir manufacture is usually carried out by the cycloaddi~ion of phthalimido-or azidoacetyl chloride ~ith a corresponaing N-protected imine (e.g. be~zaldehyde (2,4-dime~hoxybenzyl)imine) in the presence of a base, whereafter the phthalimide or azide group in the l-protected N-(2-o~o-3-azetidinyl)-phthalimide or -azide obtained i6 converted into the amino group (the phthalimide group by reaction with hydrazine.
methylhydrazine or dimethylaminopropanamine, the azide grou~ by reduction with ammonium sulphid~ or,with elemen-tary hydrogen and a catalyst such as palladium/carbon).
and the liberated amino group is protected by reaction wi~h an acyl chloride, e.g. carbobenzoxy chloride, for reason~ of the further processing.
The direct cycloaddition of N-carbobenzoxyglycine chloride with a N-pratected imine gi~es, however, only low yields of the desired azetidinone: ee J. Chem. Soc., 1880 (1975). N-Carbob~zoxyglycine chloride it6el~ iS an un-stable compound which decomposes to unusable byproducts even at low temperatures. This direct cycloaddition has thus been regarded as being impracticable; see Tetrahedron 37. 2321 (1980).
It has now surprisingly been found tha~ a direct cycloaddi~ion with good yields is achieved when a N-carbo-benzoxyglycine alkali metal salt i6 used in place of N-car-Nt/17.7~84 bobenzoxyglycine chlo~ide and the cycloaddition with theN~protected imine undertaken in the presence of a base is carried out under the additional in~luence of a specific sulphonic acid chlocide, espe-cially of p-chlorobenzene~ul-phonyl chloride.
By choosing a N-protected imine with suitable sub-stitution ~see formula III hereina~er) ~wo new optical centres are induced in the cycloaddition product (a~etidinone), whereby the substituen~ in the 3- and 4-po6ition are i~ cis-relationship and, further; only on~ of ~he two possible diastereo~eric product~ is foLmed with high diastereoselectivity. The present novel 6ynthesi6 therefore leads to optically unifor~ process products, as will be evident from the Pollowing.
The present invention i8 concerned, in particula~, with a process for the manufacture of optically uniform azeti-dinones of the general formula ROCONH ~ ~ ~ R2 ~
o~ ~Rl whecein R signifies benzyl, ~-(trimethyl-8ilyl ) -lower alkyl or B-halo-lower alkyl, R signifies a readily cleavable protecting group, R signifies a lower, optionally oxy-gen-containing, hydrocarbon group linked via a carbon atom and R3 signifies a lowec hydrocarbon group linked via a carbon atom, whereby R~ and R~ ca~ also be linked with one another to form a ring, ~.5~ 5;5 which proce~s comprises reacting an alkali metal ~alt of a carboxylic acid of the general formula XOCONHC~2COOH II
wherein R has the above significance.
with an optically unifor~ compound of the general formula H ~ R2 III
N
R
wherein Rl, R2 and R have the abovP
significance~
in the presence of a base and a ~ulphonic acid chloride of the general formula R -S02-cl IV
wherein R4 signifie~ phenyl. lower alkyl-phenyl, halophenyl, lower alkyl or halo-lower alkyl.
In the above proce~s products of formula I the fol-lowing come i~to con~ideration, ~or ex~mple, as readily cleavable protecting group~ Rl: benzyl, 2,4- or 3,4-di-~ower alkoxy~benzyl, especially 2,4 or 3,4-dimethoxy-benzyl, di~-(lower alkoxy)phenyl]methyl, especially di-(4-methoxyphenyl)methyl, or 4-(lower alkoxy~phenyl, espec-ially 4-methoxyphenyl: further, lower 2-alkenyl or a group of the formula -CH2-CHtOR )2 (a~ or . CH2CH2 - S ~ (b) [~n ~he ein R5 signifie~ lower alkyl and n ~ignifies the number 0 or 1.
The term "readily cleavable protecting group" i~ to be interpreted in the widest sense, and thus al80 lncludes group~ which are not directly cleavable per 6e, but which can be converted into a directly cleavable protecting grvup by a simple chemical trans~ormation. Thus, e.g. the ~ollowing groups R are converted prior to the cleavage into the cleavable groups given afterward~:
lower 2-alkenyl~ lower l-alkenyl ~5 -C~2-CH~oR5~2 -CH2-CHO--~-CO-CH(OH)2 --CH2CH2--S~ CH2CH2--S~ CH=CH2 ~ --CH0 The transformation and cleavage of the~e groups are illustrated in more detail in European Patent Publication No.101 598.
The ~erm t~lower 2-alkenyl~ denotes an olefi~ic hydro-carbon group which can be straight-chain or branched.
which has a double bond in the 2-posi~ion and which ~,S ~L~5~;
preferably contains up to 8, especially up to 4, carbon atoms such as e.g. 2-propenyl (allyl), 2-methallyl, 2-butenyl, 2-hexenyl, 2-heptenyl, 2-octenyl et~. The term "lower alkyl" denotes a satura~ed hydrocarbon gro~p which can be straight-chai~ or branched and which preerably contains up to 8, especially up to 4, carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, i~opentyl, ~-hexyl, -n-hep~yl, n-octyl etc. The term "lower alkoxy" denotes a lower alkyl group linked via an oxygen a~om.
Preerred groups Rl are: Z-propenyl (allyl), 2,2-di-methoxyethyl, ~,2-diethoxyethyl, 2-phenylthioethyl, 2-phenyl~ulphinylethyl, 2,4- or 3,4-dimethoxyben2yl a~d benzyl. Allyl, benzyl and 2,4-dimethoxybenzyl are the mos~
preferred groups denoted by R .
Preferred groups ~ 2 are those in which R2 ~ignifies lower alkyl, phenyl-lower alkyl, lower alkoxy-alkyl, e.g. lower alkoxymethyl, and R3 si~nifie~ lower alkyl or phenyl-lower alkyl~ The groups H 2 ~ R
ca~ also repre ent a S- or 6-membered 0-heterocycle which optionally contains a further oxygen atom no~ direc~ly linked with the centre o~ shirality and which can be optionally substituted by lower alkyl, lower alkoxy, oxo or spirocyelo-lower alkyl. Examples of ~uch groups, which are llkawise preferred, areo ~s~ s ~ CH~
The group ~ ~(~)-2,2-dimethyl-1,3-dioxolan-4-yl is egpecially preferred.
In the p~ocess product~ of for~ula I ~ i~ preferably benzyl. However, as already men~ioned, R can also ~ignify R~(trimethylsilyl)-lower alkyl, e.g. ~-(trimethylsilyl)-ethyl, or ~-halo-lower alkyl, e.g. ~-trichlo~oethyl, ~-di-chloroethyl, B-chloroethyl or ~-trichloroisopropyl.
A~ alkali metal fialts of a carboxylic acid of ~ormula II there come into con~ideration th~ potassium, ~odium and also the llthium ~alt~. The potas~ium ~alts are pre~er-red. ..
As the sulphonic acid chloride of formula IV there i~
preferably used p-chlorobenzene~ulphonyl chloride. For ~he purpose of the present invention there are, however, also suitable p-toluenesulphonyl chloride and methanesul-ph0nyl chloride~
The reaction of the compound~ of formulae II, III and IV i~ carLied out in the presence of a base, for example a ~ertiary amine such a~ triethylamine, and preferably in an i~ert organic solvent, especially in anhydrous form~whereby ethers ~uch a8 tetrahydcofuran, diethyl ethec, t-butyl methyl ether, dioxan, ethylene glycol dimethyl ether or the like, halogenated hydrocarbons such as methylene chloride. chloroform, 1,2-dichloroethane or the like, acetoni~rile, dimethylformamide or ~he like prefer-ably com0 into consideration. The temperature of the reaction preferably lieæ in the r~ange of about -300 to about 500C.
The conversion o~ a compound of formula I into ~n antimicrobially valuable ~-la~am antibiotic is de6cribed e.g. in European Patent Publication No. 73061 and in European Patent Publication No. 101 598. The cleavage of R in the significa~cQ "benzyl" which is necessary is carried out in the 6ame manner as when Rl is "2,4- or 3,4-di(lower alkoxy)benzyl", i.e. oxidatively with the aid of a b~fered peroxodisulpha~e such as pota6sium peroxodi-sulphate/dipotas~ium hydrogen ~ulphate. The benzyl group can, however. alfio be cleav~d off reductively by the actio~ of an alkali metal. Q.g. oP sodium or lithium, in liquid ammonia.
Exam~le 1 30 g of anhydrous magnesium sulphate and 17.7 g (71.6 mmol) of N-carbobenzoxyglycine potas6ium salt are dis-per~ed in 400 ml of methylene chloride. After the ad-dition of 20 ml (1~3 mmol) of triethylamine the suspen~ion obtained i8 stirred vigorously at room temperature for 1 l/Z hours and ~ubsequently cooled to 5C. Thi6 6uspen~i.0n i8 trea~ed ~ith 10.0 g (35.~ mmol) of isopropylidene-D-glyceraldehyde (2,4-dimethoxybenzyl)imine (prepared from
methylhydrazine or dimethylaminopropanamine, the azide grou~ by reduction with ammonium sulphid~ or,with elemen-tary hydrogen and a catalyst such as palladium/carbon).
and the liberated amino group is protected by reaction wi~h an acyl chloride, e.g. carbobenzoxy chloride, for reason~ of the further processing.
The direct cycloaddition of N-carbobenzoxyglycine chloride with a N-pratected imine gi~es, however, only low yields of the desired azetidinone: ee J. Chem. Soc., 1880 (1975). N-Carbob~zoxyglycine chloride it6el~ iS an un-stable compound which decomposes to unusable byproducts even at low temperatures. This direct cycloaddition has thus been regarded as being impracticable; see Tetrahedron 37. 2321 (1980).
It has now surprisingly been found tha~ a direct cycloaddi~ion with good yields is achieved when a N-carbo-benzoxyglycine alkali metal salt i6 used in place of N-car-Nt/17.7~84 bobenzoxyglycine chlo~ide and the cycloaddition with theN~protected imine undertaken in the presence of a base is carried out under the additional in~luence of a specific sulphonic acid chlocide, espe-cially of p-chlorobenzene~ul-phonyl chloride.
By choosing a N-protected imine with suitable sub-stitution ~see formula III hereina~er) ~wo new optical centres are induced in the cycloaddition product (a~etidinone), whereby the substituen~ in the 3- and 4-po6ition are i~ cis-relationship and, further; only on~ of ~he two possible diastereo~eric product~ is foLmed with high diastereoselectivity. The present novel 6ynthesi6 therefore leads to optically unifor~ process products, as will be evident from the Pollowing.
The present invention i8 concerned, in particula~, with a process for the manufacture of optically uniform azeti-dinones of the general formula ROCONH ~ ~ ~ R2 ~
o~ ~Rl whecein R signifies benzyl, ~-(trimethyl-8ilyl ) -lower alkyl or B-halo-lower alkyl, R signifies a readily cleavable protecting group, R signifies a lower, optionally oxy-gen-containing, hydrocarbon group linked via a carbon atom and R3 signifies a lowec hydrocarbon group linked via a carbon atom, whereby R~ and R~ ca~ also be linked with one another to form a ring, ~.5~ 5;5 which proce~s comprises reacting an alkali metal ~alt of a carboxylic acid of the general formula XOCONHC~2COOH II
wherein R has the above significance.
with an optically unifor~ compound of the general formula H ~ R2 III
N
R
wherein Rl, R2 and R have the abovP
significance~
in the presence of a base and a ~ulphonic acid chloride of the general formula R -S02-cl IV
wherein R4 signifie~ phenyl. lower alkyl-phenyl, halophenyl, lower alkyl or halo-lower alkyl.
In the above proce~s products of formula I the fol-lowing come i~to con~ideration, ~or ex~mple, as readily cleavable protecting group~ Rl: benzyl, 2,4- or 3,4-di-~ower alkoxy~benzyl, especially 2,4 or 3,4-dimethoxy-benzyl, di~-(lower alkoxy)phenyl]methyl, especially di-(4-methoxyphenyl)methyl, or 4-(lower alkoxy~phenyl, espec-ially 4-methoxyphenyl: further, lower 2-alkenyl or a group of the formula -CH2-CHtOR )2 (a~ or . CH2CH2 - S ~ (b) [~n ~he ein R5 signifie~ lower alkyl and n ~ignifies the number 0 or 1.
The term "readily cleavable protecting group" i~ to be interpreted in the widest sense, and thus al80 lncludes group~ which are not directly cleavable per 6e, but which can be converted into a directly cleavable protecting grvup by a simple chemical trans~ormation. Thus, e.g. the ~ollowing groups R are converted prior to the cleavage into the cleavable groups given afterward~:
lower 2-alkenyl~ lower l-alkenyl ~5 -C~2-CH~oR5~2 -CH2-CHO--~-CO-CH(OH)2 --CH2CH2--S~ CH2CH2--S~ CH=CH2 ~ --CH0 The transformation and cleavage of the~e groups are illustrated in more detail in European Patent Publication No.101 598.
The ~erm t~lower 2-alkenyl~ denotes an olefi~ic hydro-carbon group which can be straight-chain or branched.
which has a double bond in the 2-posi~ion and which ~,S ~L~5~;
preferably contains up to 8, especially up to 4, carbon atoms such as e.g. 2-propenyl (allyl), 2-methallyl, 2-butenyl, 2-hexenyl, 2-heptenyl, 2-octenyl et~. The term "lower alkyl" denotes a satura~ed hydrocarbon gro~p which can be straight-chai~ or branched and which preerably contains up to 8, especially up to 4, carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, i~opentyl, ~-hexyl, -n-hep~yl, n-octyl etc. The term "lower alkoxy" denotes a lower alkyl group linked via an oxygen a~om.
Preerred groups Rl are: Z-propenyl (allyl), 2,2-di-methoxyethyl, ~,2-diethoxyethyl, 2-phenylthioethyl, 2-phenyl~ulphinylethyl, 2,4- or 3,4-dimethoxyben2yl a~d benzyl. Allyl, benzyl and 2,4-dimethoxybenzyl are the mos~
preferred groups denoted by R .
Preferred groups ~ 2 are those in which R2 ~ignifies lower alkyl, phenyl-lower alkyl, lower alkoxy-alkyl, e.g. lower alkoxymethyl, and R3 si~nifie~ lower alkyl or phenyl-lower alkyl~ The groups H 2 ~ R
ca~ also repre ent a S- or 6-membered 0-heterocycle which optionally contains a further oxygen atom no~ direc~ly linked with the centre o~ shirality and which can be optionally substituted by lower alkyl, lower alkoxy, oxo or spirocyelo-lower alkyl. Examples of ~uch groups, which are llkawise preferred, areo ~s~ s ~ CH~
The group ~ ~(~)-2,2-dimethyl-1,3-dioxolan-4-yl is egpecially preferred.
In the p~ocess product~ of for~ula I ~ i~ preferably benzyl. However, as already men~ioned, R can also ~ignify R~(trimethylsilyl)-lower alkyl, e.g. ~-(trimethylsilyl)-ethyl, or ~-halo-lower alkyl, e.g. ~-trichlo~oethyl, ~-di-chloroethyl, B-chloroethyl or ~-trichloroisopropyl.
A~ alkali metal fialts of a carboxylic acid of ~ormula II there come into con~ideration th~ potassium, ~odium and also the llthium ~alt~. The potas~ium ~alts are pre~er-red. ..
As the sulphonic acid chloride of formula IV there i~
preferably used p-chlorobenzene~ulphonyl chloride. For ~he purpose of the present invention there are, however, also suitable p-toluenesulphonyl chloride and methanesul-ph0nyl chloride~
The reaction of the compound~ of formulae II, III and IV i~ carLied out in the presence of a base, for example a ~ertiary amine such a~ triethylamine, and preferably in an i~ert organic solvent, especially in anhydrous form~whereby ethers ~uch a8 tetrahydcofuran, diethyl ethec, t-butyl methyl ether, dioxan, ethylene glycol dimethyl ether or the like, halogenated hydrocarbons such as methylene chloride. chloroform, 1,2-dichloroethane or the like, acetoni~rile, dimethylformamide or ~he like prefer-ably com0 into consideration. The temperature of the reaction preferably lieæ in the r~ange of about -300 to about 500C.
The conversion o~ a compound of formula I into ~n antimicrobially valuable ~-la~am antibiotic is de6cribed e.g. in European Patent Publication No. 73061 and in European Patent Publication No. 101 598. The cleavage of R in the significa~cQ "benzyl" which is necessary is carried out in the 6ame manner as when Rl is "2,4- or 3,4-di(lower alkoxy)benzyl", i.e. oxidatively with the aid of a b~fered peroxodisulpha~e such as pota6sium peroxodi-sulphate/dipotas~ium hydrogen ~ulphate. The benzyl group can, however. alfio be cleav~d off reductively by the actio~ of an alkali metal. Q.g. oP sodium or lithium, in liquid ammonia.
Exam~le 1 30 g of anhydrous magnesium sulphate and 17.7 g (71.6 mmol) of N-carbobenzoxyglycine potas6ium salt are dis-per~ed in 400 ml of methylene chloride. After the ad-dition of 20 ml (1~3 mmol) of triethylamine the suspen~ion obtained i8 stirred vigorously at room temperature for 1 l/Z hours and ~ubsequently cooled to 5C. Thi6 6uspen~i.0n i8 trea~ed ~ith 10.0 g (35.~ mmol) of isopropylidene-D-glyceraldehyde (2,4-dimethoxybenzyl)imine (prepared from
2~-dimethoxybenzylamine and isopropylidene~L-glyceralde-hyde in 20 ml of methylene chloride). lS.l g (~1.6 mmol)of p-chlorobenzene~ulphonyl chloride in 50 ml of methylene chloride are subsequently added dropwise at 5C within 45 minute~. The su~pension is stirred at room temperature for 3 hours and filtered. Ths filtrate is evaporated, the yellow-brown oil obtained is dissolved in 300 ml of ethyl acetate and wa6hed successively twice ~with 190 ml of lN
aqueous hydrochloric a~id, twice with loO ml of 5% aqueous sodium bicarbonate solution and once with 100 ml of aqueou8 Bodium chloride solution. The organic phase is evaporated and the oily yellow residue is crystallized at 0C by the addition of 300 ml o~ ether. There are obtained 10.5 g (62%) of benzyl (3S,4S)-cis-1-(2,4-di-methoxybenzyl)-4-t(~)- 2,2-dimethyl-1,3-dioxolan-4~yl)-2-oxo-3-azeeidinecarbamate of melting point 113-114C.
.
When allylamine i8 u~ed in Example 1 in place of 2,4-dimethoxybenzylamine there are obtained in the same manner, af~er chromatography on 6ilica gel (0.040 to 0.063 mm), 7.05 g (67~) of benzyl (3S,4S)-ci6-l-allyl-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxo-3-azetidinecarbamate of ~elting point 94-96C.
aqueous hydrochloric a~id, twice with loO ml of 5% aqueous sodium bicarbonate solution and once with 100 ml of aqueou8 Bodium chloride solution. The organic phase is evaporated and the oily yellow residue is crystallized at 0C by the addition of 300 ml o~ ether. There are obtained 10.5 g (62%) of benzyl (3S,4S)-cis-1-(2,4-di-methoxybenzyl)-4-t(~)- 2,2-dimethyl-1,3-dioxolan-4~yl)-2-oxo-3-azeeidinecarbamate of melting point 113-114C.
.
When allylamine i8 u~ed in Example 1 in place of 2,4-dimethoxybenzylamine there are obtained in the same manner, af~er chromatography on 6ilica gel (0.040 to 0.063 mm), 7.05 g (67~) of benzyl (3S,4S)-ci6-l-allyl-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxo-3-azetidinecarbamate of ~elting point 94-96C.
Claims (9)
1. A process for the manufacture of optically uniform azetidinones of the general formula I
wherein R signifies benzyl, .beta.-(trimethyl-silyl)-lower alkyl or .beta.-halo-lower alkyl, R1 signifies a readily cleavable protecting group, R2 signifies a lower, optionally oxy-gen-containing, hydrocarbon group linked via a carbon, atom and R3 signifies a lower hydrocarbon group linked via a carbon atom, whereby R2 and R3 can also be linked with one another to form a ring, which process comprises reacting an alkali metal salt of a carboxylic acid of the general formula wherein R has the above significance, with an optically uniform compound of the general formula III
wherein R1, R2 and R3 have the above significance, in the presence of a base and a sulphonic acid chloride of the general formula wherein R4 signifies phenyl. lower alkyl-phenyl, halo-phenyl, lower alkyl or halo-lower alkyl.
wherein R signifies benzyl, .beta.-(trimethyl-silyl)-lower alkyl or .beta.-halo-lower alkyl, R1 signifies a readily cleavable protecting group, R2 signifies a lower, optionally oxy-gen-containing, hydrocarbon group linked via a carbon, atom and R3 signifies a lower hydrocarbon group linked via a carbon atom, whereby R2 and R3 can also be linked with one another to form a ring, which process comprises reacting an alkali metal salt of a carboxylic acid of the general formula wherein R has the above significance, with an optically uniform compound of the general formula III
wherein R1, R2 and R3 have the above significance, in the presence of a base and a sulphonic acid chloride of the general formula wherein R4 signifies phenyl. lower alkyl-phenyl, halo-phenyl, lower alkyl or halo-lower alkyl.
2. A process according to claim 1, wherein an alkali metal salt of a carboxylic acid of formula II in which R
signifies benzyl is used.
signifies benzyl is used.
3. A process according to claim 1 or 2, wherein a potassium salt of a carboxylic acid of formula II is used.
4. A process according to claim 1, wherein a compound of formula III in which the group signifies the group is used.
5. A process according to claim 4, wherein a compound of formula III in which R1 signifies allyl, benzyl or 2,4-dimethoxybenzyl is used.
6. A process according to claim 1, wherein a compound of formula IV in which R4 signifies p-chlorophenyl is used.
7. A process according to claim 1, wherein triethyl-amine is used as the base.
8. A process according to claim 1, wherein the reaction is carried out in an anhydrous inert organic solvent.
9. A process according to claim 8, wherein the anhydrous inert organic solvent is anhydrous methylene chloride.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH5365/83 | 1983-10-03 | ||
| CH536583 | 1983-10-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1251455A true CA1251455A (en) | 1989-03-21 |
Family
ID=4292341
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000462331A Expired CA1251455A (en) | 1983-10-03 | 1984-09-04 | Process for the manufacture of optically uniform azetidinones |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0138113B1 (en) |
| JP (1) | JPS6092263A (en) |
| KR (1) | KR850003392A (en) |
| CN (1) | CN85100624A (en) |
| AT (1) | ATE33830T1 (en) |
| AU (1) | AU572194B2 (en) |
| CA (1) | CA1251455A (en) |
| DE (1) | DE3470736D1 (en) |
| DK (1) | DK411384A (en) |
| IL (1) | IL73089A (en) |
| NZ (1) | NZ209684A (en) |
| PH (1) | PH19418A (en) |
| ZA (1) | ZA847585B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60139667A (en) * | 1983-12-27 | 1985-07-24 | Takeda Chem Ind Ltd | Preparation of azetidinone |
| US5142039A (en) * | 1987-07-31 | 1992-08-25 | Eli Lilly And Company | β-lactam antibiotics |
| ATE88186T1 (en) * | 1987-07-31 | 1993-04-15 | Lilly Co Eli | METHOD OF DEPROTECTING 3AMINOAZETIDINONES. |
| US5239068A (en) * | 1987-07-31 | 1993-08-24 | Eli Lilly And Company | Bicyclic β-lactam antibiotics |
| US4983732A (en) * | 1987-07-31 | 1991-01-08 | Eli Lilly And Company | Method of deprotection of 3-amino azetidinones |
| CN112175173B (en) * | 2020-10-09 | 2022-04-19 | 中国科学技术大学 | Preparation method of degradable poly-alpha-olefin material with controllable olefin insertion rate |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1262128A (en) * | 1981-08-27 | 1989-10-03 | Christian N. Hubschwerlen | .beta.-lactams |
| CA1251454A (en) * | 1983-01-20 | 1989-03-21 | Gerard Schmid | PROCESS FOR THE MANUFACTURE OF .beta.-LACTAMES |
| DK36784A (en) * | 1983-02-25 | 1984-08-26 | Hoffmann La Roche | PROCEDURE FOR PREPARING CHIRAL ALDEHYDES |
| JPS60139667A (en) * | 1983-12-27 | 1985-07-24 | Takeda Chem Ind Ltd | Preparation of azetidinone |
-
1984
- 1984-08-28 DK DK411384A patent/DK411384A/en not_active Application Discontinuation
- 1984-09-04 CA CA000462331A patent/CA1251455A/en not_active Expired
- 1984-09-26 IL IL73089A patent/IL73089A/en unknown
- 1984-09-26 NZ NZ209684A patent/NZ209684A/en unknown
- 1984-09-26 AT AT84111448T patent/ATE33830T1/en not_active IP Right Cessation
- 1984-09-26 EP EP84111448A patent/EP0138113B1/en not_active Expired
- 1984-09-26 ZA ZA847585A patent/ZA847585B/en unknown
- 1984-09-26 DE DE8484111448T patent/DE3470736D1/en not_active Expired
- 1984-09-28 AU AU33705/84A patent/AU572194B2/en not_active Ceased
- 1984-09-28 PH PH31277A patent/PH19418A/en unknown
- 1984-10-02 JP JP59205690A patent/JPS6092263A/en active Pending
- 1984-10-02 KR KR1019840006096A patent/KR850003392A/en not_active Application Discontinuation
-
1985
- 1985-04-01 CN CN198585100624A patent/CN85100624A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| IL73089A (en) | 1988-02-29 |
| DK411384D0 (en) | 1984-08-28 |
| JPS6092263A (en) | 1985-05-23 |
| CN85100624A (en) | 1986-07-09 |
| PH19418A (en) | 1986-04-10 |
| ATE33830T1 (en) | 1988-05-15 |
| EP0138113A1 (en) | 1985-04-24 |
| IL73089A0 (en) | 1984-12-31 |
| AU572194B2 (en) | 1988-05-05 |
| DK411384A (en) | 1985-04-04 |
| EP0138113B1 (en) | 1988-04-27 |
| KR850003392A (en) | 1985-06-17 |
| AU3370584A (en) | 1985-04-18 |
| DE3470736D1 (en) | 1988-06-01 |
| ZA847585B (en) | 1985-05-29 |
| NZ209684A (en) | 1987-08-31 |
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| Date | Code | Title | Description |
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| MKEX | Expiry |