CA2015580A1 - Process for the preparation of penem compounds - Google Patents
Process for the preparation of penem compoundsInfo
- Publication number
- CA2015580A1 CA2015580A1 CA002015580A CA2015580A CA2015580A1 CA 2015580 A1 CA2015580 A1 CA 2015580A1 CA 002015580 A CA002015580 A CA 002015580A CA 2015580 A CA2015580 A CA 2015580A CA 2015580 A1 CA2015580 A1 CA 2015580A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- alkoxy
- cycloalkyl
- phenyl
- denotes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/06—Preparation by forming the ring or condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pens And Brushes (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
Abstract of the disclosure Compound I
is obtained by reaction of compound II
with compound III
is obtained by reaction of compound II
with compound III
Description
5~
HO~CHST ~RTIENGES~LLSCHAFT HOE 89/F 135K Dr. v.F./PP
D~cription A proce~s for the pr~paration of penem co~pounds The invention relates to ~ process for the preparation of penem compound~.
Penem derivativ~s of th~ formula I ~re valuable compound~
with antibiotic propertie~. A synthetic process di~closed in the literature for penem derlvatives I entails intra-molecular cyclization of a~etidinone derivatives o~ the foxmula II with trialkyl phosphites. However, this process often provides only poor yields. Moreover, the reaction i~ ~low and requires elevated reactlon ~emper-atures, for example reflux in toluene. Under these reaction conditions there ~8 frequently partial inver~ion of configuration a~ C-5, which re~ults in undesired (5S,6S~-penems.
It has now been found that the de cribed di~adv~nt~ges of the known proc~ss can be avo~ded if dialkyl alkylpho~pho-nites are uæed in place o~ trialkyl phosphites for the cyclization reaction. These novel roagent~ permit the reaction ~emperature~ to be lower, for ~xample room temperature, ~nd re~ult ~n ~horter reaction t~mes. ~i~her yield~ and purer products nre achieved ~hereby. In addition, the unde~ired ~so~erization to (5S,65)~pen~m6 25 i8 avoided. ~he dialkyl al~ylphosphonates and dialkyl alkylthiophosphonate6 formed as by-products c~n bs remo~ed in a ~trai~htforw~rd ~anner.
Hence the inventisn relates to a process for the prepar-ation of penem derivatives o~ the formula I, in which the preferred configuration i~ ~5~,6S) R3~"6 and in which Rl denote~ hydrogen, (Cl-C~)-alkyl, (C~-C~)-alkoxy, (Cl-C~)-alkylthio, phenoxy, phenyl (the phenyl ring~
bei~g unsub6tituted or sub~tituted oncs or twice by carboxyl, (Cl-C~)-alkoxycarbonyl, allyloxyc~rbo~yl, aminocarbonyl, (C1-C4)-alkylaminocarbonyl, cyano, F, Cl or Br), (C3-C6) cycloalkyl, (C3-C6)-cycloalkyloxy, (C5-C~)-oxacycloalkyl (saturated or ~ingly or doubly unsaturated~, (c3-c6)-oxocycloalkyl~ (C3-C6)-[l,l-bis-~cl-c3)-alkyloxy]-cyclo~lkyl~ (C3_CB)_1(C1-C3) alkYl-imino]-cycloalkyl, (C3-C6)-[arylimino~cycloalkyl, (c3-c6)-hydro~yiminocycloalkyl~ (C3-C6)-(C~-C3-alkYl-oxyimino)-cycloalkyl, in which the cyclo~lkyl radical i8 unsubstituted or ~ubstituted onGe or twice by Cl-C3-alkyl, preferably methyl, by (Cl-C3)-alkoxy, preferably methoxy, by halogen, preferably chlorine, or by methylene and i~ ~aturated or c~n contain one or two double bond~, RZ denotes hydxog~n or 8 customary carbo~yl protective group which can be elimin~ted by hydroly~i~, photol-y8i8, oxidation, reduction or enzymatically, R3 denote~ hydrogen, ~Cl-C4)-alkyl J (Cl-C4)-~lkenYl, (Cl-C4)-alkoxy,(C~-r7~-cycloalkyl,phenyl,2-oxo-1,3~
dioxolyl, triazolyl, th~zolyl, ~mino, ~cyl~mino or alkoxy.
Suitable and parti~ularly preferred ~ub~t~tuents ~re tne ~ollowings Rl hydrogen, (Cl-C4)-alkyl (for e~ample ~ethyl, ethyl, hydro~ymethyl and aminsmethyl)~ (Cl-C4)-alkoxy (for example methoxy ~nd ethoxy)~ (Cl-C3~-~lkylthio ~ior example methylthio, ethylthio ~nd propyl~hio~, phenoxy (for example 4-carboxamldophenoxy or 4-cy~nophenoxy), phenyl (~or sxample 4 carboxamidophenyl or 4-cyanophenyl), ~a~urated or un~aturated (C5-c~) -oxacycloalkyl (for example tetrahydrofuryl or furyl), (C4-C6)-oxocycloalkyl (for example l-oxo-3-cyclobutyl), 3-hydroxyiminocyclobutyl,3~methosyiminocyclobu~yland 3,3-dimethoxycyclobutyl.
R3 l-hydroxyethyl ~in which the OH group iB free or pro~ected by trimethylsilyl, diphenyl-tert.-butyl-8ilyl, allyloxycarbonyl, trichloroethylogycarbonyl or 4-nitrobenzyloxyc~sbonyl)~ (Cl~C3)-alkoxy (for ex~mple methoxy or ethoxy), (Cl-C3)-alksnyl, ~or example triazolylethylene or ~hiazolyle~hylene.
The (Cl-C4)-alkyl and (Cl-C4)-alkoxy group~ in the 8ub-6titutent Rl are either unsubatituted or sub~tituted once or twice by hydro~yl, (C1-C4)-alkoxy, (C~-C~)-acyloxy, amino, (Cl-C4)-al~ylamino, (Cl~C~)-acylamino, ~er~apto, (C~-C4)-alkylthio or heterocyclylthio, for example thiaz-olyl-, thiadiazolyl-, pyridylth~o.
Phenyl nuclei are likewise un~ubstituted or substituted once or twice by carboxyl, (Cl~C~ lkoxycarbonyl, ~llyl-oxycarbonyl, ~minoc~rbonyl, (C1 C~)-al~ylaminocarhonyl~
cyano or haloqenl preferably F9 Cl, Br.
The (C,-C4)-alkyl and (C1~C~)-alkoxy group~ in R3 are ~ither unsubstituted or substituted by hydroxyl, (Cl-C~)-alkoxy, (C1 ~4~-~cyloxy~ amino, ~ C,-C4 )-alkyl~mino, (Cl-C4)acylamino, merc~pto, (C1-C~ ylthio or hetero-cyclylthio, it being pos~ible for ~ OH group to b~ ~ree or protected by trimethylsilyl, diphenyl-tert.-butyl_ eilyl, allyloxycarbonyl, trichloro0tho~ycarbonyl or 4-nitrobenzyloxycarbonyl.
In the process ~ccording to the invention, the c~mpounds of the formula I are prepared by reacting a compound of the formula II
R3 S ~
`r~
~a~o ~ ~2R2 in which X denote~ oxygen or sulfur, ~nd Rl, R2 and ~3 have the above ~neaning, wi~h ~ ~rivalent S organic pho phorus compound of the ~ormula III
oR4 R6 _ p ~' ~ oR5 in which R6 denotes (C1-C~ alkyl, for example methyl, e~hyl or trifluoromethyl, phenyl ~hich can be ~ubstitu~ed by:
(cl-c3)-alkyl or (C~-C3)-alkoxy, and R4 and R5 are identical or dif ferent and denote ( C1-C4 ) -alkyl/ allyl, b~nzyl, or phe~yl which can 1~ ~ub~ti-tuted by ( Cl-C3 ) -allcyl or ~ Cl-C3 ) -alkoxy .
The reaction between a compound II and a ~o~pound III can be carried out in a ~uitable ors~anic 801VeIlt~ for example in tetrahydrofuran, ethyl ~cetate, an ~rQ~n~tic hydro~
carbon such as benzene, toluene or xyl~3ne, or ~ halo~eJl-ated hydroc~rbon ~uch a~ dichlor~methane, trichloro-methan or 1,1, 2 -trichloroeth~ne .
The reaction teinperature can v~ry between ~10C and 160C, preferably between +20C and ~70~C.
~he concentration of the compound II to be cycli~ed i6 between 1 mmol/l and 100 ~mol/l, preferably between 2 mmol/l and 20 ~mol/l .
% ~
~he nmount of the compound III can be bet~een 2 and 8 mole-eguivalents, preferably between 2 and 6 mole-equivalents, relative to II.
The compounds of the foxmulae II and III ~re known or can be prepared by processe~ di~closed in the literature.
The examples which follow ~erve to Illustrate ~he inven-tion further.
~sample 1 4-Nitrobenzyl (5R,6S)-6-~(lR~-tert.-butyldimethyl~ilyl-oxyethyl]-2-(4-aminocarbonylphenoxy)pen~m-3-carboxylate 130 mg (0.2 mmol) of (3S,4R)~4-[(sminocarbonyl)-pheno~y-thiocarbonylthio]-3-[(lR)-tert.-butyldimethyls~lyloxy-ethyl)3-1-(4-nitrobenzyloxycarbonyl)-azetidin-2-one were dissolved in 90 ml of CHCl3 under an argon atmo~phere at 55C. To this was added within 30 minutes a ~olution of 90 mg (0.8 mmol3 of dimethyl methylpho~phonite CH3P(OCH3) 2 in 10 ml of CHC13, and, after addition wa~ complete, the mixture was then ~tirred for 2 hours and, after cooling, worked up. Extraction with 1 N NhHCO3 ~olution, 1 ~ XHSO~
~olution and water wa~ carried out, and the or~anic pha~e was dried with magnesi~m Rulfa~e and ~oncentrated in vacuo. The crude product proYided, a~ter ~lash c~romato-graphy (SiO2 70-20~ ~m + 10 % H2O; ~ir~t toluene + ~thyl acetate 20 ~ 1, then 1 ~ 1 for elution)~ the ti~le ~ompound in 83 % yield.
The compounds I listed in Table 1 w~re obtained analo-gously from the stArting ~ub~tances II li~ted in ~able 2 under the reaction condition~ ted ln Table 3.
- 6~ is~30 ^ ~ ~ ~ s X~ I ~ I " oô ~ ~ S ~
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æ ~ s ~ ~ . ~ ~ . . ~ ~ ~ ~ . s ~ ~ x ~ ~ ~. ~ 3 ~ ~ " " .N 7--T ~ ~ _ E E ^ 11 ~ _ 0 o --~ -- Ew mo~ ~ ~ S ~ __s~ ~cn ~,_~~ x-- O
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~ ~ ~- ~ _ ~able 2 Starting compounds Ex~ple Rl _ R2 -- R3 - X
-O~H2 -PNB -CH(OT3DMS) S
2 -O~CONH2 -CH2CH~H2 " S
3 -O~CON112 -cH2CH?S~e3 " . S
4 OCH3 - CH2C14=CH2 S
OCH3 - PNB ,1 5 OCH3 -CH~CH251Me~ " S
7 a -PNB " S
8 O PNB 1l S
9 SCH3 CH2CH-~H2 S
- 12 ~ 5~
Ex~pl ~ Rl R2 R3 X
SCH3 -PN~ " S
11 SCH3 -cH2cH2s~Me3 12 ~ -CH~CH2SiMe3 " O
13 ,~ -cHzcH2s~Me3 " O
14 ~ -CH2CH2S~Me3 "
~ -CH2cH2siMe3 " s ..
16 ~C02CH,~CH-CH2 -cH2cH2s~Me3 " O
O -CH2CH2SiMe3 'l o O - CH2CH-CH2 ~ o 19 O~H3 -CH2cH2siMe3 "
-- 13 - ~$~55~
Table 3 Reaction condi~ions for the cycli~ation reaction ~ o~ ~~ ~n oo o o ~ o u ~ C~ ~
_ .
_ r~ ~O
o ~ u~ ~7 .n u~ u~ Y'>
HO~CHST ~RTIENGES~LLSCHAFT HOE 89/F 135K Dr. v.F./PP
D~cription A proce~s for the pr~paration of penem co~pounds The invention relates to ~ process for the preparation of penem compound~.
Penem derivativ~s of th~ formula I ~re valuable compound~
with antibiotic propertie~. A synthetic process di~closed in the literature for penem derlvatives I entails intra-molecular cyclization of a~etidinone derivatives o~ the foxmula II with trialkyl phosphites. However, this process often provides only poor yields. Moreover, the reaction i~ ~low and requires elevated reactlon ~emper-atures, for example reflux in toluene. Under these reaction conditions there ~8 frequently partial inver~ion of configuration a~ C-5, which re~ults in undesired (5S,6S~-penems.
It has now been found that the de cribed di~adv~nt~ges of the known proc~ss can be avo~ded if dialkyl alkylpho~pho-nites are uæed in place o~ trialkyl phosphites for the cyclization reaction. These novel roagent~ permit the reaction ~emperature~ to be lower, for ~xample room temperature, ~nd re~ult ~n ~horter reaction t~mes. ~i~her yield~ and purer products nre achieved ~hereby. In addition, the unde~ired ~so~erization to (5S,65)~pen~m6 25 i8 avoided. ~he dialkyl al~ylphosphonates and dialkyl alkylthiophosphonate6 formed as by-products c~n bs remo~ed in a ~trai~htforw~rd ~anner.
Hence the inventisn relates to a process for the prepar-ation of penem derivatives o~ the formula I, in which the preferred configuration i~ ~5~,6S) R3~"6 and in which Rl denote~ hydrogen, (Cl-C~)-alkyl, (C~-C~)-alkoxy, (Cl-C~)-alkylthio, phenoxy, phenyl (the phenyl ring~
bei~g unsub6tituted or sub~tituted oncs or twice by carboxyl, (Cl-C~)-alkoxycarbonyl, allyloxyc~rbo~yl, aminocarbonyl, (C1-C4)-alkylaminocarbonyl, cyano, F, Cl or Br), (C3-C6) cycloalkyl, (C3-C6)-cycloalkyloxy, (C5-C~)-oxacycloalkyl (saturated or ~ingly or doubly unsaturated~, (c3-c6)-oxocycloalkyl~ (C3-C6)-[l,l-bis-~cl-c3)-alkyloxy]-cyclo~lkyl~ (C3_CB)_1(C1-C3) alkYl-imino]-cycloalkyl, (C3-C6)-[arylimino~cycloalkyl, (c3-c6)-hydro~yiminocycloalkyl~ (C3-C6)-(C~-C3-alkYl-oxyimino)-cycloalkyl, in which the cyclo~lkyl radical i8 unsubstituted or ~ubstituted onGe or twice by Cl-C3-alkyl, preferably methyl, by (Cl-C3)-alkoxy, preferably methoxy, by halogen, preferably chlorine, or by methylene and i~ ~aturated or c~n contain one or two double bond~, RZ denotes hydxog~n or 8 customary carbo~yl protective group which can be elimin~ted by hydroly~i~, photol-y8i8, oxidation, reduction or enzymatically, R3 denote~ hydrogen, ~Cl-C4)-alkyl J (Cl-C4)-~lkenYl, (Cl-C4)-alkoxy,(C~-r7~-cycloalkyl,phenyl,2-oxo-1,3~
dioxolyl, triazolyl, th~zolyl, ~mino, ~cyl~mino or alkoxy.
Suitable and parti~ularly preferred ~ub~t~tuents ~re tne ~ollowings Rl hydrogen, (Cl-C4)-alkyl (for e~ample ~ethyl, ethyl, hydro~ymethyl and aminsmethyl)~ (Cl-C4)-alkoxy (for example methoxy ~nd ethoxy)~ (Cl-C3~-~lkylthio ~ior example methylthio, ethylthio ~nd propyl~hio~, phenoxy (for example 4-carboxamldophenoxy or 4-cy~nophenoxy), phenyl (~or sxample 4 carboxamidophenyl or 4-cyanophenyl), ~a~urated or un~aturated (C5-c~) -oxacycloalkyl (for example tetrahydrofuryl or furyl), (C4-C6)-oxocycloalkyl (for example l-oxo-3-cyclobutyl), 3-hydroxyiminocyclobutyl,3~methosyiminocyclobu~yland 3,3-dimethoxycyclobutyl.
R3 l-hydroxyethyl ~in which the OH group iB free or pro~ected by trimethylsilyl, diphenyl-tert.-butyl-8ilyl, allyloxycarbonyl, trichloroethylogycarbonyl or 4-nitrobenzyloxyc~sbonyl)~ (Cl~C3)-alkoxy (for ex~mple methoxy or ethoxy), (Cl-C3)-alksnyl, ~or example triazolylethylene or ~hiazolyle~hylene.
The (Cl-C4)-alkyl and (Cl-C4)-alkoxy group~ in the 8ub-6titutent Rl are either unsubatituted or sub~tituted once or twice by hydro~yl, (C1-C4)-alkoxy, (C~-C~)-acyloxy, amino, (Cl-C4)-al~ylamino, (Cl~C~)-acylamino, ~er~apto, (C~-C4)-alkylthio or heterocyclylthio, for example thiaz-olyl-, thiadiazolyl-, pyridylth~o.
Phenyl nuclei are likewise un~ubstituted or substituted once or twice by carboxyl, (Cl~C~ lkoxycarbonyl, ~llyl-oxycarbonyl, ~minoc~rbonyl, (C1 C~)-al~ylaminocarhonyl~
cyano or haloqenl preferably F9 Cl, Br.
The (C,-C4)-alkyl and (C1~C~)-alkoxy group~ in R3 are ~ither unsubstituted or substituted by hydroxyl, (Cl-C~)-alkoxy, (C1 ~4~-~cyloxy~ amino, ~ C,-C4 )-alkyl~mino, (Cl-C4)acylamino, merc~pto, (C1-C~ ylthio or hetero-cyclylthio, it being pos~ible for ~ OH group to b~ ~ree or protected by trimethylsilyl, diphenyl-tert.-butyl_ eilyl, allyloxycarbonyl, trichloro0tho~ycarbonyl or 4-nitrobenzyloxycarbonyl.
In the process ~ccording to the invention, the c~mpounds of the formula I are prepared by reacting a compound of the formula II
R3 S ~
`r~
~a~o ~ ~2R2 in which X denote~ oxygen or sulfur, ~nd Rl, R2 and ~3 have the above ~neaning, wi~h ~ ~rivalent S organic pho phorus compound of the ~ormula III
oR4 R6 _ p ~' ~ oR5 in which R6 denotes (C1-C~ alkyl, for example methyl, e~hyl or trifluoromethyl, phenyl ~hich can be ~ubstitu~ed by:
(cl-c3)-alkyl or (C~-C3)-alkoxy, and R4 and R5 are identical or dif ferent and denote ( C1-C4 ) -alkyl/ allyl, b~nzyl, or phe~yl which can 1~ ~ub~ti-tuted by ( Cl-C3 ) -allcyl or ~ Cl-C3 ) -alkoxy .
The reaction between a compound II and a ~o~pound III can be carried out in a ~uitable ors~anic 801VeIlt~ for example in tetrahydrofuran, ethyl ~cetate, an ~rQ~n~tic hydro~
carbon such as benzene, toluene or xyl~3ne, or ~ halo~eJl-ated hydroc~rbon ~uch a~ dichlor~methane, trichloro-methan or 1,1, 2 -trichloroeth~ne .
The reaction teinperature can v~ry between ~10C and 160C, preferably between +20C and ~70~C.
~he concentration of the compound II to be cycli~ed i6 between 1 mmol/l and 100 ~mol/l, preferably between 2 mmol/l and 20 ~mol/l .
% ~
~he nmount of the compound III can be bet~een 2 and 8 mole-eguivalents, preferably between 2 and 6 mole-equivalents, relative to II.
The compounds of the foxmulae II and III ~re known or can be prepared by processe~ di~closed in the literature.
The examples which follow ~erve to Illustrate ~he inven-tion further.
~sample 1 4-Nitrobenzyl (5R,6S)-6-~(lR~-tert.-butyldimethyl~ilyl-oxyethyl]-2-(4-aminocarbonylphenoxy)pen~m-3-carboxylate 130 mg (0.2 mmol) of (3S,4R)~4-[(sminocarbonyl)-pheno~y-thiocarbonylthio]-3-[(lR)-tert.-butyldimethyls~lyloxy-ethyl)3-1-(4-nitrobenzyloxycarbonyl)-azetidin-2-one were dissolved in 90 ml of CHCl3 under an argon atmo~phere at 55C. To this was added within 30 minutes a ~olution of 90 mg (0.8 mmol3 of dimethyl methylpho~phonite CH3P(OCH3) 2 in 10 ml of CHC13, and, after addition wa~ complete, the mixture was then ~tirred for 2 hours and, after cooling, worked up. Extraction with 1 N NhHCO3 ~olution, 1 ~ XHSO~
~olution and water wa~ carried out, and the or~anic pha~e was dried with magnesi~m Rulfa~e and ~oncentrated in vacuo. The crude product proYided, a~ter ~lash c~romato-graphy (SiO2 70-20~ ~m + 10 % H2O; ~ir~t toluene + ~thyl acetate 20 ~ 1, then 1 ~ 1 for elution)~ the ti~le ~ompound in 83 % yield.
The compounds I listed in Table 1 w~re obtained analo-gously from the stArting ~ub~tances II li~ted in ~able 2 under the reaction condition~ ted ln Table 3.
- 6~ is~30 ^ ~ ~ ~ s X~ I ~ I " oô ~ ~ S ~
~ O ~ E ~ o N ~
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----E--` O t~ ~ N _ ~ o N ~ _ O ~ O ~ ~ ~ X ~n X L
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t_~ o ~ 0 ^ ~ E ~ ~ ^ U O -- ~ er O
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~ m ~~ E _~ 0 ~'~ o-- ~9 ~ ~ W--~ ~ E N
æ ~ s ~ ~ . ~ ~ . . ~ ~ ~ ~ . s ~ ~ x ~ ~ ~. ~ 3 ~ ~ " " .N 7--T ~ ~ _ E E ^ 11 ~ _ 0 o --~ -- Ew mo~ ~ ~ S ~ __s~ ~cn ~,_~~ x-- O
r` ~ ~ ~ ~ ^~ ^ô 3 -o a E ~ ~ IE ~ 8 ~ N ~T ~
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; ~
~ ~ ~- ~ _ ~able 2 Starting compounds Ex~ple Rl _ R2 -- R3 - X
-O~H2 -PNB -CH(OT3DMS) S
2 -O~CONH2 -CH2CH~H2 " S
3 -O~CON112 -cH2CH?S~e3 " . S
4 OCH3 - CH2C14=CH2 S
OCH3 - PNB ,1 5 OCH3 -CH~CH251Me~ " S
7 a -PNB " S
8 O PNB 1l S
9 SCH3 CH2CH-~H2 S
- 12 ~ 5~
Ex~pl ~ Rl R2 R3 X
SCH3 -PN~ " S
11 SCH3 -cH2cH2s~Me3 12 ~ -CH~CH2SiMe3 " O
13 ,~ -cHzcH2s~Me3 " O
14 ~ -CH2CH2S~Me3 "
~ -CH2cH2siMe3 " s ..
16 ~C02CH,~CH-CH2 -cH2cH2s~Me3 " O
O -CH2CH2SiMe3 'l o O - CH2CH-CH2 ~ o 19 O~H3 -CH2cH2siMe3 "
-- 13 - ~$~55~
Table 3 Reaction condi~ions for the cycli~ation reaction ~ o~ ~~ ~n oo o o ~ o u ~ C~ ~
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Claims (5)
1. A process for the preparation of a penem compound I
in which R1 denotes hydrogen, (C1-C4)-alkyl, (C1-C12)-alkoxy, (C1-Cl2)-alkylthio, phenoxy, phenyl (the phenyl rings being unsubstituted or substituted once or twice by carboxyl, (C1-C4)-alkoxycarbonyl, allyloxycarbonyl, aminocarbonyl, (C1-C4)-alkylaminocarbonyl, cyano, F, Cl or Br), (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyloxy, (C5-C6)-oxacycloslkyl (saturated or singly or doubly unsaturated), (C3-C6)-oxocycloalkyl, (C3-C6)-[1,1-bis-(C1-C3)-alkyloxy]-cycloalkyl, (C3-C8)-[(C1-C3)-alkyl-imino]-cycloalkyl, (C3-C6)-[arylimino]cycloalkyl, (C3-C6)-hydroxyiminocycloalkyl, (C3-C6)-(C1-C3-alkyl-oxyimino)-cycloalkyl, in which the cycloalkyl radical is unsubstituted or substituted once or twice by C1-C3-alkyl, by (C1-C3) alkoxy, by halogen, or by methylene and is saturated or can contain one or two double bonds, R2 denotes hydrogen or a customary carboxyl protective group which can be eliminated by hydrolysis, photol-ysis, oxidation, reduction or enzymatically, R3 denotes hydrogen, (C1-C4) -alkyl, (C1-C4)-alkenyl, (C1-C4)-alkoxy,(C4-C7)-cycloalkyl,phenyl,2-oxo-1,3-dioxolyl, triazolyl, thiazolyl, amino, acylamino or alkoxy.
which comprises reacting a compound of the formula II
in which X denotes oxygen or sulfur, and R1, R2 and R3 have the above meaning, with a trivalent organic phosphorus compound of the formula III
in which R6 denotes (C1-C4)-alkyl, phenyl which can be substitu-ted by (C1-C3)-alkyl or (C1-C3)-alkoxy, and R4 and R5 are identical or different and denote (C1-C4)-alkyl, allyl, benzyl, or phenyl which can be substi-tuted by (C1-C3)-alkyl or (C1-C3)-alkoxy.
in which R1 denotes hydrogen, (C1-C4)-alkyl, (C1-C12)-alkoxy, (C1-Cl2)-alkylthio, phenoxy, phenyl (the phenyl rings being unsubstituted or substituted once or twice by carboxyl, (C1-C4)-alkoxycarbonyl, allyloxycarbonyl, aminocarbonyl, (C1-C4)-alkylaminocarbonyl, cyano, F, Cl or Br), (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyloxy, (C5-C6)-oxacycloslkyl (saturated or singly or doubly unsaturated), (C3-C6)-oxocycloalkyl, (C3-C6)-[1,1-bis-(C1-C3)-alkyloxy]-cycloalkyl, (C3-C8)-[(C1-C3)-alkyl-imino]-cycloalkyl, (C3-C6)-[arylimino]cycloalkyl, (C3-C6)-hydroxyiminocycloalkyl, (C3-C6)-(C1-C3-alkyl-oxyimino)-cycloalkyl, in which the cycloalkyl radical is unsubstituted or substituted once or twice by C1-C3-alkyl, by (C1-C3) alkoxy, by halogen, or by methylene and is saturated or can contain one or two double bonds, R2 denotes hydrogen or a customary carboxyl protective group which can be eliminated by hydrolysis, photol-ysis, oxidation, reduction or enzymatically, R3 denotes hydrogen, (C1-C4) -alkyl, (C1-C4)-alkenyl, (C1-C4)-alkoxy,(C4-C7)-cycloalkyl,phenyl,2-oxo-1,3-dioxolyl, triazolyl, thiazolyl, amino, acylamino or alkoxy.
which comprises reacting a compound of the formula II
in which X denotes oxygen or sulfur, and R1, R2 and R3 have the above meaning, with a trivalent organic phosphorus compound of the formula III
in which R6 denotes (C1-C4)-alkyl, phenyl which can be substitu-ted by (C1-C3)-alkyl or (C1-C3)-alkoxy, and R4 and R5 are identical or different and denote (C1-C4)-alkyl, allyl, benzyl, or phenyl which can be substi-tuted by (C1-C3)-alkyl or (C1-C3)-alkoxy.
2. The process as claimed in claim 1, wherein the reaction of compound II with III is carried out in an organic solvent.
3. The process as claimed in claim 1, wherein the reac-tion is carried out at between +10°C and +160°C.
4. The process as claimed in claim 1, wherein R1 denotes hydrogen, (C1-C4 )-alkyl, (C1-C4)-alkoxy, (C1-C3)-alkylthio, phenoxy, phenyl (the phenyl nuclei being substituted by (C1-C4)-alkoxycarbonyl, amino-carbonyl or cyano), (C5-C6)-oxacycloalkyl, (C4-C6)-oxocycloalkyl, 3-hydroxyiminocyclobutyl, 3-methoxy-iminocyclobutyl,3,3-dimethoxycyclobutyl,3 methoxy-2-cyclobuten-1-yl, 2-methoxy-1-cyclobuten-1-yl and 4-methoxy-3-cyclohexen-1-yl R3 denotes 1-hydroxyethyl (in which the OH group is free or protected by trimethylsilyl, diphenyl-tert.-butylsilyl, allyloxycarbonyl, trichloroethoxy-carbonyl or 4-nitrobenzyloxycarbonyl), (C1-C3)-alkoxy, (C1-C3)-alkenyl.
5. The process for the preparation of penem compounds of the formula I as claimed in claim 1, and substantially as described herein.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19893914389 DE3914389A1 (en) | 1989-04-29 | 1989-04-29 | Prodn. of penem antibiotics - by reacting 4-acyl:thio-1- oxalyl-2-azetidinone cpds. with phosphonite di:ester |
| DEP3914389.9 | 1989-04-29 | ||
| DEP3917287.2 | 1989-05-27 | ||
| DE19893917287 DE3917287A1 (en) | 1989-05-27 | 1989-05-27 | Prodn. of penem antibiotics |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2015580A1 true CA2015580A1 (en) | 1990-10-29 |
Family
ID=25880482
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002015580A Abandoned CA2015580A1 (en) | 1989-04-29 | 1990-04-27 | Process for the preparation of penem compounds |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0399228A1 (en) |
| JP (1) | JPH02306978A (en) |
| KR (1) | KR900016224A (en) |
| AU (1) | AU620982B2 (en) |
| CA (1) | CA2015580A1 (en) |
| FI (1) | FI902110A0 (en) |
| NO (1) | NO173871C (en) |
| PT (1) | PT93893A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3839987A1 (en) * | 1988-11-26 | 1990-05-31 | Hoechst Ag | PENEM DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
| WO1992003443A1 (en) * | 1990-08-20 | 1992-03-05 | Suntory Limited | Antibacterial penem compounds |
| PL169584B1 (en) * | 1990-08-20 | 1996-08-30 | Suntory Ltd | Method of obtaining novel penemic esters |
| GB9216102D0 (en) * | 1992-07-29 | 1992-09-09 | Smithkline Beecham Plc | Pharmaceutical substances |
| ATE522521T1 (en) | 2002-03-26 | 2011-09-15 | Nippon Soda Co | METHOD FOR PRODUCING A CYCLIC CONNECTION |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8321677D0 (en) * | 1983-08-11 | 1983-09-14 | Erba Farmitalia | Preparation of penems |
| US4806637A (en) * | 1986-03-17 | 1989-02-21 | Schering Corporation | 6-(Hydroxyethyl)-2-(heterocyclylthio)-penem-3-carboxylates |
| GB2195627A (en) * | 1986-08-12 | 1988-04-13 | Hoechst Uk Ltd | Penem derivatives |
| EP0275002A1 (en) * | 1987-01-09 | 1988-07-20 | Hoechst Aktiengesellschaft | Process for the production of 7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene derivatives |
-
1990
- 1990-04-25 EP EP90107815A patent/EP0399228A1/en not_active Withdrawn
- 1990-04-26 FI FI902110A patent/FI902110A0/en not_active Application Discontinuation
- 1990-04-27 PT PT93893A patent/PT93893A/en not_active Application Discontinuation
- 1990-04-27 CA CA002015580A patent/CA2015580A1/en not_active Abandoned
- 1990-04-27 AU AU53906/90A patent/AU620982B2/en not_active Ceased
- 1990-04-27 JP JP2115038A patent/JPH02306978A/en active Pending
- 1990-04-27 NO NO901893A patent/NO173871C/en unknown
- 1990-04-27 KR KR1019900005962A patent/KR900016224A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| FI902110A0 (en) | 1990-04-26 |
| PT93893A (en) | 1990-11-20 |
| NO173871B (en) | 1993-11-08 |
| NO901893D0 (en) | 1990-04-27 |
| JPH02306978A (en) | 1990-12-20 |
| KR900016224A (en) | 1990-11-13 |
| AU620982B2 (en) | 1992-02-27 |
| EP0399228A1 (en) | 1990-11-28 |
| AU5390690A (en) | 1990-11-01 |
| NO901893L (en) | 1990-10-30 |
| NO173871C (en) | 1994-02-16 |
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