CA2051865A1 - Process for the preparation of carbapenem compounds - Google Patents
Process for the preparation of carbapenem compoundsInfo
- Publication number
- CA2051865A1 CA2051865A1 CA002051865A CA2051865A CA2051865A1 CA 2051865 A1 CA2051865 A1 CA 2051865A1 CA 002051865 A CA002051865 A CA 002051865A CA 2051865 A CA2051865 A CA 2051865A CA 2051865 A1 CA2051865 A1 CA 2051865A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- cycloalkyl
- hydrogen
- alkoxy
- phenyl
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- C07D477/02—Preparation
- C07D477/04—Preparation by forming the ring or condensed ring systems
Abstract
Abstract of the disclosure Process for the preparation of carbapenem compounds compound I
I
is obtained by reactinc3 compound IV
IV
with compound V
V
in a suitable organic solvent at temperatures from 50 to 180°C.
I
is obtained by reactinc3 compound IV
IV
with compound V
V
in a suitable organic solvent at temperatures from 50 to 180°C.
Description
2~18~
HOECHST ARTIENGESELLSCHAFT HOE 90/F 283R Dr. VF/AP
Proc~ss for the preparation of carbapenem compounds The invention relates to a proces6 for the preparation of carbapenem compound6.
Carbapenem derivatives of the formula I ~re valu~ble compounds having antibiotic properties. Synthesi~ methods known from the literature make UBe of the intermediates of the compounds of the formulae II and III, whose preparation is time-consuming:
OR(5) R~ R~2) R(3) 0 4 3 C00R(4) OR(s) R(~ R(2) .~0 I
0~ _ N COOR(4) OR(5) R~ R (2) /~, R (3) o m 'F
OOOR(4) - 2 _ ~.05~Q~
A further process variant con~ists in the cyclization of the precursor IV (oxalimide cyclization):
OR(~) h~R(O
~T/~ lV
`F
CC~aR4) In the literature, the cyclization reagent which i6 used exclu6ively i6 trLmethyl pho6phite or triethyl phosphite.
The di6advantage is that the yields are often very low becau6e of the high reaction temperatures and long reaction times which are necessary.
Surpri~in~ly, it has now baen found that these disad-vantages can be avoided when the precursor IV is cyclized using dialkyl alkylphosphonite6. Compared with alkyl-pho~phites, the6e novel rea~ents lead to a cyclization under considerably milder reaction condition6 and there-fore to con~iderably higher yields of end product I.
The invention therefore relates to a process for the preparation of carbapenem derivatives of the formula I
OR(5) R~ /U(2) /~ ~r ~ _, R (3) ~1~ 1 o " 3 C00'1~4) in which:
R(l) and Rl2) are hydrogen, (Cl-C4)alkyl, (C1-C4)alkenyl, (Cl-C4)alkoxy,(C4-C~)cycloalkylor(C3-C~,)spirocyclyl, R(3) is hydrogen, (Cl-C4)alkyl, (Cl-Cl2)alkylthio ~where 20the alkyl groups are un~ubstituted or mono- or 2~:18~
di6ub6tituted by hydroxyl, protected hydroxyl, (Cl-C4)alkoxy, (Cl-C4)alkyloxycarbonyl, (Cl-C4)acyloxy~
~nino~ (C1-C4)alkylamino, (Cl-C4)acylamino, thiol, (Cl-C4)alkylthio or heterocyclylthio, for example thiazolyl, thiadiazolyl, pyridylthio], phenyl, heterocyclyl, phenylthio, heterocyclylthio lwhere the phenyl and heterocyclyl ring~ axe un~ub~titu~ed or mono- or disub6tituted by hydroxyl, p~otacted hydroxyl, carboxyl, (C1-C4)alkoxycarbonyl, allyloxy-carbonyl, aminocarbonyl, (C1-C~)alkylnminocarbonyl, cyano, F, Cl, Br], (C3-C~)cycloalkyl, (C3-C6)cyclo-alkylthio, (C5-C6)oxacycloalkyl [saturated, mono- or diunsaturated], (C3-C6)oxocycloalkyl, (C3-C6)~
[l,l-bis-(C1-C3)alkyloxy]cycloalkyl,(C3-C6)-[(Cl-C3)-alkylimino]cycloalkyl~(c3-c6)-[phenylimino]
cycloalkyl, ( C3-c~ ) ( hydroxyimino)cycloalkyl, (C3-C6)-~(C1-C~)alkyloxyimino]cycloalkyl, in which radical~
the cycloalkyl radical is un~ubstituted or mono- or di~ubstituted by (C1-C3)alkyl, preferably methyl, by (C1-C3)alkoxy, preferably methoxy, by halogen ~uch a6 F, Cl, Br, preferably chlorine, or by m~thylene, and i8 saturated or can contain one or two double bonds, R~4) i~ hydrogen or a customary carboxyl protective group which can be eliminated by hydrolysis, photolysi~, oxidationr reduction or enzymatically, R(5) is hydrogen or a customnry alcohol protective group which can be eliminated by hydroly~is, photoly~
oxidationl, reduction or enzymatically.
The following nre example~ of particularly preferred sub~tituents:
R(1) and (R(2) are hydrogen, (C1-C4)alkyl, (C1-C~)nlkenyl, (C~~C4)alkoxy,~C4-C~)cycloalkylor(C3-C~)~pirocyclyl, R~3) i~ hydrogen, (C,-C~)alkyl (for ex~nple methyl, ethyl, hydrox~nethyl and aminomethyl), (C,-C~)hydroxyalkyl, (C,-C3)alkylthio (for example methylthio, ethylthio and propylthio, methoxycarbonylmethylthio), phenyl (for example 4-carboxamidophenyl, protected 3,4-di-hydroxyphenyl, 4-fluorophenyl or 4-cyanophenyl), _ 4 ~
heterocyclyl, for example pyridyl, phenylthio, ~aturated or un~aturated (C5-C6~oxacycloalkyl (for example tetrahydrofuryl or furyl)~ (C4_C6)OXQCYC1O-alkyl ~or ex~mple 1-oxocyclobut-3-yl), 3-hydroxy-iminocyclobutyl, 3-methoxyiminocyolobutyl and 3,3 dimethoxycyclobutyl, R(4) is a carboxyl protective group such a~ ~llyl, p-nitrobenzyl or trimethylsilylethyl, R(S) i~ hydro~en or an alcohol pro~ective group such as trimethyl~ilyl,dimethyl-tert.-butylsilyl,diphenyl-tert.-butyl~ilyl, allyloxycarbonyl, trichloroethyl-o~ycarbonyl or 4-nitrobenzyloxycarbonyl.
The a6ymmetric centers C-l, C-5, C-6 and c-a can exi~t both in the R configuration and in the S configuration.
The compoundR of the ormula I are prepared by the proces6 uccording to th0 invention by reacting a compound of the formula IV
OR(5) R~R a) ~ ~ R (3) ~F
C~R;4) in which X is oxygen or ~ulfur nnd R(l), R(2~, R(3), R(4) and R(5) are a~ defined above with a trivalent organic phosphorus compound of the formula V
OR (6) R(8) P V
OR (7) in which:
R(6) and R(7) are (Cl-C41alkyl, allyl, benzyl or phenyl - 5 - 20~
which can be subst$tuted by (Cl-C3)alkyl or (Cl-C3~alkoxy, and R(6) and R(7) can be identical or different, and R(8) is (C,-C4)alkyl, for example me~hyl, ethyl or tri-fluoromethyl, phenyl which can be ~ubstituted by (Cl-C3)al~yl or (Cl-C3~alkoxy.
The reaction between a compound IV and a compound V can be carried out in a suitable organic solvent, for example in tetrahydrofuran, ethyl ~cetate, an aromatic hydro-carbon ~uch a~ benzene, toluene, xylene or mesitylene, or in a halogenated hydrocarbon ~uch a~ dichloromethane, trichloromethane or 1,1,2-trichloroethane.
The reaction temperature can vary between 50 and 180DC, preferably between 70 and 165C.
The concentration of the compound IV to be cyclized i~
between 1 mmol/l and 150 mmol/l, preferably between 2 mmol/l and 50 mmol/l.
The amount of the compound V can be between 2 and 8 mol equivalents, preferably between 2 and 6 mol equivalents, relative to IV.
The dialkyl alkylpho~phonates and dialkyl alkylthiophoM-phonate~ which are formed a8 0eparate product~ can be ffeparated of~ in ~imple fa~hion.
The compounds of the formulae IV and V are known or can be prepared by methods known from the literature.
The examples which follow are intended to further illustrate the invention.
- 6 - ~3 Example 1 Allyl (lR,5S,6S)-6-[(lR)-tert. butyldimethylsilyloxy-ethyl)-2 (methoxycarbonylmethylthio)-1-methylcarbapen-2-em-3-carboxylate A solution of 1.0 g (2 mmol) of (3S,4S)-l-allyloxy-carbonylcarbonyl-3-[(lR)-tert-butyldimethyl6ilyloxy-ethyl)-4-[(2R)-1-methoxycarbonylmethylthio-1-oxopropyl]-azetidin-2-one in 50 ml of dry xylene is heated to the boil, and 1.36 g (10 mmol) of diethyl methylphosphonite are added. After 15 minutes, the mixture i8 cooled, the solution i5 concentrated in vacuo, and the residue i~
chromatographed over silica gel (deactivated with 10~ of water) using toluene:ethyl acetate tlO:l). After the product fraction6 have been concentrated, a colorles~, crystalline ~olid i~ obtained. Yield: 740 mg (78~ of theory).
The compounds I listed in Table 1 were obtained analo-gously from the starting substances IV li~ted in Table 2 under the reaction conditions listed in Table 3.
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- 10~ 8b~
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~ ~ u~ V ~ I T
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tl~
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O I r~ a5 N C~ T~ g N ~ N N I
~ E ^ I ~ E, ~ T = ~ 8 ~ o x ~ ~ O ~ O 0~ æ E O t.) T ~ 8 _ U~ ~ ~ ~
I ~ N
_ VN I T
_ o C
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u I
E~ X ~ , _ %051~
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.C
HOECHST ARTIENGESELLSCHAFT HOE 90/F 283R Dr. VF/AP
Proc~ss for the preparation of carbapenem compounds The invention relates to a proces6 for the preparation of carbapenem compound6.
Carbapenem derivatives of the formula I ~re valu~ble compounds having antibiotic properties. Synthesi~ methods known from the literature make UBe of the intermediates of the compounds of the formulae II and III, whose preparation is time-consuming:
OR(5) R~ R~2) R(3) 0 4 3 C00R(4) OR(s) R(~ R(2) .~0 I
0~ _ N COOR(4) OR(5) R~ R (2) /~, R (3) o m 'F
OOOR(4) - 2 _ ~.05~Q~
A further process variant con~ists in the cyclization of the precursor IV (oxalimide cyclization):
OR(~) h~R(O
~T/~ lV
`F
CC~aR4) In the literature, the cyclization reagent which i6 used exclu6ively i6 trLmethyl pho6phite or triethyl phosphite.
The di6advantage is that the yields are often very low becau6e of the high reaction temperatures and long reaction times which are necessary.
Surpri~in~ly, it has now baen found that these disad-vantages can be avoided when the precursor IV is cyclized using dialkyl alkylphosphonite6. Compared with alkyl-pho~phites, the6e novel rea~ents lead to a cyclization under considerably milder reaction condition6 and there-fore to con~iderably higher yields of end product I.
The invention therefore relates to a process for the preparation of carbapenem derivatives of the formula I
OR(5) R~ /U(2) /~ ~r ~ _, R (3) ~1~ 1 o " 3 C00'1~4) in which:
R(l) and Rl2) are hydrogen, (Cl-C4)alkyl, (C1-C4)alkenyl, (Cl-C4)alkoxy,(C4-C~)cycloalkylor(C3-C~,)spirocyclyl, R(3) is hydrogen, (Cl-C4)alkyl, (Cl-Cl2)alkylthio ~where 20the alkyl groups are un~ubstituted or mono- or 2~:18~
di6ub6tituted by hydroxyl, protected hydroxyl, (Cl-C4)alkoxy, (Cl-C4)alkyloxycarbonyl, (Cl-C4)acyloxy~
~nino~ (C1-C4)alkylamino, (Cl-C4)acylamino, thiol, (Cl-C4)alkylthio or heterocyclylthio, for example thiazolyl, thiadiazolyl, pyridylthio], phenyl, heterocyclyl, phenylthio, heterocyclylthio lwhere the phenyl and heterocyclyl ring~ axe un~ub~titu~ed or mono- or disub6tituted by hydroxyl, p~otacted hydroxyl, carboxyl, (C1-C4)alkoxycarbonyl, allyloxy-carbonyl, aminocarbonyl, (C1-C~)alkylnminocarbonyl, cyano, F, Cl, Br], (C3-C~)cycloalkyl, (C3-C6)cyclo-alkylthio, (C5-C6)oxacycloalkyl [saturated, mono- or diunsaturated], (C3-C6)oxocycloalkyl, (C3-C6)~
[l,l-bis-(C1-C3)alkyloxy]cycloalkyl,(C3-C6)-[(Cl-C3)-alkylimino]cycloalkyl~(c3-c6)-[phenylimino]
cycloalkyl, ( C3-c~ ) ( hydroxyimino)cycloalkyl, (C3-C6)-~(C1-C~)alkyloxyimino]cycloalkyl, in which radical~
the cycloalkyl radical is un~ubstituted or mono- or di~ubstituted by (C1-C3)alkyl, preferably methyl, by (C1-C3)alkoxy, preferably methoxy, by halogen ~uch a6 F, Cl, Br, preferably chlorine, or by m~thylene, and i8 saturated or can contain one or two double bonds, R~4) i~ hydrogen or a customary carboxyl protective group which can be eliminated by hydrolysis, photolysi~, oxidationr reduction or enzymatically, R(5) is hydrogen or a customnry alcohol protective group which can be eliminated by hydroly~is, photoly~
oxidationl, reduction or enzymatically.
The following nre example~ of particularly preferred sub~tituents:
R(1) and (R(2) are hydrogen, (C1-C4)alkyl, (C1-C~)nlkenyl, (C~~C4)alkoxy,~C4-C~)cycloalkylor(C3-C~)~pirocyclyl, R~3) i~ hydrogen, (C,-C~)alkyl (for ex~nple methyl, ethyl, hydrox~nethyl and aminomethyl), (C,-C~)hydroxyalkyl, (C,-C3)alkylthio (for example methylthio, ethylthio and propylthio, methoxycarbonylmethylthio), phenyl (for example 4-carboxamidophenyl, protected 3,4-di-hydroxyphenyl, 4-fluorophenyl or 4-cyanophenyl), _ 4 ~
heterocyclyl, for example pyridyl, phenylthio, ~aturated or un~aturated (C5-C6~oxacycloalkyl (for example tetrahydrofuryl or furyl)~ (C4_C6)OXQCYC1O-alkyl ~or ex~mple 1-oxocyclobut-3-yl), 3-hydroxy-iminocyclobutyl, 3-methoxyiminocyolobutyl and 3,3 dimethoxycyclobutyl, R(4) is a carboxyl protective group such a~ ~llyl, p-nitrobenzyl or trimethylsilylethyl, R(S) i~ hydro~en or an alcohol pro~ective group such as trimethyl~ilyl,dimethyl-tert.-butylsilyl,diphenyl-tert.-butyl~ilyl, allyloxycarbonyl, trichloroethyl-o~ycarbonyl or 4-nitrobenzyloxycarbonyl.
The a6ymmetric centers C-l, C-5, C-6 and c-a can exi~t both in the R configuration and in the S configuration.
The compoundR of the ormula I are prepared by the proces6 uccording to th0 invention by reacting a compound of the formula IV
OR(5) R~R a) ~ ~ R (3) ~F
C~R;4) in which X is oxygen or ~ulfur nnd R(l), R(2~, R(3), R(4) and R(5) are a~ defined above with a trivalent organic phosphorus compound of the formula V
OR (6) R(8) P V
OR (7) in which:
R(6) and R(7) are (Cl-C41alkyl, allyl, benzyl or phenyl - 5 - 20~
which can be subst$tuted by (Cl-C3)alkyl or (Cl-C3~alkoxy, and R(6) and R(7) can be identical or different, and R(8) is (C,-C4)alkyl, for example me~hyl, ethyl or tri-fluoromethyl, phenyl which can be ~ubstituted by (Cl-C3)al~yl or (Cl-C3~alkoxy.
The reaction between a compound IV and a compound V can be carried out in a suitable organic solvent, for example in tetrahydrofuran, ethyl ~cetate, an aromatic hydro-carbon ~uch a~ benzene, toluene, xylene or mesitylene, or in a halogenated hydrocarbon ~uch a~ dichloromethane, trichloromethane or 1,1,2-trichloroethane.
The reaction temperature can vary between 50 and 180DC, preferably between 70 and 165C.
The concentration of the compound IV to be cyclized i~
between 1 mmol/l and 150 mmol/l, preferably between 2 mmol/l and 50 mmol/l.
The amount of the compound V can be between 2 and 8 mol equivalents, preferably between 2 and 6 mol equivalents, relative to IV.
The dialkyl alkylpho~phonates and dialkyl alkylthiophoM-phonate~ which are formed a8 0eparate product~ can be ffeparated of~ in ~imple fa~hion.
The compounds of the formulae IV and V are known or can be prepared by methods known from the literature.
The examples which follow are intended to further illustrate the invention.
- 6 - ~3 Example 1 Allyl (lR,5S,6S)-6-[(lR)-tert. butyldimethylsilyloxy-ethyl)-2 (methoxycarbonylmethylthio)-1-methylcarbapen-2-em-3-carboxylate A solution of 1.0 g (2 mmol) of (3S,4S)-l-allyloxy-carbonylcarbonyl-3-[(lR)-tert-butyldimethyl6ilyloxy-ethyl)-4-[(2R)-1-methoxycarbonylmethylthio-1-oxopropyl]-azetidin-2-one in 50 ml of dry xylene is heated to the boil, and 1.36 g (10 mmol) of diethyl methylphosphonite are added. After 15 minutes, the mixture i8 cooled, the solution i5 concentrated in vacuo, and the residue i~
chromatographed over silica gel (deactivated with 10~ of water) using toluene:ethyl acetate tlO:l). After the product fraction6 have been concentrated, a colorles~, crystalline ~olid i~ obtained. Yield: 740 mg (78~ of theory).
The compounds I listed in Table 1 were obtained analo-gously from the starting substances IV li~ted in Table 2 under the reaction conditions listed in Table 3.
-- 7 ~ 18 ~ ~
^., ~ I V ~L T ~ R ,~
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U
_~ ~
C _ t~ ~
_ I j 0 l 11 i~
x ~ !_,m - 8 - 2 0 ~
E ~ I ,~ c ," . ~ 9, C 9B
a ~ , A ~ ~ q ~ æ 0O
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N X ~ $ g ~
C`J ~ ~,. c~ t O . ~ I -- ~ ~ ~ ~ E I E ~ 5 :~ ~ E ~ V ~
_, o t,.) " c C ~ ' E O T ~ ~ ~') _ _ I N
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~ E ^ I ~ E, ~ T = ~ 8 ~ o x ~ ~ O ~ O 0~ æ E O t.) T ~ 8 _ U~ ~ ~ ~
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Claims (5)
1. A process for preparing a carbapenem compound I
I
in which:
R(1) and R(2) are hydrogen, (C1-C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkoxy,(C4-C7)cycloalkylor(C3-C6)spirocyclyl, R(3) is hydrogen, (C1-C4)alkyl, (C1-C12)alkylthio lwhere the alkyl groups are unsubstituted or mono- or disubstituted by hydroxyl, protected hydroxyl, (C1-C4)alkoxy, (C1-C4)alkyloxycarbonyl, (C1-C4)acyloxy, amino, (C1-C4)alkylamino, (C1-C4)acylamino, thiol, (C1-C4)alkylthio or heterocyclylthio], phenyl, heterocyclyl, phenylthio, heterocyclylthio [where the phenyl. and heterocyclyl rings are unsubstituted or mono- or disubstituted by hydroxyl, protected hydroxyl, carboxyl, (C1-C4)alkoxycarbonyl, allyloxy-carbonyl, aminocarbonyl, (C1-C4)slkylaminoearbonyl, cyano, F, C1, Br], (C3-C8)cycloalkyl, (C3-C8)cycelo-alkylthio, (C5-C6)oxacyeloalkyl [saturated, mono- or diunsaturated], (C3-C6)oxocycloalkyl, (C3-C6)-[1,1-bis-(C1-C3)alkyloxy]cycloalkyl,(C3-C6)-[(C1-C3)-alkylimino]cycloalkyl,(C3-C6 )-[phenylimino]cyclo-alkyl, (C3-C6) -(hydroxyimino)cycloalkyl, (C3-C6)-[(C1-C3)alkyloxyimino]cycloalkyl, in which radicals the cycloalkyl radical is unsubstituted or mono- or disubsituted by (C1-C3)alkyl, by (C1-C3)alkoxy, by halogen or by methylene, and is saturated or can contain one or two double bonds, R(4) is hydrogen or H customary carboxyl protective group which can be eliminated by hydrolysis, photolysis, oxidation, reduction or enzymatically, R(5) is hydrogen or an alcohol protective group, which comprises reacting a compound of the formula IV
IV
in which X is oxygen or sulfur and R(1), R(2), R(3), R(4) and R(5) are as defined above with a trivalent organic phosphorus compound of the formula V
V
in which R(6) and R(7) are (C1-C4)alkyl, allyl, benzyl or phenyl which can be substituted by (C1-C3)alkyl or (C1-C3)alkoxy, and R(6) and R(7) can be identical or different, and R(8) is (C1-C4)alkyl, phenyl which can be substituted by (C1-C3)alkyl or (C1-C3)alkoxy.
I
in which:
R(1) and R(2) are hydrogen, (C1-C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkoxy,(C4-C7)cycloalkylor(C3-C6)spirocyclyl, R(3) is hydrogen, (C1-C4)alkyl, (C1-C12)alkylthio lwhere the alkyl groups are unsubstituted or mono- or disubstituted by hydroxyl, protected hydroxyl, (C1-C4)alkoxy, (C1-C4)alkyloxycarbonyl, (C1-C4)acyloxy, amino, (C1-C4)alkylamino, (C1-C4)acylamino, thiol, (C1-C4)alkylthio or heterocyclylthio], phenyl, heterocyclyl, phenylthio, heterocyclylthio [where the phenyl. and heterocyclyl rings are unsubstituted or mono- or disubstituted by hydroxyl, protected hydroxyl, carboxyl, (C1-C4)alkoxycarbonyl, allyloxy-carbonyl, aminocarbonyl, (C1-C4)slkylaminoearbonyl, cyano, F, C1, Br], (C3-C8)cycloalkyl, (C3-C8)cycelo-alkylthio, (C5-C6)oxacyeloalkyl [saturated, mono- or diunsaturated], (C3-C6)oxocycloalkyl, (C3-C6)-[1,1-bis-(C1-C3)alkyloxy]cycloalkyl,(C3-C6)-[(C1-C3)-alkylimino]cycloalkyl,(C3-C6 )-[phenylimino]cyclo-alkyl, (C3-C6) -(hydroxyimino)cycloalkyl, (C3-C6)-[(C1-C3)alkyloxyimino]cycloalkyl, in which radicals the cycloalkyl radical is unsubstituted or mono- or disubsituted by (C1-C3)alkyl, by (C1-C3)alkoxy, by halogen or by methylene, and is saturated or can contain one or two double bonds, R(4) is hydrogen or H customary carboxyl protective group which can be eliminated by hydrolysis, photolysis, oxidation, reduction or enzymatically, R(5) is hydrogen or an alcohol protective group, which comprises reacting a compound of the formula IV
IV
in which X is oxygen or sulfur and R(1), R(2), R(3), R(4) and R(5) are as defined above with a trivalent organic phosphorus compound of the formula V
V
in which R(6) and R(7) are (C1-C4)alkyl, allyl, benzyl or phenyl which can be substituted by (C1-C3)alkyl or (C1-C3)alkoxy, and R(6) and R(7) can be identical or different, and R(8) is (C1-C4)alkyl, phenyl which can be substituted by (C1-C3)alkyl or (C1-C3)alkoxy.
2. The process as claimed in claim 1, wherein the compound IV is reacted with V in an organic solvent.
3. The process as claimed in claim 1, wherein the reaction is carried out between +50°C and +180°C.
4. The process as claimed in claim 1, wherein R(1) and R(2) are hydrogen, (C1-C4 )alkyl, (C1-C4)alkenyl, (C1-C4)alkoxy, (C4-C7)cycloalkyl or (C3-C6)spiro-cyclyl, R(3) is hydrogen, (C1-C4 )alkyl, hydroxy (C1-C4)alkyl, (C1-C3)alkylthio, phenyl, heterocyclyl, phenylthio, saturated or unsaturated (C5-C6)oxacycloalkyl, (C4-C6)oxocycloalkyl, 3-hydroxyiminocyclobutyl, 3-methoxyiminocyclobutyl and 3,3-dimethoxycyclo-butyl, R(4) is a carboxyl protectlve group selected from the group comprising allyl, p-nitrobenzyl and trimethyl-silylethyl, R(5) is hydrogen or an alcohol protective group selected from the group comprising trimethylsilyl, dimethyl-tert.-butylsilyl, diphenyl-tert.-butylsilyl, allyloxycarbonyl, trichloroethoxycarbonyl or 4-nitrobenzyloxycarbonyl.
5. The process as claimed in claim 1 and substantially as described herein.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4029731.4 | 1990-09-20 | ||
| DE4029731A DE4029731A1 (en) | 1990-09-20 | 1990-09-20 | Prepn. of carba:penem derivs. as antimicrobials |
| DEP4033033.8 | 1990-10-18 | ||
| DE19904033033 DE4033033A1 (en) | 1990-10-18 | 1990-10-18 | Prepn. of carba:penem derivs. as antimicrobials |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2051865A1 true CA2051865A1 (en) | 1992-03-21 |
Family
ID=25897013
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002051865A Abandoned CA2051865A1 (en) | 1990-09-20 | 1991-09-19 | Process for the preparation of carbapenem compounds |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0476649A3 (en) |
| JP (1) | JPH04279587A (en) |
| KR (1) | KR920006359A (en) |
| AU (1) | AU8457591A (en) |
| CA (1) | CA2051865A1 (en) |
| FI (1) | FI914383A (en) |
| IE (1) | IE913297A1 (en) |
| IL (1) | IL99513A0 (en) |
| NO (1) | NO913692L (en) |
| NZ (1) | NZ239839A (en) |
| PT (1) | PT99005A (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5317016A (en) * | 1991-08-20 | 1994-05-31 | Shionogi Seiyaku Kabushiki Kaisha | Pyrrolidylthiocarbapenem derivative |
| US6346617B1 (en) | 1997-08-26 | 2002-02-12 | Merck & Co., Inc. | Crystalline 2-hydroxymethyl carbapenem intermediate compounds and process for synthesis thereof |
| ATE245647T1 (en) * | 1997-08-26 | 2003-08-15 | Merck & Co Inc | OPTIONALLY PROTECTED 3-HYDROXYMETHYLCARBAPENEMS AND THEIR SYNTHESIS |
| US6395894B2 (en) | 1998-04-16 | 2002-05-28 | Philip J. Pye | Process for the synthesis of carbapenem intermidiates, and compounds produced |
| CA2328219A1 (en) * | 1998-04-16 | 1999-10-21 | Merck & Co., Inc. | Titanium catalyzed preparation of carbapenem intermediates |
| ATE263766T1 (en) | 1998-06-17 | 2004-04-15 | Merck & Co Inc | METHOD FOR SYNTHESIS OF CARBAPENEM INTERMEDIATE PRODUCTS |
| US6194568B1 (en) | 1998-07-13 | 2001-02-27 | Merck & Co., Inc. | Process for synthesizing carbapenem intermediates |
| CA2519794A1 (en) | 2003-04-08 | 2004-10-21 | Sumitomo Pharmaceuticals Co., Ltd. | Novel carbapenem compounds |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK329381A (en) * | 1980-07-24 | 1982-01-25 | Takeda Chemical Industries Ltd | METHOD FOR PREPARING 1,1-DISUBSTITUTED CARBA-Z-PENEM AND SALTS AND ESTERS THEREOF |
| KR900006449B1 (en) * | 1982-08-24 | 1990-08-31 | 상꾜 가부시끼가이샤 | Process for the preparation of azetidinone derivatives |
| US4894450A (en) * | 1987-05-11 | 1990-01-16 | Merck & Co., Inc. | Process for 2-(aminoalkylthio) carbapenems |
| US4820815A (en) * | 1987-09-01 | 1989-04-11 | University Of Notre Dame Du Lac | Azetidinone N-phosphonomethyl esters |
-
1991
- 1991-09-17 IL IL99513A patent/IL99513A0/en unknown
- 1991-09-18 FI FI914383A patent/FI914383A/en not_active Application Discontinuation
- 1991-09-18 NZ NZ239839A patent/NZ239839A/en unknown
- 1991-09-19 EP EP19910115935 patent/EP0476649A3/en not_active Withdrawn
- 1991-09-19 IE IE329791A patent/IE913297A1/en unknown
- 1991-09-19 AU AU84575/91A patent/AU8457591A/en not_active Abandoned
- 1991-09-19 KR KR1019910016375A patent/KR920006359A/en not_active Application Discontinuation
- 1991-09-19 CA CA002051865A patent/CA2051865A1/en not_active Abandoned
- 1991-09-19 NO NO91913692A patent/NO913692L/en unknown
- 1991-09-19 PT PT99005A patent/PT99005A/en not_active Application Discontinuation
- 1991-09-20 JP JP3268935A patent/JPH04279587A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| KR920006359A (en) | 1992-04-27 |
| NZ239839A (en) | 1992-12-23 |
| FI914383A (en) | 1992-03-21 |
| FI914383A0 (en) | 1991-09-18 |
| EP0476649A2 (en) | 1992-03-25 |
| EP0476649A3 (en) | 1992-09-16 |
| NO913692L (en) | 1992-03-23 |
| NO913692D0 (en) | 1991-09-19 |
| PT99005A (en) | 1992-08-31 |
| IE913297A1 (en) | 1992-02-25 |
| AU8457591A (en) | 1992-03-26 |
| JPH04279587A (en) | 1992-10-05 |
| IL99513A0 (en) | 1992-08-18 |
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