Note: Descriptions are shown in the official language in which they were submitted.
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~
-- 3 --
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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