PROCESS FOR THE PREPARATION OF PENEM COMPOUNDS

PROCEDE DE PREPARATION DE PENEMES

English Abstract

- 1 -
HOE 89/F 135K
Abstract of the disclosure
Compound I
<IMG>
is obtained by reaction of compound II
<IMG>
with compound III
<IMG>

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a penem compound I
<IMG>
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

- 15 -
<IMG>
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
<IMG>
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

- 16 -
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.

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)

- 2
R3~"6
C02R2
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

-- 3 --
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 ~
S ~ I ~ E ~ ~ C
_ 1~ ~ _5 ~ 0 a~ S ~ L
G ff~ I E I ~ ~ o ~ ^ E
oe .o co ~o x 0 ~ ~ ~ ~ 5 N o a O ~1) o _~
~'d .. ~ ~ C ~ ~ S '~
_ ~ t ^x - o~--S
~ ~o~ z ~ ~ ~ 11 0 u~ X O ~ u E ~ o æ 1-
u~ _ ~ ~ ~ ~ ~ _3
~ ~ 5 X t,~ S t ~ 1 ~ C
1~ ~ I` e 0 s~J ~ 1. s3 ~ ~~ a~ s o
~ o 0~ n ~ D--~
o~ 7 ~ ~ 7 C~ o ~ ~--~ ~ V) Z
. r~
o ~ Ei
c
~a ~
S ~ ~ S~
a
c.
.
~ K

s~
-- 7 --
~ ~ E ", ,' ~ ^ E S
.~ ~ ~ O ~ O ~ ~
^ ~ Il o _ o In ~ ~o ^
- ~ o x~ I~ a ~
^ E E ~^ ^ ^ L-- ^ ^-- o ^~ -- --~-.D ^
T _~ ~ --'~ ~ i O 11 QO
_S S ~ ^S ~ S ^Vl
E Ll~---- ~ > ~ ^ O ~ ~N ~ C u~ ~
G U~ ~ _ ~ ~t ~ --~ O ~ ~-- ~ ~ C~ ^
c ~ t 0 S,,~
~o . ,~v ~ 1 1I y N ~ N ^~ co E O ~~ ~ c S
. . _ _ _1 L `~ ~ 0 S
_ ~ O N ~ 6D ~ ^N
_ ~ ~ O ~ T 'r O
E ~ o ~ s ~ ~ l s ll ~ L
----E--` O t~ ~ N _
~ o
N ~ _ O ~ O ~ ~ ~ X ~n X L
~ -~ ^ - Z ~ L lv~ z _--11 CL_
u~ --~, ~ ô & ~ D ~ O "~ o
X ~ ~9 T ^ P~ X
T
~ .
.
11 S
t~ ~
oS~ ,~
.
c
0 _~
~ ~ I~
O C:
~V
-
~I ~r ~ ~ ~
X
w

- 8~ 5~
N ~ ~ ~ ~ E ~ ,o ,~ s
N ~ 0 ~ O O ~ 11 5 5 19 ~ ~ CO ^O
^ O ^ ~ ~ O
L ~ J ^ 11 ^ ~ ~
u~ X . ~ ~ 5 ~ ~ o E _l
_ ~ , S 4~ Y ~ _.~ S O
E ~ ~ , O N N ~ ~D N 8 ~ ~ . ~ I ~s , . o _ . ~
0 ~ C C~~ E
~----5 ~ o Lr~
o ~ __~, x s ~ E ~ ~,~ C ~ Il G
e~ J O ~_ x :~: ^0 ~ X
:1~ ~ eC E 11 î~ N N~__ N C --~ ~ <--~ N ~ ~ _ ^~
z~ ^ ^ ^ 3 . ~ 5 0 ~~
S~N-- ~ ~ O Y 11 ~D O 1~ a~ X ~ ~ O ~ X I ~ a V~
z _--~o E ~-- ~ ^ ^ E s ~ Z ~ E ~ vl
S OD K
G ~
C~ O
S
~ a~
O S S:
a~ 1 m s:
CL ~ Q. L~
._
I
~ s~
6,,
o~ o

- 9 ~
~ T ~ _ . ~
_ T ~J ~ 1 2 ~ ~ e
",, 2 ^ ^ ~ --
u~1 _ N ~^-- L ~
E ~' ~ ~ , X:S:-- ^ N
t~ ' ~
~ ~ N ~ NE ~ ~--~ E i~) E NN E ~`
_ ~ Q K ~ ~ S
~ ~ ~ o .-- ~
~ ~ O ~ ~ ~ O
_ ~ ~ , ~ E _, e _~ ~
~ _, ^~t S ~ t ~
.. -- ~ X ~ Q O t~ O O
_ ~ , 5 e V~ O, ~ o 5 _cr t~D t~
t_~ o ~ 0 ^ ~ E ~ ~ ^ U O -- ~ er O
1~ ~ E ~ N E t`J ~ ~ `~--' N fll S ~
O ~_ I I.D T ^ ~0 11 ~D S ^ ~ ^ O ^
_ ~ T ~ ~ _ ~ ~ ~D ~ ~ ' ~t -- ^ S
Y ~ ~ ~
~ ~_o ~T _ E ~ ~ E ~ o~ ,
2 ~ ~ O T-- o ~ 0 ~ ~ ~ ~ O ~ ~ L
~1 0 ~ 2 1 ^__0 ~ S ~o" ~ ', ~ ~ o N ~ X V
. . ~ S S I ~ ~., L
E E E _1 0 0 ~ n E ~
O
. _ .
t~
a: 4
C~: l~
O e~
L--
O = ~ ~ ~ .
e ~
o a 3
o ~ I Q ~` ~ '
~ ~ ~ ~ ~n
K

2~5~
10 --
S "~ 5
-- E-- , u~ ^ ~ S ~ E ~~
. ,.~ T ~ L
EL ~ o I ~, O _ C--~ ~ T II~ D ~ N O E _
C ~T~tS~ 1 E ~ ~7o ~3~ .s
_ ~ ~ E r ~ ~ t'~ ~ ~ '--.
~ 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 ~
o ~ x 0 r~ a~~ N ~
~3 ~-~o~t ~v~o~u ~t~cO ~ ,~,3_~
~ O
O
o 1 ~
:~:
nl N
; ~
~ ~ ~- ~ _

~able 2
Starting compounds
R3 S - C - R
C 2
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'>
5~ O~O~
E ~ u o n 0 1~ 0 0
~- ~ L~
C
~: >
~ o oo~ooo~c~ooooooooooo
_.
._
o
~1 N
~ N
_ ~ ~ ~-~
_.
S ~ S ~ S
~5' ~ x:r
C~ ~ ~ ~5~
- ~ ~
'

Representative Drawing