Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
PROCESS FOR SYNTHESIZING CARBAPENEM
SIDE CHAIN INTERMEDIATES
BACKGROUND OF THE INVENTION
The present invention relates to the synthesis of carbapenem
side chains, and in particular, to side chains or portions thereof containing
a pyrrolidine group, which is bonded to the carbapenem nucleus through
a thioether linkage. Typically, the pyrrolidine is a portion of the side
chain, and is substituted at the two position with any of a variety of
substituents.
Conventionally, these intermediate compounds are prepared
from a 4-hydroxyproline derivative of the formula:
HO
CONR~R2
N
R
Such synthetic schemes typically require the extensive use of protecting
groups.
Similarly, a method of converting trans-4-hydroxy-L-proline
to a thiolactone of the formula:
O
S
N
C(O)CH3
has been described. However, this thiolactone is unsuitably protected for
synthesis of carbapenem antibiotics.
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EP 551 993 Al published on July 21, 1993 relates to a
synthesis which utilizes active esterifying agents and base, followed by
treatment with hydrogen sulfide, or an alkali metal salt of hydrogen
sulfide, and base.
The present invention is an improvement over these other
processes, utilizing a sulfide source which surprisingly improves the
process when commercial quantities are synthesized.
SUMMARY OF THE INVENTION
A process for synthesizing a compound of the formula 1:
p O
1
is described wherein P is a protecting group
comprising
(a) reacting a compound of formula 2:
H 0,,,~,,
C02H
I
P
2
wherein P is as previously defined with diphenylphosphinic chloride to
produce a compound of formula 3:
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HO,,,~,,.
N C~O~P
O p ' /
3
(b) reacting compound 3 with methanesulfonyl chloride to
produce a compound of formula 4:
H3CSO3 0,,~,,,
~C,O~P
Ipl II
P O
and
(c) combining compound 4 with an alkali metal sulfide or
non-alkali metal sulfide in water to produce a compound of formula 1.
More particularly, the process described herein relates to a
process for producing a compound of the formula 5:
HS
'~C(O)NR'Rz
N
P
5
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wherein P is a protecting group;
R~ and R2 are independently selected from hydrogen, aryl and
heteroaryl, said aryl and heteroaryl groups being unsubstituted or
substituted with from 1-3 groups selected from the group consisting of:
C 1 _q. alkyl, C ~ _4 alkoxy, C 1 _4 alkylthio, halo, hydroxy, C02H,
C02C1_4 alkyl, NH2, NHCl_4 alkyl, N(Cl_4 alkyl)2, S03H, CN,
NHC(O)C1_4 alkyl, S02NH2, S02C1_4 alkyl, aryl and heteroaryl;
comprising: (a) reacting a compound of the formula 2:
H 0,,,,,,.
~C02H
N
P
2
wherein P is as previously defined with diphenylphosphinic chloride to
produce a compound of the formula 3:
HO,,,,,,
~C.O~P
ii II
P O O
3
(b) reacting compound 3 with methanesulfonyl chloride to
produce a compound of formula 4:
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H3CSO3 gin,,,,,
C.O~P
P O O
4
(c) combining compound 4 with an alkali metal sulfide or
non-alkali metal sulfide in water to produce a compound of formula 1:
P O
1
and
(d} reacting compound 1 with NHR1R2 wherein R~ and R2 are as
previously defined to produce a compound of formula 5:
DETAILED DESCRIPTION OF THE INVENTION
The invention is described using the following definitions
unless otherwise specified.
Alkyl and the alkyl portions of substituent groups include
monovalent hydrocarbon chains containing from 1-4 carbon atoms which
are straight or branched as appropriate.
Aryl refers to 6-10 membered mono- and bicyclic ring
systems, containing carbon atoms with alternating (resonating) double
bonds. Preferred aryl groups are phenyl and naphthyl.
Heteroaryl refers to aromatic 5-10 membered mono- and
bicyclic ring systems, containing from 1-4 heteroatoms, O, S or N.
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Preferred nitrogen containing monocyclic heteroaryl groups include
pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl
and l, 2, 4-triazolyl. Preferred heteroaryl groups containing oxygen as
the only heterotom include furanyl. Preferred heteroaryl groups
containing sulfur as the only heterotom include thienyl.
Preferred bicyclic heteroaryl groups include benzthiazolyl,
benzimidazolyl, quinolinyl and isoquinolinyl, indolyl and isoindolyl.
When substituted, the aryl and heteroaryl groups may be
substituted with 1-3 groups selected from the group consisting of: Cl-4
alkyl, C 1-4 alkoxy, C 1 _4 alkylthio, halo, hydroxy, C02H, C02C 1 _4 alkyl,
NH2, NHC 1 _4 alkyl, N(C 1 _4 alkyl)2, NHC(O)C 1 _4 alkyl, S03H, CN,
S02NH2, S02C1-4 alkyl, aryl and heteroaryl.
When necessary, the substituents which are optionally
present on aryl and heteroaryl can be in protected form.
Examples of suitable protecting groups include the following
without limitation: t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl,
trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyl-
oxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl (t-BOC), 2,2,2-
trichloroethyloxycarbonyl benzhydryl, o-nitrobenzyl, p-nitrobenzyl,
2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl,
trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethyl-
silyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl,
4-pyridylmethyl, t-butyl, allyloxycarbonyl, di-C,_,o alkylphosphoryl,
diarylphosphoryl and di-ar-C,_,o alkylphosphoryl. Preferred silyl
protecting groups are trimethylsilyl and triethylsilyl. Preferred carboxyl
protecting groups are p-nitrobenzyl and allyl. Preferred phosphoryl based
protecting groups include diisopropylphosphoryl.
Many other suitable hydroxyl and carboxyl protecting
groups are known in the art. See, e.g., Greene, T. W., et al. Protective
Groups in Or anic Synthesis, John Wiley & Sons, Inc., 1991.
P represents a protecting group on the proline nitrogen atom.
Thus, in one aspect of the invention, P represents a member selected from
the group consisting of: t-butylmethoxyphenylsilyl, t-butoxydiphenyl-
silyl, trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitro-
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benzyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl (t-BOC),
2,2,2-trichloroethyloxycarbonyl benzhydryl, o-nitrobenzyl, p-nitrobenzyl,
2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl,
trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethylsilyl)
ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl,
4-pyridylmethyl, t-butyl, allyloxycarbonyl, di-C,-,o alkylphosphoryl,
diarylphosphoryl and di-ar-C,_,o alkylphosphoryl.
More particularly, P represents a protecting group which is
selected from the group consisting of: t-BOC, diisopropylphosphoryl and
p-nitrobenzyloxycarbonyl.
Most particularly, P represents diisopropylphosphoryl.
Compound 2 used herein as a starting material is N
protected trans-4-hydroxy-L-proiine. The 2-carboxyl group is activated
using the compound diphenylphosphinic chloride, which is reacted with
I S compound II in a solvent in the presence of excess base. Solvents which
are useful herein include dichloromethane, acetonitrile, toluene,
fluorobenzene, tetrahydrofuran, or mixtures thereof. Bases which are
useful for this reaction include trialkylamines. Preferred trialkylamines
include diisopropylethylamine (DIPEA) and triethylamine.
Typically an amount of diphenylphosphinic chloride which
is about equimolar to the starting compound can be used. The reaction
between compound 2 and diphenylphosphinic chloride is typically run at
reduced temperature, below about 0°C to as low as about -40°C.
Preferably, the reaction temperature is maintained at about -10°C.
Compound 3, with the diphenylphosphinyloxycarbonyl
group at position two, is reacted with methanesulfonyl chloride (MsCl)
to produce compound 4. This reaction is conducted in a solvent, in the
presence of a slight molar excess of pyridine, collidine, lutidine and the
like, using a slight molar excess of MsCI. This mesylation reaction may
be conducted over about 1-4 hours, at a reduced temperature, e.g., about
0°C to as low as about -40°C. Preferably, the reaction
temperature is
maintained at about -10°C.
Compound 4 is thereafter combined with an alkali metal
sulfide or non-alkali metal sulfide and water to form the thiolactone 1.
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Essentially the reaction can be conducted at about -10°C to about
room
temperature. Preferably the sulfide and water are added quickly, and the
reaction is aged for several hours at ambient temperature.
As used herein, "alkali metal sulfide" refers to the group I
metal sulfides, such as the sulfides of sodium and potassium. Preferably
the alkali metal sulfide is Na2S.
As used herein, "non-alkali metal sulfides" and "alkaline
earth metals" are used interchangeably to include the group II alkaline
earth metal sulfides selected from the group consisting of: magnesium,
calcium and barium. Preferred are calcium and barium.
The preferred non-alkali metal sulfide, most notably CaS,
provides an unexpected advantage in that side products of the reaction
have low solubility in water, and thus can be removed as a precipitate.
In a preferred aspect of the process described herein, the
amine HNR'RZ is m-aminobenzoic acid.
In another preferred aspect of the process, the compound of
formula 5 is reacted with an acid to produce a compound of formula 6:
HS
~C(O)NR~R2
N
H
6
More particularly, a compound of formula 2'
H 0,,,
C02H
N
P(O)(OiPr)2
2'
is reacted with diphenylphosphinic chloride to produce a compound of
formula 3'
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H 0,,,
.~C02P(O)(Ph)2
N
P(O)(OiPr)2
3'
compound 3' is reacted with mesyl chloride to produce compound 4'
MsO,,,
.~ C02P(O)(Ph)2
N
P(O)(OiPr)2
4'
compound 4' is reacted with a member selected from the group consisting
of: Na2S, K2S, CaS and BaS to produce a compound of formula 1':
(iPrO)2P(O) ~N~~!~O
S
1'
compound 1' is reacted with m-aminobenzoic acid to produce 5'
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C02 H
HS
?--~C(O)NH
N
P(O)(OiPr)z
s'
and compound 5' is reacted with acid to produce a compound of formula
6'
C02H
HS
'~C(O)NH
N
H
6'
or a salt or solvate thereof.
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In a preferred aspect of the invention, the thiolactone
compound 1 is reacted with the amine HNR1R2 in the presence of an
organic acid to produce compound 5. Examples of suitable organic acids
include formic acid, acetic acid and propionic acid. Most preferably, the
reaction is conducted in the presence of acetic acid. Preferably, this
reaction is carried out in the presence of an organic solvent, such as
methylene chloride.
After the conversion of compound 4' to compound 1', the
latter is combined with ammonia or a primary or secondary amine to form
compounds of formula 5', which can be deprotected to give compound 6'
or salt thereof. In the isolation of 6' solvents, such as C~_5 alcohols, C1_3
alkanoic acids, toluene, acetonitrile, ethyl acetate and others may be
added to improve crystallization, or otherwise facilitate isolation.
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Also, addition of a trialkyl or triaryl phosphine, e.g., tri-n-butylphosphine,
at this stage may be useful in reducing the formation of disulfides
corresponding to compound (' and/or improving the rejection of other
impurities.
Most primary and secondary amines HNR1R2 wherein Rl
andlor RZ represent H, aryl or heteroaryl react with compound 1 upon
slight heating. Generally, the reaction proceeds from about RT to about
100°C over a few minutes to several hours.
The acid that is used to convert compound 5' to compound
G' can be varied within wide limits. For example, concentrated HCl can
be used and is preferred.
The invention described herein can be conducted in
essentially a single reaction vessel, thus allowing for economical
production of compounds 6' from compound 2.
The invention is further illustrated with the following non-
limiting examples.
EXAMPLE ONE
~1 S. 4S~-5-DIISOPROPYLPHOSPHORYL-2-THIA-5-
AZAB ICYCLO f 2.2.11 HEPTAN-3-ONE
HO,,,,.
N/ _ CO H diphenylphosphinic
2 chloride
P(O)(OiPr)2
1-2
HO,,,,, O
methanesulfonyl
P \ ~ chloride
P(O)(OiPr)2
1-3
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MsO,,,,, O
CO2 P \ / CaS/H20
Slurry
1_4 ~ \
P(O)(OiPr)2
(iPrO)2(O)P~ O
1-1
The following starting materials were utilized:
Startin Material uantit
Diisopropylphosphoryl 5.0 g, 16.93 mmol
h drox roline
Diiso ro leth lamine 6.34 mL, 36.44 mmol
Diphenylphosphinic 3.36 mL, 17.61 mmol
chloride
P ridine 1.48 mL, 18.29 mmol
Methanesulfon 1 chloride1.43 mL, 18.46 mmol
Calcium sulfide 1.49 , 20.66 mmol
Dichloromethane 100 mL
Water 350 mL
The mesylate mixed anhydride was formed according to
WO 97/06154 published on February 20, 1997, incorporated herein by
reference, and stirred with cooling at -15°C for 15 min.
Calcium sulfide (1.49 g) was added as a solid and washed
with water (30 mL), resulting in a three phase reaction mixture. The
mixture was stirred rapidly and the cooling bath removed, allowing the
mixture to reach room temperature.
r
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The solids quickly went into solution, and a white solid
precipitate was formed.
The mixture was stirred for 45 min and then filtered through
a coarse filter. The solid on the filter was washed with dichloromethane
and the filtrate separated.
The organic layer (approx. 200 mL) was washed with 1 M
HCl (50 mL), and 8% NaHC03 (50 mL). The aqueous bicarbonate layer
was back extracted and the combined extracts were washed with brine
and the layers weighed. The presence of the title compound (4.04 g) was
confirmed by HPLC.
EXAMPLE TWO
HO,,~I
~ H diphenylphosphinic
N chloride
t-BOC O
2-2
HO,,~,. O
methanesulfonyl
chloridc
N
t-BOC O
2-3
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MsO,,,, O
O-P \ ~ CaS
--
N ~ \ H2o
t-BOC O
2-4
t-BOC O
2-1
A. Synthesis of trans-N-t-butoxycarbonyl-2-
dinhenylphosphinyloxvcarbonyl-4-h~~~roline
H 0,,~,I DIpEA
OH dry THF
-2o°c
diphenylphosphmic
t-BOC ~ chloride
2-2
HO
O-P~ \
II
o b
2-3
A solution of compound 2-2 (35.0 g, 151 mmol.) and DIPEA
(60 mL, 344 mmol) in dry THF ( 1.0 L) was combined over 20 min with a
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solution of diphenylphosphinic chloride (37.5 g, 155 mmol) in THF (50
mL) at -20°C. The reaction mixture was stirred at -20°C for 90
minutes
to produce compound 2-3, which can be isolated and characterized or
used in the next part without isolation.
B. Synthesis of trans-N-t-butoxycarbonyl-2-diphenylphosphinyl
oxycarbonyl-4-methanesulfonxloxy-L-proline
HO,,,, O
\ ~ methanesulfonyl
0-P chloride
N ~ ~ \
t-BOC O
2-3
MsO,
O-P~ \
II
o b
2-4
Without isolation and characterization, after stirring the
reaction mixture from part A for 90 minutes at -20°C, pyridine (13.0
mL,
161 mmol) was added followed by a solution of methanesulfonyl chloride
( 19.8 g, 171 mmol) in THF (50 mL) over 15 minutes. The reaction
mixture was stirred at -20°C for 2 hours and allowed to warm to -
5°C
over an additional 30 minutes producing compound 2-4. The
methanesulfonyl substituted compound can be isolated and characterized,
or used in the next reaction without isolation and characterization.
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C. Synthesis of N-t-butoxycarbonyl-2-thia-5-azabicyclo[2.2.1]heptan-
3-one
MsO,,,, O
O-P \ ~ CaS/H20
\ Slurry
t-BOC O
2-4
t-BOC O
2-1
After allowing the reaction from part B to warm to -5°C,
a slurry of CaS (45.0 g, 187 mmol) in H20 (60 mL) is added in one
portion. The mixture is allowed to warm to room temperature and is
stirred for 6 hrs. The resulting suspension is filtered and the filtrate is
then partitioned between toluene and water. The organic Iayer is washed
with HCl (2.0 M), NaHC03 ( 1.0 M) and brine, dried over MgS04 and
concentrated in vacuo.
EXAMPLE THREE
HS
t-BOC O
~C(O}NR 1 R2
N
2-1
t-BOC
3-5
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The thiolactone 2-1 from Example Two without isolation,
can be combined with the amine shown below in column one to produce
the cis N-protected 4-thiol substituted proline derivative shown below in
column two.
TABLE ONE
Amine Product (3)
(3_1) HS
NH4Cl ~''C(O)NH2
N
i
t-BOc
3-5-1
(3-2)
HS
NH2 ~C(O)NH
N
I
t-BOC
3-5-2
(3-3)
NH2 HS
~C(O)NH ~
N C02H
C02H t-BOC
3-5-3
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(3-4)
HS
~C(O)NH
N S C02H
H2N ~S ~C02H
t-BOC
3-5-4
(3-5)
HS
NH2 ~C(O)NH ~
N C02H
t'(O)(OiPr)
C02H
3-5-5
(1) 4.0 eq. of NH4C1 in Et3N; solvent CH30H;
reaction time: 30 min at RT;
(2) 1.25 eq. of aniline; solvent toluene; reaction time:
2 hrs at 100°C;
(3) 1.25 eq. of 3-aminobenzoic acid; solvent toluene;
reaction time: 2 hrs at 100°C;
(4) 1.25 eq. of 5-amino-2-carboxythiophene; solvent
toluene; 2 hrs at 100°C;
(5) P represents diisopropylphosphoryl. (iPr = isopropyl).
EXAMPLE FOUR
Using the procedures set forth in Example Two, Part A, the
compounds of column one are reacted with diphenylphosphinic chloride
to produce the compounds in column two.
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TABLE TWO
HO,,,,,,,
HO,,,,
C02P(O)(Ph)2
C02H N
N
O~O ~ O O
4-3-1 / N02
N02 ph - phenyl
4-2-1
HO~~,,,, HO,,,,,,
C02H ~ C02P{O)(Ph)2
N N
\ ~O \
O O ~ O
/ /
4-2-2 4-3-1
HO,,,,,,, HO,,,~,.
~'C02H ~C02P(O)(Ph)2
N N
0 0 0
4-2-3 I 4-3-3
SUBSTITUTE SHEET (RULE 26)
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EXAMPLE FIVE
Using the procedures set forth in Example One, Part B, the
compounds of column one are reacted with methanesulfonyl chloride to
produce the compounds in column two.
TABLE THREE
5-4-1
MsO,,
~C02P(O)(Ph)2
4-3-1 N
O~O
N02
Ph = phenyl
5-4-2
4-3-2 MsO,,,,,
~
C02P(O)(Ph)2
N
O~O
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5-4-3
MsO,,,,,,,
4-3-3
~C02P(O)(Ph)2
N
~O~
O
EXAMPLE SIX
Using the procedures set forth in Example Two, Part C, the
compounds of column one are reacted with CaS in water to produce the
compounds in column two.
TABLE FOUR
6-1-1
NOZ
w
5-4-1
OII
Ol~N. / O
S
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G-1-2
5_4.2 OII
OJ~N.~O
I S
fi-1-3
5-4-3
OJ~N / O
S
EXAMPLE SEVEN
Using the procedures set forth in Example Three, the
compounds of column one are reacted with the amine in column two to
produce the compounds in column three.
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TABLE FIVE
Amine NHR1R2 P rrolidine
7_5_1 1
HS
(1)
~C(O)NH2
6-1-1 NH4Cl N
\
O
/ N02
7-5-2 1
(2) . H S
NH2 ~C(O)NH-Ph
6-1-1 N
~O \
/ O
/ N02
Ph = Phenyl
7-5-3 1
(3) HS
NH ~C(O)NH
6-1-1 N
\ C02H
O~O
/ C02H
/ N02
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7_5_4 1
(4) H S
~C(O)NH
N s C02H
6-1-1
H2N S C02H O'~'O \
N 02
7-5-5 I
HS
(1)
6-1-2 ~C(O)NH2
NH4Cl N
O
7_5_6 1
(2) HS
6-1-2 NH2 ~C(O)NH-Ph
N
/ p p
/
Ph = Phenyl
7_5_7 1
(3) HS
._
6-1-2 NH2 ~C(O)NH
N
O ~ C02H
C02 H O
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7_5_8 1
(q.) H S
~C(O)NH
6-1-2 / N S C02H
H2N S/\C02H O~O w
7_5-9 1
HS
(1)
~C(O)NH2
6-1-3 ~ NH4Cl N
~O~
O
7-5-10 1
(2) HS
NH2 ~'~'C(O)NH-Ph
6-1-3 N
/ O O~
Ph = Phenyl
7-5-11 l
(3) HS
NH ~'C(O)NH
N
6-1-3 l
O~ C02H
/ O
C02H
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(4) 7-5-12 1
HS
- _ ~ , C(O)NH ~ I
613 H2N S~C02H N S~C02H
O~O
(3)
7-5-13 '
NH2 HS
1-1 ~ ~C(O)NH ~
I / N
CO H
CO H ~(O)(piPr)
2
1: Tri-n-butylphosphine may be added.
While certain preferred embodiments have been described
herein in detail, numerous alternative embodiments are contemplated as
falling within the scope of the invention.
