Efficient synthesis of oral THF 1β-methylcarbapenem (OCA-983) via the Wittig process

Article abstract of DOI:10.1081/SCC-100000586

An efficient and reproducible synthesis of orally active 2-tetrahydrofuranylthio-1β-methylcarbapenem 16 (OCA-983) via the Wittig process was developed. The intramolecular reductive cyclization of the thioester-oxalimide 13 with triethyl phosphite to the 2-tetrahydrofuranylthio-1β-methylcarbapenem 14 was carried out in two steps in order to obtain a reproducible yield.

Full text of DOI:10.1081/SCC-100000586

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
EFFICIENT SYNTHESIS OF ORAL THF 1β-
METHYLCARBAPENEM (OCA-983) VIA THE WITTIG
PROCESS
Panayota Bitha & Yang-I Lin
To cite this article: Panayota Bitha & Yang-I Lin (2001) EFFICIENT SYNTHESIS OF ORAL THF 1β-
METHYLCARBAPENEM (OCA-983) VIA THE WITTIG PROCESS, Synthetic Communications, 31:4,
587-594, DOI: 10.1081/SCC-100000586
To link to this article: http://dx.doi.org/10.1081/SCC-100000586
Published online: 16 Aug 2006.
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Date: 18 September 2015, At: 09:27

SYNTHETIC COMMUNICATIONS, 31(4), 587–594 (2001)
EFFICIENT SYNTHESIS OF ORAL THF
1β-METHYLCARBAPENEM (OCA-983) VIA
THE WITTIG PROCESS
Panayota Bitha and Yang-I Lin∗
Chemical Sciences, Wyeth-Ayerst Research, Pearl River,
NY 10965
ABSTRACT
An efficient and reproducible synthesis of orally active
2-tetrahydrofuranylthio-1β-methylcarbapenem 16 (OCA-983) via
the Wittig process was developed. The intramolecular reductive
cyclization of the thioester-oxalimide 13 with triethyl phosphite to
the 2-tetrahydrofuranylthio-1β-methylcarbapenem 14 was carried
out in two steps in order to obtain a reproducible yield.
Recently, orally active 2-tetrahydrofuranylthio-1β-methylcarbapenems 1
have been reported (1–4). These 2-tetrahydrofuranylthio-1β-methylcarbapenems
1 have the spectrum of antimicrobial activity against gram-positive and gram-
negative organisms comparable to those of imipenem and meropenem with the ex-
ceptionofdecreasedantipseudomonalactivity. Mostimportantly, theydemonstrate
potent oral activity against gram-positive and gram-negative bacterial infections
in mice.
Orally active 2-tetrahydrofuranylthio-1β-methylcarbapenems 1 were origi-
nally prepared via intermediate 2 (M2-Process) and intermediate 3 (F2-Process)
∗Corresponding author.
587
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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BITHA AND LIN
OH
OH
OTBS
O
Br
M2-Process
2 Steps
F2-Process
4 Steps
OP(OPh)2
SR
4
4
N
N
N
5 Steps
5 Steps
O
COOPNB
O
O
O
COOPNB
2: M2-Phosphate
COONa
TBS
3: F2-Intermediate
1
Wittig Process
OTBS
5 Steps
NHR′
OH
O
SR = S
O
NH
O
4: AZ-Acid
Scheme 1.
(Scheme 1) (3–6). As the preparation of both p-nitrobenzyl (1R, 5R, 6S)-6-[(1R)-
1-hydroxyethy]-2-[(diphenylphosphono)oxyl]-1-methylcarbapen-2-em-3-carbox-
ylate (M2-phosphate) (2) (7,8) and the intermediate 3 (9,10) alone required five
steps from a commercially available (3S,4S)-3-[(R)-1-(tertbutyldimethylsilyloxy)-
ethyl]-4-[(R)-1-carboxyethyl]-2-azetidinone (4), the entire process for the prepara-
tion of the 2-tetrahydrofuranylthio-1β-methylcarbapenems 1 from 4 thus
involved seven steps in 18% overall yield and nine steps in 13% overall yield,
respectively. Therefore, a more efficient synthesis of the 2-tetrahydrofuranylthio-
1β-methylcarbapenems 1 was needed. Since 1978, three general syntheses of car-
bapenems have been developed (9–15). Of these three syntheses, the Wittig process
(16–20) has been increasingly utilized for the preparation of carbapenems; partic-
ularly, via the intramolecular cyclization of thioester-trialkoxyphosphorane 7. The
thioester-trialkoxyphosphorane 7 was prepared in situ form thioester-oxal-imide
6, which was synthesized in two steps from 4 (Scheme 2). The disadvantage of
OTBS
OTBS
OTBS
SR
SR
SR
4
O
O
O
NH
O
N
N
P(OR′′)3
O
O
O
CO2R′
CO2R′
7
5
6
OTBS
NHR′
SR
CO2R′
1
N
O
O
SR = S
8
Scheme 2.

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ORAL THF 1β-METHYLCARBAPENEM
589
the Wittig process via the thioester-trialkoxyphosphorane 7 was that the yields
were often low because of the high reaction temperature (110◦–140◦C) and long
reaction time necessary for the formation of the thioester-trialkoxyphosphorane 7.
This problem may be mitigated by using more reactive dialkyl alkylphosphonites
at a lower reaction temperature (21,22). Alternatively, since the conversion of 6
to 8 involves two steps (a second order reaction of 6 with trialkyl phosphite for
the first step and an unimolecular cyclization reaction of 7 for the second step),
the first step can be carried out without solvent at 50◦C, and the second step can
be carried out at a high dilution and at a high reaction temperature. Indeed, by
doing the conversion in two steps under two different conditions according to the
nature of the reactions, we are able to convert 6 to 8 reproducibly in excellent
yield. Here, we report a new and efficient five step synthesis of the orally active 2-
tetrahydrofuranylthio-1β-methylcarbapenem (OCA-983) via the Wittig process.
CHEMISTRY
Reaction of tetrahydrofuranyl thiol 9 with p-nitro-carbobenzyloxy-L-valine-
N-hydroxysuccinimide ester (PNZ-L-valine O-Su ester) 10 (4) in the presence
of diisopropylethylamine in dichloromethane gave tetrahydrofuranyl thiol 11 in
excellent yield (Scheme 3). As depicted in Scheme 4, reaction of AZ-acid 4 with
the tetrahydrofuranyl thiol 11 in the presence of 1,3-dicyclohexylcarbodiimide and
4-dimethylaminopyridine in dichloromethane gave thioester 12 (89% yield), which
reacted with chlorooxalic acid p-nitrobenzyl ester in the presence of triethylamine
in tetrahydrofuran to give thioester-oxalimide 13 (82% yield). Reaction of 13 with
2.1 equivalents of triethyl phosphite without solvent at 50◦C followed by dilution
with p-xyleneandheatingat138◦CgavetheTBS-protected1β-methylcarbapenem
14 reproducibly in 72% yield. The deprotection of the t-butyldimethylsilyl (TBS)
group in 14 was carried out in the presence of ammonium hydrogen difluroride
in a mixture of dry DMF and N-methyl-2-pyrrolidinone (23) to give 15. This
was hydrogenated over 10% palladium on carbon in a mixture of p-dioxane and
sodium phosphate buffer (pH = 6.5) in a Parr Hydrogenator to give the desired
2-tetrahydrofuranylthio-1β-methylcarbapenem 16 in 70% yield. Thus, the desired
orally active 2-tetrahydrofuranylthio-1β-methylcarbapenem 16 (OCA-983) was
obtained from the commercially available AZ-acid 4 in 30% overall yield.
.
NH2 HCl
NH-L-Val-PNZ
O
O
OSu
+ PNZ-HN
O
HS
HS
9
10
11
Scheme 3. CH2Cl2/(iPr)2EtN/rt/93%; PNZ = CO2PNB

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590
BITHA AND LIN
NH-L-Val-PNZ
NH-L-Val-PNZ
OTBS
OTBS
O
OTBS
OH
S
S
a
b
c
O
O
O
NH
O
NH
O
N
O
O
O
CO2PNB
4
12
13
NH-L-Val-PNZ
NH-L-Val-PNZ
O
NH-L-Val
OTBS
O
OH
O
OH
e
O
d
O
S
S
S
N
N
N
O
CO2PNB
14
CO2PNB
CO2H
15
16
Scheme 4. (a) 11/DCC/DMAP/CH2Cl2/rt/89%; (b) ClCOCO2CH2C6H4NO2-p/TEA/THF,
82%; (c) (1) P(OEt)3, 50◦C, 100%; (2) p-xylene, 138◦C, 72%; (d) NH4F.HF/DMF/NMP,
81%; (e) Pd/C/p-dioxane/ph 6.5 buffer, 70%.
In summary, modification in the intramolecular reductive cyclization of the
thioester-oxalimide 13 with triethylphosphite resulted in an efficient synthesis of 2-
tetrahydrofuranylthio-1β-methylcarbapenem 14, which was efficiently converted
to orally active 2-tetrahydrofuranylthio-1β-methylcarbapenem 16, OCA-983
(1–4).
EXPERIMENTAL
NMR spectra were determined with a NT-300 WB (1H at 300 MHz, 13C
at 75 MHz) and a GE-500 (1H at 500 MHz 13C at 125 MHz) spectrometers, and
chemical shifts (δ) are expressed in part per million relative to internal tetramethyl-
silane. IR spectra were measured on a Nicolet 20-SXB FT-IR spectrometer. Mass
spectra were recorded on a VG ZAB-SE spectrometer (for fast atom bombard-
ment spectra-FAB). The FAB matrix was dithiothreitol/dithioerythritol (5/1 w/w).
Chromatographic separations were done using either thin layer plates (Analtech
silica gel GF), flash column-silica gel or reversed phase thin layer or preparative
plates (Analtech RPS-F).
2,5-Anhydro-1-[[[(4-nitrophenyl)methoxyl]carbony]-
L-valyl]amino-1,4-dideoxy-3-thio-D-threo-pentitol (11)
In a 300-mL, 3-necked, flame-dried flask kept in an ice bath under ar-
gon, the solution of 2,5-anhydro-1-amino-1,4-dideoxy-3-thio-D-threo-pentitol hy-
drochloride (9) (24) (4 g; 23.57 mmol) and diisopropylethylamine (5.3 mL; 30.7
mmol; 1.3 equivalents) in dichloromethane (100 mL) was prepared. The solution
of (S)-[1-[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl-2-methylpropyl]carbamic acid
(4-nitrophenyl)methyl ester (10) (9.3 g; 23.57 mmol) in dichloromethane (70 mL)

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591
was added slowly via addition funnel. The ice bath was removed and the solu-
tion stirred at room temperature for 6 h. A bright yellow spot (Rf = ∼0.5; SH
stain) appeared on a silica gel thin layer chromatography plate eluted with ethyl
acetate. The spot was also UV-positive. The solution was evaporated to dryness.
The residue was crystallized from ethyl acetate to give 9.05 g (93.3%) of 11.
1H NMR (CDCl3) δ 0.9–1.0 (m, 6H); 3.8–4.0 (m, 3H); 3.7–3.8 (m, 2H); 3.4–3.5
(m, 1H); 3.3–3.4 (m, 1H); 2.4–2.5 (m, 1H); 2.1–2.2 (m, 1H); 1.9–2.0 (m, 1H); 1.6
(d, 1H, SH, J = 8.1 Hz); 0.97 (d, 3H, Me, J = 6.8 Hz); 0.93 (d, 3H, Me J = 6.8
Hz); Electrospray-MS m/z 412.1 (M + H)+.
S-[(2R,3R)-Tetrahydro-2-[[[(S)-3-methyl-2-[[[(4-nitrophenyl)-
methoxy] carbonyl]amino]-1-oxobutyl]amino]methyl]-3-furanyl]
(.alpha., 2S, 3S)-3-[(R)-1-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-
ethyl]-.alpha.-methyl-4-oxo-2-azetidineethanethiolate (12)
(3S,4S)-3-[(R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-[(R)-1-carboxye-
thyl]-2-azetidinone (4) (18.08 g, 60 mmol) and 1,3-dicyclohexylcarbodiimide
(DCC, 13.62 g, 66 mmol) were slurried in anhydrous methylene chloride (500
mL). To this mixture was added dimethylaminopyridine (DMAP, 0.6 g, 4.9 mmol),
followed by the addition of a solution of the thiol 11 (20.58 g, 50 mmol) in anhy-
drous methylene chloride (100 ml). The resulting suspension was stirred at room
temperature for 5.5 h under nitrogen. Solids were removed by filtration, and the
filtrate was washed with 5% aqueous acetic acid, sodium bicarbonate, and then
dried over magnesium sulfate. The organic phase was evaporated to dryness to
give, after flash column chromatography (70% ethyl acetate/hexanes), 34.7 g of
12. 1H NMR (CDCl3) δ : 8.22 (2H, d; J = 8.76 Hz), 7.53 (2H, d; J = 8.51 Hz),
6.49 (1H, s), 6.23 (1H, t), 5.73 (1H, d; J = 8.6 Hz), 5.22 (2H, s), 3.76–4.18 (7H,
m), 3.43 (2H, m), 3.29–3.07 (2H, m), 2.4 (1H, m), 2.15 (1H, m), 1.95 (1H, m), 1.22
(3H, d; J = 4.26), 1.24 ((3H, d; J = 6.93), 1.18 (3H, d; J = 6.27), 0.97 (3H, d; J
= 6.8 Hz), 0.94 (3H, d; J = 6.9 Hz), 0.87 (9H, s), 0.1 (6H, s); Electrospray-MS
m/z 695.2 (M + H)+.
(p-Nitrophenyl)methyl (2S, 3S)-3-[(R)-[[(1,1-dimethylethyl)-
dimethylsilyl]oxy]ethyl]-2-[(R)-1-methyl-2-oxo-2[[(2R,
3R)-tetrahydro-2-[[[(S)-3-methyl-2-[[(4-
nitrophenyl)methoxy]carbonyl]amino]-
1-oxobutyl]amino]methyl]-3-furanyl]thio]
ethyl]-.alpha., 4-dioxo-1-azetidineacetate (13)
The thioester 12 (34.7 g, 50 mmol) and triethylamine (14.1 mL, 100 mmol)
were dissolved in anhydrous tetrahydrofuran (265 mL), under nitrogen. To this

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BITHA AND LIN
solution was added a solution of chlorooxoacetic acid (4-nitrophenyl)methyl ester
(88.3 mmol) in tetrahydrofuran (235 mL). The resulting suspension was stirred at
room temperature overnight. The solids were then filtered and the filtrate evapo-
rated to dryness. The resulting thick oil was dissolved in ethyl acetate and washed
twice with 100-mL portions of water. The organic phase was removed, dried
over magnesium sulfate, and evaporated to dryness to give, after flash column
chromatography (30–50% ethyl acetate/hexanes), 33.11 g (82%) of 13. 1H NMR
(CDCl3) δ : 8.21 (2H, d, J = 8.67), 8.2 (2H, d, J = 8.41 Hz), 7.57 (2H, d, J = 8.52
Hz), 7.5 (2H, d, J = 8.61), 6.36 (1H, t), 5.57 (1H, d; J = 9 Hz), 5.36–5.49 (2H,
m), 5.2(2H, s), 4.43 (1H, t), 4.28 (1H, m), 4.09 (3H, m), 3.7–3.9 (2H, m), 3.5–3.6
(3H, m), 3.1–3.2 (1H, m), 2.4–2.5 (1H, m), 2.32 (1H, m), 1.9–2.1 (1H, m), 1.27
(3H, d; J = 7.2 Hz), 1.17 (3H, d; J = 6.3 Hz), 0.94 (3H, d; J = 6.9 Hz), 0.90 (3H,
d; J = 6.9 Hz), 0.77 (9H, s), 0.1 (6H, d); Electrospray-MS m/z 902.45 (M + H)+.
(1R, 5S, 6S)-6-[(R)-1-(tert-Butyldimethylsilanyloxyl)ethyl]-2-[[(2R,
3R)-2-[[[(S)-2- (4-nitrobenzyloxycarbonyl)amino-
3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-
1-methylcarbapen-2-em-3-carboxylic Acid 4-Nitrobenzyl Ester (14)
The oxalimide 13 (874 mg, 0.9689 mmol) was dissolved in triethyl phosphite
(0.35 mL, 2.035 mmol), and the resulting thick solution was heated without sovlent
at 50◦C for 4 h. Thirty-seven milliliters of p-xylene were then added, and the light
yellow solution was heated at 138◦C for 12 h under nitrogen. The solution was
evaporated to dryness to give, after flash column chromatography (70% ethyl
acetate/hexanes), 607 mg (72%) of 14. 1H NMR (CDCl3) δ : 8.22 (4H, d; J = 8.1
Hz), 7.65 (2H, d; J = 8.79), 7.5 (2H, d; J = 8.67), 6.25 (1H, m) 5.50 (1H, d;
J = 7.82), 5.46 (1H, d; J = 13.9 Hz), 5.24 (1H, d; J = 13.9 Hz), 5.19 (2H, s),
3.75–4.3 (9H, m), 3.2–3.4 (3H, m), 2.3–2.4 (1H, m), 2.0–2.15 (1H, m), 1.2–1.3
(6H, m), 0.91–0.98 (6H, m), 0.86 (9H, s), 0.1 (6H, d); Electrospray-MS m/z 870.3
(M + H)+.
(1R, 5S, 6S)-6-[(R)-1-Hydroxyethyl]-2-[[(2R, 3R)-2-[[[(S)-2-
(4-nitrobenzyloxycarbonyl) amino-3-methyl-1-oxobutyl]-
amino]methyl]tetrahydro-3-furanyl]thio]-1-methylcarbapen-
2-em-3-carboxylic Acid 4-Nitrobenzyl Ester (15)
A suspension of 14 (3.13 g, 3.6 mmol) and ammonium hydrogen difluo-
ride (0.821 g, 14.4 mmol) in a mixture of dry DMF (13.8 mL) and N-methyl-2-
pyrrolidinone(5.1mL)waspreparedundernitrogenandstirredatroomtemperature
for 48 h. The reaction mixture was diluted with ethyl acetate (25 mL) and water

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593
(25 mL), stirred for 30 min, and the two phases separated. The organic phase was
washed with water and evaporated to dryness to give, after flash column chro-
matography (ethyl acetate) 2.24 g (82.4%) of 15. 1H NMR (CDCl3) δ 8.2 (m, 4H);
7.65 (d, 2H, J = 8.8 Hz); 7.5 (d, 2H, J = 8.7 Hz); 6.29 (m, 1H); 5.52 (d, 1H, J =
13.9 Hz); 5.23 (d, 1H, J = 13.9 Hz); 5.19 (s, 2H); 3.8–4.3 (m, 9H); 3.25–3.5 (m,
3H); 2.35–2.5 (m, 2H); 2.0–2.2 (m, 1H); 1.37 (d, 3H J = 6.3 Hz); 1.28 (d, 3H, J =
7.3 Hz); 0.96 (d, 3H, J = 6.8 Hz); 0.92 (d, 3H, J = 6.8 Hz); Electrospray-MS m/z
756.2 (M + H)+. Rotation [α]D25 + 49◦ (c 0.7, CHCl3) after crystallization from
EtOAc. Anal. calcd. for C35H41N5O12S: C, 55.6; H, 5.47; N, 9.27; S, 4.24. Found:
C, 55.3; H, 5.13; N, 9.13; S, 4.20.
(1R, 5S, 6S)-2-[[(2R, 3R)-2[[[(s)-2-Amino-3-methyl-1-oxobutyl]-
amino]methyl]tetrahydro-3-furanyl]thio]-6-[(R)-1-hydroxyethyl]-
1-methylcarbapen-2-em-3-carboxylic Acid (16)
A solution of 15 (5.00 g, 6.6 mmol) in p-dioxane (85 mL) was prepared.
To the solution was added sodium phosphate buffer (pH 6.5; 0.1M; 85 mL) and
10% palladium on charcoal (1.05 g). The mixture was hydrogenated in a Parr
Hydrogenator at 49 lb psi for 5.5 h. The p-dioxane was removed under reduced
pressure and the aqueous mixture was washed with ethyl acetate (2 × 50 mL) and
chromatographed (CHP-20P resin, water-10% acetonitrile/water) to give 2.04 g
(70%) of 16. 1H NMR (D2O) δ 4.1–4.17 (m, 3H); 3.96 (q, 1H); 3.78 (m, 2H); 3.58
(d, 1H, J = 6.0 Hz); 3.2–3.4 (m, 4H); 2.34 (m, 1H); 2.0–2.1 (m, 2H); 1.27 (d, 3H,
J = 6.3 Hz); 1.18 (d, 3H, J = 7.2 Hz); 0.99 (d, 6H, J = 6.9 Hz). HRFAB-MS m/s
Calculated for C20H31N3O6S (M + H)+ 442.2012; Found 442.2022; LRFAB-MS
m/z 442.3 (M + H)+. Rotation [α]D25 +59.9◦ (c 1.0, H2O) after crystallization from
EtOH/H2O. Anal. calcd. for C20H31N3O6S: C, 54.4; H, 7.08; N, 9.52; S, 7.26.
Found: C, 54.1; H, 7.27; N, 9.46; S, 7.20.
ACKNOWLEDGMENTS
The authors thank Drs. S. A. Lang and T. Mansour for their support and
helpful discussion.
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Received in the USA May 10, 2000

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