Improved Large-scale One-pot Synthesis of Pure Doripenem Hydrate (S-4661)

Full text of DOI:10.1080/00304948.2016.1194130

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Improved Large-scale One-pot Synthesis of Pure
Doripenem Hydrate (S-4661)
K. Rajasekhara Raju, N. M. Mahesh, B. Shankar Reddy & K. Mohana Raju
To cite this article: K. Rajasekhara Raju, N. M. Mahesh, B. Shankar Reddy & K. Mohana
Raju (2016) Improved Large-scale One-pot Synthesis of Pure Doripenem Hydrate
(S-4661), Organic Preparations and Procedures International, 48:4, 342-349, DOI:
10.1080/00304948.2016.1194130
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Date: 20 August 2016, At: 00:23

Organic Preparations and Procedures International, 48:342–349, 2016
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2016.1194130
Improved Large-scale One-pot Synthesis of Pure
Doripenem Hydrate (S-4661)
1
K. Rajasekhara Raju, N. M. Mahesh, B. Shankar Reddy,
and K. Mohana Raju
,2
1
1
2
1
Chemical Research and Development, AurobindoPharma Ltd, Survey No.71
and 72, Indrakaran (V), Sangareddy (M), Medal District 502329, Telangana,
India
2
Synthetic Polymer Laboratory, Department of Polymer Science and
Technology, Sri Krishnadevaraya University, Anantapur 515055, Andhra
Pradesh, India
1
2
3
4
5
Carbapenems such as imipenem, biapenem, meropenem, ertrapenem and panipenem
Figure 1) display broad potent anti-bacterial activity. Introduction of a methyl group at
the 1b-position in the carbapenem skeleton enhances metabolic stability toward renal
(
6
dehydropeptidase-1(DHP-1) and leads to higher anti-bacterial potency.
Doripenemhydrate{(4R,5S,6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-{((3S,5S)-
5
-[(sulfamoylamino)methyl}pyrrolidin-3-yl]thio}-1-azabicyclo[3.2.0]hept-2-ene-2-car-
boxy-lic acid hydrate, S-466, 5] is highly potent compared to meropenem against Gram-
positive bacteria. It is also superior to imipenem against Gram-negative bacteria including
pseudomonas aeruginosa. Doripenem hydrate (5) is marketed in the United States as
DoribaxTM and is prescribed as a single agent used for the treatment of complicated uri-
nary tract infections including pyelonephiritis caused by Escherichia coli. Pseudomonas
aeruginosa is one of the most common Gram-negative organisms associated with nosoco-
mial infections. The maximum daily dose is 1.5 g in three equal portions.
Some problems were encountered in the preparation of 5 in the first generation
7
process (Route 1, Scheme 1) involving the reaction of side-chain protected com-
pound 1a with enolphosphate 3a as shown in Scheme 1. The deprotection of the
side-chain of 1a with strong base led to the formation of less pure 2a and the gener-
ation of high levels of its disulfide; the process also required a chromatographic
purification on Diaion HP-20 and gave a lower yield of 5 at pilot scale-level (49%).
8
Similarly, the preparation of 5 from the reaction of compound 1b with enol phos-
, 10
phate 3b
9
11
via the modified Nishino procedure (Route 2, Scheme 1) gave lower
overall yields (64% from 3b) of less pure products (97% a/a) when compared to the
present process (99.68% a/a). Other major problems include i) the deprotection of
1b with H SO , which led to less pure 5, ii) more numerous isolation steps when
2 4
compared to the present process, iii) use of very large amount of inorganic salts
Received January 8, 2016; in final form May 4, 2016.
Address correspondence to K. Rajasekhara Raju, Chemical Research and Development,
AurobindoPharmaLtd, Survey No.71 and 72, Indrakaran (V), Sangareddy (M), Medal District
502329, Telangana, India. E-mail: krsrajuk@gmail.com
342

One-pot Synthesis of pure Doripenem Hydrate
343
Figure 1
during preparation of 5 and iv) utilization of large volumes of solvent (THF) for the
removal of p-toluidine (by-produt from the reductive deprotection of the ester) and
other organic impurities in doripenem. The present article reports improved proce-
1
2
dures for the Nishino route based on our patent.
The use of valeryl chloride and methanol for the deprotection of 1b yielded
highly pure compound 2b, and subsequently compound 4b did not need to be iso-
lated. The magnesium chloride previously used in the catalytic hydrogenolysis of 4b
evidently crystallized along with 5, and presence of the salts required separation
using column chromatography, a process which is typically not favored on a com-
mercial scale. In our improved procedure, instead of using magnesium chloride, a
buffered solution was utilized thereby avoiding the complications involved in the
previous processes. The use of Pd/C (1.5 w/w based on 3b) in the hydrogenolysis of
compound 4b in the Nishino method resulted in a palladium residual level of
4
30 ppm in 5 as well as 4 ppm in the sterile Active Pharmaceutical Ingredient
1
1
API) 5. In our process, the residual palladium was controlled to be less than
(
1
3–18
0
.75 ppm by pre-reduction of Pd (Pd/C). Some of the other processes
reported
in the literature are not viable industrially or economically due to lower yields (48–
2% from 3b) and lesser purity (95–99%) of 5; in contrast, our improved process
6
gave crude 5 in 71% yield and purity of 99.68% a/a. The present work describes an
improved process to increase the yield and purity necessary to meet regulatory
requirements. This process does not involve chromatographic purification and reverse
osmosis. Tedious work-ups and repeated purifications for the removal of impurities
and residual metal content from 5 have been avoided to minimize cost.

3
44
Raju et al.
PNB = p-nitrobenzyl; PMZ = p-methoxybenzyl
Reagents and conditions for first-generation process (Route 1): (i) NaOMe and MeOH.
(
(
ii) N,N-dimethyl-formamide (DMF) and N-ethyldiisopropyl amine (DIPEA) (iii) AlCl and anisole
iv) Column chromatography.
3
Reagents and conditions for Nishino’s process (Route 2): (i) H SO , MeOH, reflux
2
4
(
ii) DIPEA, DMF, 0-5 °C, EtOAc and toluene (iii) Pd/C, THF, MgCl and demineralised (DM)
2
water (iv) demineralised water, activated carbon and isopropanol.
Scheme 1
Removal of the S-acetyl and N-t-Boc groups of 1b according to the literature pro-
1
cedure led to compound 2b having 90.42% a/a pure (HPLC) along with impurities of 6,
1
7
and 8 (Figure 2) in the amounts of 0.48% a/a, 0.57% a/a and 1.86% a/a respectively.
In the preparation of 5 from 2b using the process depicted in Scheme 2, impurities
derived from doripenem such as tert-butyl doripenem 9 and compound 10 (Figure 2) in
the amounts of 0.14% a/a and 0.61% a/a respectively were observed. Removal of these
impurities in 5 requires multiple purifications, resulting in a substantial decrease in the
yield. Compound 2b obtained in that process contains1.85% a/a of its disulfide 8, that is
carried through to the next step as the corresponding disulfide 11, which required ethyl
acetate extraction of 5 for its removal.
We found that deprotection of 1b with excess of methanolic HCl (2 mole ratio) at
ꢀ
4
8–50 C for 12 h gave an unacceptable level of 7 (Table, Entry 2). Subsequently, the
deprotection of 1b was performed using valeryl chloride in methanol varying the condi-
tions of mole ratios, temperature and reaction times, the results are summarized in
Table 1. Based on these data, the deprotection of the side-chain 1b with 0.5 mole

One-pot Synthesis of pure Doripenem Hydrate
345
Figure 2
ꢀ
equivalent of valeryl chloride at 48–50 C resulted in compound 2b having 97.35% a/a
HPLC purity, 0.05% a/a of 6 and 0.06% a/a of 7 (Table 1, Entry 5). In this process, the
formation of 6 and 7 were greatly reduced thus minimizing the presence of 9 and 10 in
the final doripenem hydrate 5.
In addition, we studied the condensation of 2b with 3b in the presence of a base such
as N,N-diisopropylamine (DIPA) or N-ethyldiisopropylamine (DIPEA)) to provide 4b
ꢀ
and the results are shown in Table 2. The reaction at ¡40 C with 1.4 equivalent of
Reaction conditions:(i)Valeryl chloride, methanol, 48 -50 °C and 18 h;(ii)DIPEA, DMF,-40 to -20°C
and 10h; (iii) Morpholine-acetic acid buffer pH at 7.0-7.3, Pd/C, THF, EtoAc,isopropanol and DM
water, 18-20 °C and 2.5h
Scheme 2

3
46
Raju et al.
Table 1
Preparation of 2b by using acid or acid chloride
b
Compound 2b purity by HPLC (% a/a)
Time Temp.
ꢀ
a
Entry Acid/acid chloride m/r (h)
( C)
2b
6
7
8
1
2
3
4
5
6
Sulfuric acid
3
2
3
9
7
8
60–62
60–62
48–50
60–62
90.42
97.54
95.63
97.36
97.6
0.48
0.09
0.10
0.10
0.05
0.10
0.57
0.41
0.12
0.10
0.06
0.08
1.86
1.24
2.24
1.17
1.57
1.07
Methanolic HCl
Valeryl chloride
Valeryl chloride
Valeryl chloride
Valeryl chloride
1
0.7
0.5 18 48–50
0.5 12 60–62
97.65
(
a) Mole ratio and (b) after work-up 2b purity.
N-ethyl- diisopropylamine results in a product with the highest purity of 95.88% a/a in
1
0h (Table 2, Entry 3). After completion of the reaction and adjustment of the pH to 2.8–
.0 with 1N HCl, 4b was extracted into ethyl acetate and the organic extract was concen-
3
trated to afford crude 4b. Although we initially explored the isolation of 4b by crystalliza-
tion from toluene, this procedure requires large volumes of toluene to remove the
moisture present in the crude 4b by azeotropic distillation. Furthermore, the purity of the
crystallized compound 4b was not improved. To overcome this problem, the crude 4b
was used directly for the synthesis of 5.
Initially, the protected doripenem 4b was hydrogenated according to the reported
1
6
biphasic process, which resulted in unacceptable yield and quality. Hydrogenation of
the protected doripenem in the presence of Pd/C was explored under different conditions
(
(
Table 3). When conducted with or without base, less pure 5 was obtained in lower yield
Table 3, Entries 6 and 7). However, when the reaction was performed in different buffer
solutions such as sodium acetate, 3-morpholinopropanesulfonic acid (MOPS), N-methyl-
morpholine (NMM)-acetic acid or N-methylmorpholine-oxalic acid, fruitful results were
obtained with the use of N-methylmorpholine-acetic acid at pH 7.0–7.3.
The deprotection of compound 4b using Pd/C (1.5 w/w based on 3b) in a mixture of
tetra-hydrofuran and a buffer solution of N-methylmorpholine and acetic acid afforded 5
with a purity and yield of 99.55% a/a and 72% respectively, with Pdresidual levels of
4
lesser yields of less pure product. Pre-reduced Pd/C
30 ppm. Utilization of lesser quantity of Pd/C leads to prolonged reaction time and
1
9,20
(1.5 w/w based on 3b) gave 5 in
excellent purity (99.68% a/a) and good yield (71%) respectively with residual Pd of
Table 2
Preparation of 4b using different organic bases with various conditions
Compound 4b purity by HPLC (a/a %)
Time
Entry Base Mole ratio (h)
Temp
ꢀ
( C)
4b
2b
3b
1
2
3
4
DIPA
1.3
1.3
1.4
2
1
¡40
93.68
92.84
95.88
86.34
0.92
1.88
1.14
1.24
0.06
2.27
1.41
1.65
DIPEA
DIPEA
DIPEA
12 ¡40 to ¡20
10 ¡40 to ¡20
3
¡40

One-pot Synthesis of pure Doripenem Hydrate
347
Table 3
Preparation of 5 in the presence of various buffer solutions
Purity (% a/a) of 5 by HPLC
tert-Butyl
doripenem 9
Compound
10
Yield (%) of
5 based on 3b
Entry
Buffer
5
1
2
3
4
5
6
7
NMM/MOPS
CH COONa
97.32
96.13
0.07
0.09
0.08
0.06
0.08
0.20
0.16
0.05
ND
ND
ND
ND
0.05
0.07
51.16
46.17
52.96
59.75
71.29
50.25
43.46
3
NaOH/MOPS
NMM/Oxalic acid
NMM/Acetic acid
2, 6-Lutidine
—
95.32
98.30
99.57
93.43%
91.22%
38.44 ppm. The isolated 5 with pre-reduced catalyst yields 90% less Pdresidual relatively
compared to the use of unreduced Pd/C.
In conclusion, we have developed a new method for one-step synthesis of 5 in 71%
yield and purity of 99.68% a/a. This present process is significantly free from palladium,
inorganic salts and meets the regulatory norms in terms of quality.
Experimental Section
1
13
H NMR and C NMR spectral data were obtained in dimethylsulfoxide (DMSO-d ) on
6
5
00 MHz and 75 MHz spectrometers respectively. The chemical shift values are reported
on the d scale in parts per million (ppm), downfield from tetramethylsilane (TMS, d D
.0) as an internal standard. IR spectra were recorded in the solid state as KBr dispersions
0
using a Perkin-Elmer spectrum on a Fourier transform (FT)-IR spectrophotometer. The
mass spectrum was recorded using a Perkin-Elmer PE SCIEX-API 2000, equipped with
an ESI source used online with an HPLC system after the ultraviolet (UV) detector.
HPLC chromatographic purity was determined by using the area normalization method.
The HPLC procedure for monitoring the reaction is as follows: Column: Inertsil ODS-
3
4
V, 250 mm £ 4.6 mm, and 5 m, Flow rate: 1 mL/min, Detector: UV, 295 nm, Temp:
ꢀ
0 C, Run time: 40 min, Elution: gradient, Buffer: Diammonium hydrogen orthophos-
phate (2.64 g) was dissolved in 1000 mL of water and pH was adjusted to 7.0 § 0.05 with
a solution of 2% v/v of orthophosphoric acid, Mobile phase A: Buffer and Acetonitrile
(98:2 v/v) and Diluent: Mobile phase A and Mobile phase B (98:2 v/v). Mobile phase B:
Acetonitrile. HPLC method was used to identify the doripenem related substances: Run
time 50 min, Buffer pH 6.0 § 0.05 and remaining parameters same as reaction monitoring
conditions. The thermal analysis was carried out on a DSC Q 1000 TA. The thermogram
ꢀ
was recorded from 30 to 250 C. The solvents and reagents were used without purification.
Preparation of (4R,5S,6S)-6-[(R)-1-Hydroxyethyl)-4-methyl-7-oxo-3-{(3S,5S)-
5
2
-[(sulfamoylamino)methyl)pyrrolidin-3-yl]thio}-1-azabicyclo[3.2.0]hept-2-ene-
-carboxylic Acid Hydrate (Doripenem Hydrate, 5]
A mixture of (2S, 4S)-4-(acetylthio)-2-(((tert-butoxycarbonyl)(sulfamoyl)amino) methyl)
pyrrolidine-1-carboxylic 4-nitrobenzoic anhydride (1b,17.1kg, 32.1mol) and valeryl
ꢀ
chloride (1.7 kg, 14.09 mol) in methanol (75 L) was heated to 50 C and stirred at

3
48
Raju et al.
ꢀ
4
8–50 C for 18 h. After completion of reaction, the reaction mixture was diluted with
dichloromethane (150 L) and water (150 L). The separated organic layer was washed with
demineralised water (150 L), followed by 1% w/v aqueous NaCl solution (150 L). After
washings the organic layer was concentrated to oil which was dissolved in N, N-dimethyl-
formamide (30 L). The solution was added to (4R,5R,6S)-4-nitrobenzyl3-((diphenoxyphos-
phoryl)oxy)-6-((R)-1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-car-
ꢀ
boxylate (3b, 15kg, 25.23 mol) in N,N-dimethylformamide (45 L) at -40 C. Later N-ethyl
diisopropylamine (4.53 kg, 35.05 mol) was added to reaction mass and stirred for 4 h at
ꢀ
ꢀ
¡
40 C. The temperature of reaction was then raised to ¡20 C and stirred for 6 h. The
reaction mixture was diluted with ethylacetate (150 L), water (90 L) and acidified to
pH 2.8 with 1N aqueous hydrochloric acid (12.45 L) at 5 C. The two layers were sepa-
rated, and the aqueous layer extracted with ethyl acetate (90 L). The combined organic
ꢀ
ꢀ
layers washed with 0.25% w/v aqueous NaCl solution (2£ 150 L) at 15 C and concen-
ꢀ
trated to a sticky mass which was dissolved in tetrahydrofuran (195 L) at 20 C. A buffer
solution (pH 7.1), prepared by mixing N-methylmorpoline (2.55 kg, 25.21 mol), acetic
ꢀ
acid (1.095 kg, 18.25 mol) and water (82.5 L) at 20 C, which was added to the above
reaction mass. The solution was added to pre-reduced Pd/C, obtained by stirring 10% w/w
Pd/C (22.5 kg, 50% w/w wet) in DM water (82.5 L) for 1 h under hydrogen atmosphere
ꢀ
ꢀ
(
(
0.3 Mpa) at 20 C. The reaction mixture was stirred for 2.5 h under hydrogen atmosphere
0.8 Mpa) at 20 C. The reaction mass was filtered through a Celite bed and the filtrate was
washed with a mixture of water (15 L) and tetrahydrofuran (15 L). The aqueous filtrate
ꢀ
obtained was extracted with ethyl acetate (210 L) at 20 C. After addition of seed crystals
ꢀ
of doripenem (0.03 Kg) at 18 C and slow addition of of isopropanol (507 L) over a period
ꢀ
of 5 h, the slurry mass was cooled to 0–5 C and stirred for 8 h. The slurried mass was
ꢀ
filtered at 0–5 C to give the wet product which was washed with 20% v/v aqueous isopro-
ꢀ
ꢀ
panol (30 L, 0–5 C) and dried under vacuum at 45–50 C for 8 h to give doripenem hydrate
5
(7.89 kg with 71% yield and 99.68% a/a HPLC purity).
1
Moisture content by KF: 4.38% w/w. H NMR (500 MHz, DMSO ): d 1.23 (d, 3 H,
d6
J D 7.2 Hz), 1.30 (d, 3H, J D 6.5 Hz), 1.77 (ddd, 1H, J D 6.6, 9.2 and 14.9 Hz), 2.75 (dt,
H, J D 14.3 and 8.0 Hz), 3.38 (dq, 1H, 1H, J D 7.2 and 9.3 Hz), 3.44 (dd, 1 H, J D 4.2
and 12.4 Hz), 3.44 (dd, 1H, J D 8.3 and 15.0 Hz), 3.48(dd, 1H, J D 2.5 and 6.1 Hz), 3.55
dd, 1H, J D 4.8 and 15.0 Hz), 3.72 (dd, 1H, J D 7.0 and 12.4 Hz), 3.95 (qd, 1 H, J D 4.8
1
(
and 8.5 Hz), 4.06 (qd, 1H, J D 7.4 and 4.2 Hz), 4.24 (dd, 1H, J D 2.5 and 9.3 Hz), 4.26
1
3
m, 1 H). C NMR (75 MHz, DMSO-d6):16.6, 21.8, 34.6, 39.6, 42.0, 44.4, 52.3, 55.3,
(
C
58.1, 59.2, 64.4, 132.6, 137.4, 164.2, 173.4. ESI-MS: 421.1 [M C H] . FT-IR (KBr
cm ): 3534, 3394, 3261, 2978, 2965, 1714, 1631, 1567, 1539, 1455, 1365, 1321, 1162,
¡
1
ꢀ
ꢀ
and 1144. DSC: 144.30 C (10 C/ min).
Acknowledgements
The authors are grateful to colleagues in the Analytical Research Department of APL
Research center, a division of Aurobindo Pharma Ltd, Hyderabad for their valuable con-
tribution to this work. They also thank the management for giving permission to publish
this work.
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One-pot Synthesis of pure Doripenem Hydrate
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