An Efficient and Scalable Synthesis of tert-Butyl (3aR,6aS)-5-Oxohexahydrocyclo penta[c]pyrrole-2(1H)-carboxylate: A Pharmacologically Important Intermediate

Article abstract of DOI:10.1021/acs.oprd.6b00399

Hexahydrocyclopentapyrrolone derivatives constitute an important class of bicycles, and it represents an essential pharmacophore for diversified pharmacological activities. A highly efficient process for the synthesis of tert-butyl(3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 1 has been developed. The improved process involves transformation of isoindole 4 to diacid 5, using an inexpensive KMnO₄ mediated oxidative cleavage as a key step. The developed process was cost-effective, high yielding, kilogram scalable, and commercially viable for synthesis of 1.

Full text of DOI:10.1021/acs.oprd.6b00399

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Communication
An Efficient and Scalable Synthesis of tert-butyl
3aR,6aS)-5-oxohexahydrocyclo- penta[c]pyrrole-2(1H)-
(
carboxylate: A Pharmacologically Important Intermediate
Rajesh H Bahekar, Pradip A. Jadav, Amitgiri D. Goswami, Hardik A. Shah, Bhushan N. Dave,
Darshan A. Joshi, Jignesh P. Pethani, Dipam Patel, Sameer Agarwal, and Ranjit C Desai
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00399 • Publication Date (Web): 23 Jan 2017
Downloaded from http://pubs.acs.org on January 23, 2017
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An Efficient and Scalable Synthesis of tert-butyl (3aR,6aS)-5-oxohexahydrocyclo-
penta[c]pyrrole-2(1H)-carboxylate: A Pharmacologically Important Intermediate
#
Rajesh H. Bahekar*, Pradip A. Jadav, Amitgiri D. Goswami, Hardik A. Shah, Bhushan N. Dave,
Darshan A. Joshi, Jignesh P Pethani, Dipam Patel, Sameer Agarwal and Ranjit C. Desai*
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Zydus Research Center, Cadila Healthcare Ltd., SarkhejꢀBavala N.H. 8A, Moraiya,
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Ahmedabad 382 210, India; ZRC communication no: 505
ABSTRACT
Hexahydrocyclopentapyrrolone derivatives constitute an important class of bicycles and it
represents an essential pharmacophore for diversified pharmacological activities. A highly
efficient process for the synthesis of tertꢀbutyl(3aR,6aS)ꢀ5ꢀoxohexahydrocyclopenta[c]pyrroleꢀ
2
(1H)ꢀcarboxylate 1 has been developed. The improved process involves transformation of
isoindole 4 to diacid 5, using an inexpensive KMnO mediated oxidative cleavage as a keyꢀstep.
4
The developed process demonstrated cost effective, high yielding, kilogram scalable and
commercially viable synthesis of 1.
KEYWORDS
Hexahydrocyclopentapyrrolone, synthesis, PausonꢀKhand cyclocarbonylation, tertꢀbutyl
(
3aR,6aS)ꢀ5ꢀoxohexahydrocyclopenta[c]pyrroleꢀ2(1H)ꢀcarboxylate, KMnO , oxidative cleavage.
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INTRODUCTION
Carbocyclic or heterocyclic scaffolds constitute the basic skeleton of numerous bioactive
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compounds and pharmaceutical products. Hexahydrocyclopentapyrrolone (Figure 1) derivatives
represent an essential pharmacophore for diversified pharmacological activities such as
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antibacterial agents, autotaxin inhibitors, α4β2 inhibitors, CCR5 antagonist, DPPꢀIV
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inhibitors, FAAH inhibitors, Glutamate receptor modulators, HSP90 inhibitors, JAK
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inhibitor, cꢀMET protein kinase inhibitors, Retinol binding proteinꢀ4 antagonist and Typeꢀ1
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glycine transporter (GlyT1) inhibitors.
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N R
Figure 1. Hexahydrocyclopentapyrrolone
An interesting structure of hexahydrocyclopentapyrrolone derivatives as well as their
pharmacological potential generated tremendous interest in these compounds. Thus, various
routes for the synthesis of hexahydrocyclopentapyrrolone derivatives have been documented in
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literature.
Reported procedures include the synthesis of hexahydrocyclopentapyrrolone
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3ꢀ16
derivatives mainly from tetrahydroisoindoledione
or, a reductive PausonꢀKhand
cyclocarbonylation
cyclocarbonylation.
of
tertꢀbutyl
allyl(2ꢀpropynyl)carbamate
or
an
asymmetric
1
7ꢀ21
14
A
patent from Vertex Phamaceuticals
reported synthesis of tertꢀbutyl 5ꢀ
oxohexahydrocyclopenta[c]pyrrole ꢀ2(1H)ꢀcarboxylate 1, with overall 35% yield (Route 1,
Scheme 1). The process involved expensive ruthenium (IV) oxide (RuO ) as an oxidizing agent
2
for the transformation of isoindole 4 to diacid 5, which makes the process commercially nonꢀ
viable. The synthesis of NꢀCbz protected compound 1 is reported using potassium permanganate
(
KMnO ) mediated oxidative cleavage of NꢀCbz protected compound 4 to corresponding diacid
4
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5, with 39% overall yield. Alternatively, cocyclization of alkynes with alkenes and carbon
monoxide by dicobalt octacarbonyl, under PausonꢀKhand reaction conditions led to the
17ꢀ21
formation of compound 1 (Route 2 and 3, Scheme 1).
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Scheme 1. Reported Synthesis of tertꢀbutyl 5ꢀoxohexahydrocyclopenta[c]pyrrole ꢀ2(1H)ꢀ
carboxylate (1)
Route-1:
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Route-2a-b:
Route-3a-c:
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Based on this concept, Jeong et al., reported an improved process for the synthesis of tosyl
protected compound 1 (2ꢀtosylhexahydrocyclopenta[c]pyrrolꢀ5(1H)ꢀone 1a), via intramolecular
PausonꢀKhand cyclization of Nꢀ(tosyl)allylpropargylamine 6, accelerated by trimethylamine Nꢀ
1
8
oxide (TMANO), under inert atmosphere (Route 2a, Scheme 1). Same group also reported
synthesis of 1a, using cobaltꢀpropagyl alcohol complex 7 and allyl tosylamide, via Nicholas
reaction, in presence of boron trifluoride diethyl etherate (BF Et O), followed by PausonꢀKhand
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cyclization
(Route
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Scheme
1).
Under
both
the
conditions,
2ꢀ
tosylhexahydrocyclopenta[c]pyrrolꢀ5(1H)ꢀone 9 was obtained as major product, while the
desired compound 1a (16% overall yield) as a minor product (Route 2aꢀb, Scheme 1).
2
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Becker et al. reported a synthesis of compound 1, with 57% yield, without contamination by the
corresponding unsaturated enone 9, via intramolecular reductive PausonꢀKhand reaction of the
hexacarbonyldicobalt complex of Nꢀ(tertꢀbutyloxycarbonyl)allylpropargylamine 8, under dryꢀ
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state adsorption conditions (Route 3a, Scheme 1). Guillemont et al. reported an efficient
synthesis of compound 1 (overall 71% yield), via intramolecular reductive PausonꢀKhand
reaction of the compound 8 with 1,1,3,3ꢀtetramethylꢀ2ꢀthiourea, under pressure of carbon
monoxide (3 bar), in an autoclave, followed by hydrogenation (Route 3b, Scheme 1). Chung et
2
1
al. reported one pot Cobalt Nanoparticles on Charcoal (CNC) catalyzed carbonylative
cycloaddition of alkyne and carbon monoxide, followed by hydrogenation and the reductive
PausonꢀKhand reaction to get compound 1(Route 3c, Scheme 1). However, PausonꢀKhand
reaction requires high temperature and long reaction time due to slow decarbonylation and
expensive reagents.
The use of oxometal reagents may lead to an excess of residual heavy metal in the final product.
Second, these methods involve high manufacturing costs, due to the application of expensive raw
materials and reagents. Moreover, these processes often involve cumbersome reaction work up
and chromatography. Herein, we report an efficient, scalable and commercially viable process
for the plant scale manufacturing of tertꢀbutyl (3aR,6aS)ꢀ 5ꢀoxohexahydrocyclopenta[c]pyrrole ꢀ
2(1H)ꢀcarboxylate 1, starting from readily available inexpensive reagents, with an excellent
overall yield.
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RESULTS AND DISCUSSION
As depicted in Scheme 2, synthesis of compound 1 was carried out starting from a commercially
available (3aR,7aS)ꢀ3a,4,7,7aꢀtetrahydroꢀ1Hꢀisoindoleꢀ1,3(2H)ꢀdione 2. Lithium aluminum
2
2
hydride facilitated reduction of compound 2 afforded corresponding amine (3) almost in
quantitative yield, which without further purification was immediately transformed to its Boc
protected derivative (4) in high yields (95% yield over 2 steps). Importantly, this twoꢀstep
reaction sequence was carried out in common solvent (THF). Workup protocol was optimized
and instead of column chromatography, treatment of crude reaction mixture with glycine and
sodium carbonate (to remove excess of Boc anhydride, as BocꢀGlyꢀOH), followed by extraction
with a nonpolar solvent (hexane), afforded compound 4, with improved yield (95%) and high
purity (94% by GC).
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Scheme 2. Improved synthesis of compound 1
With the readily available compound 4, we further investigated the oxidative cleavage to diacid 5
using various oxometal reagents (Table 1). Ruthenium (IV) oxide is known for the conversion of
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compound 4 to 5. However, this reaction condition not only required expensive ruthenium
catalyst, but also needs chromatographic purifications, due to presence of traces of ruthenium,
periodate and iodate, in the crude reaction mixture. Hydrogen peroxide (H O ) sodium
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2 ,
hypochlorite (NaOCl), and osmium tetroxide (OsO ), although frequently used for such
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oxidative cleavage reaction, did not lead to significant amount of product (Table 1, entries 2ꢀ4).
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Next, use of KMnO was investigated. In literature, synthesis of adipic acid is reported by direct
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oxidation of cyclohexene, using KMnO . A recent patent from Mnemosyne Pharmaceuticals
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described the conversion of NꢀCbz derivative of compound 4 to its corresponding diacid 5 using
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KMnO , albeit with lower yield and purity. Our succeeding investigations found that KMnO4
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was the most effective agent for the transformation of compound 4 to 5. Treatment of compound
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with KMnO (3 equivalent) and tetrabutyl ammonium bromide (TBAB, 0.15 equivalent), in nꢀ
4
pentane, at 0 °C afforded crude compound 5. The work up protocol was altered and the
purification of crude product via solvent treatment (Hexane/EtOAc, 2:1) delivered the best yield
(85%), with excellent 94% purity (entry 5). The heavy metal content analysis results of
compound 5 confirmed absence of manganese traces. Further, replacing the solvent from nꢀ
pentane to nꢀhexane or nꢀheptane resulted in similar yields (refer Supporting Information, Table
S1). However, a lower yield was found at room temperature (entry 6, Table S1).
To ensure a safe implementation of the reaction conditions, a safety evaluation of the process
was carried out by performing a reaction calorimetry (RC). The reaction calorimetry data
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established low severity (9 C rise in adiabatic temperature during nꢀpentane addition to
ο
compound 4 and 6 C rise during KMnO mediated oxidative cleavage of compound 4 to 5).
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Since, nꢀpentane, a classꢀ2 solvent is usually a less preferred solvent for the large scale
manufacturing (highly flammable, explosive and causes dizziness, headache and skin irritation),
we recommend appropriate safety measures, such as closed delivery system, proper air
ventilation (including breathing protection), explosionꢀproof electrical equipments and protective
gloves should be used while handling nꢀpentane on a large scale.
Subsequently, treatment of 2,2'ꢀ(1ꢀ(tertꢀbutoxycarbonyl)pyrrolidineꢀ3,4ꢀdiyl)diacetic acid (5)
with acetic anhydride and sodium acetate under DieckmannꢀCondensation reaction conditions
afforded compound 1 with an improved yield (67%). Notably, compound 1 was purified by
reprecipitation from cyclohexane, thereby, eliminating column chromatographic purification.
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Table 1. Optimization of oxidative cleavage reaction
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d
entry oxidizing agents
yield of 5
80%
purity of 5
a or c
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RuO & NaIO4
65%
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b
OsO4
12%
93%
92%
90%
94%
65%
a
H O & Na WO ·2H O
19%
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NaOCl & TMCAC
23%
c
KMnO (3 eq.), TBAB, 0 °C
85%
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KMnO (3 eq.), TBAB, rt
62%
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a) % yield after column chromatography; b) crude yield; c) % yield after solvent treatment;
d) Purity by HPLC.
Compared with the reported synthesis, the overall yield was improved from 35% to 54%, mainly
due to improvement in yield from 80% to 95% for intermediate 4, 80% to 85% for intermediate 5
and 55% to 67% in the final step. All the steps were run on kilogram scale and no
chromatography was needed. From a process stand point, column chromatographic purification
of advanced intermediates may not be considered as an efficient strategy due to the loss of a
significant component of the API, which can contribute to higher costs. Thus, improved process
using commercially available isoindole 2 to 1 was significantly optimized with high yields and
easy workup.
Additionally, we mapped our improved process for the total solvent consumption, considering as
a parameter for green chemistry. Data analysis of the solvent consumption comparison for one
kilogram synthesis of compound 1, adopting Scheme 1(Route 1) or Scheme 2 (Figure 2) revealed
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7% reduction (4.4 fold, from 1518 L to 347 L) in the total solvent consumption with our
improved process. In addition, this improved process also resulted in significant reduction in raw
material cost (RMC). For example, as per the literature process (Scheme 1, Route 1), RMC of 1
would be approximately $3950/kg, whereas with the newly developed process, the RMC comes
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material costing).
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Solvent consumption (per kg of compound1)
Figure 2: Solvent consumption comparison for per kg synthesis of compound 1, adopting
Scheme 1 (Route 1) and Scheme 2.
We also explored an alternative novel route for the gram scale synthesis of compound 1, starting
from readily available benzyl amine (Scheme 3). Benzyl protected pyrrolidine diester 12 was
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5
obtained via 2ꢀsteps reported procedure, starting from benzyl amine. Debenzylation of 12 under
hydrogenation conditions followed by protection with Boc group afforded compound 13 in 89%
yield, on gram scale. Hydrolysis of 13 with sodium hydroxide, followed by cyclization using
acetic anhydride afforded compound 1 in 5ꢀsteps, with 42% overall yield.
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Scheme 3. Novel route for the synthesis of compound 1
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CONCLUSION
In conclusion, we have developed an efficient synthesis of tertꢀbutyl 5ꢀ
oxohexahydrocyclopenta[c]pyrroleꢀ2(1H)ꢀcarboxylate 1,
a
pharmacologically important
intermediate. The process involves an inexpensive KMnO mediated oxidative cleavage of
4
isoindole 4 to diacid 5, as a keyꢀstep. This approach afforded compound 1 in 4ꢀsteps with 54%
overall yield, in kilogram scale. Major highlights of our improved process include (i) simplified
reaction workup; (ii) no usage of chromatography; (iii) optimal solvent consumption; (iv) an
economical synthetic sequence; and (v) higher overall yield. Taken together, this developed
process demonstrated cost effective, high yielding, and commercially viable synthesis of 1 and
has the potential for large scale manufacturing. Additionally, an alternative novel route afforded
compound 1, in gram scale, in 5ꢀsteps, with 42% overall yield, starting from benzyl amine.
EXPERIMENTAL SECTION
General Methods
Melting points were recorded on a scientific melting point apparatus and are uncorrected. IR
spectra were recorded as neat (for oils) or on KBr pellet (for solid) on FTꢀIR 8300 Shimadzu and
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ꢀ1
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are reported in wavenumbers ν (cm ). NMR spectra were measured on a Varian Unity 400 ( H at
1
3
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00 MHz, C at 100 MHz), magnetic resonance spectrometer. Spectra were taken in the
indicated solvent at ambient temperature. Chemical shifts (δ) are given in parts per million (ppm)
with tetramethylsilane as an internal standard. Multiplicities are recorded as follows: s = singlet,
d = doublet, t = triplet, q = quartet, br = broad. Coupling constants (J values) are given in Hz.
Mass spectra are recorded on PerkinꢀElmer Sciex API 3000. ESIꢀQꢀTOFꢀMS measurements
were performed with a micrOTOFꢀQ II (Bruker Daltonics) mass spectrometer. HPLC analysis
were carried out at λmax 220 nm using column ODS Cꢀ18, 150 mm x 4.6 mm x 4 ꢂm on
AGILENT 1100 series. Reactions were monitored using thin layer silica gel chromatography
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(
TLC) using 0.25 mm silica gel 60F plates from Merck. Plates were visualized by treatment with
UV, acidic pꢀanisaldehyde stain, KMnO stain with gentle heating. Products were purified by
4
column chromatography using silica gel 100ꢀ200 mesh and the solvent systems indicated.
All reactions involving air or moisture sensitive compounds were performed under nitrogen
atmosphere in flame dried glassware. Tetrahydrofuran (THF) and diethyl ether (Et O) were
2
freshly distilled from sodium/ benzophenone under nitrogen atmosphere. Other solvents used for
reactions were purified according to standard procedures. Starting reagents were purchased from
commercial suppliers and used without further purification unless otherwise specified.
Synthesis of tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1)
2,3,3a,4,7,7a-hexahydro-1H-isoindole (3).
In a 100 L fixed glass assembly, THF (23 L) was charged and cooled externally with dry ice to ꢀ
5
to 0 °C. Lithium aluminum hydride powder (1.0 kg, 26.3 mol) was added portion wise, over a
period of 1.5 hour, while maintaining internal temperature below 5 °C. Tetrahydrophthalimide
(2) (1.53 kg, 10.13 mol) was added portion wise, over a period of 1 hour, maintaining an internal
temperature below 5 °C. Reaction mixture was warmed to room temperature and stirred for 1 h.
The reaction mixture was then heated at 66 ꢀ 67 °C for 16 h. Reaction mixture was cooled to
room temperature and subsequently up to ꢀ10 °C with dry ice. The reaction mixture was
quenched with dropwise addition of ice water (750 mL), while maintaining internal temperature
below 5 °C. Upon completion of water addition, the reaction mixture turned to thick slurry.
Additional THF (6 L) and solid sodium sulfate (~1.5 kg) were added followed by dropwise
addition of KOH solution (15%; 180 g KOH dissolved in 1.2 L of water), over a period of 1 h,
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while maintaining an internal temperature below 5 °C. Additional water (1 L) and solid sodium
sulfate (2 kg) were added and the reaction mixture was slowly warmed to room temperature. At
room temperature it was stirred for another 30 minutes and the solid inorganic material was
filtered off through HyFlo SuperCel bed. Inorganic solid impurity was washed twice with THF
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(
2 x 1.5 L), combined THF layer was dried over sodium sulfate, filtered and concentrated in
vacuo to yield compound 3 as oil (1.589 kg, contains 20% THF), which was used in next the
reaction, without any further purification.
tert-butyl 3a,4,7,7a-tetrahydro-1H-isoindole-2(3H)-carboxylate (4).
5
0 L SS reactor was charged with compound 3 (1.589 kg, 10.12 mol, contains 20% THF),
dissolved in THF (23 L) and cooled up to 0 to ꢀ5 °C. Bocꢀanhydride (2.793 kg, 2.94 L, 12.65
mol) was added drop wise, while maintaining an internal temperature between 0ꢀ5 °C, over a
period of 30 minutes. The reaction mixture was warmed to room temperature and stirred at room
temperature for 16 h. A solution of glycine (0.60 kg, 7.99 mol) and sodium carbonate (1.80 kg,
1
6.98 mol) in water (12 L) was added to the reaction mixture at room temperature and stirred for
additional 20 h. The reaction mixture was concentrated under reduced pressure to remove THF
and dried under vacuum. The nꢀHexane (25 L) and additional water (8 L) were added and stirred
at room temperature for 15 minutes. The reaction mixture was filtered through HyFlo SuperCel
and the layers were separated. Aqueous layer was extracted with nꢀhexane (2 x 20 L) and the
combined organic layer was washed with water (2 x 20 L) and brine (20 L). Hexane layer was
stirred with activated charcoal (~500 g), for 1 hour at room temperature, filtered through HyFlo
SuperCel. Combined hexane was dried over sodium sulfate, filtered, concentrated in vacuo to
1
afford compound 4 (2.15 kg, 95%) as a brown oil. % Purity: 93.72% (GC); H NMR (CDCl ,
3
4
00 MHz) δ : 1.47 (s, 9H), 1.89ꢀ194 (m, 2H), 2.20ꢀ2.33 (m, 4H), 3.08 (dd, J = 6.2 Hz, J = 10.2
1 2
1
3
Hz, 1H), 3.17 (dd, J = 4.8 Hz, J = 10.4 Hz, 1H), 3.37ꢀ3.43 (m, 2H), 5.65 (s, 2H).; C NMR
1
2
(CDCl , 100 MHz)
δ
: 24.63, 24.68, 28.49, 33.35, 34.23, 50.86, 50.92, 78.88, 124.19, 124.50,
3
ꢀ1
1
55.22; IR (CHCl3):
ν
= 756, 1128, 1170, 1217, 1411, 1685, 2937, 2978, 3009 cm ; TOFMS:
+
+
[
C H NO + H ]: calculated 224.1645, found 168.0958 (MꢀtBu + H) (100%), 246.1382 (M +
1
3
21
2
+
Na) (5%).
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,2’-(1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid (5).
A 200 L glass liner reactor (equipped with a condenser and a thermometer pocket) was charged
with a solution of compound 4 (2.0 kg, 8.969 mol), dissolved in nꢀpentane (10.0 L) and cooled
externally to 0 °C. Freshly prepared solution of potassium permanganate (4.248 kg, 26.906 mol)
and tetrabutylammonium bromide (0.431 kg, 1.781 mol) dissolved in water (80 L) was added to
reaction mixture at 0ꢀ5 °C, in 2.5 h. Reaction mixture was further stirred at 0ꢀ5 °C for 1 h.
The reaction mixture was filtered through HyFlo SuperCel, residual solid was slurry washed
with water (2 x 8 L). The combined filtrate was washed with ethyl acetate (12 L) and the organic
layer was separated. The aqueous layer was acidified with 1N HCl solution (pH ~ 3) and
extracted with ethyl acetate (3 x 40 L). The combined ethyl acetate layer was washed with brine
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(28 L), treated with activated charcoal (900 g) and filtered through HyFlo SuperCel. The organic
solvent was distilled under vacuum to afford title compound (2.55 kg) as off white solid, which
was purified by solvent treatment. Ethyl acetate (3.825 L) was added and the solid was stirred for
3
0 minutes, at room temperature, slowly nꢀhexane (7.65 L) was added and stirred for 90 minutes.
Solid product was filtered in vacuo and washed with 30% ethyl acetate in nꢀhexane (1 x 2.5 L).
Product was dried for 2 h to yield compound 5 (2.187 kg, 85%) as a white solid. MP: 162ꢀ163
o
1
C, % purity: 94.09% (HPLC); H NMR (DMSOꢀd , 400 MHz)
δ : 1.38 (s, 9H), 2.10ꢀ2.18 (m,
6
2
H), 2.28ꢀ2.32 (m, 2H), 2.49ꢀ2.50 (m, 2H, merged with DMSO peak), 2.97ꢀ3.03 (m, 2H), 3.33ꢀ
1
3
.40 (m, 2H). 12.23 (bs, 2H); H NMR (CD OD, 400 MHz)
δ : 1.46 (s, 9H), 2.26 (ddd, J = 2.8
1
3
Hz, J = 9.2 Hz, J = 16.0 Hz, 2H), 2.43 (dd, J = 5.2 Hz, J = 16.0 Hz, 2H), 2.69 (m, 2H), 3.16
2
3
1
2
1
3
(dd, J = 5.2 Hz, J = 10.8 Hz, 2H), 3.49ꢀ3.54 (m, 2H).; C NMR (DMSOꢀd , 100 MHz) δ :
1
2
6
28.49, 32.97, 36.49, 37.31, 50.10, 50.20, 78.67, 154.05, 173.96; IR (KBr):
ν
= 871, 933, 1143,
ꢀ1
+
1166, 1292, 1411, 1689, 1708, 2881, 2929, 2980, 3001 cm ; TOFMS: [C H NO ꢀ H ]:
13
21
6
calculated 286.1296, found 286.1031(100%).
tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1).
A 50L glass assembly (equipped with a double surface condenser and a thermometer pocket)
was charged with acetic anhydride (10.42 kg, 9.65 L, 102.09), followed by slow addition of
compound 5 (2.0 kg, 6.968 mol). The reaction mixture was heated at 135 °C for 45 minutes.
Sodium acetate (0.486 kg, 5.924 mol) was added to the reaction mixture portion wise, over a
period of 30 minutes and additionally, the mixture was stirred at 135 °C for 30 minutes. The
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reaction mixture was cooled up to 5ꢀ10 °C, MeOH (10 L) was added dropwise, while
maintaining an internal temperature between 10 ꢀ15 °C, addition of methanol was completed
within 2 h and the reaction mixture was cooled up to ꢀ5 °C. The reaction mixture was poured into
10 L ice water and slowly solid sodium carbonate (~12 kg, pH ~10) was added, followed by
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cyclohexane addition (~50 L). The reaction mixture was stirred for 15 minutes and filtered
through HyFlo SuperCel to remove solid inorganic waste and the organic layer was separated
from the aqueous layer. The aqueous layer was extracted with cyclohexane (2 x 40 L). The
combined organic solvent was dried over sodium sulfate and concentrated in vacuo to afford
crude product (~ 1.44 kg).
The crude product was purified by recrystallization from cyclohexane. The crude product was
dissolved in cyclohexane (6 L) at 60 °C. Allowed it to cool gradually to room temperature and
then cooled up to 5ꢀ10 °C in an ice bath, for 1 hour. The off white colored solid product was
filtered and dried in vacuo to afford pure compound 1 (1.051 kg, 67%) as a white solid. MP: 70ꢀ
o
25
1
7
4
1
1 C (uncorrected); [α] +0.40° (c 1.00 CHCl ); % purity: 98.5% (HPLC); H NMR (CDCl ,
D 3 3
00 MHz)
δ : 1.46 (s, 9H), 2.15 (dd, J = 4.8 Hz, J = 19.6 Hz, 2H), 2.47 (dd, J = 7.4 Hz, J =
1 2 1 2
1
3
9.6 Hz, 2H), 2.93 (bs, 2H), 3.16ꢀ3.28 (m, 2H), 3.65ꢀ3.67 (m, 2H).; C NMR (CDCl , 100
3
MHz)
δ : 38.49, 39.36, 42.32, 50.51, 50.77, 79.49, 154.39, 217.65; IR (KBr): ν = 638, 771, 877,
ꢀ1
1
118, 1166, 1247, 1367, 1402, 1691, 1741, 2877, 2910, 2958, 2976, 3005 cm ; TOFMS:
+
+
[
C H NO + H ]: calculated 226.1438, found 152.0663 (MꢀOtBu) (100%), 170.0755 (MꢀtBu +
12 19 3
+
+
H) (40%), 248.1166 (M+Na) (5%). Anal. Calcd for C H NO : C, 63.98; H, 8.50; N, 6.22.
12
19
3
Found: C, 63.89; H, 8.27; N, 5.97.
Dimethyl 4,4'-(benzylazanediyl)(2E,2'E)-bis(but-2-enoate) (11).
To a stirred solution of benzyl amine 10 (100 g, 0.933 mol) and DIPEA (386 g, 2.99 mol), in dry
MeOH (2 L), at room temperature under inert atmosphere, in a 5 L 4ꢀneck round bottom flask
(equipped with a condenser and a thermometer pocket) was added (E)ꢀmethyl 4ꢀbromobutꢀ2ꢀ
enoate (418 g, 3.80 mol) in a single portion. Reaction mixture was heated to 45 °C and stirred for
16 h. Reaction mixture was then evaporated under reduced pressure to give crude product.
Crude product was purified by column chromatography over silica gel with 10% EtOAc/nꢀ
hexane as eluent to furnish compound 11, (258 g, 91% yield) as yellow oil. % purity: 93.4%
1
(UPLC); H NMR (CDCl , 400 MHz)
δ : 3.23 (dd, J = 1.6 Hz, J = 6.0 Hz, 4H), 3.62 (s, 2H),
1 2
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2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
5
5
5
5
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7
5
.75 (s, 6H), 6.07 (dt, J = 1.6 Hz, J = 16.0 Hz, 2H), 6.97 (dt, J = 6.0 Hz, J = 16.0 Hz, 2H),
1
2
1
2
1
3
.25ꢀ7.34 (m, 5Hꢀmerged with CDCl proton).; C NMR (CDCl , 100 MHz)
δ : 51.53, 53.42,
3
3
8.37, 122.66, 127.28, 128.41, 128.55, 128.76, 138.24, 145.84, 166.58; IR (CHCl3):
ν
= 758,
ꢀ1
+
1215, 1278, 1437, 1660, 1720, 2806, 2953, 3020, 3421 cm ; TOFMS: [C H NO + H ]:
17
21
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
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calculated 304.1543, found 304.1703(100%).
Dimethyl 2,2'-(1-benzylpyrrolidine-3,4-diyl)diacetate (12).
In a 20 L glass assembly (equipped with a condenser and a thermometer pocket) was charged
compound 11 (250 g, 0.825 mol) and dry MeOH (7.5 L) at room temperature, under inert
atmosphere. To this mixture was added freshly activated magnesium turnings (198 g, 8.25 mol)
and mixture was heated at 70 °C for 6 h. The reaction mixture was cooled up to 5ꢀ10 °C, ice cold
2N HCl (2 L) was added slowly, followed by addition of ethyl acetate (5 L). Reaction was stirred
for 15 minutes, filtered through HyFlo SuperCel, to remove solid inorganic waste and the ethyl
acetate layer was separated from the aqueous layer. The aqueous layer was extracted with ethyl
acetate (2 x 3 L). Combined ethyl acetate layer was dried over sodium sulfate and concentrated
in vacuo to afford compound 12 (212 g, 84%). Product was used for next step without any
1
further purification. % purity: 90.9% (HPLC); H NMR (CDCl , 400 MHz)
δ : 2.25ꢀ2.33 (m,
3
4H), 2.39 (dd, J = 5.6 Hz, J = 15.6 Hz,) 2.74ꢀ2.76 (m, 2H), 2.94 (dd, J = 7.0 Hz, J = 9.4 Hz),
1
2
1
2
1
3
3.62 (s, 2H), 3.66 (s, 6H), 7.23ꢀ7.27 (m, 1H), 7.30ꢀ7.31 (m, 4H).; C NMR (CDCl , 100 MHz)
δ
3
:
34.51, 36.16, 51.63, 59.20, 60.23, 126.88, 128.20, 128.55, 139.01, 173.14; IR (CHCl3):
ν
=
ꢀ1
+
758, 1165, 1217, 1437, 1734, 2796, 2953, 3020, 3448 cm ; TOFMS: [C H NO + H ]:
17
23
4
calculated 306.1700, found 306.1865 (100%).
Dimethyl 2,2'-(1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetate (13).
To a stirred solution of compound 12 (200 g, 0.655 mol) in dry MeOH (2 L), at room
temperature, in a hydrogenation vessel was added 10% wet Pd/C (20 g, 0.183 mol, 10% w/w of
starting material) and Boc anhydride (171 g, 0.7864 mol). Above reaction was subjected for
o
hydrogenation, at 50 psi for 12 h at 25 C. Reaction mixture was filtered through celite and
1
concentrated to get compound 13 (184 g, 89%) as yellow oil. % purity: 90.15% (HPLC); H
NMR (CDCl , 400 MHz)
δ
:1.46 (s, 9H), 2.25ꢀ2.31 (m, 2H), 2.36ꢀ2.43 (m, 2H), 2.72 (m, 2H),
3
3
.08 (dd, J = 5.6 Hz, J = 11.2 Hz, 1H), 3.15 (dd, J = 5.2 Hz, J = 11.2 Hz, 1H), 3.69 (s, 3H),
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.71 (s, 3H).; C NMR (CDCl , 100 MHz)
δ
: 28.42, 32.81, 49.90, 50.14, 51.78, 79.39, 154.49,
3
1
72.30, 172.82; IR (CHCl3):
ν = 756, 1166, 1367, 1413, 1685, 1735, 2877, 2955, 2980, 3009
ꢀ1
+
+
cm ; TOFMS: [C H NO + H ]: calculated 316.1755, found 216.1317(MꢀBoc + H) (100%),
15
25
6
+
338.1767(M + Na) (20%).
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2
,2'-(1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid (5).
To a stirred solution of compound 13 (180 g, 0.571 mol), in MeOH (1.8 L) and water (0.9 L), in
a 5L four neck round bottom flask, at room temperature was added NaOH (91.38 g, 2.284 mol).
o
o
Reaction was stirred for 18 h at 25 C. The reaction mixture was cooled up to 0 to 5 C and
acidified using 10% citric acid solution (pH 6). Further, ethyl acetate was added (4 L), stirred for
15 minutes and organic layer was separated from the water layer. The water layer was extracted
with ethyl acetate (2 x 1 L). Combined ethyl acetate layer was dried over sodium sulfate and
concentrated in vacuo to afford compound 5 (151 g, 92%), as white powder. Characterization
data for 5 have been reported above. Finally, compound 5 (150 g, 0.522 mol) was converted to
compound 1 (79 g, 67%), following the procedure described in Schemeꢀ2.
ASSOCIATED CONTENT
Supporting Information
1
13
GC, HPLC, UPLC, TOFMS, H & C NMR and IR spectra of all new compounds.
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: rajeshbahekar@zyduscadila.com and ranjitdesai@zyduscadila.com
Notes
The authors declare no competing financial interest
ACKNOWLEDGMENTS
Authors thank the management of Zydus Research Centre, Cadila Healthcare Ltd. for support
and encouragement and the analytical department for providing analytical data.
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REFERENCES
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1
1. Cioffi, C. L.; Racz, B.; Freeman, E. E.; Conlon, M. P.; Chen, P.; Stafford, D. G.;
Schwarz, D. M. C.; Zhu, L.; Kitchen, D. B.; Barnes, K. D.; Dobri, N.; Michelotti, E.;
Cywin, C. L.; Martin, W. H.; Pearson, P. G.; Johnson, G.; Petrukhin, K. J. Med. Chem.
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2. Lowe, J. A.; DeNinno, S. L.; Drozda, S. E.; Schmidt, C. J.; Ward, K. M.; Tingley III, F.
D.; Sanner, M.; Tunucci, D.; Valentine, J. Bioorg. Med. Chem. Lett. 2010, 20(3), 907ꢀ
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11.
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An Efficient and Scalable Synthesis of tert-butyl (3aR,6aS)-5-oxohexahydrocyclo-
penta[c]pyrrole-2(1H)-carboxylate: A Pharmacologically Important Intermediate
Rajesh H. Bahekar*, Pradip A. Jadav, Amitgiri D. Goswami, Hardik A. Shah, Bhushan N. Dave,
Darshan A. Joshi, Jignesh P Pethani, Dipam Patel, Sameer Agarwal and Ranjit C. Desai*
Zydus Research Center, Cadila Healthcare Ltd., Sarkhej-Bavala N.H. 8A, Moraiya,
Ahmedabad 382 210, India
GRAPHICAL ABSTRACT
A highly efficient, improved and cost effective process for the synthesis of
hexahydrocyclopentapyrrolone
derivatives,
tert-butyl(3aR,6aS)-5-
oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 1 has been developed. The process
provides commercially viable kilogram scale synthesis of 1.
1
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