An cost-effective and safe process of L-cis-4,5-methanoproline amide, the key synthetic intermediate of saxagliptin, via an improved Simmons-Smith reaction

Article abstract of DOI:10.3987/COM-14-13164

L-cis-4,5-Methanoproline amide, a key intermediate of saxagliptin, was synthesized by an improved Simmons-Smith reaction. The zinc carbenoid was formed through Zn/CuBr and CH₂I₂, under the optimized condition, the title compound was gained with 68% yield and excellent diastereomeric selectivity (40:1 d.r.). The absence of the flammable and expensive ZnEt₂ makes this procedure very attractive in large scale production.

Full text of DOI:10.3987/COM-14-13164

HETEROCYCLES, Vol. 91, No. 4, 2015
719
HETEROCYCLES, Vol. 91, No. 4, 2015, pp. 719 - 725. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 26th December, 2014, Accepted, 19th February, 2015, Published online, 3rd March, 2015
DOI: 10.3987/COM-14-13164
AN
L-cis-4,5-METHANOPROLINE AMIDE, THE KEY SYNTHETIC
INTERMEDIATE OF SAXAGLIPTIN, VIA AN IMPROVED
SIMMONS-SMITH REACTION
COST-EFFECTIVE
AND
SAFE
PROCESS
OF
Ding ding,‡ Xianhua Pan,‡ Wansheng Yu, Xiaojun Li, Suke Chen, and Feng
Liu*
School of Perfume and Aroma Technology, Shanghai Institute of Technology, 100
Haiquan Rd., Shanghai, 201418, P.R. China
E-mail: liufeng@sit.edu.cn
‡ These two authors (Ding ding and Xianhua Pan) contributed equally to this work
and should be considered as co-first authors.
Abstract – L-cis-4,5-Methanoproline amide, a key intermediate of saxagliptin,
was synthesized by an improved Simmons-Smith reaction. The zinc carbenoid
was formed through Zn/CuBr and CH2I2, under the optimized condition, the title
compound was gained with 68% yield and excellent diastereomeric selectivity
(40:1 d.r.). The absence of the flammable and expensive ZnEt2 makes this
procedure very attractive in large scale production.
INTRODUCTION
Saxagliptin (Onglyza) 1 (Figure 1), a highly potent, orally available reversible dipeptidyl peptidase IV
(DPP-IV) inhibitor, was jointly developed by Bristol-Myers Squibb Company and AstraZeneca Company,
and recently approved by the US FDA for the treatment of type 2 diabetes mellitus.1,2 Compared with
sitagliptin, the most widely prescribed DPP-IV inhibitor, saxagliptin shows more safety and less side
effects.
Figure 1. Structure and synthetic segments of saxagliptin

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HETEROCYCLES, Vol. 91, No. 4, 2015
Saxagliptin could be assembled by two segments: L-cis-4,5-methanoproline amide 2 and N-Boc-hydroxy-
adamantylglycine 3.3,4 The general protocol of compound 2 in the literatures were synthesized from
L-pyroglutamic acid, which have the core L-proline derivative structure (Scheme 1).4 L-Pyroglutamic
acid was transferred to dihydropyrrole 4 by a 6 steps procedure, then the chiral five-three fused ring was
prepared by a typical Simmons-Smith reaction, with Et2Zn and CH2I2.
Scheme 1. Reported protocol to 2
But the harzard reaction condition, such as the use of flammable and expensive reagent (Et2Zn), and the
very low reaction temperature, made the process cumbersome, uneconomical and difficult to handle on
large scale. Herein, we wish to make some practical and efficient improvement of the Simmons-Smith
reaction, on the base of the literatures’ procedure, to achieve an economical and easily scaled up process
for the synthesis of L-cis-4,5-methanoproline amide 2.
RESULTS AND DISCUSSION
Following a reference procedure with modifications,4 dihydropyrrole 4 was prepared (Scheme 2). Thus,
methyl esterfication and Boc-protection of L-pyroglutamic acid 5 gave 6. Reduction of 6 with LiEt3BH
and treated with acetic anhydride and Na2CO3 formed L-2,3-dehydroproline ester 7. Hydrolysis of 7 with
aq. LiOH in THF and then treated with MsCl and ammonia could transform the ester to carboxamide, to
give dihydropyrrole carboxamide 4.
Reagents and conditions: (a) SOCl2, MeOH; (b) (Boc)2O, DMAP; (c) LiEt3BH, THF, 5-10 °C; (d) Na2CO3, Ac2O; (e) LiOH,
MeOH-H2O; (f) MsCl, NMP, NH3.
Scheme 2. Synthesis of dihydropyrrole carboxamide 4
With the key intermediate 4 in hand, the improved stereoselective Simmons-Smith cyclopropanation was
examined. The original Simmons-Smith reaction was usually carried out with copper-activated zinc (Zn/

HETEROCYCLES, Vol. 91, No. 4, 2015
721
Cu couple) and diiodomethane (CH2I2), then the active intermediate IZnCH2I was formed, which could be
used for the stereospecific conversion of alkenes to cyclopropanes, through a “butterfly-type” transition
structure (Scheme 3).5
Scheme 3. Zn-Cu Couple participated Simmons-Smith reaction
Due to the irreproducible of the in situ prepared Zn/Cu couple, lots of efforts were focus on the alternative
of the zinc reagent, such as Sm/activator,6 R3Al,7 EtZnI,8 Et2Zn9 and Zn/copper halide.10 Among all the
above Zn reagents, Zn/copper halide was most attractive, on account of the low cost, convenience and
safety of the procedure. So, our improvement of the cyclopropanation was based on Zn/CuX, we then
investigated the reaction with respect to the following four key variables: (1) halides, (2) the equivalent of
the copper halides, (3) solvent, and (4) the reaction temperature (Table 1).
Table 1. Simmons-Smith cyclopropanation reactiona
b
c
Entry
Halides
Eq.
solvent
Tempreture °C
Yield %
dr (syn/anti)
1
2
CuCl
CuBr
CuI
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.05
0.1
0.1
0.1
Et2O
Et2O
20
20
20
20
20
20
20
20
20
20
20
35
0
35
48
30:1
40:1
40:1
3
Et2O
30
d
4
CuOTf
CuBr2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
Et2O
<10
trace
25
/
d
5
Et2O
/
6
THF
45:1
d
7
DCM
MTBE e
DIPE f
MTBE
MTBE
MTBE
MTBE
MTBE
<10
68
/
8
45:1
40:1
35:1
40:1
20:1
45:1
45:1
9
55
10
11
12
13
14
70
57
61
49
-20
45
a Reaction conditions: CH2I2 (1.0 eq) was added to a mixture of CuX and Zn dust (1.0 eq) in solvent,
reacted to reflux for 1 h, then cooled, 4 (1.0 eq) was added to the carbenoid and stirred at the specified
temperature. b Isolated yield. c Diastereomeric ratios (dr) determined by HPLC analysis at the end of the
reaction. d Diastereomeric ratios (dr) not calculated. e Methyl tert-butyl ether. f Di-isopropyl ether.

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HETEROCYCLES, Vol. 91, No. 4, 2015
Firstly, Zinc dust and 0.1 equivalent of CuCl was mixed and warmed to reflux in Et2O under N2, CH2I2
was then added to form the zinc carbenoid, IZnCH2I, then the dihydropyrrole carboxamide 4 was reacted
with this in-situ formed carbenoid at 20 °C, after work up, L-cis-4,5-methanoproline amide 2 was gained
with 35% isolated yield and 30:1 dr (Table 1, entry 1). Different copper halides were tested (Table 1,
entries 2-5) and we choose CuBr (Table 1, entry 2) to continue our optimization. We then scanned the
solvents, it was found that ethers were more effective than alkyl halides (compared entry 2, 6, 8, 9 and
entry 7), which revealed that the oxygen element of the non-polar solvent may partly participated the
reaction. More CuBr loading could improve the reaction yield but the diastereomeric selectivity was
lowered (Table 1, entry 10), but less CuBr was proved to be not satisfied (Table 1, entry 11). Then we
tried to warm up the cyclopropanation temperature to enhance the yield, but this attempt was not
successful, a lot of decompose products were obtained and the diastereomeric selectivity was also
influenced (Table 1, entry 12). Lower temperatures could remain the diastereomeric ratio, but the
solubility of the reaction mixture was decreased and then the yield was affected (Table 1, entry 13, 14).
Finally, with the optimized condition, we got the title product 2 with the yield of 68% and excellent
diastereomeric selectivity (40:1 dr), almost equal to the literature procedures.4
In conclusion, we have developed an improved Simmons-Smith reaction for the production of
L-cis-4,5-methanoproline amide, a key intermediate of saxagliptin. In our protocol, Et2Zn was
successfully replaced by a cheaper and safety Zn/CuBr mixture, which makes this procedure practical and
economical attractive.
EXPERIMENTAL
1
Melting points were determined with a SGW X-4 micro melting point apparatus. H NMR spectra were
recorded using an Avance 500 MHz spectrometer. All chemical shifts were reported in δ units relative to
tetramethylsilane. ESI-MS were recorded on a Waters Quaptro Premier XE Mass Spectrometer. High
resolution mass spectra were recorded on a Brucker Solaril X70 mass spectrometer. HPLC were
determined on Dionex Ultimate 3000. Optical rotations were obtained on a Perkin-Elmer 241 Autopol
polarimeter.
Starting Materials. All chemicals used in this study were commercially available.
(S)-1-tert-Butyl 2-methyl 5-oxopyrrolidine-1,2-dicarboxylate (6). L-Pyroglutamic acid 5 (387.3 g, 3
mol) was slurried in MeOH (1 L), thionyl chloride (652.1 g, 5.7 mol) was added in a manner so that the
temperature was maintained between -5–0 °C. After complete addition of the thionyl chloride, the
reaction mixture was heated to 25–30 °C and stirred for 5 h. Then the reaction mixture was evaporated
under vacuum (T < 45 °C) to approximately 15% of its original volume. The remaining oil was then
dissolved in toluene (1 L). Triethylamine (303.6 g, 3 mol) was added dropwise so that the temperature

HETEROCYCLES, Vol. 91, No. 4, 2015
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was maintained between -5–0 °C, then filtered. The filtrate was used in the next step directly. To another
5 L three necked bottle, Boc2O (870 g, 3.99 mol), 4-dimethlyaminopyridine (54.9 g, 0.45 mol) and
toluene 1 L were combined and cooled to -5–0 °C. The filtrate was added dropwise while keep the
tempreture between 0–5 °C. After addition, the reaction mixture was heated to 25–30 °C and stirred for
12 h (monitored by TLC, DCM/MeOH = 7/1). To the reaction vessel was added saturated aqueous NaCl
(1 L) and 2 N HCl to adjust the pH to 2-3. The aqueous phase was extracted with EtOAc (200 mL×3), the
combined organic layer was washed with brine and dried over magnesium sulfate. Concentrated under
reduced pressure and the residue was stirred for 3 h, then filtered to give 6 (580.9 g, HPLC: 97.3%, yield:
80% for 2 steps) as an orange-red solid, the product can be used in the next step without further
20
purification. [α]D - 29.7 (c 1.0, CHCl3). {lit.11 [α]D20 - 30.4 (c 1.0, CHCl3)}.
1H NMR (500 MHz, CDCl3) δ 4.63 (dd, J = 9.4, 3.0 Hz, 1H), 3.79 (s, 3H), 2.64-2.50 (m, 1H), 2.39-2.26
(m, 2H), 2.04 (ddt, J = 13.2, 9.6, 3.3 Hz, 1H), 1.50 (s, 9H). ESI-MS m/z: 244.2 (M+1)+.
(S)-1-tert-Butyl 2-methyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (7). To a stirred solution of
compound 6 (580.9 g, 2.4 mol) in THF (3 L) at 0 °C was added LiEt3BH (1 M in THF, 2.6 L, 2.6 mol)
droply while maintaining the batch temperature in the range of 5–10 °C. After stirring for 2 h, the reaction
was cooled to 0 °C and quenched by careful addition of saturated aqueous ammonium chloride solution (1
L). The organic and aqueous layers were separated, the aqueous layer was extracted with DCM (500
mL×3). The combined organic layer was washed with brine (500 mL×3). Dried the organic layer over
anhydrous sodium sulfate and distilled off the solvent completely to get a pale yellow oil. In a 3L three
necked bottle, the crude product gained in the last step, potassium carbonate (524.4 g, 3.8 mol), acetic
anhydride (388.0 g, 3.8 mol), DMF (1.8 L) were combined and heated to 120 °C. After stirring for 3 h,
the reaction was cooled to 0 °C and quenched by careful addition of water (1 L). Then, added petroleum
ether (1 L) .The reaction mixture was stirred for 20 min. Layers were separated, the aqueous layer was
extracted with petroleum ether (500 mL×2). The combined organic layer was washed with brine (500
mL×2) and concertrated to get the title compound 7 as a yellow oily liquid (415.4 g, HPLC: 96.5%, yield:
76 % for 2 steps), which could be used in the next step without further purification.
1H NMR (500 MHz, CDCl3) δ 6.62 (m, 1H), 5.00 (m, 1H), 4.66 (dd, J = 12.0, 5.0 Hz, 1H), 3.80 (s, 3H),
3.17-2.99 (m, 1H), 2.82-2.57 (m, 1H), 1.50 (s, 9H). ESI-MS m/z: 228.2 (M+1)+.
(S)-tert-Butyl 2-carbamoyl-2,3-dihydro-1H-pyrrole-1-carboxylate (4). Compund 7 (415.0 g, 1.9 mol)
was slurried in 2.1 L MeOH/water (2:1), lithium hydroxide monohydrate (119.6 g, 2.85 mol) was added
in portions while maintaining the batch temperature in the range of -5–0 °C. After complete addition of
the lithium hydroxide monohydrate, the reaction mixture was heated to 25–30 °C and stirring for 1 h,
MeOH was removed by vacuum distillation and the aqueous layer was back-extracted with methyl
tert-butyl ether. Add 1 L methyl tert-butyl ether to the aqueous layer and then add 20% phosphoric acid

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HETEROCYCLES, Vol. 91, No. 4, 2015
solution dropwise to adjust pH to 2–3. Layers were separated, the aqueous layer was extracted with 400
mL methyl tert-butyl ether. The combined organic phase was dried and filtered, methyl tert-butyl ether
solution of intermediate was obtained, and the solution can be used in the next step directly. Transferred
the methyl tert-butyl ether solution to a reaction vessel, cooled to -15 °C. Added N-methylmorpholine
(252.5 g, 2.5 mol) and MsCl (228 g, 2 mol) dropwise respectively, while maintaining the batch
temperature no more than -8 °C. The reaction mixture was stirred for 0.5 h under this temperaure.
Ammonia gas was bubbled into and stirred for 1.5 h. Added saturated aqueous NaCl solution (1 L) to the
solution and stirred for 1 h. Then add 20% phosphoric acid solution dropwise to adjust pH to 5–6. The
organic layer washed with saturated aqueous NaHCO3 (500 mL×2)，dried over anhydrous magnesium
sulfate. Distilled off the solvent completely from the organic layer under reduced pressure to get the title
compound 4 as pale yellow viscous, recrystallized from i-PrOH to form a off white solid (359.7 g, HPLC:
1
98.4%, yield: 89.2 % for 2 steps). H NMR (500 MHz, CDCl3) δ 7.31 (m, 1H), 6.88 (br, 1H), 6.48-6.45
(m, 1H), 4.95 (m, 1H), 4.34 (dd, J = 12.5, 6.0 Hz, 1H), 2.86-3.00 (m, 1H), 2.44-2.51 (m, 1H), 1.41 (s, 9H).
ESI-MS m/z: 213.2 (M+1)+.
L-cis-4,5-Methanoproline amide (2). Zinc powder (6.5 g, 0.1 mol), copper bromide (1.4 g, 0.01 mol)
and methyl tert-butyl ether (100 mL) were added respectively under nitrogen atmosphere. Diiodomethane
(1.66 g, 0.5 mL) was added with stirring, then the solution was heated to reflux to initiate the reaction.
After initiation of the reaction, the system would continue to reflux by itself. Added diiodomethane (26.8
g, 0.1 mol) dropwise, then stirring at 20 °C for 30 min. To the vessel the compound 4 (21.2 g, dissolved
in 50 mL methyl tert-butyl ether) were added in a manner so that the temperature was maintained at
20 °C. After complete addition (about 1 h), the reaction were stirred for another 3.5 h. After the reaction
was completed (monitored by TLC, hexane/EtOAc = 1/1.5), added saturated aqueous NaHCO3 solution
(200 mL). Filtered it after 1 h stirring. The filter cake was washed with EtOAc (100 mL×2), and the
filtrate was extracted with EtOAc (200 mL×2). Combination of organic phase, dried over anhydrous
sodium sulfate. After removal of solvent by vacuum distillation we got a white solid. The crystallization
was completed by addition of 200 mL MeOH /water (1:1 v/v) additional aging for 1 h at 20 °C. The solid
was isolated by filtration (15.4 g, 68%), Diastereomeric ratio (dr = 40:1) was determined by HPLC
20
20
1
analysis. [α]D 33.7 (c 0.71, MeOH). {lit.4d [α]D 35.2 (c 0.71, MeOH)}. Mp 56-58 ºC. H NMR (500
MHz, DMSO-d6) δ 6.30 (br s, 2H), 4.08 (s, 1H), 2.25-2.09 (m, 2H), 1.88-1.81 (m, 1H), 1.46 (s, 9H), 1.08
(s, 1H), 0.41-0.29 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 172.1, 155.2, 81.7, 54.1, 38.8, 36.2, 28.4, 13.6,
9.1; ESI-MS m/z: 227.2 (M+1)+; HRMS calcd for C11H18N2NaO3 (M+Na) + requires 249.1215, found
249.1204.

HETEROCYCLES, Vol. 91, No. 4, 2015
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ACKNOWLEDGEMENTS
This work was supported by the National Natural Science Foundation of China (Grants 21302126) and
Shanghai Engineering Technology Research Center of Fragrance and Flavor (12DZ2251400).
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