Synthesis of (R)-3-(tert-Butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic Acid, a Key Intermediate, and the Formal Synthesis of Sitagliptin Phosphate

Article abstract of DOI:10.1002/asia.202000092

An alternate formal synthesis of Sitagliptin phosphate is disclosed from 2,4,5-trifluorobenzadehyde in 8 linear steps with an overall yield of 31%. The chiral β-amino acid moiety present in sitaglitpin is installed via an asymmetric hydrogenation followed by a stereoselective Hofmann rearrangement as the key steps. The key chiral intermediate Boc-amino acid 1 prepared by this novel route was further converted to Sitagliptin phosphate following the known literature protocol.

Full text of DOI:10.1002/asia.202000092

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: A Novel Synthesis of (R)-3-(t-Butoxycarbonylamino)-4-(2,4,5-
trifluorophenyl)butanoic Acid, a Key Intermediate, and the Formal
Synthesis of Sitagliptin phosphate
Authors: Kurella Sreenivasulu, Pramod S. Chaudhari, Srinivas
Achanta, Abhishek Sud, Vilas Dahanukar, Christopher J.
Cobley, Fiona Llewellyn-Beard, and Rakeshwar Bandichhor
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To be cited as: Chem. Asian J. 10.1002/asia.202000092
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10.1002/asia.202000092
Chemistry - An Asian Journal
COMMUNICATION
A Novel Synthesis of (R)-3-(t-Butoxycarbonylamino)-4-(2,4,5-
trifluorophenyl)butanoic Acid, a Key Intermediate, and the Formal
Synthesis of Sitagliptin phosphate
Kurella Sreenivasulu, [a] Dr.Pramod S. Chaudhari, [a] Dr.Srinivas Achanta, [a] Dr.Abhishek Sud, [a] Dr.Vilas Dahanukar,
[a] Dr.Christopher J. Cobley, [b] Dr.Fiona Llewellyn-Beard, [b] and Dr.Rakeshwar Bandichhor* [a]
[a] Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories Ltd, Bachupally, Qutubullapur, R.R. Dist. 500072, Telangana, India
Email:rakeshwarb@drreddys.com
[b] Integrated Product Development Cambridge, Dr Reddy’s Laboratories Ltd, 410 Cambridge Science Park, Milton Road, Cambridge, CB24 9JU, UK
Supporting information for this article is given via a link at the end of the document
Abstract: An alternate formal synthesis of Sitagliptin phosphate is
disclosed from 2,4,5-trifluorobenzadehyde in 8 linear steps with an
F
overall yield of 31.16%. The chiral -amino acid moiety present in
sitaglitpin is installed via an asymmetric hydrogenation followed by a
F
NH2 H3PO4
stereoselective Hofmann rearrangement as the key steps. The key
F
N
O
N
chiral intermediate Boc-amino acid 1 prepared by this novel route was
further converted to Sitagliptin phosphate following the known
literature protocol.
N
N
CF3
Sitagliptin phosphate
F
F
HCl
HN
Diabetes Mellitus is among the top 10 global causes of death
since 2010 and, JanuviaTM ranks among the top 10 highest-selling
drugs for the treatment of type II diabetes mellitus.1 For this
reason, a number of pharmaceutical companies and research
groups across the world engaged in innovating shorter and cost
effective synthetic routes for Sitagliptin,2 the active ingredient in
JanuviaTM. Efforts from the researchers of Merck, in collaboration
with Solvias and Codexis, led to the development of efficient,
green, robust, and safe manufacturing processes. The efforts
from these researchers were recognized worldwide and honored
with The Presidential Green Chemistry Challenge awards in 2006
and 2010.[3,18,19,20] A continuos flow process has also been
described by Wang and co-workers.21
NHBoc
OH
N
N
N
+
F
CF3
O
9
8
F
O
O
F
O
OMe
OH
NH2
OH
F
F
F
F
O
4c
7
Scheme 1. Retrosynthetic analysis of Sitagliptin phosphate.
The chiral β-amino acid moiety present in sitagliptin has inspired
the synthetic community and several synthetic routes for the
construction of this moiety were reported in the past decade.2,4
Although a number of synthetic strategies are known for the
construction of the chiral β -amino acid moiety in general, only a
few have found their way into the synthesis of sitaglitpin. Herein,
we report our efforts that led to the synthesis of sitagliptin
featuring asymmetric hydrogenation of α,β-unsaturated ester
followed by a stereoselective Hofmann rearrangement as the key
steps for the installation of the β-amino acid moiety.
Initial efforts focused on the preparation of dimethyl itaconic acid
derivative 3 in one step via Stobbe condensation between
dimethyl succinate and 2,4,5-trifluorobenzadehyde (Scheme 2).5
Unfortunately, attempted chemoselective hydrolysis failed and led
to a mixture of products (4a, 4b, and 4c) with extensive
degradation.
F
O
F
F
O
O
O
OMe
OMe
NaOMe, MeOH
reflux
OMe
OMe
+
F
F
Our retrosynthetic analysis is outlined in Scheme 1. From the
outset, we envisioned that chiral amido acid 7 should serve as the
precursor for the installation of the chiral β-amino center present
in sitaglitin via the Hofmann rearrangement. Synthesis of the
chiral amido acid 7 was envisioned from the asymmetric
hydrogenation of the monoester of itaconic acid derivative 4c
followed by amidation. The monoester of itaconic acid 4c could
arise from the selective hydrolysis of the dimethyl ester of itaconic
acid derivative 3.
F
O
3
2,4,5-trifluoro
benzaldehyde
dimethyl
succinate
1
2
F
F
O
F
O
F
F
O
OMe
OH
Aq.NaOH
F
OH
OH
+
+
OH
OMe
F
F
O
O
4c
O
4a
4b
Scheme 2. Attempted synthesis of monoester itaconic acid 4c via Stobbe
condensation.
1
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10.1002/asia.202000092
Chemistry - An Asian Journal
COMMUNICATION
An alternative route was evaluated for the synthesis of monoester
itaconic acid derivative 4c (Scheme 3). The synthesis started with
the preparation of Wittig reagent 6 following a known literature
protocol from maleic anhydride.6 Ensuing Wittig reaction between
2,4,5-trifluorobenzadehyde 1 and Wittig reagent 6 provided
monoester itaconic acid derivative 4c in very high yields.
With the chirality of the monoester 5 in place, we focused our
efforts on converting it to the corresponding amide to set the stage
for Hofman rearrangement. The amidation reaction of monoester
5 with ammonia as a nucleophile proved extremely challenging
and the results are summarized in Table 2.
Table 2. Amidation of Ester 5.
O
O
Ph3P
O
PPh3
OMe
OH
MeOH
Acetone
O
PPh3
+
O
16h/RT
90%
16h/RT
92%
O
O
O
5
6
maleic
anhydride
S.No.
Reaction conditions
Yield
(%)
F
F
O
O
O
O
F
1
2
3
4
5
NH4OH (excess), 25 oC, 24 h
NH4OH (excess), 80 oC 24 h
7N NH3 in MeOH (10 eq), 25 oC, 24h
7N NH3 in MeOH (10 eq), 80 oC, 24h
NR
NR
NR
<5
DCM, Toluene
25 oC, 20h
Ph3P
OMe
OH
OMe
OH
O
+
F
87%
F
F
4c
1
6
NaCN (10 mol%), 7N NH3 in MeOH (10 eq), 50 oC,
48h sealed tube
CaCl2 (3 eq), 7N NH3 in MeOH (10 eq), 80 oC, 24h,
Autoclave (1.7 bar pressure observed)
Li3N (5 eq), MeOH , 80 oC, 24h, Autoclave (1.7 bar
pressure observed)
NR
Scheme 3. Synthesis of monoester of itaconic acid derivative 4c.
6
7
8
9
80
This set the stage for asymmetric hydrogenation and ligand
screening for asymmetric hydrogenation commenced with the
commercially available DuPhos and BPE family of
bisphospholane ligands (Scheme 4).7 These ligands were
demonstrated to be effective for the Rh catalyzed asymmetric
63
Ammonium carbamate (10 eq), CAL B (150 mg,
NR
NR
NOVOZYME 435 solid), t-BuOH (5mL), 45 oC, 3days
Enzymes: CAL B (Solid), PLE, Alcalase, PPL and
Candida rugosa lipase were tried with identical
reaction conditions of 8.
hydrogenation of itaconate derivatives.8 Among the precatalysts
10b
screened [{(R,R)-Ph-BPE}Rh(cod)]BF4
provided the highest
conversion (>99%) and enantioselectivity (99%). Although
[{(S,S)-Et-DuPhos} Rh(cod)]BF4 provided modest
[a] Determined by chiral HPLC
No significant product formation (Table 2, entries 1-4) was
observed with NH3 as the nucleophile even under harsh
conditions. The effect of various additives such as sodium
cyanide9 (Table 2, entry 5), calcium chloride10 (Table 2, entry 6),
and lithium nitride11 (Table 2, entry 7) was evaluated. The best
result was obtained with calcium chloride (80% yield and 98% ee)
as the addditve. Although the product was also isolated in 63%
yield with lithium nitride, further experimentation was abandoned
due to the safety concerns of lithium nitride on large scale.
Surprisingly, we did not observe any product formation under
enzymatic conditions (Table 2, entry 8 & 9). With the chiral amide
7 in hand, several reagents were examined to effect Hoffman
rearrangement12 and the results are shown in Table 3.
enantioselectivity (95% ee), conversion during hydrogenation was
low (<90%). The substituted mono methyl succinate was isolated
in quantitative yield with >99% ee(Fig7 in SI).
R
P
P
Ph
P
Ph
R
R
P
Ph
Ph
R
R = Me; (S,S)-Me-DuPhos
Et; (S,S)-Et-DuPhos
= i-Pr; (S,S)-i-Pr-DuPhos
(R,R)-Ph-BPE
=
Scheme 4. DuPhos and BPE ligands
Table 3. Screening conditions for Hoffmann rearrangement.
Table 1. Catalyst screening for the asymmetric hydrogenation of 4c.
S.No.
Reaction conditions
HPLC
(ee%)
40%
40%
50%
50%
24%
Yielda
(%)
S.No.
Precatalyst
Conv.a
(%)
eea
(%)
99
1
2
3
4
5
PIFAb (1.1), RT/16h/ACN:H2O (1:1)
PIFA (1.1), 6ooC/6h/ACN:H2O (1:1)
PIDAc(1.2)/EtOAC:ACN:H2O (2:2:1)/rt/16h
Lead (IV)acetate/tBuOH/reflux/24h
83
83
85
30
65
1
2
3
4
[{(R,R)-Ph-BPE}Rh(cod)]BF4
[{(S,S)-Me-DuPhos}Rh(cod)]BF4
[{(S,S)-Et-DuPhos} Rh(cod)]BF4
[{(R,R)-iPr-DuPhos}Rh(cod)]BF4
>99
63
86
88
95
NaOCl(1)/NaOH(3.4)/ACN:Water (1:1)/0-
70 oC/2h
30
92
6
Br2(1.1)/NaOtBu(3.3)/tBuOH-THF(1:1.3)/0-
58%
15
55oC/1h
[a] Determined by chiral HPLC
2
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COMMUNICATION
7
8
Br2(1.1)/DBU(3)/tBuOH-THF(1:4)/90oC/9h
Br2(1.5)/DBU(3.5)/tBuOH-THF/50oC/12h
>99%
15
55
2007, 6, 109-110; f) See: www.diabetes.org; g) See: http://www.who.int.
95.2%
[2]
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[a] isolated yield [b] Bis(trifluoroacetoxy)iodo)benzene and
[c] diacetoxyiodobenzene
Surprisingly,
reagents
such
as
Bis(trifluoroacetoxy)
iodo)benzene,13 diacetoxyiodobenzene,14 lead(IV) acetate,15
bromine in sodium tert-butoxide-butanol and sodium hypochlorite
with sodium hydroxide16 led to significant racemization despite
providing modest to good yields of the desired product 8.
Racemization was observed to a higher level with strongly acidic
and basic conditions (Table 3, entries 1-6). Gratifyingly, the use
of bromine in combination with Hunig’s base or DBU17 in tert-
butanol led to formation Boc protected product 8 with >99% ee
but with low yield (Table 3, entry 7). This is presumably due to the
evaporation of bromine from the reaction mixture at 90 oC.
Lowering the reaction temperature provided a modest yield of
55% when the reaction was conducted at 50 oC for 12h (Table 3,
entry 8). Finally, conversion of the Boc-protected amino acid 8 to
Sitagliptin phosphate was accomplished in three steps following
the known protocol reported in the literature.4a
[3]
See:
a)
https://www.epa.gov/greenchemistry/presidential-green-
chemistry-challenge-2006-greener-synthetic-pathways-award;
https://www.epa.gov/greenchemistry/presidential-green-chemistry-
challenge-2010-greener-reaction-conditions-award.
b)
[4]
[5]
[6]
a) H. Gao, J. Yu, C. Ge, q. Jiang, Molecules 2018, 23, 1440-1452; b) W.
Y. Kwak, H. Y. Mok, S-H. Y, Bull. Korean Chem. Soc. 2017, 38, 976-979.
For a similar reaction: a) H. Jiang, W. Wang, C. Qiao, Chin. J. Chem.
2010, 2, 263-268
F
F
N
NH2 H3PO4
HN
HCl
N
F
F
N
NHBoc
OH
CF3
F
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52, 2033-2036.
9
N
O
N
N
F
N
O
8
CF3
Sitagliptin phosphate 10
Scheme 1. Synthesis of Sitagliptin Phosphate.
[7]
In summary, we have developed
a
novel, route using
[8]
[9]
commercially available starting materials featuring
a
stereoselective
catalytic
asymmetric
reduction,
and
stereoselective Hoffmann rearrangement for the installation of
chiral β-amino center present in sitagliptin.
[10] a) M. W. Bundesmann, S. B. Coffey, S. W. Wright, Tetrahedron. Lett.
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Supporting Information
Spectroscopic data and experimental details for the preparation
of all new compounds are available in supporting information. This
material is available free of charge via the Internet at
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Acknowledgements
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We thank the management of the Dr. Reddy’s Laboratories Ltd.
for the support and encouragement. Technical help from the
analytical department is also appreciated.
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Keywords: Sitagliptin phosphate • Asymmetric Hydrogenation •
Hoffmann rearrangement
[20] For recent advance in enzyme catalyzed synthesis of sitagliptin
fromMerck, see: a) M. D. Truppo, H. Strotman, G.
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3
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COMMUNICATION
E. Sorochinsky, S. Fustero, V. A.Soloshonok, H. Liu, Chem. Rev.
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1038−1051.
4
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COMMUNICATION
Entry for the Table of contents
F
O
O
F
F
O
O
Rh catalyst
OMe
OH
OMe
OH
o
F
MeOH, 25 C, 10 bar, H2, 3h
F
F
S/C (500:1)
4c
5
A Novel Synthesis of (R)-3-(t-Butoxycarbonylamino)-4-(2,4,5-trifluoro phenyl) butanoic Acid which is a key
starting material for synthesis of sitagliptin has been developed by using commercially available starting
materials featuring a stereoselective catalytic asymmetric reduction, and stereoselective Hoffmann
rearrangement for the installation of chiral β-amino center present in sitagliptin.
5
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