C. S. Subbaiah, W. Haq / Tetrahedron: Asymmetry 25 (2014) 1026–1030
1029
119.4, 119.6, 127.3, 128.4, 129.0, 138.5, 145.5, 147.9, 148.0, 150.5,
154.9, 157.3, 165.6; MS (ESI) m/z: 610.9 (M+H)+. HRMS (ESI)
(M+H)+: calcd for C34H28F6N2O2: 611.2128; found: 611.2121.
4.7. (R)-tert-Butyl 4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-
[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)-
butan-2-ylcarbamate 9
(R)-3-(tert-Butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)buta-
noic acid 7 (200 mg, 0.59 mmol) and 3-(trifluoromethyl)-5,6,7,8-
tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinehydrochloride 8 (115 mg,
0.59 mmol) in anhydrous DCM (3 mL) were cooled to 0 °C. To that
solution was added HOBT (96 mg, 0.7 mmol), followed by EDCÁHCl
(134 mg, 0.7 mmol) and DIEPA (152 mg, 1.18 mmol). After being
stirred for 24 h, DCM was evaporated, and the viscous residue
was partitioned between ethyl acetate and saturated aqueous
NaHCO3 solution. The aqueous layer was extracted with ethyl
acetate. The combined organic phase was washed with brine, dried
over Na2SO4, and concentrated. The crude product was purified by
column chromatography eluting with 80% ethyl acetate in
hexane to afford 9 as a white powder (280 mg, 92% yield).
4.5. (R)-2-(tert-Butoxycarbonylamino)-3-(2,4,5-trifluorophenyl)
propanoic acid 5
The heterocyclic intermediate 4 (690 mg, 1.13 mmol) was
refluxed in 57% HI (10 mL) for 3 h. The reaction mixture was evap-
orated under vacuum, after which water (23 mL) containing Na2-
CO3 (1.6 g, 15 mmol) was added (reaction mixture pH should be
basic), and cooled to 0 °C. Di-tert-butyl dicarbonate (567 mg,
2.3 equiv) in 1,4-dioxane (14 mL) was added slowly and stirred
for 12 h, then slowly warmed up to rt. Water was added to the
reaction mixture and extracted with ether. The aqueous layer
was acidified with aqueous citric acid solution up to pH 2 and
extracted with ethyl acetate. The combined organic layer was
washed with brine, dried over anhydrous Na2SO4, filtered, and
evaporated under vacuum. The crude product was purified by col-
umn chromatography eluting with 30% ethyl acetate in hexane and
afforded a white powder in about quantitative yield. Mp: 107–
Mp: 189–192 °C; {lit.8a mp: 188–191 °C}; [
a]
25.1 = +20.8 (c 0.11,
D
CHCl3); {lit.8a 20 = +22.2 (c 1.0, CHCl3)}; 1H NMR
[a]
D
(500 MHz, CDCl3) d 1.35 (s, 9H), 2.93–2.67 (m, 4H), 4.17–3.97 (m,
5H), 4.92 (s, 1H), 5.07–5.00 (m, 1H), 5.28 (s, 1H), 6.88 (s, 1H),
7.08–7.06 (d, J = 6.36 Hz, 1H). 13C NMR (125 MHz, CDCl3) d 28.2,
32.9, 36.7, 38.0, 39.2, 41.8, 42.6, 43.1, 43.6, 48.2, 48.4, 79.7,
105.2, 105.3, 105.4, 105.5, 117.1, 119.0, 119.1, 121.4, 143.7,
144.0, 145.6, 147.7, 147.9, 149.4, 149.9, 150.2, 155.2, 157.1,
169.5, 169.9; MS (ESI) m/z: 507.9 (M+H)+. HRMS (ESI) (M+H)+:
calcd for C21H23F6N5O3: 508.1778; found: 508.1778.
110 °C; [
a
]
25.3 = À1.5 (c 0.12, CH3OH); {lit.16
[
a
]
20 = À3.5 (c 1.0,
D
D
CH3OH)}; 1H NMR (400 MHz, CD3OD) d 1.37 (s, 9H), 2.87–2.82
(m, 1H), 3.31–3.22 (m, 1H), 4.38–4.34 (m, 1H), 7.23–7.07 (m,
2H); 13C NMR (100 MHz, CD3OD) d 27.2, 30.4, 30.7, 53.2, 54.5,
79.2, 80.1, 104.6, 104.8, 104.8, 105.1, 118.9, 119.0, 119.1, 121.1,
121.3, 145.1, 145.2, 147.5, 147.6, 150.0, 150.1, 150.2, 155.2,
155.3, 155.5, 156.2, 157.6, 157.7, 173.1; MS (ESI) m/z: 219.9
(M+1HÀt-Boc)+. HRMS (ESI) (M+1HÀt-Boc)+: calcd for C14H16F3-
NO4: 220.0585; found: 220.0576.
4.8. Sitagliptin phosphate 1
To a solution of 9 (100 mg, 0.19 mmol) in MeOH (2 mL) was
added 1 mL of conc. HCl in 2 mL of MeOH at rt. After stirring
for 4 h, the solvent was removed under vacuum followed by par-
titioning between ethyl acetate and 1 M aqueous sodium
hydroxide solution. The aqueous layer was extracted with ethyl
acetate. The combined organic phase was washed with brine,
dried over Na2SO4, and concentrated. The crude product was
subjected to column chromatography with CH2Cl2/MeOH/NH4OH
(900:50:2.5), then CH2Cl2/MeOH/NH4OH (900:100:5) to give a
colorless oil (74 mg, 93%) of sitagliptin as a free base. To a solu-
tion of the free base (74 mg, 0.18 mmol) in EtOH (1 mL) was
added phosphoric acid (85 wt %, 16.8 mg, 0.17 mmol). The result-
ing mixture was treated at 80 °C for 30 min. The reaction mix-
ture was allowed to cool to rt and filtered. The solid residue
was then recrystallized (iPrOH) to give the title compound as a
white powder (88 mg, 96%). Mp: 213–216 °C; {lit.5a mp 215–
4.6. (R)-3-(tert-Butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)
butanoic acid 7
To a solution of (R)-2-(tert-butoxycarbonylamino)-3-(2,4,5-tri-
fluorophenyl)propanoic acid 5 (465 mg, 1.45 mmol) in 12 mL of
diethyl ether at À20 °C were added sequentially 0.214 mL
(1.54 mmol) of triethylamine and 0.200 mL (1.54 mmol) of isobu-
tylchloroformate, and stirred for 15 min. A cooled solution of
diazomethane was added until a yellow color persisted and stirring
was continued for 1 h. The excess diazomethane was quenched by
the dropwise addition of acetic acid. The reaction mixture was
diluted with ethyl acetate, and washed sequentially with saturated
aqueous sodium bicarbonate solution and brine, dried over anhy-
drous Na2SO4, and concentrated in vacuum. The crude product
was purified by column chromatography eluting with 20% ethyl
acetate in hexane to afford diazoketone 6 (440 mg, 88%). To a solu-
tion of diazoketone (440 mg, 1.27 mmol) in 15 mL of 1,4-dioxane/
water (5:1) was added 30 mg (0.127 mmol) of silver benzoate. The
resultant solution was sonicated for 90 min before diluting with
ethyl acetate and being washed sequentially with 1 M hydrochloric
acid and brine, dried over sodium sulfate, and concentrated under
vacuum. The crude product was purified by column chromatogra-
phy eluting with 25% ethyl acetate in hexane to afford 7 as a white
powder (400 mg, 94%). Mp: 121–124 °C; {lit.15 mp: 124–125 °C};
217 °C}; [
a
]
D
25.2 = À73.1 (c 0.13, H2O); {lit.5a
[
a]
D
20 = À74.4 (c
1.0, H2O)}; 1H NMR (400 MHz, D2O) d 2.88 (ddd, J = 17.5, 10.1,
7.5 Hz, 1H), 3.10–2.92 (m, 3H), 4.06–3.93 (m, 3H), 4.27–4.17
(m, 2H), 4.95–4.88 (m, 2H), 7.13–7.03 (m, 1H), 7.26–7.18 (m,
1H); 13C NMR (100 MHz, D2O) d 30.9, 31.0, 33.7, 33.8, 38.0,
38.7, 41.2, 41.8, 43.1, 43.4, 48.2, 105.5, 105.7, 105.8, 106.0,
113.6, 116.3, 118.4, 118.4, 118.5, 118.5, 118.6, 118.6, 118.9,
119.0, 119.0, 119.1, 119.1, 119.2, 119.3, 121.7, 143.1, 143.5,
143.6, 143.9, 144.0, 145.2, 145.3, 147.6, 147.7, 148.0, 148.1,
150.4, 150.5, 151.0, 155.1, 155.1, 157.5, 157.6, 170.1, 170.2; MS
(ESI) m/z: 408 (M+H)+. HRMS (ESI) (M+H)+: calcd for C16H15F6N5-
O: 408.1254; found: 408.1252.
[a] [a]
24.3 = +27.8 (c 0.13, CHCl3); {lit.15 20 = +32.3 (c 1.0, CHCl3)};
D D
1H NMR (400 MHz, CDCl3) d 1.37 (s, 9H), 2.66–2.57 (m, 2H), 2.88 (d,
J = 4.9 Hz, 2H), 4.14 (br s, 1H), 5.07 (br s, 1H), 6.94–6.87 (m, 1H),
7.09–7.03 (m, 1H); 13C NMR (100 MHz, CDCl3) d 28.2, 29.6, 32.9,
33.9, 37.9, 38.4, 47.6, 48.8, 79.9, 81.3, 105.1, 105.3, 105.4, 105.6,
119.0, 119.1, 121.3, 145.3, 145.4, 147.5, 147.7, 150.0, 150.2,
150.3, 155.0, 155.2, 156.9, 157.5, 175.1, 176.2; MS (ESI) m/z:
355.9 (M+Na)+. HRMS (ESI) (M+Na)+: calcd for C15H18F3NO4Na:
356.1080; found: 356.1068.
Acknowledgements
C.S.S. thanks UGC, New Delhi, India for the award of a Senior
Research Fellowship. We gratefully acknowledge the SAIF Division
of CSIR-CDRI for providing the spectroscopic data. CDRI communi-
cation No. 8710.