232 JOURNAL OF CHEMICAL RESEARCH 2010
3-R-[(R)-(α-methylbenzyl)benzylamino]-4-(2,4,5-trifluoro-phenyl)-
butyric acid methyl ester (9): A solution of (R)-(α-methylbenzyl)
benzylamine (63.3 g, 0.3 mol) in anhydrous THF (300 mL) was
cooled to –78 °C and 2.5M n-BuLi (100 mL, 0.25 mol) was added
dropwise, the mixture was allowed to warm to –20 °C in 1 hour and
cooled down to –78 °C again. The resultant pale pink lithium amide
solution was stirred for 45 min whereupon 4-(2,4,5-trifluorophenyl)-
but- 2-enoic acid methyl ester (4) (57.5 g, 0.25 mol) was added drop-
wise as a solution in anhydrous THF (300 mL). The resultant deep
yellow enolate solution was stirred for a further 30 minutes before
saturated aqueous ammonium chloride (100 mL) was added to quench
the reaction. The solvent was removed under reduced pressure and the
residue was diluted with water (500 mL) and extracted with EtOAc
(3 × 300 mL). The combined organic extracts were washed with satu-
rated NaCl (800 mL), dried over anhydrous Na2SO4, filtered and the
solvent was evaporated under reduced pressure. The oily crude prod-
uct was chromatographed (silica gel; 1:10 ethyl acetate–petroleum
ether as eluent) to afford 83.8 g (0.19 mol, 76%) of 9. [α]D20 = –9.5
(c 1.0, CHCl3); IR (cm–1): 3305, 2931, 1744, 1633, 1512, 1400, 1348,
and Et N (60 g, 0.3 mol) at 0 °C. After being stirred at room tempera-
ture fo3r 24 h, distilled water (400 mL) was added to the reaction mix-
ture, the layers were separated, the organic phase was washed with
distilled water (400 mL) and dried over anhydrous magnesium sul-
fate. The solution was filtered and concentrated in a vacuum to give a
residue that was recrystallised from toluene to give 13 (96.2 g,
0.19 mol) in 95% yield. It was assayed by chiral HPLC to be 98.2%
ee. [α]D20 = + 22.2 (c 1.0, CHCl3). M.p. 188–191 °C. IR (cm–1): 3374,
2897, 1686, 1635, 1519, 1368, 1164, 1128, 1016. 1H NMR (400 MHz,
CDCl ) δ 7.18–7.05 (m, 1H), 7.02–6.85 (m, 1H), 5.31 (s, 1H), 5.15–
4.76 (3m, 2H), 4.43–3.78 (m, 5H), 2.98–2.92 (m, 2H), 2.71–2.61 (m,
2H), 1.36 (s, 9H). ESI-MS: 508.0 (M+ +1). HRMS Calcd for:
C21H23F N5O3Na (M + Na)+ requires 530.1598, found 530.1604.
(3R)-63-amino-4-(2,4,5-trifluoro-phenyl)butyl]-5,6,7,8-tetrahydro-
[3-(trifluoromethyl)- 1,2,4-triazolo[4,3-a]pyrazine (1): To a solution
of 13 (96.2 g, 0.19 mol) in MeOH (300 mL) was added a mixture of
50 mL conc. HCl and 250 mL MeOH at room temperature. After stir-
ring for 3 hours, the solvent was removed by distillation in a vacuum,
and the resulting solution was neutralised with 2 M aq. ammonia to
pH 8. The aqueous layer was extracted with EtOAc (300 mL X 3), the
combined organic layers were washed with saturated NaCl (500 mL),
dried over anhydrous Na SO4, filtered, concentrated and recrystallised
from toluene to give the2free base 1 (69.2 g, 0.17 mol) in 90% yield.
The optical purity was assayed to be >99% ee. [α]D20 = –22.8 (c 1.0,
CHCl3). M.p. 108–112 °C. IR (cm–1): 3360, 2870, 1644, 1517, 1437,
1342, 1237, 1140, 941, 808. 1H NMR (400 MHz, CDCl ) δ 7.19–7.02
(m, 1H), 7.02–6.81 (m, 1H) 5.06 (dd, J = 50.1, 18.2 Hz3, 1H), 4.95 (s,
2H), 4.43–3.77 (m, 5H), 3.60 (s, 1H), 2.92–2.28 (m, 4H). ESI-MS:
408.0 (M+ +1). HRMS Calcd for: C16H15F6N5ONa (M + Na)+ requires
430.1082, found 430.1087.
1
1259, 1214, 833. H NMR (400 MHz, CDCl3) δ 7.48–7.15 (m,10H),
7.11–7.06 (m, 1H), 6.80–6.72 (m, 1H), 3.83 (q, J = 5.4 Hz, 1H), 3.66
(s, 3H), 3.59 (d, J = 3.3 Hz, 2H), 3.38–3.46 (m, 1H), 2.81–2.73
(m, 2H), 2.44–2.35 (m, 2H), 1.40 (d, J = 6.6 Hz, 3H). ESI-MS: 442.2
(M+ +1). HRMS Calcd for C26H26F3NO2Na (M + Na)+ requires
464.1815, found 464.1809.
3-R-tert-Butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric
acid methyl ester (11): 9 (83.8 g, 0.19 mol) was dissolved with
absolute MeOH (500 mL) and treated with 20% Pd(OH)2 on activated
carbon (5 g). The mixture was then stirred at room temperature
overnight under 5 atm. of hydrogen. After removal and recovered of
the catalyst by filtration, the solvent was evaporated under reduced
pressure. 10% HCl (500 mL) and CH2Cl2 (500 mL) was added to the
residue and stirred for 10 minutes, the organic layer was discarded.
The aqueous layer was neutralised with K2CO3, then extracted with
CH2Cl2 (2 × 500 mL). The combined organic layers were washed with
saturated NaCl (800 mL), dried over anhydrous Na2SO4 and filtered.
To this CH2Cl2 solution was added Et3N (45.5 g, 0.45 mol) and Boc2O
(65.4 g, 0.3 mol) at room temprature. The mixture was stirred for
8 hours before water (500 mL) was added, the layers were separated,
the organic layer was washed with saturated NaCl (500 mL), dried
over anhydrous Na2SO4, filtered and concentrated to provide the
crude product 62 g, which was 94.5% ee by HPLC analysis. This was
recrystallised from toluene to give a pale yellow solid 11 (54.6 g,
0.157 mol), 83% for two steps. [α]D20 = + 13.5 (c 1.0, MeOH). M.p.
75–78 °C. lit.11 [α]D20 = + 15.2 (c 1.0, MeOH). M.p. 88–88.5 °C.} IR
(cm–1): 3364, 2980, 1733, 1683, 1519, 1422, 1368, 1332, 1252, 1210,
1155, 1095, 1029, 842. 1H NMR (400 MHz, CDCl3) δ 7.17– 6.97 (m,
1H), 6.97–6.75 (m, 1H), 5.18 (t, J = 9.6 Hz, 1H), 4.23–4.05 (m, 1H),
3.70 (s, 3H), 2.85 (d, J = 6.9 Hz, 2H), 2.55 (dd, J = 10.3, 5.4 Hz, 2H),
1.38 (s, 9H). ESI-MS: 347.7 (M+ +1).
Sitagliptin phosphate: To the solution of free base 1 (69.2 g,
0.17 mol) in ethanol (1000 mL), phosphoric acid (85 wt%, 10 g) was
added in one portion, and the temperature of the solution was raised
to 80 °C. After 30 minutes the mixture was cooled to 30 °C, and the
white solid which was formed was filtered and recrystallised from
i-PrOH, Sitagliptin Phosphate (82.4 g, 0.164 mol, 96%) was collected
as a white powder, the purity is 99.2%, The ee was assayed to be
20
99.5%. [α]D20 = –72.9 (c 1.0, H2O). M.p. 213–216 °C. {lit.10 [α]D
=
1
–74.4 (c 1.0, H2O). M.p. 215–217 °C.} H NMR (400 MHz, D2O) δ
7.23–7.05 (m, 1H), 7.05–6.86 (m, 1H), 4.85–4.80 (m, 2H), 4.16 (d,
J = 5.5 Hz, 1H), 4.10 (dt, J = 13.1, 6.0 Hz, 1H), 3.89–3.81 (m, 3H),
3.11–2.76 (m, 3H), 2.73 (ddd, J = 17.5, 10.1, 7.5 Hz, 1H).
The authors are grateful to the Shanghai Municipal Education
Commission, Research Fundation for Outstanding Young
Teachers in University (Grant No. YYY09021 A06/
4052K090094) for financial support.
Received 5 February 2010; accepted 22 March 2010
Published online 29 April 2010
3-R-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl) butyl]-
5,6,7,8-tetrahydro-[3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine
(13): A solution of 11 (76 g‚ 0.22 mol) in ethanol 300 mL was placed
to a three-necked round-bottomed flask, a solution of 300 mL aqueous
NaOH (16 g, 0.4 mol, 1.8 equiv) was added to the ethanol solution at
r.t. The mixture was stirred for 2.5 hours at which point TLC assay
indicated complete consumption of the ester starting material. The
ethanol was removed by distillation in a vacuum, and the resulting
solution was transferred to an extractor. 2 N HCl (200 mL, 0.4 mol,
1.8 equiv) and 500 mL of CH2Cl2 were added to the solution with
cooling. The layers were separated, and the aqueous layer was back-
extracted with 500 mL of CH2Cl2. The combined organic layers were
washed with saturated NaCl (500 mL), dried over anhydrous Na2SO4,
filtered and concentrated to provide a pale yellow coloured crude
product (66 g, 0.2 mol) in 91% yield. The crude acid which was
obtained above was mixed with 3-(trifluoromethyl)-5,6,7,8-tetrahy-
dro-1,2,4-triazolo[4,3-a] pyrazine hydrochloride (2, 45.6 g, 0.2 mol)
and dissolved in anhydrous DCM (400 mL). To the above solution
was added HOBT (27 g, 0.2 mol) followed by EDCI (38.2 g, 0.2 mol)
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