Novel and enantioselective syntheses of (R)- and (S)-3-hydroxy-4-(2,4,5- trifluorophenyl)butanoic acid: A synthon for sitagliptin and its derivatives

Article abstract of DOI:10.1016/j.tet.2012.01.095

A new synthetic strategy for (R)- and (S)-3-hydroxy-4-(2,4,5- trifluorophenyl)butanoic acid, a building block in the preparation of sitagliptin and its derivatives, was developed. Pd(OAc)₂ catalyzed coupling of 2,4,5-trifluoro-1-iodobenzene wit

Full text of DOI:10.1016/j.tet.2012.01.095

Tetrahedron 68 (2012) 2607e2610
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Novel and enantioselective syntheses of (R)- and (S)-3-hydroxy-4-(2,4,5-
trifluorophenyl)butanoic acid: a synthon for sitagliptin and its derivatives
Meryem Fistikci a, Ozlem Gundogdu a, Derya Aktas a, Hasan Secen a, M. Fethi Sahin b,
,
a,
*
Ramazan Altundas a , Yunus Kara
*
a Department of Chemistry, Faculty of Sciences, Ataturk University, 25240 Erzurum, Turkey
b Department of Pharmaceutical Research & Development, FARGEM Inc., Sancaklar, 81100 Duzce, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 August 2011
Received in revised form 11 January 2012
Accepted 31 January 2012
Available online 4 February 2012
A new synthetic strategy for (R)- and (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid, a building
block in the preparation of sitagliptin and its derivatives, was developed. Pd(OAc)2 catalyzed coupling of
2,4,5-trifluoro-1-iodobenzene with allyl alcohol gave 3-(2,4,5-trifluorophenyl)propanal in a yield of 95%.
L-Proline catalyzed reaction of the 3-phenylpropanal (in only 1.2 molar equiv) with nitrosobenzene
followed by reduction with NaBH4 and Pd/C catalyzed hydrogenation gave (R)-3-(2,4,5-trifluorophenyl)
propane-1,2-diol with >99% ee and 65% yield. Selective tosylation of primary hydroxyl group of the 1,2-
propandiol unit followed by cyanide displacement afforded (R)-3-hydroxy-4-(2,4,5-trifluorophenyl)bu-
Keywords:
(R)- and (S)-3-Hydroxy-4-(2,4,5-
trifluorophenyl)butanoic acid
Sitagliptin
tanenitrile (80%). The nitrile was converted to the title
90%. Thus, (R)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid was prepared enantioselectively from
the starting material in four steps and 45% overall yield. The reaction sequence was repeated with
b-hydroxy acid under basic hydrolysis in a yield of
D-
D
- andL-Proline
proline as the catalyst to give (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid in 45% overall yield
and >99% enantiomeric excess.
Aminoxylation
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
b-Hydroxy acid 3b has been used as a key compound in the
preparation of b-amino-acid 2. The use of b-hydroxy acid 3b in the
Sitagliptin (1), a
b
-amino acid, has been reported to be a potent,
synthesis of sitagliptin (1) was first reported by Merck.4 The key
step of their synthesis is to use (S)-BinapRuCl2 to catalyze the
asymmetric hydrogenation of the ketone in methyl 4-(2,4,5-
trifluorophenyl)-3-oxo-butanoate. Niddam-Hildesheim has re-
competitive, reversible inhibitor of the dipeptidyl peptidase IV
(DPP-IV) enzyme, which offers a new mechanism in achieving
glycemic control.1,2 Sitagliptin is constituted from
b
-amino acid and
triazolopyrazine units. Several synthetic methods for the prepara-
tion of sitagliptin have been developed by the coupling of -amino
cently described an enzymatic method for the preparation of b-
b
hydroxy-acid 2 from the same ketone derivative.5 Most recently,
Kim et al. have also prepared compound 3b by the arylation of (S)-
epichlorohydrin with 2,4,5-trifluorophenylmagnesium bromide via
a ring opening followed by simple functional group manipulations.6
acid 2 with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]tri-azolo
[4,3-a]pyrazine units to give 1. Therefore, syntheses of sitagliptin
(1) are mainly differentiated from each other by the preparation of
b
-amino acid 2, its corresponding ester, or N-protected derivatives.
Besides the importance of
-amino acid 2, 3b alone had DPP-IV activity. Zhu et al. have
found that imidazopyrazinone derivatives of -hydroxy acid 3b also
exhibit DPP-IV inhibitory effects.7 Meanwhile Kong and Liu have
b-hydroxy acid 3b in the preparation
The main challenge in this area is to enantioselectively prepare the
stereocenter present in the
of b
b
-amino acid unit.3
b
CF3
F
F
F
F
N
also reported that benzopyranyl esters of b-hydroxy acid 3b have
N
OH
OH
potential as insulin sensitizers in the treatment of diabetes.8
N
N
OH
O
NH2
O
NH2
O
In this paper we describe a novel, straightforward and efficient
synthesis of both the R and S enantiomeric forms of b-hydroxy acid
F
F
F
F
F
3, a building block in the preparation of antidiabetic drugs.
1 Sitagliptin
2 (R)
3a ;
3b ;
OH (R)
(S)
OH
2. Results and discussion
Our synthesis started from 2,4,5-trifluoro-1-iodobenzene (4). In
a recent paper, Pd(OAc)2 catalyzed Heck reaction of 4-fluoro-phenyl
iodide with allyl alcohol was reported to give 3-(4-fluorophenyl)
* Corresponding authors. Tel.: þ90 442 231 4406; fax: þ90 442 236 0962; e-mail
address: yukara@atauni.edu.tr (Y. Kara).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.095

2608
M. Fistikci et al. / Tetrahedron 68 (2012) 2607e2610
propanal in good yield.9 A slight modification of this procedure,
compound 4 was reacted with allyl alcohol to give 3-(2,4,5-
trifluorophenyl)propanal (5) in a yield of 95%. Many recent syn-
allowed us to obtain either 3a or 3b isomers of 3-hydroxy-4-(2,4,5-
trifluorophenyl)butanoic acid in high enantiomeric purities (>99%)
and in an overall yield of 65%. This protocol is attractive because of
the affordable chiral catalysts, the short synthetic sequence, and the
good overall yield. All reaction sequences are simple and can be
theses incorporated the proline catalyzed enantioselective a-ami-
noxylation of aldehydes and ketones using nitrosobenzene as the
oxygen source.10 In this reaction, a chiral enamine intermediate is
formed followed by reaction with nitrosobenzene to form the
corresponding oxyamine enantioselectively.
applicable to the large scale synthesis of b-hydroxynitrile 9 and b-
hydroxy acid 3. Aldehyde 5, synthesized for the first time in this
work, may find use as an important starting material in the alter-
native preparation of sitagliptin or sitagliptin derivatives
(Scheme 1).
One of the elegant applications of this method was performed
by Talluri and Sudalai11 in the total synthesis of (R)-selegiline using
3-phenylpropanal. In this method,
L-proline catalyzed oxy-
amination of 3-phenylpropanal followed by the reduction of the
carbonyl group with NaBH4. Reduction of the OeN bond by Pd/C
catalyzed hydrogenation gave (R)-3-phenyl-1,2-propandiol.
3. Experimental
3.1. General
Employing this method to prepare b-hydroxy acid 3 however,
gave suboptimal results. The same reaction conditions were applied
to propanal 5, but only a 30e40% yield of oxyamine 6a was ob-
tained. Modifying the amounts of L-proline, nitrosobenzene, and
aldehyde 5 systematically did not improve the reaction yield nor
did extended reaction times.
All commercial reagents and chromatography solvents were
used as obtained unless otherwise stated. Anhydrous solvents were
distilled over appropriate drying agents prior to use. Analytical thin
layer chromatography (TLC) was performed on Merck silica gel 60
F254. Fluka Silica gel 60 (0.063e0.2 mm) was used for column
chromatography.
After these observations, we thought that a minimal amount of
water might be crucial for the catalytic cycle of
L
-proline. The role
Visualization of TLC was accomplished with UV light (254 nm)
and by staining with ethanolic PMA (phosphomolybdic acid) so-
lution. HPLC was carried out on a Thermo Finnigan Spectra System
P1000 with a chiral column (CHIRALPAKÒ AS, n-hexane/i-PrOH, 211
and 220 nm) and a polarimetric chiralyser detector for the rotation
of enantiomers. Elemental analyses were performed on a Leco
CHNS-932. MS was recorded using a varian GC/MS/MS.
Specific rotations were measured on a Bellingham Stanley ADP
220 589 nm polarimeter in a 1 dm tube. IR spectra were recorded
on PerkineElmer Spectrum One FT-IR Spectrometer. NMR spectra
were recorded using a Varian 400 MHz NMR instrument (1H NMR
at 400 MHz, 13C NMR at 100 MHz) or a Bruker 400 MHz instrument
(1H NMR at 400 MHz, 13C NMR at 100 MHz).
of H2O in the proline catalyzed reactions was also reported in
previous papers.12 When we repeated the reaction in wet DMSO
(DMSO/H2O, 97:3), we found that the yield slightly increased. As
suggested in previous oxyamination studies,10 we also screened
other solvent systems, such as CH2Cl2, CHCl3, and CH3CN, but no
enhancement in yield was achieved. We also observed that the
oxyamine 6a was not very stable on silica gel or standing in the
refrigerator. Therefore, the quick filtration of crude oxyamine 6a
through a pad of silica gel with EtOAc and direct reduction of the
OeN bond improved the overall yield to 65% from 5. We also tried
to reduce the amount of aldehyde needed as previously described
methods require at least 3 equiv of aldehyde. We found that using
only 1.2 equiv of aldehyde were enough to achieve the optimal
conditions. Furthermore, the use of CHCl3 in the catalytic hydro-
genation as a dry HCl producer improved the formation of diol 7a
as a clean product.
3.1.1. 3-(2,4,5-Trifluorophenyl)propanal (5). To a stirred solution of
2,4,5-trifluoroiodobenzene (4) (1.50 g, 5.87 mmol), Pd(OAc)2
(26 mg, 2 mol %), triethylbenzylammonium chloride (1.32 g,
5.79 mmol), and NaHCO3 (0.98 g, 11.7 mmol) in 4 mL of DMF was
added allyl alcohol (0.67 g, 0.79 mL, 11.6 mmol) under N2 atm. The
resulting dark brown solution was heated at 45 ꢀC for 20 h. The
reaction was quenched with saturated NH4Cl (10 mL) and extracted
with EtOAc (3ꢃ25 mL). The combined organic layers were dried
over Na2SO4, filtered, and concentrated in vacuo. The crude product
was purified by a silica gel column to give 5 (1.04 g; 95%). Light
yellow liquid. (Rf: 0.2, 5:95 EtOAc/hexanes). GC/MS/MS (CI) (150 eV)
m/z (rel intensity, %) 189.1 (Mþþ1, 13), 144.9 (100). 1H NMR
We continued our efforts to improve the yield, so we changed
the oxyamination reagent to the readily available p-nitro-
nitrosobenzene, which is more electrophilic due to its electron
poor character. Unfortunately the oxyamination of 5 was repeated
with p-nitronitrosobenzene in our already established conditions,
and it resulted in
nitrosobenzene.
a lower yield than that achieved with
With 7a in hand, the primary tosylate was formed selectively
at 0 ꢀC, and subsequently displaced with NaCN in DMF to give
butanenitrile 9a in 65% yield. Hydrogen peroxide catalyzed hy-
(400 MHz, CDCl3)
d
¼9.80 (br s, 1H, CHO), 7.04 (ddd, 1H, H-60,
drolysis of the nitrile 9a with aqueous NaOH gave
b
-hydroxy acid
JH,F¼15.6, 8.4, 6.8 Hz), 6.88 (dt, 1H, H-30, JH,F¼10.0, 6.8 Hz), 2.92 (A2
part of A2X2 system, quasi t, 2H, 2ꢃH-3, J¼7.2 Hz), 2.78 (X2 part of
A2X2 system, quasi t, 2H, 2ꢃH-2, J¼7.2 Hz). 13C NMR (100 MHz,
3a. The specific optical rotation of the obtained acid 3a (½a D26
ꢁ
ꢂ8.00) was different from that of 3b (½a D26
þ16.3), which is well
ꢁ
defined in the literature.4 In order to determine the enantiopurity
of carboxylic acid 3a, we converted 3a to its ethyl ester 10a and
ran a chiral HPLC analysis, which showed an enantiomeric purity
of >99% (Scheme 1).
CDCl3)
d
¼200.4 (C-1), 156.1 (ddd, C-20, JC,F¼242.7, 9.1, 2.6 Hz), 148.9
(ddd, C-40, JC,F¼248.4, 14.1, 12.4 Hz), 146.8 (ddd, C-50, JC,F¼243.4,
12.4, 3.7 Hz), 123.8 (ddd, C-10, JC,F¼18.1, 5.5, 4.3 Hz), 118.4 (dd, C-60,
JC,F¼19.0, 5.7 Hz), 105.6 (dd, C-30, JC,F¼28.1, 20.6 Hz), 43.7 (C-2), 21.4
(C-3). IR (neat) 3065, 2934, 2829, 2725,1725,1632,1522,1425,1388,
Applying the same sequence to propanal 5 using D-proline as
a catalyst, we successfully obtained diol (R)-7b, cyanide (R)-9b, and
carboxylic acid (R)-3b. Interestingly, the specific optical rotation of
1333, 1211, 1152, 1099 cmꢂ1
.
(R)-3b was also lower than those reported in the literature: (½a D26
ꢁ
3.1.2. (R)-3-(2,4,5-Trifluorophenyl)propane-1,2-diol (7a). To a solu-
tion of 3-(2,4,5-trifluorophenyl)propanal (300 mg, 1.59 mmol) (5)
þ9.0). Chiral HPLC of (R)-3b was analyzed by its corresponding
ethyl ester 10b, which showed its enantiomeric purity to be >99%.
in 2 mL of DMSO/H2O (97:3) was added
L-proline (30 mg,
In conclusion,
L
- or
D
-proline catalyzed hydroxylation of alde-
0.26 mmol) at rt. After the reaction mixture was stirred for 3 min,
nitrosobenzene (142 mg, 1.33 mmol) was added in one portion to
give a green solution. The reaction mixture was stirred for 30 min
at 30 ꢀC. After the color of the solution turned orange, the tem-
perature was lowered to 0 ꢀC and diluted with MeOH (4 mL).
hyde 5 was achieved in one step without the separation of the
oxyamination intermediate. We showed that the use of aldehyde 5
in 1.2 molar equiv was enough to achieve optimal yield. Simple
functional group manipulations, such as cyanation and hydrolysis

M. Fistikci et al. / Tetrahedron 68 (2012) 2607e2610
2609
F
F
F
F
F
F
I
OH
ii
i
OH
iii
O
R
R
F
F
F
F
F
F
4
5
ONHPh
ONHPh
6a; R=
6b; R=
OH
OH
7a; R=
7b; R=
iv
F
F
F
F
v
vi
OTs
COOH
CN
R
R
R
F
F
F
F
F
8a; R1= OH
9a; R1=
OH
OH
OH
OH
3a; R=
3b; R=
8b; R1=
9b; R1=
OH
vii
F
COOEt
R
F
F
10a; R= OH
OH
10b; R=
Scheme 1. (i) Ally alcohol, Pd(OAc)2 (cat.), NaHCO3, benzyltriethylammonium chloride, DMF, 45 ꢀC, 18 h, 95%. (ii) (a) PhNO, Proline (cat.), DMSO/H2O (97:3), 30 ꢀC; (b) NaBH4, MeOH,
0 ꢀC; (iii) H2, Pd/C, CHCl3, EtOH; 5 (L-proline)/7a; 5 (D-proline)/7b, 65%; (iv) TsCl, NEt3, CH2Cl2, 0 ꢀC, 15 h; (v) NaCN, DMF, 75 ꢀC, 19 h, (7a/9a; 7b/9b; 65%); (vi) 3 M NaOH, H2O2
100 ꢀC, 3 h 90%; (vii) EtOH, H2SO4 (cat.), 70 ꢀC, 18 h.
NaBH4 (200 mg, 5.26 mmol) was added carefully. The reaction
mixture was stirred for 30 min and then quenched with 15 mL of
a saturated (NH4)2SO4 solution. The organic phase was extracted
with EtOAc (3ꢃ20 mL). The combined organic layers were dried
over Na2SO4 and filtered. The solvent was evaporated to give
crude 6a (410 mg). The crude product was submitted to Pd/C
catalyzed hydrogenation without further purification and
identification.
3.1.3. (S)-3-(2,4,5-Trifluorophenyl)propane-1,2-diol (7b). The pro-
cedure above described for 7a was applied using D-proline in a yield
of 65%. White solid. ½a D26
ꢂ36 (c 1, EtOH).
ꢁ
3.1.4. (R)-3-Hydroxy-4-(2,4,5-trifluorophenyl) butanenitrile (9a). To
a solution of TosCl (493 mg, 2.6 mmol) in CH2Cl2 (10 mL) was added
NEt3 (262 mg, 0.36 mL, 2.59 mmol) under N2 atm at 0 ꢀC. The re-
action mixture was stirred for 1 h. After that, a solution of (R)-3-
(2,4,5-trifluorophenyl)propane-1,2-diol (486 mg, 2.36 mmol) (7a)
in CH2Cl2 (10 mL) was slowly added into this mixture. The reaction
mixture was stirred for 15 h at rt. Water was added and the reaction
layer was separated. The aqueous layer was extracted with CH2Cl2
(3ꢃ25 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated in vacuo. The crude product was filtered
through a pad of silica gel with EtOAc/hexanes to obtain 8a
(657 mg). It was used in the next reaction without further purifi-
cation and identification.
To a solution of 6a (410 mg) in EtOH (15 mL) were added CHCl3
(0.5 mL; a source of dry HCl) and 40 mg of Pd/C (%10). The reaction
flask was purged with hydrogen gas three times before being
allowed to stir under a hydrogen balloon for 12 h. Then, the re-
action mixture was filtered and the solvent was evaporated. The
residue was dissolved in EtOAc (40 mL) and 20 mL of a saturated
(NH4)2SO4 solution was added. The organic phase was separated
and dried over Na2SO4 and filtered. Evaporation of the solvent and
chromatography of the residue on a silica gel column gave 7a
(177 mg; 65%, according to PhNO). White solid. Mp: 68e69 ꢀC. (Rf:
Compound 8a (657 mg, 1.82 mmol) and NaCN (268 mg,
5.47 mmol) was dissolved in DMF (6 mL) under N2 atm. The re-
action mixture was stirred for 19 h at 75 ꢀC. After the reaction was
completed, the reaction mixture was quenched with H2O (30 mL)
and extracted with EtOAc (3ꢃ25 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by silica gel column to give 9a (336 mg;
0.2, 50% EtOAc/hexanes). ½a D26
þ36 (c 1, EtOH). Anal. Calcd for
ꢁ
C9H9F3O2: C, 52.43; H, 4.40. Found: C, 52.43; H, 4.71. 1H NMR
(400 MHz, CDCl3)
d
¼7.08 (ddd, 1H, H-60, JH,F¼16.0, 8.8, 7.2 Hz), 6.90
(dt, 1H, H-30, JH,F¼9.6, 6.8 Hz), 3.94e3.86 (m, 1H, H-2), 3.66 (A part
of AB system, dd, 1H, H-1a, J1a,1b¼11.2 Hz, J1a,2¼2.9 Hz), 3.46 (B part
of AB system, dd, 1H, H-1b, J1a,1b¼11.2 Hz, J1b,2¼7.0 Hz), 2.84 (br s,
2H, OH), 2.79 (A part of AB system, dd, 1H, H-3a, J3a,3b¼14.1 Hz,
J2,3a¼5.2 Hz), 2.71 (B part of AB system, dd,1H, H-3b, J3a,3b¼14.1 Hz,
65%). Light yellow oil (Rf: 0.2, %20 EtOAc/hexanes). ½a D26
þ2 (c 1,
ꢁ
CHCl3). 1H NMR (400 MHz, CDCl3)
d
¼7.11 (ddd, 1H, H-60, JH,F¼15.7,
J2,3b¼7.9 Hz). 13C NMR (100 MHz, CDCl3)
d
¼156.3 (ddd, C-20,
8.6, 6.9 Hz), 6.94 (dt, 1H, H-30, JH,F¼10.0, 6.4 Hz), 4.24e4.12 (m, 1H,
H-3), 2.92 (A part of AB system, dd, 1H, H-4a, J4a,4b¼14.1 Hz,
J3,4a¼4.9 Hz), 2.83 (B part of AB system, dd, 1H, H-4b,J3,4b¼14.1 Hz,
J3,4b¼7.8 Hz), 2.61 (A part of AB system, dd, 1H, H-2a, J2a,2b¼16.7 Hz,
J2a,3¼4.8 Hz), 2.52 (B part of AB system, dd, 1H, H-2b, J2a,2b¼16.7 Hz,
J2b,3¼6.5 Hz). 2.39 (br s, 1H, OH). 13C NMR (100 MHz, CDCl3)
JC,F¼242.4 Hz, 9.1, 2.1 Hz), 149.0 (ddd, C-40, JC,F¼248.6, 14.2,
12.6 Hz), 146.8 (ddd, C-50, JC,F¼243.3, 12.4, 3.1 Hz), 121.4 (ddd, as dt,
C-10, JC,F¼17.7, 4.9, 4.9 Hz), 119.4 (dd, C-60, JC,F¼19.0, 6.1 Hz), 105.5
(dd, C-30, JC,F¼28.4, 20.6 Hz), 71.8 (C-2), 66.1 (C-1), 32.4 (C-3). IR
(neat) 3256, 2930, 1632, 1518, 1442, 1424, 1377, 1329, 1212, 1150,
1096, 1028, 843 cmꢂ1
.
d
¼156.3 (ddd, C-20, JC,F¼243.5, 8.9, 2.8 Hz), 149.5 (ddd, C-40,

2610
M. Fistikci et al. / Tetrahedron 68 (2012) 2607e2610
JC,F¼249.8, 14.3, 12.5 Hz), 147.0 (ddd, C-50, JC,F¼237.3, 12.3, 3.2 Hz),
120.0 (ddd, C-10, JC,F¼17.2, 5.3, 4.1 Hz), 119.6 (ddd, C-60, JC,F¼19.1, 5.8,
1.2 Hz), 117.3 (C-1) 105.9 (dd, C-30, JC,F¼28.4, 20.7 Hz), 67.4 (C-3),
35.7 (C-4), 25.9 (C-2). IR (neat) 3449, 2929, 2255, 1633, 1520, 1425,
1334, 1212, 1153, 1075 cmꢂ1. HRMS (ES): MHþ, found 216.0631.
C10H9F3NO requires 216.0636.
1H, H-2a, J2a 2b
,
¼16.8 Hz, J2a,3¼3.2 Hz), 2.43 (B part of AB system, dd,
1H, H-2b, J2a,2b¼16.8 Hz, J2b,3¼9.2 Hz), 1.27 (t, 3H, OCH2CH3,
J¼7.0 Hz). 13C NMR (100 MHz, CDCl3)
d
¼172.7 (s, eCO), 156.2 (C-20,
ddd, JC,F¼242.6, 9.2, 2.6 Hz), 149.0 (C-40, ddd, JC,F¼260.9, 14.3,
12.4 Hz), 146.8 (C-50, ddd, JC,F¼243.1, 12.4, 3.4 Hz), 121.3 (C-10, ddd,
JC,F¼18.0, 5.6, 4.2 Hz), 119.6 (C-60, ddd, JC,F¼19.0, 6.0, 1.2 Hz), 105.4
(C-30, dd, JC,F¼28.8, 20.7 Hz), 67.8(C-3), 61.1 (OCH2CH3), 40.6 (C-2),
35.2(C-4), 14.3 (OCH2CH3). IR (neat) 3722, 3483, 3055, 2983, 2933,
1732, 1633, 1520, 1425, 1334, 1268, 1210, 1190, 1152, 1099,
1030 cmꢂ1. HRMS (ES): MHþ, found 263.0899. C12H14F3O3 requires
263.0895.
3.1.5. (S)-3-Hydroxy-4-(2,4,5-trifluorophenyl) butanenitrile (9b).
The procedure above described for 9a was applied to diol 7b to give
nitrile 9b in a yield of 66%. ½a D26
ꢂ2 (c 1, CHCl3).
ꢁ
3.1.6. (R)-3-Hydroxy-4-(2,4,5-trifluorophenyl) butanoic acid (3a). To
a mixture of nitrile 9a (440 mg, 2.04 mmol) in 3 M NaOH (12 mL)
was added 35% aqueous H2O2 (4 mL). The reaction mixture was
heated at 100 ꢀC for 3 h. After the reaction was completed, the
reaction mixture was cooled to 0 ꢀC. To remove organic impurities,
Et2O (50 mL) was added and the ether phase was dispatched. Then
the aqueous phase was acidified with 6 M HCl (ca. pH¼1) and was
extracted with Et2O (50 mL), and dried over Na2SO4. Filtration and
evaporation of the solvent gave 3a (437 mg, 90%). White solid. Mp
3.1.9. (S) Ethyl 3-hydroxy-4-(2,4,5-trifluoro-phenyl)butanoate (10b).
The procedure above described for 10a was applied to nitrile 3b to
give carboxylic acid 10b in a yield of 86%. Light yellow oil (Rf: 0.86, %
50 EtOAc/hexanes) ½a D26
þ13 (c 1, CHCl3).
ꢁ
Acknowledgements
The authors would like to thank the Ministry of Science, In-
dustry and Technology, the Republic of Turkey, FARGEM for their
financial support (Grant No: 00484.STZ.2009-2). The authors also
thank Dr. B. Shook, Jhonson&Jhonson, USA, and Bilal Altundas for
his support in critical reading of this article.
86e87 ꢀC (lit.4 Mp 84 ꢀC) ½a 2D6
ꢁ
ꢂ8 (c 1, CHCl3), (lit.4) ½a D26
ꢁ
þ16.3 (c 1,
CHCl3). 1H NMR (400 MHz, CD3OD)
d
¼7.24 (ddd,1H, H-60, J6 -F¼15.6,
0
8.8, 6.8 Hz), 7.09 (ddd, quasi dt, 1H, H-30, J3 -F¼10.4, 6.4 Hz),
4.25e4.19 (m, 1H, H-3), 2.84 (A part of AB system, dd, 1H, H-4a,
J4a,4b¼13.6 Hz, J3-4a¼4.4 Hz), 2.74 (B part of AB system, dd, 1H, H-4b,
J4a,4b¼13.6 Hz, J3,4b¼7.6 Hz), 2.48 (A part of AB system, dd, 1H, H-2a,
J2a,2b¼15.4 Hz, J2a,3¼5.2 Hz). 2.42 (B part of AB system, dd, 1H, H-2b,
J2a,2b¼15.4 Hz, J2b,3¼8 Hz). 13C NMR (100 MHz, CD3OD)
0
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.01.095.
d
¼173.9(eCO2H), 156.5 (C-20, ddd, JC,F¼242.7, 9.4, 2.1 Hz), 148.8 (C-
40, ddd, JC,F¼246.3, 14.3, 12.7 Hz), 146.6 (C-50, ddd, JC,F¼241.1, 12.6,
3.5 Hz), 122.3 (C-10, ddd, JC,F¼18.3, 5.8, 4.2 Hz), 119.3 (C-60, dd,
JC,F¼19.3, 6.2 Hz), 104.9 (C-30, dd, JC,F¼29.2, 21.0 Hz), 67.8(C-3), 41.4
(C-2), 35.4(C-4). IR (neat) 3747, 3428, 3064, 2933, 2621, 1714, 1633,
1520, 1426, 1334, 1281, 1212, 1153, 1101 cmꢂ1. HRMS (ES): MHþ,
found 235.0570. C10H10F3O3 requires 235.0582.
References and notes
1. Thornberry, N. A.; Weber, A. E. Curr. Top. Med. Chem. 2007, 7, 557e568.
2. Aschner, P.; Kipnes, M. S.; Lunceford, J. K.; Sanchez, M.; Mickel, C.; Williams-
Herman, D. E.Sitagliptin Study, G. Diabetes Care 2006, 29, 2632e2637.
3. For a graphical synthetic routes for sitaglaptin see review: Sun, G. F.; Cai, Z. Y.;
Zhou, W. C. Chinese J. Pharm. 2008, 39, 383e386.
4. Hansen, K. B.; Balsells, J.; Dreher, S.; Hsiao, Y.; Kubryk, M.; Palucki, M.; Rivera,
N.; Steinhuebel, D.; Armstrong, J. D.; Askin, D.; Grabowski, E. J. J. Org. Process
Res. Dev. 2005, 9, 634e639.
3.1.7. (S)-3-Hydroxy-4-(2,4,5-trifluorophenyl) butanoic acid (3b).
The procedure above described for 3a was applied to nitrile 9b to
give carboxylic acid 3b in a yield of 90%. White solid. ½a D26
þ8 (c 1,
ꢁ
5. Niddam-Hildesheim, V. WO Patent 045507, 2009; Chem. Abstr. 2009, 150,
396693.
CHCl3).
6. Kim, N. D.; Chang, J. Y.; Jung, J. H.; Lee, H. S.; Kim, D. J.; Chang, Y. K.; Lee, G. S.
WO Patent 040717, 2011; Chem. Abstr. 2011, 154, 434511.
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J. Med. Chem. 2010, 45, 4953e4962.
3.1.8. (R) Ethyl 3-hydroxy-4-(2,4,5-trifluoro-phenyl)butanoate (10a).
(S)-3-Hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid (3a) (51 mg)
was dissolved in EtOH (3 mL) and 2 drops of H2SO4 was added. The
reaction mixture was heated at 70 ꢀC for 18 h. After the reaction was
completed, the reaction mixture was cooled to rt and concentrated
in vacuo. The residue was diluted with 10 mL of H2O and extracted
with 15 mL of EtOAc. The organic phase was dried over Na2SO4.
After filtration, the solvent was removed in vacuo to afford 10a
8. Kong, D.; Liu, Y. CN Patent 101481371, 2009; Chem. Abstr. 2009, 151, 245398.
9. Boros, E. E.; Edwards, C. E.; Foster, S. A.; Fuji, M.; Fujiwara, T.; Garvey, E. P.;
Golden, P. L.; Hazen, R. J.; Jeffrey, J. L.; Johns, B. A.; Kawsuji, T.; Kiyama, R.; Koble,
C. S.; Kurose, N.; Miller, W. H.; Mote, A. L.; Murai, H.; Sato, A.; Thompson, J. B.;
Woodward, M. C.; Yoshinaga, T. J. Med. Chem. 2009, 52, 2754e2761.
10. (a) Hayashi, Y.; Shoji, M. Catal. Fine Chem. Synth. 2007, 5, 194e199; (b) Kotkar, S.
P.; Sudalai, A. Tetrahedron Lett. 2006, 47, 6813e6815; (c) Sunden, H.; Dahlin, N.;
Ibrahem, I.; Adolfsson, H.; Cordova, A. Tetrahedron Lett. 2005, 46, 3385e3389;
(d) Bogevig, A.; Sunden, H.; Cordova, A. Angew. Chem., Int. Ed. 2004, 43,
1109e1111.
(48 mg, 86%). Light yellow oil (Rf: 0.86, %50 EtOAc/hexanes) ½a D26
ꢁ
ꢂ13 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3)
d
¼7.12 (ddd, 1H, H-60,
11. Talluri, S. K.; Sudalai, A. Tetrahedron 2007, 63, 9758e9763.
12. (a) Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33e57;
(b) Yang, L.; Liu, R. H.; Wang, B.; Weng, L. L.; Zheng, H. Tetrahedron Lett. 2009,
50, 2628e2631.
JH,F¼17.2, 8.8, 6.2 Hz),6.90 (dt, 1H, H-30, JH,F¼9.7, 6.8 Hz), 4.28e4.20
(m, 1H, H-3), 4.17 (q, 2H, OCH2CH3, J¼7.0 Hz), 3.17 (br s, 1H, eOH),
2.78 (quasi d, 2H, 2ꢃH-4, J3,4¼6.4 Hz), 2.52 (A part of AB system, dd,