Nonracemic synthesis of GK-GKRP disruptor AMG-3969

Article abstract of DOI:10.1021/jo500336e

A nonracemic synthesis of the glucokinase-glucokinase regulatory protein disruptor AMG-3969 (5) is reported. Key features of the synthetic approach are an asymmetric synthesis of the 2-alkynyl piperazine core via a base-promoted isomerization and a revised approach to the synthesis of the aminopyridinesulfonamide with an improved safety profile.

Full text of DOI:10.1021/jo500336e

Note
pubs.acs.org/joc
Nonracemic Synthesis of GK−GKRP Disruptor AMG-3969
Matthew P. Bourbeau,*,† Kate S. Ashton,† Jie Yan,‡ and David J. St. Jean, Jr.†
†Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
‡Amgen Inc. 360 Binney Street, Cambridge, Massachusetts 02142, United States
S
* Supporting Information
ABSTRACT: A nonracemic synthesis of the glucokinase−glucokinase
regulatory protein disruptor AMG-3969 (5) is reported. Key features of
the synthetic approach are an asymmetric synthesis of the 2-alkynyl
piperazine core via a base-promoted isomerization and a revised approach to
the synthesis of the aminopyridinesulfonamide with an improved safety
profile.
e recently reported the development of a series of
Wdisruptors of the glucokinase (GK)−glucokinase regu- 5.
latory protein (GKRP) protein−protein interaction. Animals
dosed with these compounds show improved metabolic
profiles, and thus these compounds may hold potential for
the treatment of diabetes in humans.1−3 As part of our research
program, a significant quantity of compound AMG-3969 (5)
was required for in vivo efficacy and toxicology studies. This
material demand caused us to re-evaluate our synthetic
approach to 5 with an eye toward improving efficiency and
safety. The original synthetic approach to 5 began from
protected piperazanone 1 (prepared in 81% yield from 2-
piperazinone), which was treated with propynyl Grignard to
afford alkynone 2 (Scheme 1).1 Boc cleavage promoted by TFA
and reduction of the resulting imine afforded racemic 2-alkynyl
piperazine 3 that was further elaborated to chloropyridine 4.
Displacement of the chloride with ammonia at elevated
temperature, followed by chiral supercritical fluid chromatog-
raphy (SFC), afforded 5 in 99% ee. When we considered how
to improve on our original approach to the synthesis of 5, there
were two particular aspects that we focused on. The first was
the synthesis of the 2-alkynyl piperazine core. We hoped to
develop an asymmetric method to install the propynyl group,
obviating the need for a large-scale, late-stage enantiomer
separation. To the best of our knowledge, there are no prior
examples in the literature of the asymmetric synthesis of 2-
alkynyl piperazines. Second, we sought to develop an
alternative method for the installation of the aminopyridine
functional group. Aminolysis of chloropyridine 4 required
forcing conditions which resulted in significant pressurization of
the reaction vessel (∼110 psi). Differential scanning calorimetry
analysis of this reaction also showed a large exotherm at 140
°C. For an exotherm of this magnitude, we would prefer to run
the reaction 100 °C cooler than the exotherm temperature,
which in this case would be significantly below the temperature
required for conversion. Thus, an alternative method to install
the aminopyridine was required for large-scale preparations of
Our revised retrosynthetic analysis of 5 led us to protected
sulfonyl chloride 6 and 2-propynylpiperazine 7 (Figure 1).
Compound 7 was expected to be synthesized by palladium-
catalyzed cross-coupling of aryl bromide 8 with piperazine 9. It
was postulated that 9 could be prepared by base-promoted
isomerization of terminal alkyne 10. While there is good
precedence for KOtBu-mediated isomerization of terminal
alkynes, we were uncertain whether such a transformation
would potentially erode the enantiopurity of the product.4
Compound 10 could be readily prepared from chiral diketo-
piperazine 11, itself the product of commercially available
glycine and propargylglycine derivatives 12 and 13.
The synthesis began with 1-[bis(dimethylamino)methylene]-
1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-
phosphate-mediated amide coupling of ethyl 2-(benzylamino)-
acetate (14) and (2S)-2-((tert-butoxycarbonyl)amino)-4-penty-
noic acid (propargyl glycine, 15, purchased from Matrix
Scientific; Scheme 2). Boc cleavage and treatment with
ammonia in methanol resulted in the formation of piperazine-
dione 16 in good yield.5 Treatment of 16 with LiAlH4 resulted
in reduction to the corresponding piperazine, setting the stage
for the planned alkyne isomerization. The crude reduction
product was treated with KOtBu in THF for 30 min at room
temperature, resulting in complete isomerization to the alkynyl
piperazine 17. Compound 17 then underwent palladium-
mediated cross-coupling with 86 utilizing Buchwald’s RuPhos
first-generation precatalyst to afford aryl piperazine 18 in
quantitative yield.7 Benzyl group cleavage promoted by 1-
chloroethyl chloroformate afforded piperazine 7, also in
quantitative yield.8 To eliminate the need for the late-stage,
high-pressure aminolysis used in the first-generation synthesis,
Received: February 12, 2014
Published: March 28, 2014
© 2014 American Chemical Society
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Note
a
Scheme 1
a
Reagents and conditions: (a) 1-propynylmagnesium bromide, THF, 0 °C, 99%; (b) TFA, DCM, then NaBH(OAc)3 77%; (c) NH4OH, EtOH, 120
°C, 88%; (d) chiral SFC, 38%.
Figure 1. Second-generation retrosynthetic analysis of 5.
a
Scheme 2
a
Reagents and conditions: (a) HATU, DIPEA, DMF then TFA, DCM, then NH3, MeOH, 78%; (b) LiAlH4, THF, 0 °C to reflux, then KOtBu, 67%;
(c) 8, RuPhos first-generation precatalyst, NaOtBu, 80 °C, 100%; (d) 1-chloroethyl chloroformate, K2CO3, 100%; (e) NaNO2, HCl, then AcOH,
CuCl, CuCl2, SO2, 64%; (f) 18, Et3N, then TFA, 49%.
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Note
piperazinedione 16 (37.3 g, 154 mmol) and 150 mL of THF. The
suspension was cooled to 0 °C, then lithium aluminum hydride (1 M
in THF, 539 mL, 539 mmol) was slowly added. After the addition was
complete, the mixture was heated at 80 °C for 12 h. The mixture was
then cooled to 0 °C, and solid sodium sulfate decahydrate was added
until effervescence ceased. The mixture was then filtered, and the
filtrate was concentrated to give (3S)-1-benzyl-3-(2-propyn-1-yl)-
piperazine (18.1 g) as a yellow oil. This material was combined with an
additional 20.7 g of crude amine synthesized in a similar manner. The
combined lots were used directly in the next step without purification.
To a solution of (3S)-1-benzyl-3-(2-propyn-1-yl)piperazine (38.8 g,
181 mmol) in THF (200 mL) was added potassium t-butoxide (40.6 g,
362 mmol) portionwise. After the addition was complete, the reaction
mixture was stirred at room temperature for 30 min and then
quenched with water (500 mL) and diluted with EtOAc (1 L). The
organic phase was dried (Na2SO4), filtered, and concentrated to give a
solid. Purification via silica gel chromatography (0−7% MeOH in
CH2Cl2) followed by recrystallization from 100% hexanes provided
(3S)-1-benzyl-3-(1-propyn-1-yl)piperazine 17 (26.0 g, 67%) as tan
crystalline solid: 1H NMR (400 MHz, CDCl3) δ 7.36−7.18 (m, 5 H),
3.59 (br d, J = 8.8 Hz, 1 H), 3.51 (s, 2 H), 2.98 (d, J = 11.9 Hz, 1 H),
2.88−2.76 (m, 2 H), 2.65 (d, J = 11.0 Hz, 1 H), 2.22−2.05 (m, 2 H),
1.84−1.76 (s, 3 H), 1.73 (br s, 1 H); 13C NMR (101 MHz, CD3OD) δ
138.5, 130.7, 129.5, 128.5, 80.3, 78.9, 64.0, 59.8, 53.8, 48.0, 45.5, 3.2;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C14H19N2 215.1548,
Boc-protected aminopyridyl sulfonyl choride 20 (purchased
from Green Chempharm, Inc.) was utilized, which was
synthesized from commercially available aniline 19.9 Finally,
piperazine 7 was coupled with sulfonyl chloride 20, followed by
TFA deprotection of the Boc group to deliver compound 5 in
good yield. HPLC characterization of compound 5 prepared via
the second-generation approach showed the resulting product
to be >99% ee, indicating that the alkyne isomerization had
occurred with complete retention of configuration. This
protocol has been utilized to prepare >60 g lots of compound
5. Compared to the original route, this new approach resulted
in a significantly higher overall yield of 5 (original route from 2-
piperazinone: 7 steps longest linear sequence, 14% yield; new
route from Boc-(S)-propargylglycine: 5 steps longest linear
sequence, 26% yield).
In summary, we have developed an improved synthesis of the
GK−GKRP disruptor 5 featuring a novel asymmetric route to
the 2-alkynyl piperazine core and a safer, more easily scalable
route to the aminopyridine sulfonamide. In particular, the
alkyne isomerization used to generate the chirally pure alkynyl
piperazine 17 may offer a potentially useful method for the
synthesis of other 2-alkynyl piperazines.
20
found 215.1551; mp 65−68 °C, [α]D = −55.4 (c = 2.9, MeOH).
EXPERIMENTAL SECTION
(S)-2-(4-(4-((6-Aminopyridin-3-yl)sulfonyl)-2-(prop-1-yn-1-
yl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol,
AMG-3969 (5). A 2 L round-bottomed flask was charged with (S)-1-
benzyl-3-(prop-1-yn-1-yl)piperazine 17 (50.0 g, 233 mmol), 2-(4-
bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (98.0 g, 303 mmol),
300 mL of dioxane, and sodium tert-butoxide (56.1 g, 583 mmol).
After nitrogen gas was bubbled through the solution for 5 min,
chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-
(2-aminoethylphenyl)]palladium(II),methyl-tert-butylether adduct
(6.80 g, 9.33 mmol) was added, and the mixture was then heated to
70 °C under an inert atmosphere. After 12 h at 80 °C, the mixture was
allowed to cool to room temperature, concentrated, and partitioned
between water and EtOAc. The organic extracts were separated,
washed with brine, dried (MgSO4), filtered, and concentrated to give a
brown solid. This solid was dissolved in CH2Cl2 and passed through a
plug of silica gel (approx 1 kg) to give (S)-2-(4-(4-benzyl-2-(prop-1-
yn-1-yl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol 18
(110 g) as a brown oil. The product was carried on without additional
purification: 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.6 Hz, 2 H),
7.44−7.39 (m, 2 H), 7.38−7.32 (m, J = 7.3, 7.3 Hz, 2 H), 7.30−7.27
(m, J = 7.2 Hz, 1 H), 7.06−6.95 (m, J = 9.2 Hz, 2 H), 4.47−4.38 (m, 1
H), 3.73 (d, J = 13.5 Hz, 1 H), 3.54 (d, J = 13.5 Hz, 1 H), 3.50−3.44
(m, 1 H), 3.40−3.30 (m, 1 H), 3.07−2.94 (m, 2 H), 2.41−2.31 (m, 2
H), 1.82 (d, J = 2.2 Hz, 3 H); 13C NMR (101 MHz, CD3OD) δ 150.9,
137.4, 128.9, 127.9, 127.4, 126.9, 123.4 (q), 121.9, 115.5, 79.5, 77.1
■
General Considerations. Unless otherwise noted, all reagents
were commercially available and used as received. H NMR and 13C
1
NMR spectra were recorded on a 400 MHz (101 MHz for 13C) NMR
spectrometer at ambient temperature. Data are reported as follows:
chemical shift (ppm, δ units) from an internal standard, multiplicity (s
= singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br =
broad), coupling constant (Hz), and integration. Silica gel
chromatography was performed using a medium-pressure liquid
chromatography system, and melting point data were generated
using a melting point apparatus.
(3S)-1-Benzyl-3-(2-propyn-1-yl)-2,5-piperazinedione (16). A
1 L round-bottomed flask was charged with (2S)-2-((tert-butoxy-
carbonyl)amino)-4-pentynoic acid 15 (42.0 g, 197 mmol, purchased
from Matrix Scientific), ethyl 2-(benzylamino)acetate 14 (40.0 g, 207
mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]-
pyridinium 3-oxide hexafluorophosphate (90 g, 240 mmol), and 200
mL of DMF. To this was added N,N-diisoproylethylamine (38.2 g,
51.5 mL, 296 mmol). After 15 min at room temperature, the mixture
was diluted with water (300 mL) and extracted with a mixture of 20%
EtOAc in diethyl ether (1 L). The layers were separated, and the
organic extracts were washed with 2 M aqueous HCl, water, saturated
aqueous NaHCO3, and then brine. The organics were dried (MgSO4),
filtered, and concentrated to give an off-white solid. To this was added
200 mL of CH2Cl2 and trifluoroacetic acid (227 g, 152 mL, 1.97 mol).
After being stirred at room temperature for 30 min, the mixture was
concentrated. Residual TFA was then removed via two sequential
azeotropic distillations using toluene (100 mL each). To the resulting
oil was added ammonia (2 M in MeOH, 394 mL, 788 mmol). After
the mixture was stirred at room temperature for 30 min, the reaction
was concentrated, dissolved in EtOAc (1 L), and washed with water.
The organics were dried (MgSO4), filtered, and concentrated to give
the crude product. This material was then slurried with diethyl ether
(500 mL) to give (3S)-1-benzyl-3-(2-propyn-1-yl)-2,5-piperazinedione
(sep), 76.0, 62.0, 57.0, 52.9, 48.2, 44.2, 1.7; HRMS (ESI-TOF) m/z
20
[M + H]+ calcd for C23H23F6N2O 457.1715, found 457.1718; [α]D
=
+100 (c = 2.4, MeOH).
(S)-2-(4-(4-benzyl-2-(prop-1-yn-1-yl)piperazin-1-yl)phenyl)-1,1,-
1,3,3,3-hexafluoropropan-2-ol 18 (106 g, 232 mmol) was dissolved in
1 L of CH2Cl2. To this was added 1-chloroethyl chloroformate (74.7 g,
523 mmol) and K2CO3 (64.2 g, 464 mmol). After 20 min at room
temperature, the mixture was filtered and the filtrate was concentrated
to give an oil. Then, 500 mL of MeOH was added, and the resulting
solution was heated at 70 °C for 12 h. The solution was allowed to
cool to room temperature and then concentrated to provide the crude
product. This solid was then slurried with diethyl ether (≈500 mL) to
give (S)-1,1,1,3,3,3-hexafluoro-2-(4-(2-(prop-1-yn-1-yl)piperazin-1-
yl)phenyl)propan-2-ol 7 (92 g) as an off-white solid. The product
1
16 (37.3 g, 78%) as a white amorphous solid: H NMR (400 MHz,
CDCl3) δ 7.43−7.15 (m, 5 H), 6.53 (br s, 1 H), 4.75 (d, J = 14.7 Hz, 1
H), 4.49 (d, J = 14.5 Hz, 1 H), 4.20 (br s, 1 H), 3.96 (d, J = 17.8 Hz, 1
H), 3.83 (d, J = 18.0 Hz, 1 H), 2.94−2.73 (m, 2 H), 2.05 (br s, 1 H);
13C NMR (101 MHz, CD3OD) δ 168.0, 167.2, 136.7, 129.9, 129.5,
129.2, 79.8, 73.7, 55.3, 50.6, 50.1, 25.9; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C14H15N2O2 243.1134, found 243.1135; mp 136−144
1
was carried on without additional purification: H NMR (400 MHz,
CD3OD) δ 7.63 (d, J = 8.2 Hz, 2 H), 7.14 (d, J = 8.4 Hz, 2 H), 4.94
(br. s., 1 H), 3.73 (d, J = 13.3 Hz, 1 H), 3.59−3.40 (m, 4 H), 3.33−
3.23 (m, 1 H), 1.83 (s, 3 H); 13C NMR (101 MHz, CD3OD) δ 151.4,
129.2, 125.0, 124.7 (q), 117.9, 86.5, 78.4 (sep), 73.1, 49.4, 48.2, 45.0,
20
°C; [α]D = +33 (c = 2.8, MeOH).
(3S)-1-Benzyl-3-(1-propyn-1-yl)piperazine (17). A 1 L round-
bottomed flask was charged with (3S)-1-benzyl-3-(2-propyn-1-yl)-2,5-
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Note
42.6, 3.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H17F6N2O
367.1245, found 367.1249; mp >178 °C (decomp), [α]D20 = +160 (c =
2.3, MeOH).
AUTHOR INFORMATION
Corresponding Author
*E-mail: bourbeau@amgen.com.
■
A 2 L round-bottomed flask was charged with (S)-1,1,1,3,3,3-
hexafluoro-2-(4-(2-(prop-1-yn-1-yl)piperazin-1-yl)phenyl)propan-2-ol
7 (92 g, 251 mmol), 500 mL of CH2Cl2, and triethylamine (52.5 mL,
377 mmol). To this was added tert-butyl (5-(chlorosulfonyl)pyridin-2-
yl)carbamate 20 (73.5 g, 251 mmol). After 2 h at room temperature,
the mixture was diluted with water and the organics were separated,
dried (MgSO4), filtered, and concentrated. The resulting oil was
purified via silica gel chromatography (1.5 kg of silica, 0−50% ethyl
acetate in hexanes) to give the Boc-protected intermediate. To this was
added 500 mL of CH2Cl2 and trifluoroacetic acid (289 g, 194 mL, 2.51
mol). After being stirred at room temperature for 4 h, the mixture was
concentrated, diluted with EtOAc (500 mL), and carefully quenched
with saturated aqueous NaHCO3. The organics were then separated,
dried (MgSO4), filtered, and concentrated to provide a brown foam.
Purification via silica gel chromatography (1.5 kg of silica, 15−100%
ethyl acetate in hexanes) gave (S)-2-(4-(4-((6-aminopyridin-3-yl)-
sulfonyl)-2-(prop-1-yn-1-yl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexa-
fluoropropan-2-ol (5) (64.0 g, 49% yield) as white solid. The
enanatiomeric excess was found to be >99.5% by chiral SFC (see
Notes
The authors declare the following competing financial
interest(s): The authors are employees of Amgen, Inc.
ACKNOWLEDGMENTS
■
The authors thank Nobuku Nishimura and Steve Shaw for
assistance with the hazard evaluation of the transformation of
compound 4 to compound 5, and Kyun Gahm for the ee
determination for 5.
REFERENCES
■
(1) Lloyd, D. J.; St. Jean, D. J., Jr.; Kurzeja, R. J. M.; Wahl, R. C.;
Michelsen, K.; Cupples, R.; Chen, M.; Wu, J.; Sivits, G.; Helmering, J.;
Ashton, K. S.; Pennington, L. D.; Fotsch, C. H.; Vazir, M.; Chen, K.;
Chmait, S.; Zhang, J.; Liu, L.; Norman, M. H.; Andrews, K. A.;
Bartberger, M. D.; Van, G.; Galbreath, E. J.; Vonderfecht, S. L.; Wang,
M.; Jordan, S. R.; Ven
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iant, M. M.; Hale, C. Nature 2013, 504, 437−
1
Supporting Information): H NMR (400 MHz, CDCl3) δ 8.47 (s, 1
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Chen, M.; Chmait, S.; Croghan, M.; Cupples, R.; Fotsch, C.;
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H), 7.79 (d, J = 8.6 Hz, 1 H), 7.59 (d, J = 8.2 Hz, 2 H), 6.97 (d, J = 8.6
Hz, 2 H), 6.55 (d, J = 8.8 Hz, 1 H), 5.06 (br s, 2 H), 4.45 (br s, 1 H),
3.96 (br s, 1 H), 3.77 (t, J = 12.1 Hz, 2 H), 3.50−3.35 (m, 2 H), 2.82
(d, J = 11.0 Hz, 1 H), 2.68 (t, J = 10.9 Hz, 1 H), 1.79 (s, 3 H); 13C
NMR (101 MHz, CD3OD) δ 163.8, 152.0, 150.1, 138.2, 129.0, 124.7
(q), 123.9, 121.1, 117.5, 109.3, 82.8, 78.3 (m), 75.5, 52.0, 47.2, 44.9,
3.2; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H21F6N4O3S
523.1239, found 523.1229; mp 113−123 °C; [α]D20 = +75.1 (c = 2.2,
MeOH).
tert-Butyl (5-(chlorosulfonyl)-2-pyridinyl)carbamate (20). To
a 5 L three-necked round-bottomed flask equipped with a mechanical
stirrer, N2 inlet, a 6 N NaOH scrubber, and a temperature probe were
charged concentrated hydrochloric acid (348 mL, 11.5 mol) and
acetonitrile (1000 mL). The solution was cooled to 0 °C, and sodium
nitrite (39.6 g, 573 mmol) in water (400 mL) was added slowly over 5
min. The resulting solution was stirred at 0 °C for 10 min. tert-Butyl 5-
aminopyridin-2-ylcarbamate 19 (100 g, 478 mmol, purchased from
Green Chempharm, Inc.) in acetonitrile (200 mL) was added to the
above solution at 0 °C. The resulting reaction mixture was stirred for 1
h at 0 °C. The mixture was then cooled to −10 °C, and acetic acid
(497 mL, 8.60 mol), copper(II) chloride (32.1 g, 239 mmol), and
copper(I) chloride (0.946 g, 9.56 mmol) were added sequentially.
Sulfur dioxide (153 g, 2390 mmol) gas was then bubbled through the
mixture for 10 min at −10 to −15 °C. The resulting reaction mixture
was stirred at −10 to −5 °C for 1 h. The reaction mixture was diluted
with ice cold water (1000 mL) at which time a solid precipitated. The
solid was quickly filtered, washed with cold water (500 mL), and dried
in the filter funnel under vacuum (with N2 over the filter funnel) for
24 h to afford tert-butyl (5-(chlorosulfonyl)pyridin-2-yl)carbamate 20
(89.4 g, 64% yield) as an off white solid: 1H NMR (400 MHz, DMSO-
d6) δ 11.67 (s, 1 H), 8.44 (s., 1 H), 8.36 (d, J = 8.8 Hz, 1 H), 7.54 (d, J
= 8.8 Hz, 1 H), 1.55 (s, 9 H); 13C NMR (101 MHz, DMSO-d6) δ
152.3, 148.8, 142.5, 139.1, 136.0, 115.2, 83.2, 27.8; mp >300 °C
(decomp).
ASSOCIATED CONTENT
■
S
* Supporting Information
Reaction pressure monitoring and differential scanning
calorimetry data for the transformation of 4 to 5, copies of
the 1H and 13C spectra for all new compounds, and the
chromatogram for the ee determination of 5. This material is
available free of charge via the Internet at http://pubs.acs.org.
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