Kilogram synthesis of (S)-3-aminopyran from l -glutamic acid

Article abstract of DOI:10.1055/s-0033-1338422

We describe the development of a concise route to prepare kilogram quantities of (S)-3-aminopyran, a key intermediate in the synthesis of a Jak1 inhibitor. The chiral amine was introduced via a chiral-pool approach and involves using inexpensive, commerci

Full text of DOI:10.1055/s-0033-1338422

LETTER
▌987
letter
Kilogram Synthesis of (S)-3-Aminopyran from L-Glutamic Acid
Synthesis of (S)-3-Aminopyran
Scott Savage,*a Srinivasan Babu,b Mark Zak,c Zhongping Mao,d Jianhua Cao,d Yonghui Ge,d Dongxu Ma,d
Guoqiang Jiangd
a
Department of Small Molecule Process Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
Fax +1(650)2256238; E-mail: savage.scott@gene.com
b
Department of Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
c
Department of Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
d
Hande Sciences, 35 Tongyuan Road, Suzhou 215006, P. R. of China
Received: 31.01.2013; Accepted after revision: 25.03.2013
pool approach to introduce the desired absolute configu-
ration at the C-3 position.
Abstract: We describe the development of a concise route to pre-
pare kilogram quantities of (S)-3-aminopyran, a key intermediate in
the synthesis of a Jak1 inhibitor. The chiral amine was introduced
via a chiral-pool approach and involves using inexpensive, com-
mercially available L-glutamic acid as the key starting material.
Global protection, followed by reduction afforded the N-Boc-amino
diol. Intramolecular Mitsunobu cyclization and deprotection afford-
ed the desired compound in 30% overall yield over four steps with-
out the use of chromatography.
Our initial strategy using L-glutamic acid involved global
protection and reduction to the corresponding diol. Next,
selective monoprotection of the alcohols and subsequent
activation would set the stage for cyclization after remov-
al of the oxygen-protecting group. Finally, deprotection of
the amine would give aminopyran 1 as is shown in
Scheme 1.
Key words: aminopyran, Mitsunobu, intramolecular, cyclization,
glutamic acid, chiral pool, diols
To this end, perbenzylation of L-glutamic acid proceeded
smoothly to give the tetrabenzylated intermediate 2 which
was carried into the next step without further purifica-
tion.4 Reduction using LiAlH4 in THF yielded the diol 3
in 55% overall yield after chromatography. Monoprotec-
tion of the diol using TBSCl gave intermediate 4 in 36%
yield after chromatography. Attempted mesylation of al-
cohol 4 using methanesulfonyl chloride furnished en-
amine 6 via elimination as shown in Scheme 2. A study of
various bases to affect the activation of 4 including trieth-
ylamine, DMAP, DIPEA, and 2,6-lutidine failed to gener-
ate the desired product 5. In all of these cases, either
elimination and/or degradation products were obtained.
Janus Kinase 1 (Jak1) is a member of a family of tyrosine
kinase proteins critical to multiple signaling pathways as-
sociated with various immunological disease states.1 As
part of a program aimed at discovering and developing
potent Jak1 inhibitors, we required an efficient synthetic
route, which afforded multikilogram quantities of the (S)-
3-aminopyran hydrochloride salt 1 for use as a synthetic
intermediate (Figure 1).2
Activation of diol 3 with p-toluenesulfonyl chloride was
also attempted and the best conditions using neat pyridine,
as solvent and base at reflux temperature, yielded the de-
sired product 8 in 14% yield (Scheme 2). Attempted final
deprotection via hydrogenolysis with Pd/C or Pd(OH)2/C
gave unsatisfactory results, with either monodeben-
zylation or no reaction. Given the low yields and difficulty
in deprotection of the benzyl groups, the benzylation strat-
egy proved less than optimal, so an alternative route was
explored. Since we had shown that the activation and cy-
clization of diol 3 was achievable using p-toluenesulfonyl
O
HCl⋅H2N
1
Figure 1
Preparation of 1 posed significant challenges, including
isolation of enantiomerically pure product. Although a ra-
cemic synthesis had been reported in the literature, its use
would have required additional chiral chromatography or
diastereomeric salt resolution.3 Herein we describe efforts
to synthesize the (S)-3-aminopyran subunit using a chiral
NH2
R1
R2
R1
R2
N
N
HO
OH
O
OR3
HCl⋅H2N
LG
HO
OH
O
O
L-glutamic acid
1
Scheme 1
SYNLETT 2013, 24, 0987–0990
Advanced online publication: 10.04.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338422; Art ID: ST-2013-R0106-L
© Georg Thieme Verlag Stuttgart · New York

988
S. Savage et al.
LETTER
NBn2
NBn2
MsO
OTBS
HO
OTBS
MsCl, base
CH2Cl2
4
5
TBSCl
imidazole
CH2Cl2
NBn2
OTBS
6
NH2
NBn2
NBn2
LiAlH4
THF
BnBr, NaOH
H2O
HO
OH
BnO
OBn
HO
OH
O
O
O
O
L-glutamic acid
2
3
TsCl
pyridine
NBn2
O
HO
OTs
Bn2N
7
8
Scheme 2
chloride, we deemed that changing the steric and electron- tion, we found the combination of triphenylphosphine and
ic environment of the amine functionality would help fa- diisopropyl azodicarboxylate (Ph3P/DIAD) to be the most
cilitate the activation and cyclization. Thus the use of N- effective, affording the cyclized product 11. Notably,
Boc-protected diol 10 was investigated as a precursor for none of the undesired pyrrolidine product 12 was obtained
the activation and cyclization reactions. Preparation of the under these reaction conditions (Scheme 3). Finally, de-
diol from L-glutamic acid proceeded smoothly, generating protection with MeOH–HCl afforded aminopyran 1 in
diol 10 in an 81% overall yield.5,6 Of the many reaction quantitative yield.
conditions screened to effect six-membered ring cycliza-
NHBoc
NHBoc
NH2
LiBH4
THF
1) TMSCl, MeOH
2) Boc2O, Et3N
MeO
OMe
HO
OH
HO
OH
O
O
O
O
L-glutamic acid
9
10
Boc
N
OH
12
or
Ph3P, DIAD
THF
HCl
MeOH
O
O
HCl⋅H2N
BocHN
(overall 30% yield,
>99.9% ee)
11
1
O
O
cinnamoyl chloride
Et3N, CH2Cl2
N
O
H
HCl⋅H2N
1
13
Scheme 3
Synlett 2013, 24, 987–990
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of (S)-3-Aminopyran
989
ing the internal temperature ≤ 15 °C, a solution of 9 (1.0 kg, 3.63
mol, dissolved in 2.0 L of anhyd THF) was added dropwise. After
the addition was complete, the mixture was slowly warmed to 20 °C
and stirred overnight. The reaction mixture was then cooled to 0 °C
and MeOH (10.0 L) was added slowly to quench any excess reduc-
ing reagent. After concentration in vacuo, the residue was diluted
with H2O (5.0 L) and extracted with EtOAc. The combined organic
phase was dried over Na2SO4, filtered, and the solvent was removed
in vacuo to give crude product (0.68 kg, 85% yield) as a pale yellow
oil. IR (neat): 3343, 2987, 2957, 2941, 2916, 2865, 1679 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 5.08 (s, 1 H), 3.74–3.51 (m, 5 H), 3.44
(s, 2 H), 1.74–1.47 (m, 4 H), 1.44 (s, 9 H). 13C NMR (75 MHz,
CDCl3): δ = 156.5, 79.6, 65.0, 62.2, 52.3, 28.7, 28.4, 27.9. ESI-
HRMS: m/z [M + Na]+ calcd for C10H21NO4Na: 242.1368; found:
242.1355.
Various Mitsunobu-type conditions were evaluated to fur-
ther optimize the cyclization to afford N-Boc-aminopyran
11. Ultimately, we identified dichloromethane as the best
solvent with either DIAD or diethyl azodicarboxylate
(DEAD) working equally well in promoting the reaction
and providing 11 in 50–60% yield. The reaction sequence
shown in Scheme 3 was scaled up successfully to produce
multikilogram quantities. Although initially the removal
of triphenylphosphine oxide from N-Boc-aminopyran 11
necessitated the use of silica gel chromatography, we
identified crystallization conditions using petroleum ether
and ethyl acetate to purge this impurity. This modification
reduced the yield of the cyclization reaction to 37%, how-
ever, it resulted in faster processing and improved opera-
tional simplicity and thus made it the preferred
purification method. Determination of chiral purity of the
product was achieved via chiral HPLC using the cinnama-
mide derivative of the product as illustrated in Scheme 3.7
Preparation of (S)-tert-Butyl (Tetrahydro-2H-pyran-3-yl)car-
bamate
To a 20 L reactor equipped with a mechanical stirrer was charged
diol 10 (0.95 kg, 4.33 mol), Ph3P (2.27 kg, 8.66 mol) and CH2Cl2
(10 L). Diisopropylazodicarboxylate (1.75 kg, 8.66 mol) was then
added dropwise to the reaction mixture. The solution was stirred for
48 h at 20 °C, and the reaction was monitored for completion by
TLC. The reaction mixture was concentrated and triturated with
PE–EtOAc (12:1 v/v, 20 L). The solid was filtered off and washed
with 4-5 additional portions of PE–EtOAc (12:1 v/v, 20 L). The
combined filtrates were concentrated to ca. 10% of the original vol-
ume, and the pure product was isolated by filtration to give com-
pound 11 (320 g, 37%) as a white solid after drying; mp 94–96 °C.
IR (neat): 3357, 2948, 2847, 1678, 1518 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 4.89 (s, 1 H), 3.79 (dd, J = 11.2, 2.5 Hz, 1 H), 3.71–3.49
(m, 3 H), 3.37 (dd, J = 10.0, 5.6 Hz, 1 H), 1.94–1.82 (m, 1 H), 1.80–
1.67 (m, 1 H), 1.66–1.50 (m, 2 H), 1.45 (s, 9 H). 13C NMR (75 MHz,
CDCl3): δ = 155.2, 79.2, 71.6, 68.0, 46.0, 29.0, 28.4, 23.3. ESI-
HRMS: m/z [M + Na]+ calcd for C10H19NNaO3: 224.1263; found:
224.1258.
In summary, this route represents an inexpensive and rap-
id entry to kilogram quantities of this useful chiral build-
ing block, though further optimization is needed to
improve the process for larger-scale manufacture. Previ-
ously reported racemic preparations of 3-aminopyran
would have required chiral separation. However, our ap-
proach can provide easy access to both enantiomers of
compound 1 depending on the stereoisomer of glutamic
acid used. Mitsunobu cyclization of N-Boc-protected 3-
amino diol 10 was used as the key step in this preparation
of (S)-3-aminopyran (1). The short and efficient route re-
lied upon a chiral-pool approach employing inexpensive
and readily available starting materials. To our knowl-
edge, this is the first reported stereospecific route to ac-
cess both enantiomers of 3-aminopyran.
Preparation of (S)-Tetrahydro-2H-pyran-3-amine Hydrochlo-
ride
To a 20 L reactor equipped with a mechanical stirrer was charged
aminopyran 11 (2.0 kg, 4.97 mol) and 6 N HCl in MeOH (12 L, 72.0
mol) at 20 °C. The reaction was stirred until complete conversion of
starting material (monitored by TLC). The solution was concentrat-
ed and then triturated with EtOAc (12 L). The resulting slurry was
filtered and washed with PE (3 L). The solids were dried in vacuo
to give the target compound 1 (1.36 kg, >99%) as a white solid; mp
Preparation of (S)-Dimethyl 2-[(tert-Butoxycarbonyl)ami-
no]pentanedioate
To a 20 L reactor equipped with a mechanical stirrer was charged
MeOH (7.0 L). This was cooled to 0–5 °C, followed by slow addi-
tion of TMSCl (2.59 kg, 23.8 mol). The solution was stirred for 30
min, then L-glutamic acid (700 g, 4.76 mol) was added at 0–5 °C.
The reaction was warmed to 20 °C and stirred for 2–4 h. After the
reaction completion was checked by TLC, the solution was again
cooled to 0 °C. Et3N (3.130 kg, 31 mol) and Boc2O (1.142 kg, 5.23
mol) were slowly added to the reactor while keeping the internal
temperature below 25 °C. The resultant slurry was stirred over-
night. After concentration in vacuo, the residue was diluted with de-
ionized H2O (5.0 L) and extracted with EtOAc (10.0 L). The organic
phase was washed with 20% aq citric acid (4.0 L) and brine, then
dried over Na2SO4. After filtration and concentration in vacuo, the
crude product (1.243 kg, 95% yield) was obtained as pale yellow
1
112–114 °C. IR (neat): 2864, 2677, 2588, 2051, 1613 cm–1. H
NMR (300 MHz, DMSO-d6): δ = 8.48 (s, 3 H), 3.84 (dd, J = 11.4,
3.2 Hz, 1 H), 3.71–3.58 (m, 1 H), 3.54–3.35 (m, 2 H), 3.12 (s, 1 H),
2.06–1.89 (m, 1 H), 1.83–1.60 (m, 2 H), 1.58–1.41 (m, 1 H). 13C
NMR (75 MHz, CDCl3): δ = 67.8, 67.0, 45.9, 26.3, 22.4. ESI-
HRMS: m/z [M + H]+ calcd for C5H12NO: 102.0919; found:
102.0913.
Preparation of (S)-N-(Tetrahydro-2H-pyran-3-yl)cinnam-
amide
A solution of aminopyran 1 (0.65 g, 4.7 mmol) in CH2Cl2 (30 mL)
was cooled to 0 °C. Cinnamoyl chloride (1.2 g, 7.2 mmol) and Et3N
(1.43 g, 14.4 mmol) were added, and the mixture was stirred for 2 h
at 20 °C. The reaction mixture was washed with brine (10 mL), and
the organic phase was dried with Na2SO4, filtered, and concentrat-
ed. The residue was purified by SiO2 chromatography (CH2Cl2–
MeOH, 97:3) giving the desired product 13 (1.0 g, 90% yield) as a
white solid; mp 148–149 °C. IR (neat): 3279, 3056, 2969, 2843,
1654, 1618 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.64 (d, J = 15.7
Hz, 1 H), 7.54–7.46 (m, 2 H), 7.42–7.32 (m, 3 H), 6.42 (d, J = 15.6
Hz, 1 H), 6.02 (d, J = 7.1 Hz, 1 H), 4.20–4.10 (m, 1 H), 3.84–3.71
(m, 2 H), 3.67–3.53 (m, 2 H), 1.96–1.73 (m, 3 H), 1.67–1.54 (m, 1
H). 13C NMR (75 MHz, CDCl3): δ = 165.2, 141.2, 134.8, 129.7,
1
oil. IR (neat): 3370, 3179, 2977, 2955, 1694 cm–1. H NMR (300
MHz, CDCl3): δ = 5.17 (d, J = 7.0 Hz, 1 H), 4.34 (dd, J = 7.6, 5.4
Hz, 1 H), 3.75 (s, 3 H), 3.68 (s, 3 H), 2.42 (dt, J = 7.9, 5.5 Hz, 2 H),
2.26–2.11 (m, 1 H), 2.03–1.88 (m, 1 H), 1.44 (s, 9 H). 13C NMR (75
MHz, CDCl3): δ = 173.1, 172.6, 155.3, 80.0, 52.8, 52.4, 51.7, 30.0,
28.2, 27.7. ESI-HRMS: m/z [M + Na]+ calcd for C12H21NO6Na:
298.1267; found: 298.1255.
Preparation of (S)-tert-Butyl (1,5-Dihydroxypentan-2-yl)carba-
mate
To a 20 L reactor equipped with a mechanical stirrer was charged
anhyd THF (10.0 L) and LiBH4 (0.4 kg, 18.4 mol). While maintain-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 987–990

990
S. Savage et al.
LETTER
128.8, 127.8, 120.7, 71.4, 68.4, 45.0, 28.3, 22.7. ESI-HRMS: m/z
Johnson, T.; Kenny, J. R. Koehler M. F. T.; Bir Kohli, P.;
Kulagowski, J. J.; Labadie, S.; Liao, J.; Liimatta, M.; Lin, Z.;
Lupardus, P. J.; Maxey, R. J.; Murray, J. M.; Pulk, R.;
Rodriguez, M.; Savage, S.; Shia, S.; Steffek, M.; Ubhayakar,
S.; Ultsch, M.; van Abbema, A.; Ward, S. I.; Xiao, L.; Xiao,
Y. J. Med. Chem. 2012, 55, 6176. (c) Babu, S.; Bergeron, P.;
Dragovich, P.; Dyke, H. J.; Gibbons, P.; Gradl, S.; Hanan,
E.; Hurley, C.; Johnson, T.; Koehler, M.; Kulagowski, J. J.;
Labadie, S. S.; Lyssikatos, J. P.; Mendoza, R.; Pulk, R.;
Ward, S.; Waszkowycz, B.; Zak, M. WO 2011086053 A1,
2011.
[M + Na]+ calcd for C14H17NNaO2: 254.1157; found: 254.1154.
Acknowledgment
The authors wish to thank Nate Seagraves for MS characterization
as well as Francis Gosselin and Sushant Malhotra for careful review
of the manuscript.
References
(3) Alcudia, F.; Cobos, J.; Llera, J. M.; Zorrilla, F.; Rodriguez,
J. H. Anal. Quim., Ser. C: Quim. Org. Bioquim. 1988, 84,
148.
(1) (a) Shuai, K.; Liu, B. Nat. Rev. Immunol. 2003, 3, 900.
(b) Ghoreschi, K.; Laurence, A.; O’Shea, J. J. Immunol Rev.
2009, 228, 273. (c) Song, L.; Schindler, C. The Handbook of
Cell Signalling; Bradshaw, R. A.; Dennis, E. A., Eds.; 2nd
ed., Vol. 3; Elsevier: San Diego, 2010, 2041.
(4) (a) Rodrequez, M.; Taddei, M. Synthesis 2005, 493. (b) Cini,
E.; Lampariello, L. R.; Rodriquez, M.; Taddei, M.
Tetrahedron 2009, 4, 844. (c) Chen, W.; Zheng, X.; Ruan,
Y.-P.; Huang, P.-Q. Heterocycles 2009, 79, 681.
(d) Culhane, J. C.; Wang, D.; Yen, P. M.; Cole, P. A. J. Am.
Chem. Soc. 2010, 132, 3164. (e) Dzhekieva, L.; Rocaboy,
M.; Kerff, F.; Charlier, P.; Sauvage, E.; Pratt, R. F.
Biochemistry 2010, 49, 6411. (f) Dancy, B. C. R.; Ming, S.
A.; Papazyan, R.; Jelinek, C. A.; Majumdar, A.; Sun, Y.;
Dancy, B. M.; Drury, W. J.; Cotter, R. J.; Taverna, S. D. Cole
P. A. J. Am. Chem. Soc. 2012, 134, 5138.
(d) Kulagowski, J. J.; Blair, W.; Bull, R. J.; Chang, C.;
Deshmukh, G.; Dyke, H. J.; Eigenbrot, C.; Ghilardi, N.;
Gibbons, P.; Harrison, T. K.; Hewitt, P. R.; Liimatta, M.;
Hurley, C. A.; Johnson, A.; Johnson, T.; Kenny, J. R.; Bir
Kohli, P.; Maxey, R. J.; Mendonca, R.; Mortara, K.; Murray,
J.; Narukulla, R.; Shia, S.; Steffek, M.; Ubhayakar, S.;
Ultsch, M.; van Abbema, A.; Ward, S. I.; Waszkowycz, B.;
Zak, M. J. Med. Chem. 2012, 55, 5901.
(2) (a) Labadie, S.; Dragovich, P. S.; Barrett, K.; Blair, W. S.;
Bergeron, P.; Chang, C.; Deshmukh, G.; Eigenbrot, C.;
Ghilardi, N.; Gibbons, P.; Hurley, C. A.; Johnson, A.;
Kenny, J. R.; Kohli, P. B.; Kulagowski, J. J.; Liimatta, M.;
Lupardus, P. J.; Mendonca, R.; Murray, J. M.; Pulk, R.; Shia,
S.; Steffek, M.; Ubhayakar, S.; Ultsch, M.; van Abbema, A.;
Ward, S. I.; Zak, M. Bioorg. Med. Chem. Lett. 2012, 22,
7627. (b) Zak, M.; Mendonca, R.; Balazs, M.; Barrett, K.;
Bergeron, P.; Blair, W. S.; Chang, C.; Deshmukh, G.;
DeVoss, J.; Dragovich, P. S.; Eigenbrot, C.; Ghilardi, N.;
Gibbons, P.; Gradl, S.; Hamman, C.; Hanan, E. J.; Harstad,
E.; Hewitt, P. R.; Hurley, C. A.; Jin, T.; Johnson, A.;
(5) (a) Goswami, K.; Paul, S.; Bugde, S. T.; Sinha, S.
Tetrahedron 2012, 68, 280. (b) Suhartono, M.; Schneider,
A. E.; Duerner, G.; Goebel, M. W. Synthesis 2010, 293.
(6) Xu, Z.; Zhang, F.; Zhang, L.; Jia, Y. Org. Biomol. Chem.
2011, 9, 2512.
(7) HPLC conditions for chiral purity analysis; column:
Chiralpak IA 0.46 cm × 25 cm, 5 μm; mobile phase: n-
heptane–EtOH = 80:20 (v/v); detector: UV, λ = 214 nm;
flow rate: 1.0 mL/min; column temp = 30 °C. (S)-3-
Aminopyran: tR = 10.09 min; (R)-3-aminopyran: tR = 13.22
min.
Synlett 2013, 24, 987–990
© Georg Thieme Verlag Stuttgart · New York