Practical Asymmetric Synthesis of a Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist Ubrogepant

Article abstract of DOI:10.1021/acs.oprd.7b00293

The development of a scalable asymmetric route to a new calcitonin gene-related peptide (CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the intermediates were accessed through novel chemistry. Chiral lactam 2 was prepared by an enzyme mediated dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted in an optimized transaminase providing the desired configuration in >60:1 syn/anti. The final chiral center was set via a crystallization induced diastereomeric transformation. The asymmetric spirocyclization to form the second fragment, chiral spiro acid intermediate 3, was catalyzed by a novel doubly quaternized phase transfer catalyst and provided optically pure material on isolation. With the two fragments in hand, development of their final union by amide bond formation and subsequent direct isolation is described. The described chemistry has been used to deliver over 100 kg of our desired target, ubrogepant.

Full text of DOI:10.1021/acs.oprd.7b00293

Subscriber access provided by University of Florida | Smathers Libraries
Full Paper
Practical asymmetric synthesis of a CGRP receptor antagonist ubrogepant
Nobuyoshi Yasuda, Ed Cleator, Birgit Kosjek, Jianguo Yin, Bangping Xiang, Frank
Chen, Shen-Chun Kuo, Kevin M. Belyk, Peter R Mullens, Adrian Goodyear, John S
Edwards, Brian Bishop, Scott Ceglia, Justin Belardi, Lushi Tan, Zhiguo Jake Song,
Lisa DiMichele, Robert A. Reamer, Fabien L Cabirol, Weng Lin Tang, and Guiquan Liu
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00293 • Publication Date (Web): 19 Oct 2017
Downloaded from http://pubs.acs.org on October 20, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Organic Process Research & Development is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
10
11
12
13
Practical asymmetric synthesis of a CGRP receptor
antagonist ubrogepant
Nobuyoshi Yasuda,*[a] Ed Cleator,* [b] Birgit Kosjek,[a] Jianguo Yin,[a] Bangping Xiang,[a] Frank Chen,
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[a]
ShenꢀChun Kuo,[a] Kevin Belyk,[a] Peter R. Mullens,[b] Adrian Goodyear,[b] John S. Edwards,[b]
Brian Bishop,[b] Scott Ceglia,[c] Justin Belardi,[c] Lushi Tan,[a] Zhiguo J. Song [a] Lisa DiMichele,[a]
Robert Reamer,[a] Fabien L. Cabirol,[d] Weng Lin Tang,[d] and Guiquan Liu.[e]
[a] Department of Process Chemistry, MRL, 126 E. Lincoln Avenues, Rahway, NJ 07065, USA; [b]
Department of Process Chemistry, MSD Research Laboratories, Hertford Road, Hoddesdon, Hertford,
Hertfordshire, EN11 9BU, United Kingdom; [c] Department of Process Chemistry, MRL, 770
Sumneytown Pike, West Point, PA 19486, USA; [d] Codexis, Inc. 200 Penobscot Drive, Redwood City,
CA 94063, USA; [e] Shanghai SynTheAll Pharmaceutical Co. Ltd., 9 Yuegong Road, Jinshan District,
Shanghai, 201507, China
* Corresponding authors: nobuyoshi_yasuda@merck.com; edward_cleator@merck.com
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
1
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 22
Table of Contents graphic
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
ACS Paragon Plus Environment

Page 3 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
ABSTRACT: The development of a scalable asymmetric route to a new calcitonin geneꢀrelated peptide
(CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the
intermediates accessed through novel chemistry. Chiral lactam 2 was prepared by an enzyme mediated
dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted
in an optimized transaminase providing the desired configuration in >60:1 syn:anti. The final chiral
center was set via a crystallization induced diastereomeric transformation. The asymmetric
spirocyclization to form the second fragment, chiral spiro acid intermediate 3, was catalyzed by a novel
doubly quaternized phase transfer catalyst and provided optically pure material on isolation. With the
two fragments in hand, development of their final union by amide bond formation and subsequent direct
isolation is described. The described chemistry has been used to deliver over 100 kg of our desired target,
ubrogepant.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Key words: dynamic kinetic transamination; phase transfer catalyst; crystallization induced
diastereomeric transformation; CGRP receptor antagonist
Introduction
Migraine is a chronic neurovascular disorder, characterized by attacks of moderate to severe
headache.1 A recent survey indicated that greater than 10% of the worldꢀwide population suffer from
bouts of migraine.2 The current standard treatments are 5ꢀHT1B/1D agonists commonly known as triptans.
Unfortunately, the inherent vasoconstrictive activity of triptans makes them unsuitable for use in
patients with preꢀexisting cardiovascular disease.3 Therefore, there is a need for alternative therapies for
migraine which possess an improved cardiovascular safety profile, to ultimately fill this unmet medical
need.
3
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 22
Although the underlying mechanisms of migraine pathogenesis are complex and have not been fully
elucidated to date, calcitonin geneꢀrelated peptide (CGRP) is a 37ꢀamino acid neuropeptide that has long
been postulated to play an important role in treatment of migraine headaches. The clinical effectiveness
of antagonizing the CGRP receptor for relief of migraine pain has also been demonstrated.4
Recently a new CGRP receptor antagonist, ubrogepant has been identified and advanced into clinical
studies.5 Whilst ubrogepant could be prepared by a simple amide bond formation reaction, between the
corresponding amino lactam 2 and the spiro acid 3 (Scheme 1), the preparation of the two key coupling
partners provided a significant synthetic challenge.5b As the compound moved through the development
phases, the discovery and development of efficient and economical large scale routes to these two key
intermediates became essential to ensure successful advancement of the program into clinical studies.
Herein, we report the asymmetric synthesis of lactam 2 using a dynamic kinetic transamination (DKꢀ
TA) approach. We also describe the asymmetric synthesis of key fragment 3 employing a novel doubly
quaternized phase transfer catalyst (PTC) spirocyclization to set the chiral all carbon quaternary
stereocenter.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Final amide bond formation; synthesis of ubrogepant (1)
Results and Discussion
Chiral Synthetic Route to Lactam 2. The core framework of the lactam contains three chiral centers
including a pendant phenyl ring. The original synthetic route to 2 used a chiral serine derivative.
However, this route ultimately provided the product as racemic mixture which required a chiral SFC
separation.5b
4
ACS Paragon Plus Environment

Page 5 of 22
Organic Process Research & Development
Our strategy to address these synthetic limitations is summarized in Scheme 2. Control of the Cꢀ5 and
1
2
Cꢀ6 contiguous chiral centers was deemed the most challenging task in the lactam synthesis. We decided
to evaluate a DKꢀTA setting both chiral centers simultaneously to achieve this goal.6 With a judicious
selection of the ester, we envisioned that lactam formation would occur during the transamination
process. The Nꢀ1 side chain could be introduced by alkylation after lactam formation. Finally, the
stereochemistry at the Cꢀ3 position was expected to be controlled by a thermodynamically driven
crystallization induced diastereomeric transformation (CIDT) with appropriate choice of salt.7
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Retrosynthesis of the lactam
Early development of this strategy was accomplished using 4ꢀbromophenylacetone (4).8 The
isopropyl ester was selected for development as this provided a balance between stability with respect to
hydrolysis during the transaminase reaction and reactivity in the cyclization to form our desired lactam.
The synthesis of ketone 9 began with mesylation of NꢀBoc serine isopropyl ester 5 (Scheme 3).
Alkylation of 4 with the mesylate 6 was sluggish. It was subsequently found that mesylate 6 was rapidly
converted to alkene 7 under the alkylation conditions. The modest yields of the desired adduct 8 were
actually the result of product formed from the conjugate addition of the enolate anion of 4 to the
activated alkene 7. Since the mesylate anion could potentially compete with the enolate anion of 4, it
was removed by isolation of 7. This was found to significantly improve the alkylation step offering an
85% yield when enolization was performed with 0.5 equiv of Cs2CO3 in DMSO. Transfer hydrogenation
mediated by Pd/C of bromide 8 provided our key substrate 9 in 71% yield for transamination
development.
5
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 22
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Preparation of transamination substrate 9. Reagents and conditions: a) MsCl (1.1 equiv),
TEA (1.1 equiv), DCM, rt, 1 h, 92%; b) MsCl (1.3 equiv), TEA (2.5 equiv), DMF, 0 °C then rt,
overnight, 93%, c) Cs2CO3 (0.5 equiv), DMSO, rt, 79%; d) 10 % Pd/C, HCO2K, K2CO3, iPA, 60 °C, 2 h,
71%.
Screening of a transaminase panel from Codexis, Inc. was carried out under previously established
conditions for DK transaminations at pH 10.5 to promote epimerization of the starting material.6bꢀc The
initial results confirmed the feasibility of a dynamic kinetic reaction and delivered diverse selectivity.
The appropriate choice of enzyme enabled access to either the synꢀ or antiꢀepimer with (R)ꢀ
configuration at Cꢀ6 (Table 1, entries 1 and 2), demonstrating enzymatic catalysis as a powerful
methodology for asymmetric synthesis setting multiple stereocenters. We identified ATAꢀ301 as an
initial lead providing the desired synꢀlactam 10 with 7:1 diastereomeric ratio (dr) and >99%ee at Cꢀ6.
Unfortunately, the activity of the enzyme was low and afforded only 38% conversion even at high
loading. Given the recent development and success of protein engineering technologies,9 we envisioned
improving the activity and diastereoselectivity of the selective transaminase by directed evolution.
Scheme 4. Optimized DK transaminase conditions
6
ACS Paragon Plus Environment

Page 7 of 22
Organic Process Research & Development
Table 1. DK transaminase process improvements through enzyme evolution
1
2
3
4
5
6
7
8
9
TA variant
CDXꢀ017
ATAꢀ301
ATAꢀ401
ATAꢀ404
ATAꢀ412
ATAꢀ426
E.L.[a] wt%
300
DMSO: H2O
Conv. %[b,c ]
syn:anti[d]
1:5
9 Conc. g/L
5
5
5
5
50
50
1:4
1:4
1:4
1:2.3
1:1
1:1
94
38
95
300
300
100
50
7:1
61:1
61:1
61:1
61:1
90
95
95[e]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15
[a] Enzyme loading relative to 9. [b] DMSOꢀH2O, 0.2 M borate buffer pH 10.5, 1 M iPrNH2, 1 g/L
PLP, 45 °C. [c] Determined by HPLC. [d] syn and anti of Cꢀ5 and Cꢀ6 chiral centers. [e] 55 °C.
In collaboration with Codexis, initial enzyme evolution efforts targeted improving the selectivity at
the Cꢀ5 and Cꢀ6 chiral centers. The first round of evolution resulted in a variant that produced 10 with a
~9 fold increase in dr to 61:1. This new variant also improved activity by 2.5 fold (Table 1, entry 3). In
the subsequent rounds of evolution, we continuously improved the transaminase’s reactivity, leading to
reactions run at higher substrate concentrations. In parallel, the enzyme was engineered to tolerate
higher DMSO concentration in order to avoid limitations due to low substrate solubility under the more
aqueous conditions used previously. An additional increase in temperature stability resulted in a ~2 fold
faster reaction rate of final variant ATAꢀ426 which afforded the desired lactam 10 in 92% assay yield
and 61:1 dr in <24 hours (Scheme 4).10
The lactam product 10 was finally isolated as a crystalline 3:2 (β:α) diastereomeric mixture at the Cꢀ3
position. The Cꢀ3 position was prone to epimerization favoring the desired βꢀisomer under basic
conditions, and therefore epimerization also occurred during the Nꢀalkylation. This led us to perform the
Nꢀalkylation on the diastereomeric mixture of lactam 10.
A highly reactive alkylating reagent, trifluoroethyl triflate, was required for Nꢀalkylation.11 Selective
mono Nꢀalkylation of 10 was not trivial and the undesired N,N’ꢀdialkyl byproduct 12 was formed
7
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 22
competitively even before complete consumption of 10. An extensive screen of bases revealed that the
best base was lithium tertꢀbutoxide.
1
2
3
4
5
6
7
8
9
With both base and alkylating reagent identified, optimization showed that an excess of LiOtBu and
triflate were required to achieve a high conversion in THF. The reaction was sensitive to temperature
and it was found that best results were achieved when it was performed at subꢀambient temperatures.
Under these conditions optimal levels of selectivity were observed, with the reaction affording a 94%
conversion after 18 h. The ratio of 11 to 12 was 9.3 to 1 and the yield of 11 was 87% (Scheme 5).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Crude isolation of compound 11 still showed unreacted 10 and dialkylated 12 as impurities. However,
Boc deprotection and isolation of the free amine as a salt led to removal of these main impurities. The
desired product 13 was then recovered in 96% yield as a 4:1 diastereomeric mixture in favour of the β
isomer at the Cꢀ3 position.
The stereochemistry of the Cꢀ3 center in 13 was set by a crystallization induced diastereoselective
transformation (CIDT). After salt screening, pꢀtoluic acid salt was selected for further development.12
From the literature, CIDT based epimerizations, can be mediated by aromatic aldehydes.7 Indeed, when
crude 13 was treated with pꢀtoluic acid in the presence of 1 mol% of 3,5ꢀdichlorosalicyaldehyde at 50 oC,
crystals precipitated as the pure βꢀisomer of the pꢀtoluic acid salt 14 in 86% yield and with a 99.6% de.
The salt 14 was suitable for use in the final coupling step after a salt break.
Scheme 5. NꢀAlkylation, stepwise deprotection and dynamic crystallization. Reagents and conditions: a)
CF3CH2OTf (1.3 equiv), LiOtBu (1.2 equiv), THF, 16ꢀ22 °C, 18 h, 87%, b) 3 N HCl, TBABr (3.8
o
mol%), toluene, 35 oC, 3 h, c) 4.5 N HCl, MTBE/MeOH, 50 C, 5 h, 96%, d) pꢀtoluic acid (1.0 equiv),
3,5ꢀdichorosalicyaldehyde (1 mol%), 50 °C, 3ꢀ5 h, 86%.
8
ACS Paragon Plus Environment

Page 9 of 22
Organic Process Research & Development
Initial Medicinal Chemistry Route for Spiro Acid 3. The original route to 3 was racemic and
1
2
3
4
5
6
7
8
9
suffered from polymerization when the previously described5 double alkylation sequence was used to
form the spirocycle. Furthermore, this method required SEM protection on the nitrogen atom at the
azaindolone and SFC separation of a racemic mixture of the ester after spirocyclization. Thus, it became
evident that a more efficient, practical asymmetric synthesis of 3 would be required.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Chiral Synthetic Route to Spiro Acid 3. During a reꢀdesign of the synthesis of 3, a number of key
objectives were addressed. First, the Nꢀprotecting group was switched from the relatively expensive
SEM group to tertꢀbutyl. Next, to avoid polymerization during the spirocyclization, we decided to
disconnect the key quaternary center in order to make each bond in a stepꢀwise fashion. This provided us
with two alternatives for ring closure and both these key intermediates, B and C, (Scheme 6) were
independently prepared (R=Br). When B and C were independently subjected to the second alkylation to
form spirocycle A, a clear difference was observed. Upon spirocyclization, intermediate C, the 3ꢀisomer,
proceeded smoothly under phase transfer conditions, whilst cyclization of the corresponding 2ꢀisomer B
was substantially worse. Therefore, spirocyclization from modified precursors of intermediate C was
selected for further optimization.
Scheme 6. Retrosynthetic analysis of spiro acid
The practical synthesis of a suitable derivative of the 3ꢀisomer C became our initial target for
developing a scalable synthesis of spiro acid 2. 2,3,5ꢀTribromopyridine was initially considered as the
starting material, however chemoselectivity between Cꢀ2 and Cꢀ5 became a serious issue, therefore, 2,3ꢀ
dibromoꢀ5ꢀchloropyridine (15) was selected as the starting material (Scheme 7). A regioselective
transmetallation of the bromide at Cꢀ3 of 15 proceeded as expected13 to provide Cꢀ3 aldehyde, after
9
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 22
quenching with DMF. The aldehyde was readily reduced to the corresponding alcohol 16. The alcohol
16 was protected with a THP group, followed by a second selective transmetallation with iPrMgCl in
toluene. The resulting anion was converted to the corresponding Cꢀ2 aldehyde 17 in high yield by
addition of DMF. Condensation of aldehyde 17 with Nꢀtertꢀbutyl azaindolone 18 provided the highly
crystalline alkene as its Zꢀisomer 19. The alkene was reduced with NaBH4 which was followed by THP
deprotection to afford the primary alcohol 20. Chlorination of 20 with SOCl2 in presence of DMF
provided 21, the chloro variant of the desired intermediate C, in high yield.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 7. Preparation of benzyl chloride 21 from 15. Reagents and conditions: a) iPrMgCl LiCl, THF, ꢀ
40 °C, 30 min, then DMF; b) NaBH4, MeOH, rt, 30 min, 93%; c) DHP, conc. H2SO4, 2ꢀMeTHF, rt, 10
min; d) iPrMgCl, tolueneꢀTHF, 0 °C, 2 h, then DMF, 0 °C, 1 h, 97%; e) 18 (1.1 equiv), DBU (5 mol%),
iPA, ꢀ2 °C 2 h then rt 3 h, 87%; f) NaBH4, EtOH, rt, 1 h; g) HCl, iPA, 40 °C, 3 h, 86%; h) SOCl2,
CH2Cl2, 5 °C, 30 min, 93%.
With intermediate 21 in hand the stage was now set to evaluate the key spirocyclization. The ultimate
goal was to identify conditions which would provide some asymmetric introduction during this step. The
spirocyclization of 21 proceeded well under standard PTC conditions. We therefore screened the
10
ACS Paragon Plus Environment

Page 11 of 22
Organic Process Research & Development
spirocyclization of 21 against a library of chiral PTCs (mainly cinchona alkaloid derivatives). As a
result, the novel N,N’ꢀdoubly quaternized PTC 22 was serendipitously discovered as the most potent
catalyst.14
1
2
3
4
5
6
7
8
9
The spirocyclization of 21 was further optimized with PTC 22. When employing this new catalyst,
less solvent and only a slight excess of base were required. The ease of reaction is in direct contrast to
monoꢀquaternized PTC catalyzed reactions which often require strict reaction conditions, such as well
controlled stirring rate, temperature, high base concentrations and high catalyst loading; this novel bisꢀ
quaternary PTC reaction is mild, fast, robust and highly reproducible. Employing these conditions on
scale gave the desired spiro compound 23 (94.4% ee with 100% assay yield) in an 87% isolated yield.
The optical purity of the material isolated by crystallization was measured at 99.5% ee.
With optically pure 23 in hand, we were now in a position to complete the synthesis of the spiro acid
fragment 3. Carbonylation of 23 under conditions exemplified by the Buchwald group gave the
intermediate acid.15 Finally the tertꢀbutyl protecting group was removed under acidic conditions, either
HCl or H2SO4 were found to be suitable (Scheme 8). Ultimately the spiro acid 3 was prepared from 15
in 11 synthetic steps in a 43 % overall yield. This process is extremely robust and has successfully
produced over 100 kg of 3.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
11
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 22
Scheme 8. Completion of the spiro acid synthesis. Regents and conditions: a) 22 (0.3 mol%), 0.3 N
NaOH (1.1 equiv), toluene, ꢀ1 °C, 3 h, 83%; b) Pd(OAc)2 (1 mol%), DCPP (2 mol%), K2CO3, NMP,
CO (30 psi), 120 °C, 24 h, 95%; c) conc. HCl, 94 °C, 48 h, 94%.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With new robust syntheses of lactam 2 and spiro acid 3 in hand, the final coupling reaction and isolation
conditions were optimized (Scheme 9). After a salt break of 14, the HCl salt of lactam 2 in the aqueous
layer was directly used for the coupling in aqueous acetonitrile. The coupling reaction proceeded
smoothly with EDC (1.2 equiv) and catalytic amount of HOPO, without epimerization at the α carbon
center of the newly formed amide bond.16 After the reaction was complete, the product could be directly
crystallized by slow addition of the crude reaction stream into a mixture of ethanol and water.
Ubrogepant 1 was isolated directly as its trihydrate in a 95% yield with excellent optical and chemical
purities.
Scheme 9. Preparation of ubrogepant 1. Reagents and conditions: a) 0.6 N HCl (1.2 equiv), MTBE, b) 3
(1.0 equiv), EDC (1.2 equiv), HOPO (0.1 equiv), MeCN, H2O, pH 6.0ꢀ6.5, rt, 6ꢀ12 h, c) EtOH, H2O,
95%.
Conclusion
A new economical route to a highly potent CGRP receptor antagonist, ubrogepant, currently in phase
3 studies for acute treatment of migraine, is described. New asymmetric routes to the two main
fragments were developed in order to establish the four chiral centers. Highlights include setting both
12
ACS Paragon Plus Environment

Page 13 of 22
Organic Process Research & Development
the Cꢀ5 and Cꢀ6 chiral centers of fragment 2 in a single transformation by an enzymatic DKꢀTA. The
final chiral center at Cꢀ3 could be established by an aldehyde initiated CIDT. The spiro acid 3 was
prepared by a stepwise bond formation sequence. A highly productive asymmetric spiro cyclization was
accomplished using a novel doubly quaternized PTC to set the challenging key quaternary stereogenic
carbon center. The final coupling conditions were modified to avoid epimerization with an EDC
mediated coupling with catalytic amounts of HOPO. These conditions allowed the direct isolation of the
target compound from the reaction medium in high yield and with high purity.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
All reagents and solvents were purchased from commercial suppliers and used without further
purification, unless otherwise specified. All transaminase variants in Table 1 were purchased from
Codexis Inc. Column chromatography was performed on Merck Silica Gel 60 Å (230 X 400 meshes).
Reactions were typically monitored by HPLC analysis using an Agilent 1100 with reverse phase
columns unless otherwise specified.
1H and 13C NMR spectra were recorded using Brukerꢀ500, Brukerꢀ400 and Agilentꢀ500 MHz
spectrometers. For 1H NMR, chemical shifts are reported relative to residual protonated solvent peaks (δ
7.27, 2.50, and 1.94 ppm for CDCl3, (CD3)2SO and CD3CN, respectively). 13C NMR spectra were
1
measured at either 126 MHz or 100 MHz on the same instruments noted above for recording H NMR
spectra. Chemical shifts were again reported in accordance to residual protonated solvent peaks (δ 77.23,
39.51, and 118.69 ppm for CDCl3, (CD3)2SO and CD3CN, respectively). Multiplicities are reported
using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, om =
overlapped multiplet, br = broad resonance.
Mass spectral data were obtained on Waters SYNAPT G1 ESIꢀTOF HRMS and Waters Micromass ZQ
ESIꢀTOF LCMS. Optical purities were measured using a HPLC (Agilent 1100) or a SFC (Aurora
SFC/Agilent 1100) using chiral columns.
13
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 22
Isopropyl 2ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ4ꢀoxoꢀ3ꢀphenylpentanoate (9)
1
2
3
4
5
6
7
8
9
To Cs2CO3 (7.38 g, 22.7 mmol) was added DMSO (45.7 mL) at room temperature and stirred at room
temperature for 2 h under N2 atmosphere. To the suspension was added phenylacetone (6.94 g, 90.3%
purity, 46.7 mmol) and stirred at 18ꢀ22 °C for 40 min. To the reaction mixture was added a solution of
isopropyl 2ꢀ((tertꢀbutoxycarbonyl)amino)acrylate (7)17 (10.2 g, 44.5 mmol) in DMSO (28.8 mL) over 1
h and the mixture was stirred at the same temperature for 1 h. MTBE (110 mL) was added to the
reaction mixture. The solid was removed by filtration and rinsed with MTBE (48 mL). The filtrate and
rinse were combined, washed with 5% aqueous NaCl twice (80 mL then 70 mL). The organic layer was
concentrated and was used in the next reaction without purification (assay yield was 76.7%). Two
diastereomers can be separated for analysis by silica gel column chromatography with EtOAcꢀhexanes
(0% to 20%). In CDCl3, both diastereomers show rotamers and mainly enol forms. NMR data is
reported for each major rotamer.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Isomer A; 1H NMR (CDCl3, 500 MHz): δ 7.31 (t, J=7.4 Hz, 2H), 7.27ꢀ7.17 (m, 3H), 5.06 (m, 1H), 4.66
(dd, J=11.9, 4.7 Hz, 1H), 3.24 (ddq, J=16.1, 11.9, 2.3 Hz, 1H), 2.76 (ddq, J=16.1, 4.0, 1.9 Hz, 1H), 2.31
13
(s, 3H), 1.47 (s, 9H), 1.25 (d, J=6.5 Hz, 3H), 1.23 (d, J=6.5 Hz, 3H); C NMR (CDCl3, 126 MHz): δ
171.8, 152,1, 135.9, 128.2, 127.7, 126.2, 80.8, 68.6, 59.1, 35.6, 28.3, 21.7, 14.5; HRMS: C20H29NNaO5
386.1938 (M+Na); found 386.1947.
Isomer B; 1H NMR (CDCl3, 500 MHz): δ 7.32 (t, J=7.4 Hz, 2H), 7.24 ꢀ 7.15 (m, 3H), 5.07 (hept, J=6.3
Hz, 1H), 4.67 (dd, J=11.9, 4.7 Hz, 1H), 3.24 (ddq, J=15.8, 12.0, 2.3 Hz, 1H), 2.77 (ddq, J=15.8, 3.9, 1.9
13
Hz, 1H), 2.32 (b, 3H), 1.47 (s, 9H), 1.28 (d, J=6.3 Hz, 3H) 1.20 (d, J=6.3 Hz, 3H); C NMR (CDCl3,
126 MHz): δ 171.83, 171.76, 152.1, 136.0, 128.2, 127.7, 126.2, 115.6, 80.8, 68.6, 59.1, 35.6, 28.3, 21.7,
14.5.
Isopropyl 4ꢀ(4ꢀbromophenyl)ꢀ2ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ5ꢀoxohexanoate (8)
Compound 8 was prepared in the similar manner for 9. The crude mixture of 8 was converted to 9 under
transfer hydrogenation conditions (HCO2K, K2CO3, iPA, 10% Pd/C, at 60 °C for 2 h). The crude 9 was
used in next reaction without further purification.
14
ACS Paragon Plus Environment

Page 15 of 22
Organic Process Research & Development
Diastereoisomers of 8 can be separated by silica gel column chromatography using EtOAc hexanes (0 to
20 v/v%). In CDCl3, both isomers (8) show rotamers and mainly ketone forms. NMR data is reported for
each major rotamer.
1
2
3
4
5
6
Isomer A; 1H NMR (CDCl3, 500 MHz): δ 7.44 (d, J=8.3 Hz, 2H), 7.07 (d, J=8.3 Hz, 2H), 5.10 (d, J=7.1
Hz, 1H), 4.95 (hept, J=6.3 Hz, 1H), 4.18 (q, J=7.5 Hz, 1H), 3.76 (dd, J=8.9, 5.3 Hz, 1H), 2.64 (b, 1H),
2.06 (s, 3H), 1.68 (b, 1H), 1.43 (s, 9H), 1.24 (d, J=6.3 Hz, 3H), 1.21 (d, J=6.3 Hz, 3H); 13C NMR
(CDCl3, 126 MHz): δ 206.3, 171.7, 155.4, 137.3, 132.2, 131.1, 130.0, 121.8, 79.9, 69.4, 54.7, 52.0,
35.7, 29.1, 28.3, 21.7.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Isomer B; 1H NMR (CDCl3, 500 MHz): δ 7.46 (d, J=8.3 Hz, 2H), 7.09 (d, J=8.3 Hz, 2H), 4.98 (m, 1H),
4.89 (d, J=7.5 Hz, 1H), 4.07 (b, 1H), 3.76 (t, J=6.9 Hz, 1H), 2.37 (br, 1H), 2.08 (m, 1H), 2.04 (s, 3H),
13
1.42 (s, 9H), 1.22 (d, J=6.6 Hz, 3H), 1.20 (d, J=6.4 Hz, 3H); C NMR (CDCl3, 126 MHz): δ 206.8,
171.7, 155.4, 137.0, 132.3, 130.0, 121.8, 80.0, 69.3, 55.5, 52.3, 34.7, 29.2, 28.3, 21.7.
tertꢀButyl ((5S,6R)ꢀ6ꢀmethylꢀ2ꢀoxoꢀ5ꢀphenylpiperidinꢀ3ꢀyl)carbamate (10)
Sodium tetraborate decahydrate (26.7 g) was dissolved in water (1.4 L). After all solids were dissolved,
isopropylamine (82.8 g) was added. The pH of the buffer was adjusted to pH 10.5 using 6 N HCl. The
buffer was cooled to room temperature. Then, pyridoxalꢀ5ꢀphosphate (2.8 g) and SEQ ID NO: 1 (70 g)
were added and slowly dissolved at room temperature. The solution of 9 (197.9 g, 70.7wt%, 385 mmol)
in DMSO (1.4 L) was added to the flask over 5ꢀ10 min and the reaction was heated to 55 °C. The pH
was adjusted to 10.5 according to a handheld pH meter and controlled overnight with an automated pH
controller using 8 M aqueous isopropylamine. The reaction was aged for 24 h. After confirmation of
>95A% conversion by HPLC, the reaction was extracted by first adding 2.8 L of a mixture of iPA:IPAc
(3:4) and stirring for 20 min. The phases were separated and the aqueous layer was back extracted with
2.8 L of a mixture of iPA:IPAc (2:8). The phases were separated; the organic layers were combined and
washed with DI water (0.5 L). The HPLC based assay yield in the organic layer was 10 (114.6 g) with
>60:1 dr at the positions Cꢀ5 and Cꢀ6. The ratio of stereoisomers at position Cꢀ3 was ~1:1. The extract
was concentrated and dissolved in CH2Cl2. The organic solution was washed with water then sat. NaCl
15
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 22
aq, concentrated and crystallized from MTBE/nꢀhexane (2:3). The crystals were filtered at room
temperature and washed with MTBE/nꢀhexane (2:3) and dried to afford a cis and trans mixture (~1 :1.2)
of the lactam 10 (99.6 g, 80.0 %).
1
2
3
4
5
6
7
8
9
cis:trans (~1: 1.2) mixture but NMR integration was reported as 1:1 (for proton number counts)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Mp 87ꢀ90.9 °C; 1H NMR (CDCl3, 400 MHz): δ 7.40ꢀ7.20 (m, 8H, cis and trans), 7.16ꢀ7.12 (m, 2H, cis
and trans); 6.56 (broad s, 1H, trans), 6.35 (broad s, 1H, cis), 5.57 (broad d, J=4.6 Hz, 1H, cis), 5.34
(broad d, J= 5.7 Hz, 1H, trans), 4.33ꢀ4.15 (m, 2H, cis and trans), 3.93 (m, 1H, trans), 3.81 (m, 1H, cis),
3.41 (dt, J= 11.8, 5.0 Hz, 1H, cis), 3.29 (dt, J=8.0, 4.4 Hz, 1H, trans), 2.74 (m, 1H, cis), 2.57 (m, 1H,
trans), 2.23 (ddd, J=13.5, 8.0, 4.4 Hz, 1H, trans), 2.07 (q, J=11.8 Hz, 1H, cis), 1.46 (s, 9H, cis), 1.42 (s,
13
9H, trans), 1.05 (d, J=6.9 Hz, 3H, trans), 0.89 (d, J=6.9 Hz, 3H, cis); C NMR (CDCl3, 100 MHz): δ
171.52 (cis), 171.46 (trans), 156.04 (cis or trans), 155.93 (cis or trans), 140.8 (cis), 139.9 (trans), 128.8
(trans), 128.7 (cis), 128.6 (trans), 128.1 (cis), 127.25 (trans), 127.18 (cis), 79.98 (trans), 79.91 (cis), 52.4
(trans), 51.8 (broad, cis), 51.7 (cis), 49.0 (broad, trans), 42.1 (cis), 41.9 (trans), 32.4 (broad, trans), 30.1
(cis), 28.57 (cis or trans), 28.53 (cis or trans), 18.3 (cis), 18.1 (broad, trans); HRMS m/z cacld. for
C17H24N2NaO3 327.1679 (M+Na); found 327.1696.
(5S,6R)ꢀ3ꢀAminoꢀ6ꢀmethylꢀ5ꢀphenylꢀ1ꢀ(2,2,2ꢀtrifluoroethyl)piperidinꢀ2ꢀone (13)
To a mixture of 10 (20.0 g, 65.7 mmol) and Na2S2O3 (0.52 g, 3.3 mmol) in THF (200 mL) was added
tertꢀBuOLi (6.8 g, 85 mmol) at 20 oC. The mixture was stirred at 20 oC for 15 min followed by addition
of trifluoroethyl trifluoromethanesulfonate (20.6 g, 89 mmol) in one portion. The resulting mixture was
o
stirred for 18 h at 20 C. The reaction mixture was then quenched by addition of toluene (70 mL)
followed by 0.5 N HCl solution (50 mL). The aqueous layer was separated and extracted with toluene
(20 mL). The combined organic layer contained 87% of 11, 6% of 12 and 6% of 10 by HPLC and yield
for the desired product 11 was 87%.
16
ACS Paragon Plus Environment

Page 17 of 22
Organic Process Research & Development
Analytically pure cis and trans isomers 11 were isolated by chromatography on silica gel with ethyl
1
2
3
acetate and heptane as eluant.
4
5
6
7
11 (cis); 1H NMR (CDCl3, 500 MHz): δ 7.31 (m, 2H), 7.23 (m, 1H), 7.17 (m, 2H), 5.75 (s, broad, 1H),
8
9
4.85 (m, 1H), 4.15 (m, 1H), 3.80 (m, 1H), 3.50 (m, 1H), 3.17 (m, 1H), 2.45 (m, 2H), 1.45 (s, 9H), 0.93
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(d, J=6.7 Hz, 3H); C NMR (CDCl3, 100 MHz): δ 170.3, 155.9, 140.0, 128.6, 127.6, 127.1, 124.6 (q,
J=279 Hz), 79.7, 58.7, 52.2, 45.3 (q, J=33.7 Hz), 41.9, 28.3, 27.4, 13.4; HRMS: m/z calcd for
C19H26F3N2O3 387.1890 (M+H); found: 387.1899.
11 (trans); 1H NMR (CDCl3, 500 MHz): δ 7.40 (m, 2H), 7.30 (m, 3H), 5.55 (br, 1H), 4.53 (br, 1H), 4.45
(m, 1H), 3.78 (m 2H), 3.45 (m, 1H), 3.00 (m, 1H), 2.12 (m, 1H), 1.46 (s, 9H), 1.12 (d, J=7.0 Hz, 3H);
13C NMR (CDCl3, 100 MHz): δ 170.2, 155.9, 139.6, 128.7, 127.9, 127.4, 124.3 (q, J=279 Hz), 80.0,
59.6, 49.1, 46.9 (q, J=34.0 Hz), 42.1, 28.3, 25.3, 13.4; HRMS: m/z calcd for C19H26F3N2O3 387.1890
(M+H); found 387.1901.
The organic layer was then stirred with 3 N HCl solution (80 mL) and tetrabutylammonium bromide
(0.8 g, 2.48 mmol) at 35 °C for about 3 h until HPLC analysis indicated selective removal of the Boc
group in the unreacted 10 was complete. The aqueous layer was removed. The organic layer containing
o
11 and 12 was then concentrated under vacuum at 60 C to remove most of solvent. The residue was
dissolved in a mixture of MTBE (60 mL), MeOH (10 mL), and 4.5 N HCl solution (64 mL). The
o
diphasic solution was agitated vigorously at 50 C for about 5 h until the deprotection of 11 was
complete while 12 was mainly intact. After addition of heptane (30 mL) to the mixture, the organic layer
o
was separated at 45 C. The aqueous layer was diluted with water (60 mL) and then washed with
o
heptane (20 mL) and MTBE (10 mL) at 45 C. The combined organic layer was extracted with 0.5 N
HCl solution (20 mL). The combined aqueous solution was then mixed with MTBE (100 mL) and
basified with 10 N NaOH solution until the pH of the mixture was about 10. The organic layer was
separated and the aqueous layer was backꢀextracted with MTBE (60 mL). The combined organic layers
were washed with brine (60 mL). The resulting organic solution was suitable for the next reaction. The
17
ACS Paragon Plus Environment

Organic Process Research & Development
Page 18 of 22
solution contained 13 (15.6 g, 83% from 10) with 97% LC purity as a mixture of two diastereomers (cis
and trans) in 4 to 1 ratio, which was used in the next reaction without further purification.
1
2
3
4
5
6
7
(3S,5S,6R)ꢀ6ꢀMethylꢀ2ꢀoxoꢀ5ꢀphenylꢀ1ꢀ(2,2,2ꢀtrifluoroethyl)piperidinꢀ3ꢀaminium 4ꢀmethylbenzoate (14)
8
9
To a suspension of 4ꢀmethylbenzoic acid (6.8 g, 49.9 mmol) and 3,5ꢀdichlorosalicylaldehyde (93 mg,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
0.49 mmol) in MTBE (40 mL) was added a solution of 13 (13.9 g, 48.5 mmol) in MTBE (about 150
o
o
mL) over 1 h at 50 C. The resulting suspension was agitated for about 3 h at 50 C. The solids were
o
collected by filtration after cooling to ꢀ5 C over 1 h. The cake was washed with MTBE (50 mL). The
crystalline solids were dried in a vacuum oven to give 14 (17.6 g, 86%) with 99.5% LC purity and
99.6% de. 1H NMR (DMSOꢀd6, 400 MHz): δ 7.85 (d, J=8.1 Hz, 2H), 7.40 (m, 2H), 7.25 (m, 5H), 6.42
(br, 3H), 4.65 (m, 1H), 3.82 (m, 1H), 3.76 (m, 1H), 3.62 (m, 1H), 3.50 (m, 1H), 2.35 (s, 3H), 2.30 (m,
1H), 2.15 (m, 1H), 0.88 (d, J=6.5 Hz, 3H); 13C NMR (DMSOꢀd6, 100 MHz): δ 172.4, 168.5, 142.1,
141.1, 130.9, 129.7, 129.2, 129.0, 128.0, 125.5 (q, J=279 Hz), 59.1, 51.6, 45.1 (q, J=32 Hz), 41.6, 28.0,
21.5, 13.9. HRMS: m/z calcd for C14H18F3N2O+ 287.1366 (M+H); found 287.1359.
Preparation of compounds 16, 17, 18, 19, 20, 21, 22, and 23 has been reported.14
(S)ꢀ2'ꢀOxoꢀ1',2',5,7ꢀtetrahydrospiro[cyclopenta[b]pyridineꢀ6,3'ꢀpyrrolo[2,3ꢀb]pyridine]ꢀ3ꢀcarboxylic acid
(3)
A mixture of 23 (5.0 g, 14.5 mmol), K2CO3 (5.01 g, 36.2 mmol), Pd(OAc)2 (33 mg, 0.145 mmol), 1,3ꢀ
bis(dicyclohexylphosphino)propane (DCPP, 127 mg, 0.290 mmol) and water (0.522 mL, 29.0 mmol) in
NMP (32 mL) was heated at 120 °C under 30 psi of CO for 24 h. After cooling to room temperature, the
resulted slurry was diluted with water (100 mL). The pH was slowly adjusted to 3~4 with 2 N HCl. The
slurry was aged at room temperature for 1 h, filtered, rinsed with water (40 to 50 mL), dried under oven
at 60 °C to give Nꢀtertꢀbutyl carboxylic acid (4.64 g, 95%) as a solid. 1H NMR (DMSOꢀd6, 500 MHz): δ
8.90 (s, 1H), 8.19 (d, J=5.2 Hz, 1H), 7.54 (d, J=7.3 Hz, 1H), 6.99 (dd, J=7.3, 5.2 Hz, 1H), 3.33 (m, 4H),
1.72 (s, 9H); 13C NMR (DMSOꢀd6, 126 MHz): δ 180.2, 167.4, 167.0, 158.1, 149.8, 146.6, 135.4, 133.1,
18
ACS Paragon Plus Environment

Page 19 of 22
Organic Process Research & Development
+
130.4, 128.8, 125.5, 118.4, 58.2, 51.1, 44.6, 41.2, 28.9; HRMS: m/z calcd for C19H20N3O3 : 338.1499
1
2
3
(M+H); found: 338.1496.
4
5
6
7
8
To the Nꢀtertꢀbutyl carboxylic acid (4 g, 97%wt, 11.5 mmol) was charged 37% HCl (40 to 44 mL). The
slurry was heated at 94 °C for 48 h, cooled to room temperature. The solvent was partially removed by
reducing pressure to about total 2 vol (~ 4 mL water remained). The residue was diluted with water (20
mL) followed by adjusting pH to 2.6 with NaOH (3.5 N, 4.5 mL). The thick slurry was aged for 1 to 2 h,
filtered, rinsed with water (2 x 8 mL), followed by water/acetone (1:1, 8 mL). The wet cake was dried
to give compound 3 (3.1 g, 98%wt, 94%) as crystals. 1H NMR (DMSOꢀd6, 500 MHz): δ 13.31 (br, 1H),
11.14 (s, 1H), 8.91 (s, 1H), 8.19 (s, 1H), 8.11 (m, 2H), 7.49 (dd, J=7.3, 1.3 Hz, 1H), 6.93 (dd, J=7.3, 5,3
Hz, 1H), 3.36 (m, 4H); 13C NMR (DMSOꢀd6, 126 MHz): δ 181.1, 167.4, 167.0, 156.8, 149.8, 147.3,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ
135.4, 133.2, 130.7, 128.9, 125.5, 118.5, 51.8, 44.1, 40.7; HRMS: m/z calcd for C15H10N3O3 : 280.0728
(MꢀH); found: 280.0725.
(S)ꢀNꢀ((3S,5S,6R)ꢀ6ꢀMethylꢀ2ꢀoxoꢀ5ꢀphenylꢀ1ꢀ(2,2,2ꢀtrifluoroethyl)piperidinꢀ3ꢀyl)ꢀ2'ꢀoxoꢀ1',2',5,7ꢀ
tetrahydrospiro[cyclopenta[b]pyridineꢀ6,3'ꢀpyrrolo[2,3ꢀb]pyridine]ꢀ3ꢀcarboxamide trihydrate (1)
To a suspension of 14 (10.0 g, 98wt%, 23.2 mmol) in MTBE (70 mL) was added 0.6 N HCl (42 mL,
25.2 mmol). The mixture was stirred for 5 min. The organic layer was separated and extracted with
another 0.6 N HCl (8 mL, 4.8 mmol). The combined aqueous solution was washed with MTBE three
times (3 X 10 mL). The resulting aqueous solution was mixed with acetonitrile (35 mL) and 3 (6.66 g,
99wt%, 23.5 mmol) was added. To the resulting suspension was added 29% NaOH solution (4.25 g,
1.33 equiv) dropwise in a few min to pH 6.0ꢀ6.5. After the mixture was stirred for 15 min at room
temperature, HOPO (0.26 g, 2.34 mmol) was added followed by EDC hydrochloride (5.34 g, 27.9
mmol). The mixture was stirred at room temperature for 6ꢀ12 h until the conversion was complete.
Ethanol (30 mL) was added and the mixture was stirred at 35 oC for 10 min. The resulting solution was
cooled to room temperature and filtered. To another three neck flask was added ethanol (10 mL) and
water (30 mL) followed by 1 seeds (0.4 g). The resulting suspension was stirred for 10 min. Part of the
19
ACS Paragon Plus Environment

Organic Process Research & Development
Page 20 of 22
filtrate (10 mL) was transferred into a syringe and added to the agitated suspension slowly via a syringe
pump over 1 h. The flask was then equipped with two additional funnels. The rest of the filtrate was
transferred into one additional funnel while the other funnel was charged water (70 mL). The contents in
both funnels were charged into the suspension at the same time over an hour at room temperature. The
1
2
3
4
5
6
7
8
9
o
suspension was then cooled to 5 C over 30 min. The suspension was filtered and washed with
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
ethanol/water mixture (40 mL, 1:3). The cake was dried in a vacuum oven at 40 C, to give 13.7 g of
white solids as 1 trihydrate (95%). ¹H NMR (500 MHz, CDCl3): δ 10.15 (br s, 1H); 8.91 (br s, 1H); 8.21
(d, J=6.0 Hz, 1H); 8.16 (dd, J=5.3, 1.5 Hz, 1H); 8.01 (br s, 1H); 7.39ꢀ7.33 (m, 2H); 7.31ꢀ7.25 (m, 1H);
7.22ꢀ7.20 (m, 2H); 7.17 (dd, J=7.4, 1.6 Hz, 1H); 6.88 (dd, J=7.4, 5.3 Hz, 1H); 4.94 (dq, J=9.3, 7.6 Hz,
1H); 4.45ꢀ4.37 (m, 1H); 3.94ꢀ3.87 (m, 1H); 3.72 (d, J=17.2 Hz, 1H); 3.63ꢀ3.56 (m, 2H); 3.38ꢀ3.26 (m,
1H); 3.24 (d, J=17.3 Hz, 1H); 3.13 (d, J=16.5 Hz, 1H); 2.78 (q, J=12.5 Hz, 1H); 2.62ꢀ2.56 (m, 1H); 1.11
(d, J=6.5 Hz, 3H); 13C NMR (126 MHz, CDCl3): δ 181.4, 170.6, 166.7, 166.6, 156.9, 148.6, 148.1,
141.7, 135.8, 132.1, 131.1, 130.1, 129.7, 129.6, 128.8, 128.1, 126.3 (q, J=280.1 Hz), 119.4, 60.1, 53.1,
52.0, 46.4 (q, J=33.3 Hz), 45.2, 42.8, 41.7, 27.8, 13.5; HRMS m/z: calcd for C29H27F3N5O3 550.2061
(M+H): found 550.2059.
Acknowledgements
Authors acknowledge the helpful discussion with Drs. LouisꢀCharles Campeau, Mark Huffman,
Carmela Molinaro, Paul Bulger, Neil McGachy, Peter Dormer, Haibin Chen, Anupam P. Salim, Derek J.
Smith, David A. Entwistle, Guofeng Xu, Lantao Lin, Hongjiao Zhang, Yan Gao, and Guoyue Zhou.
Supporting Information
The supporting Information is available free of charge on the ACS Publications website at DOI:
1H and 13C NMR spectra of compounds 1, 3, 8, 9, 10, 11, and 14.
Notes
20
ACS Paragon Plus Environment

Page 21 of 22
Organic Process Research & Development
The authors declare no competing financial interest.
1
2
3
4
5
References
6
7
8
9
(1) Goadsby, P. J.; Lipton, R. B.; Ferrari M. D. N. Engl. J. Med. 2002, 346, 257.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2) Stovner, L. J.; Hagen, K.; Jensen, R.; Katsarava, Z.; Lipton R. B.; Scher, A. I.; Steiner, T. J.;
Zwart, J.ꢀA. Cephalagia 2007, 27, 193.
(3) Dahlöf, C. G. H.; Mathew, N. Cephalalgia 1998, 18, 539.
(4) (a) Moore, E. L.; Salvatore, C. A.; British J. Pharm. 2012, 166, 66. (b) Bell, I. M. J. Med. Chem.
2014, 57, 7838.
(5) (a) Fraley, M. E. Books of Abstracts, 252th ACS National Meeting, Philadelphia, PA, August 21ꢀ
25, 2016; American Chemical Society: Washington, DC, 2016; MEDIꢀ19. (b) Bell, I. M.; Fraley, M. E.;
Gallicchio, S. N.; Ginnetti, A.; Mitchell, H. J.; Paone, D. V.; Staas, D. D.; Wang, C.; Zartman, C. B.;
Stevenson, H. E. WO 2012/064910 A1.
(6) (a) Koszelewski, D.; Clay, D.; Faber, K.; Kroutil, W. J. Mol. Cat. B: Enzymatic, 2009, 60, 191. (b)
Chung, C. K.; Bulger, P. G.; Kosjek, B.; Belyk, K. M.; Rivera, N.; Scott, M. E.; Humphrey, G. R.;
Limanto, J.; Bachert, D. C.; Emerson, K. M. Org. Proc. Res. Dev. 2014, 18, 215. (c) Limanto, J.;
Ashley, E. R.; Yin, J.; Beutner, G. L.; Grau, B. T.; Kassim, A. M.; Kim, M. M.; Klapars, A.; Liu, Z.;
Strotman, H. R.; Truppo, M. D. Org. Lett. 2014, 16, 2716. (d) Cuetos, A.; Lavandera, I.; Gotor, V.
Chem. Comm. 2013, 49, 10688. (e) Peng, Z.; Wong, J. W.; Hansen, E. C.; PuchlopekꢀDermenci, A. L.
A.; Clarke, H. J. Org. Lett. 2014, 16, 860.
(7) (a) Armstrong III, J. D.; Eng, K. K.; Keller, J. L.; Purick, R. M.; Hartner Jr, F. W.; Choi, W.ꢀB.;
Askin, D.; Volante, R. P. Tetrahedron Lett. 1994, 35, 3239. (b) Brands, K. M. J.; Davies, A. J. Chem.
Rev. 2006, 106, 2711
21
ACS Paragon Plus Environment

Organic Process Research & Development
Page 22 of 22
(8) Phenylacetone (a schedule II controlled substance by US DEA) was used for larger scales without
debromination and procedure and yield with phenylacetone were similar to those with 4ꢀ
bromopheylacetone.
1
2
3
4
5
6
7
8
9
(9) Savile, K. C.; Janey, J. M.; Mundorff, E. C.; Moore, J. C.; Tam, S.; Jarvis, W. R.; Colbeck, J. C.;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Krebber, A.; Fleitz, F. J.; Brands, J.; Devine, P. N.; Huisman, G. W.; Hughes, G. J. Science 2010, 329,
305.
(10) The lactam formation minimizes the reaction reversibility and drives the equilibrium towards the
product.
(11) Xu, F.; Zacuto, M.; Yoshikawa, N.; Desmond, R.; Hoerrner, S.; Itoh, T.; Journet, M.; Humphrey,
G. R.; Cowden, C.; Strotman, N.; Devine, P. J. Org. Chem. 2010, 75, 7829.
(12) pꢀNitrobenzoic acid also provided excellent crystallization but it was not selected due to
genotoxic concern on nitro group.
(13) Burzicki, G.; VoisinꢀChiret, A. S.; Santos, J. S.ꢀde. O.; Rault, S. Synthesis, 2010, 16, 2804.
(14) Xiang, B.; Belyk, K. M.; Reamer, R. A.; Yasuda, N. Angew. Chem. Int. Ed. Engl. 2014, 53, 8375.
(15) Watson, D. A.; Fan, X.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7096.
(16) Over 1% of epimerization was observed under the original coupling conditions (EDC,
triethylamine, and HOBt in DMAc).
(17) Navarre, L.; Martines, R.; Genet, J.ꢀP.; Darses, S. J. Am. Chem. Soc., 2008, 130, 6159.
22
ACS Paragon Plus Environment