Development of a Kilogram-Scale Synthesis of a Novel MC1R Agonist

Article abstract of DOI:10.1021/acs.oprd.5b00097

Herein, we report the kilogram-scale synthesis of CD08108, a novel MC1R agonist. This synthesis has been developed to produce the first batches of this compound for preclinical and clinical studies. Two amido couplings were used to synthesize the backbone

Full text of DOI:10.1021/acs.oprd.5b00097

Subscriber access provided by NEW YORK UNIV
Full Paper
Development of a Kilogram-scale synthesis of a novel MC1R agonist
Jean-Guy Boiteau, Nicolas Rodeville, Cedric Martin, Samuel Tabet, Christine
Moureou, Franck Muller, Jean-Claude Jetha, and Isabelle Cardinaud
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00097 • Publication Date (Web): 29 May 2015
Downloaded from http://pubs.acs.org on May 31, 2015
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 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Development of a Kilogramꢀscale synthesis of a
novel MC1R agonist
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
Jean-Guy Boiteau*, Nicolas Rodeville, Cédric Martin, Samuel Tabet, Christine Moureou,
Franck Muller, Jean-Claude Jetha, Isabelle Cardinaud.
Galderma R&D Les Templiers, 2400 Route des colles BP 87, 06902 SophiaꢀAntipolis CEDEX,
France
*To whom correspondence should be addressed: Tel +33 4 92 95 29 48.
JeanꢀGuy.Boiteau@galderma.com
ACS Paragon Plus Environment
1

Organic Process Research & Development
Page 2 of 17
1
2
3
4
TABLE OF CONTENTS GRAPHIC
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
ACS Paragon Plus Environment
2

Page 3 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
ABSTRACT : Herein we report the Kilogramꢀscale synthesis of CD08108, a novel MC1R
agonist. The synthesis has been developed in order to produce first batches of this compound for
preclinical and clinical studies. Two amido couplings were used to synthesize the backbone of
the API. Improvements have been made in order to isolate crystalline intermediates and to
remove all column chromatographic steps. The crystallization of final API has been monitored
by DSC inꢀprocess control during slurry ripening of the amorphous suspension of the
hydrochloride salt.
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
KEYWORDS : CD08108, MC1R agonist, Kilogram synthesis, slurry ripening
ACS Paragon Plus Environment
3

Organic Process Research & Development
Page 4 of 17
1
2
3
4
5
6
7
8
9
INTRODUCTION: MC1R is a member of melanocortin receptor family itself a part of the
GPCR superfamily. Deficient mutation of MC1R is associated with red hair and lighter skin in
humans.1 In cultured human melanocytes, it has been demonstrated that the addition of an
MC1R agonist in culture medium stimulates cell proliferation, and increases melanogenesis.2
Vitiligo is a disease that is characterized by an hypoꢀpigmentation of the skin lesions due to loss
of melanin which severely affects the quality of life of patients, especially in populations with a
dark complexion.3 CD08108 is a full agonist of MC1R that could increase melanogenesis and
melanocyte proliferation to treat vitiligo4. We present, herein, the development of a Kilogramꢀ
scale synthesis of CD08108 and the solutions that were found in order to obtain crystalline
material.
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
RESULT AND DISCUSSION:
Scheme 1. Discovery route to CD08108
ACS Paragon Plus Environment
4

Page 5 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
The synthetic strategy to obtain 1 was performed by our medicinal chemistry colleagues
(Scheme 1). Bocꢀazetidinone 2 was firstly reacted with oꢀtolyl magnesium bromide at ꢀ78 °C in
THF to yield protected azetidine 3. Alkylation of the alcohol was performed with
cyclopropylmethyl bromide and sodium hydride in DMF, to afford compound 4 as an oil that
was purified by chromatography over silica and treated with TFA in toluene to yield azetidine 5,
also as an oil after another chromatographic step. Amido coupling of 5 and (D)ꢀBocꢀOMeꢀ
Tyrosine with EDC and HOBt afforded 6 after evaporation to dryness. Removal of the protecting
group was performed with TFA. Commercially available compound 8 was hydrogenated over
Pd/C in THF to yield the acid 9 that was engaged in a second amido coupling with 7 using
TBTU and DIPEA. Target compound 1 was purified over silica gel to yield the API as a white
amorphous solid.
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
This discovery route was appropriate to obtain small quantities of API, but to supply sufficient
quantities needed for development phases we had to improve this synthesis and develop a
process suitable to isolate compound 1 under a crystalline sate (Scheme 2). To avoid the first
cryogenic step, we looked at ways to perform the reaction at higher temperature. The reaction
could be carried at ꢀ20 °C by addition of a solution of oꢀtolylmagnesium bromide in 2ꢀMethylꢀ
tetrahydrofuran to a solution of Bocꢀazetidinone in 2ꢀMethylꢀtetrahydrofuran.5 Moving from
THF to MeTHF allowed us to introduce a washing step with aqueous hydrochloric acid, to
quench excess of Grignard reagent and remove impurities in the aqueous phase. During this
acidic wash we did not observe any removal of BOC protecting group. Then, concentration of
the organic phase and a solvent change to heptane induced in situ crystallization of compound 3
which was isolated in 79% yield.
ACS Paragon Plus Environment
5

Organic Process Research & Development
Page 6 of 17
1
2
3
4
Scheme 2. Process development route to CD08108
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
To introduce the cyclopropylmethyl group we tried to avoid the hazardous combination of
sodium hydride in DMF.6 Sodium hydride was replaced with potassium tertꢀbutoxide and the
reaction worked smoothly at room temperature. Attempts to use solvents other than DMF
resulted in incomplete reactions; therefore we decided to keep DMF as the reaction solvent.7
After complete conversion of compound 3 into compound 4, the reaction mixture was quenched
with water and extracted with DCM. Compound 4 was not isolated and the Boc deprotection step
was telescoped by adding a solution of hydrogen chloride in isopropanol to the organic extract.
Solvent change to diisopropyl ether was realized in order to crystallize azetidine 5 as the
hydrochloride salt in a 96% purity and overall yield of 63% from compound 3.8 During
laboratory experiments the cyclopropylmethyl ether was found to be quite sensitive to acidic
conditions as a significant level (up to 8 %) of free alcohol 12 was recovered after workꢀup,
despite a complete alkylation reaction (Scheme 3). It’s known that aryl cyclopropylmethyl ethers
ACS Paragon Plus Environment
6

Page 7 of 17
Organic Process Research & Development
1
2
are sensitive in acidic conditions9 but alkyl cyclopropylmethyl ethers are usually more stable and
we found only one precedent in the literature.10 During kilogramꢀscale experiment compound 12
was present at 3% in azetidine 5. Control of the purity of compounds 5 and 7 were identified as a
key, since traces of the unꢀalkylated alcohol 12 were converted during the following steps into
compound 13 and then the undesired side product 14 formed could not be removed from 1
during the final purification.
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. Side reaction during Boc removal of compound 4
HCl, Tol
60 °C
O
HO
NH
+
+
O
NH
O
N
O
HCl
HCl
12
(3%)
5
(96%)
4
O
O
NH2
NH2
N
N
HO
O
13
7
O
O
O
N
O
N
H
H
NH
HCl
NH
N
N
N
N
HCl
O
O
O
+
HO
1
14
O
O
For the amido coupling reaction of azetidine 5 with (D)ꢀBocꢀOMeꢀTyrosine, T3P in toluene
was used instead of HOBt and EDC.11,12 The reaction was complete in one hour at ꢀ10 °C
without epimerization.13 The reaction was quenched with a hydrochloric acid solution, washed
with sodium hydroxide to remove phosphates residues and finally azeotroped with toluene;
compound 6 was kept in toluene solution and was employed directly in the deprotection step by
ACS Paragon Plus Environment
7

Organic Process Research & Development
Page 8 of 17
1
2
3
4
5
6
7
8
9
addition of TFA at 60 °C. Addition of diisopropyl ether to the crude mixture induced
crystallization of compound 7 as a white crystalline powder. Attempts to switch from TFA to
hydrochloric acid were not successful as the hydrochloride salt of compound 7 was very
hygroscopic and therefore too difficult to handle. Finally, recrystallization in isopropanol was
performed to remove impurity 13 (from 1.7% to not more than 0.4%) and affords 1.3 Kg of
compound 7 with a 68% overall yield from precursor 5 and in 98.5% purity.
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
One other major issue we had to face was the sourcing of acid 8, which was available only in
small quantities. In order to secure the production of acid 9 we developed a HornerꢀWadsworthꢀ
Emmons approach (Scheme 2). The choice of a benzylic ester was supported by the amphiphilic
character of compound 9 that was fairly water soluble, the hydrogenation of both the double
bond and benzylic group was convergent and avoided a saponification step. The benzyl
diethylphosphonoacetate ylide was generated using sodium hydride in MeTHF and allowed to
react with the aldehyde 10. Attempts to switch sodium hydride to potassium tertꢀbutoxide lead to
incomplete reaction and no precipitation occurred during workꢀup. After completion of the
HornerꢀWadsworthꢀEmmons reaction a solvent switch from MeTHF to diisopropyl ether was
realized in order to crystallize compound 11 in 72% yield. This procedure was applied at a lab
scale up to 500 g, leading to a high purity material. However, during pilot production compound
11 was contaminated up to 3% with a new impurity. Based on LCMS traces the proposed
structure for this impurity is depicted on scheme 4. Compound 16 could result from a Michael
addition of a second equivalent of ylide on our compound 11, to afford compound 15 followed
by the conversion of the benzylic ester into an amide 16 due to the presence of remaining
ammonium chloride after the work up.14
ACS Paragon Plus Environment
8

Page 9 of 17
Organic Process Research & Development
1
2
3
4
Scheme 4. Proposed mechanism for the formation of impurity 16 in compound 11
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
Considering the purification experience we had for compound 9, we used this batch directly in
the hydrogenation step. Hydrogenation of 11 under 8 bars of hydrogen in a methanolꢀwater
mixture with Pd/C worked nicely. The crude solution was coꢀdistilled with methanol to remove
water and establish the required concentration ahead of being cooled to 0 °C to initiate
crystallization of acid 9. Unfortunately, when operated at scaling the purification for acid 9 was
unable to fully remove the impurity that had carried forwards from the previous step, so acid 9
contained about 2.3% of the impurity 16 never seen in the laboratory experiments. Attempts to
recrystallize compound 9 from isopropanol gave modest improvement; the impurity 16 was still
present at 1.7%. To improve the purity of this acid 9, this batch was finally was reprocessed
using a reaction with fumaric acid in methanol to yield the fumarate salt in 85 % yield. This salt
was purified by an ion exchange with a cationic resin followed by a release with ammonia. The
water solution was concentrated and then precipitated with methanol to give 3.3 Kg of acid 9
with 99% purity and in an overall yield of 46% for hydrogenation and purification.
For the final amido coupling TBTU was first used as a coupling agent in DMF and DIPEA.15
The conversion was complete but free base of compound 1 was obtained as a sticky oil and
column chromatography was still needed to obtain a >97% purity. Attempts to crystallize
compound 1 as a free base failed, we engaged a salt screening investigation and 31 different salts
ACS Paragon Plus Environment
9

Organic Process Research & Development
Page 10 of 17
1
2
3
4
5
6
7
8
9
in 20 different solvents were tested; only hydrochloric acid and galactaric acid led to a partially
crystalline material. The XRPD pattern obtained displayed very broad signals that encouraged us
to continue. We focused our attention on the hydrochloride salt of 1 and tried to find a process to
recrystallize it. A salt formation step with HCl in isopropanol was introduced during workꢀup of
the amido coupling. Other coupling agents were investigated, and despite the reaction was
complete using T3P, the precipitation of hydrochloride 1 was not efficient compared to the
TBTU process. Then TBTU was selected as coupling reagent and hydrochloride 1 was obtained
in 78% yield. This amorphous material was very hygroscopic and all attempts to obtain crystals
after recrystallization failed.16 This powder tended to retain solvents and reaching ICH residual
solvents limits upon drying were challenging. The DSC thermogram of amorphous material
showed an exothermic phenomenon (ꢁH = ꢀ15 J/g) at 185 °C which we felt could correspond to
crystallization, followed by the melting endotherm (ꢁH = 58 J/g) at 205 °C, as shown in Figure
1.17 To investigate further, we heated compound 1 at 190 °C in the solid state, and the DSC
thermogram of the resulting powder didn’t display any exothermic phenomenon associated with
a melting and the XRPD pattern presented broad peaks indicating only partial crystallization
(Figure 2). It is well known that slurryꢀripening can result in phase changes so the procedure we
developed in order to obtain crystalline material involved a gentle agitation of a suspension of
compound 1 in a specific ratio of heptane/ethanol (95/5) at 45 °C for at least 48 hours. This
slurry ripening was followed by DSC until disappearance of the exothermic phenomenon at
around 180 °C. Upon stirring we were able to observe the physical change of the powder, and the
isolated material was no longer hygroscopic. This ripening process also resulted in an increase of
the purity and the crystalline form did not longer retain solvents, so drying within ICH residual
solvents limits was readily achieved (Table 1). This crystallization process was conducted at
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
ACS Paragon Plus Environment
10

Page 11 of 17
Organic Process Research & Development
1
2
3
4
5
6
Kilogramꢀscale using DSC as an IPC and afforded the expected API with an overall yield of 74%
in a 98.0 % purity for preꢀclinical and clinical studies.
7
8
9
Table 1 : Comparison of purities after slurry ripening
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
After precipitation
96.1 %
After slurry
98.0 %
HPLC purity
% enantiomer
0.1%
0.05%
Residual solvents (ICH limits)
Isopropanol <5000 ppm
Ethyle acetate <5000 ppm
Ethanol <5000 ppm
Heptane <5000 ppm
DMF <880 ppm
763 ppm
4017 ppm
ND
ND
ND
ND
170 ppm
ND
291 ppm
ND
ACS Paragon Plus Environment
11

Organic Process Research & Development
Page 12 of 17
1
2
3
4
5
6
Figure 1. DSC thermograms of the ripening of CD08108 hydrochloride in Heptane/ethanol
95/5 at 45 °C over 66 hours.
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
a Evolution of DSC thermogram of CD08108 over time.
ACS Paragon Plus Environment
12

Page 13 of 17
Organic Process Research & Development
1
2
3
4
Figure 2. XRPD pattern of different batches of CD08108 hydrochloride.
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
a
(blue) CD08108 hydrochloride after ripening in heptaneꢀethanol 95/5 (pink) CD08108
hydrochloride after heating at 190 °C (green) CD08108 hydrochloride after precipitation.
In conclusion, we have developed a practical and scalable process for the synthesis of
CD08108 hydrochloride, a novel MC1R agonist. The synthesis has been optimized and scaledꢀup
to a kilogram scale, with an overall yield of 25% starting from Bocꢀazetidinone 2, having
addressed the following issues in so doing:
• Cryogenic Grignard addition step was performed at ꢀ20 °C in MeTHF
• The hazardous combination of NaH/DMF for the cyclopropylmethyl alkylation was
replaced with tBuOK/DMF
• T3P was found to be more efficient than EDC/HOBt to realize the first amido coupling
ACS Paragon Plus Environment
13

Organic Process Research & Development
Page 14 of 17
1
2
3
4
5
6
• Supply of 9 was secured and a purification process established to overcome a sideꢀ
product impurity
7
8
9
• The initially isolated amorphous API was converted to a crystalline form by slurry
ripening of the amorphous powder and the process was controlled using by DSC.
These key changes are summarized in the table below.
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
Table 2 : modified compared to original route
original
condition
modified
condition
step
1
yield step
yield
79%
oTolMgBr, THF, ꢀ78 °C, SiO2
NaH, DMF, SiO2
79%
90%
66%
96%
91%
41%
17%
1
2
3
4
5
6
oTolMgBr, MeTHF ꢀ20 °C
tBuOK, DMF
2
3
TFA, Tol, 60 °C, SiO2
HOBt, EDC, DMF, dryness
TFA, Tol, 60 °C
HCl, iPrOH, 40 °C
T3P, Tol, DIPEA
TFA, Tol, 60 °C
DMF, TBTU, DIPEA, HCl
Overall yield
63%
4
5
68%
74%
25%
6
DMF, TBTU, DIPEA, SiO2
Overall yield
ACS Paragon Plus Environment
14

Page 15 of 17
Organic Process Research & Development
1
2
3
4
ABBREVIATIONS
5
6
7
8
MC1R melanocortin receptor 1; GPCR G proteinꢀcoupled receptors, DSC Differential scanning
calorimetry; MeTHF 2ꢀMethylꢀtetrahydrofuran; DMF Dimethylformamide; DCM
dichloromethane; TFA trifluoroacetic acid; TBTU Oꢀ(Benzotriazolꢀ1ꢀyl)ꢀN,N,N′,N′ꢀ
tetramethyluronium tetrafluoroborate; DIPEA N,Nꢀdiisopropylethylamine; HOBt
hydroxybenzitriazole, EDC 1ꢀEthylꢀ3ꢀ(3ꢀdimethylaminopropyl)carbodiimide, T3P
Propylphosphonic anhydride solution; XRPD Xꢀray Powder Diffraction, ICH International
Conference on Harmonisation
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
ACKNOWLEDGMENT
We would like to thank Anneꢀlaurence Ghilini for key analytical support; Pierric Marchand
from Holodiag for saltꢀscreening and PCAS for the pilot production of acid 9
SUPPORTING INFORMATION
1H and 13C NMR spectra of the compound 1; procedures for synthesis, isolation and
characterization data. This information is available free of charge via the Internet at
http://pubs.acs.org/
ACS Paragon Plus Environment
15

Organic Process Research & Development
Page 16 of 17
1
2
3
4
REFERENCES
5
6
7
8
[1] Swope, V. B.; Jameson, J. A.; McFarland, K. L.; Supp, D. M.; Miller, W. E.; McGraw, D.
W.; Patel, M.A.; Nix, M. A.; Millhauser, G. L.; Babcock, G. F.; AbdelꢀMalek, Z. A. J. Invest.
Dermatol. 2012, 132, 2255
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] Levine, N.; Lemus‑Wilson, A.; Wood, S.H.; AbdelꢀMalek, Z. A.; AlꢀObeidi, F.; Hruby, V.
J.; Hadley, M. E. J. Invest. Dermatol. 1987, 89, 269‑273.
[3] AbdelꢀMalek, Z. A.; Scott, M.C.; Furumura, M.; Lamoreux, M.L.; Ollmann, M.; Barsh, G.S.;
Hearing, V.J. J. Cell. Sci. 2001, 114, 1019
[4] see BouixꢀPeter, C. WO2013001030, Oxazetidine derivatives, process for preparing them
and use thereof in human medicine and in cosmetics
[5] oꢀTolylmagnesium bromide in MeTHF were purchased from Chemetall
[6] De Wall, G. Chem. Eng. News, 1982, 60, 5
[7] The alkylation reaction was also performed in THF or MeTHF but lead to partial alkylation.
[8] The compound 5 was found to crystallize nicely in diisopropyl ether. Despite the tendency of this
solvent to form peroxides, diisopropyl ether was chosen at this stage due to time constrains to deliver
the first preclinical batches. Isopropanol was further identified as crystallization solvent for
compound 5. Isopropanol is to be used for next synthesis of this material.
[9] For general review on cyclopropyl cations see : Olah, G.A.; Reddy, V.; Prakash, V.K.S.
Chemistry of the Cyclopropyl Group, Part 2, Rappoport, Z. ed., Wiley, Chichester, 1995, 813ꢀ
859. For a more precise example see : Cheng, K.; Kim, I. J.; Lee, MꢀJ.; Adah, S. A.; Raymond,
ACS Paragon Plus Environment
16

Page 17 of 17
Organic Process Research & Development
1
2
3
4
T. J.; Bilsky, E. J.; Aceto, M. D.; May, E. L.; Harris, L. S.; Coop, A.; Dersch, C. M.; Rothman,
5
6
R. B.; Jacobsona, A. E.; Rice, K. C. Org. Biomol. Chem. 2007, 5, 1177
7
8
9
[10] Fujii, H.; Okada, K.; Ishihara, M.; Hanamura, S.; Osa, Y.; Nemoto, T.; Nagase, H.
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
Tetrahedron, 2009, 65, 10623
[11] Dunetz, J. R.; Xiang, Y.; Baldwin, A.; Ringling, J. Org. Lett. 2011, 13, 5048
[12] T3P solution in toluene was purchased from Archimica
[13] Measured from HPLC analysis with (S)ꢀenantiomer of compound 1 as reference (see
supporting information)
[14] The structure of impurity was assumed after LCMS analysis that showed a mass of 437
g.molꢀ1, with a 17 g.molꢀ1 loss for the main fragmentation peak, characteristic of a primary
amide.
[15] DMF was chosen as a solvent after checking that residual solvents in the final API were
below 50 ppm.
[16] All recrystallizations conditions tested induced a gel formation, even after seeding with
crystalline material obtained after slurry ripening.
[17] The DSC depicted in figure 1 shows the 140ꢀ230 °C temperature range, no glass transition
were observed in the 20ꢀ140 °C range.
ACS Paragon Plus Environment
17