Pilot scale process development of SL65.0102-10, an N-diazabicyclo[2.2.2]-octylmethyl Benzamide

Article abstract of DOI:10.1021/acs.oprd.6b00262

The process development and improvements for route selection, adapted to large scale for the pilot-scale preparation of SL65.0102-10, an N-diazabicyclo[2.2.2]-octylmethyl benzamide, a 5-HT₃ and 5-HT₄ receptor active ligand for the treatment of neurological disorders such as cognition impairment, are described in this article. Notable steps and enhancements are compared to the original route, including the improvement of a chiral epoxide synthesis by shortening the number of chemical steps, the deprotection of a quaternary ammonium salt, and the redesign of the final amidification coupling to avoid chromatography.

Full text of DOI:10.1021/acs.oprd.6b00262

Subscriber access provided by TUFTS UNIV
Full Paper
Pilot Scale Process Development of SL65.0102-10,
an N-Diazabicyclo[2.2.2]-octyl-methyl benzamide
Philippe J LIENARD, Philippe Gradoz, Hélène Greciet, Samir Jegham, and Didier Legroux
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00262 • Publication Date (Web): 14 Dec 2016
Downloaded from http://pubs.acs.org on December 15, 2016
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 14
Organic Process Research & Development
1
2
3
4
Pilot Scale Process Development of SL65.0102-10, an N-Diazabicyclo[2.2.2]-octyl-
methyl benzamide.
5
6
7
8
Philippe Lienard*⊥, Philippe GradozI, Hélène Greciet§, Samir Jegham# and Didier
Legroux+
9
Sanofi-Aventis, Recherche & Développement, 13 Quai Jules Guesde, 94400 Vitry-sur-
Seine, France
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
* Author to whom correspondences should be sent via email: Philippe.Lienard@sanofi.com
⊥ Pharmaceutical Science Development, Sanofi R&D, Vitry-Sur-Seine, France.
I E-mail: philippe.gradoz@free.fr
§
E-mail: Helene.Greciet@sanofi.com
# E-mail: Samir.Jegham@sanofi.com
+ E-mail: d.legroux@orange.fr
1 of 14
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 14
1
2
3
Toc Graphic
Cl
4
5
6
OH
HO
7
8
9
Chemical process development route
ꢀ 10 chemical steps (5 isolated)
Medicinal chemitry route
ꢀ 12 chemical steps (8 isolated)
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
HO
N
H2N
N
O
O
N
O
O
O
O
O
OH
H2N
Cl
O
O
N
N
O
N
H
H2N
Cl
SL65.0102-10
2 of 14
ACS Paragon Plus Environment

Page 3 of 14
Organic Process Research & Development
1
2
3
Abstract
4
5
6
7
8
9
The process development and improvements for route selection, adapted to large
scale for the pilot-scale preparation of SL65.0102-10, an N-diazabicyclo[2.2.2]-octyl-
methyl benzamide, a 5-HT3 and 5-HT4 receptor active ligand for the treatment of
neurological disorders such as cognition impairment are described in this article.
Notable steps and enhancements are compared to the original route including the
improvement of a chiral epoxide synthesis by shortening the number of chemical
steps, the deprotection of a quaternary ammonium salt, and the redesign of the final
amidification coupling to avoid chromatography.
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
Chiral epoxide, 1,2-diol, potassium phthalimide, Gabriel synthesis, amidification
coupling.
3 of 14
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 14
1
2
3
Introduction
4
5
6
7
8
9
5-HT4 receptor is a G-protein coupled receptor (GPCR) which belongs to serotonin
receptor family. The role of 5-HT4 receptor in the modulation of many diseases is well
described in the literature. 1 During the last decades, an impressive body of evidence
suggested that selective stimulation of neuronal 5-HT4 receptor subtypes could be
beneficial in the symptomatic treatment of memory disorders including many
antidepressants, antipsychotics, anorectics, anti-emetics, gastroprokinetic agents, anti-
migraine agents, hallucinogens, and antactogens. 2 Within our effort to the discovery of
memory dysfunction treatment, the SL65.0102-10, a selective 5-HT4 partial agonist (Ki
6.6 ꢀM), was discovered as promising agent for the treatment of cognition impairment.
Serotonin receptors are the target of a variety of pharmaceutical drugs; SL65.0102-10 1
emerged as a promising 5-HT3 and 5-HT4 inhibitor that was potentially useful for the
treatment of neurological disorders. 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
Scheme 1 illustrates the medicinal chemistry research approach to 1 that involves
two advanced starting materials, chiral phthalimido epoxide 2 and acid 9.
N-benzylpiperazine was alkylated with epoxide 2 to afford the chiral alcohol 4 which was
transformed into its corresponding mesylate derivative 5. Mesylate 5 was heated to obtain
quaternary ammonium salt 6 followed by hydrogenolysis to obtain protected amine 7. The
next step involved the treatment of 7 with hydrazine hydrate to deprotect the phthalimido
moiety. Amide coupling of chiral amine 8 with acid 9 resulted in SL65.0102-10 1.
Scheme 1. Medicinal chemistry synthetic route to SL65.0102-10 1
O
O
O
O
a
b
c
N
N
N
-
+, CH3SO3
N
N
N
O
O
HO
N
N
O
4
O
MsO
HN
N
O
N
N
2
5
6
bn
bn
O
3
O
O
N
N
d
e
f
O
N
N
H2N
N
N
N
N
H
H2N
O
O
O
Cl
, 3HCl
1
, 2HCl
O
8
OH
7
SL65.0102-10
H2N
9
Cl
Reagents and conditions: a) toluene, 80 to 120oC, 95%; b) CH3SO2Cl, TEA, DCM, no purification. c) toluene, reflux,
87%; d) H2/Pd/C, MeOH, 50oC, 68%; e) NH2NH2/EtOH/reflux, then 4N HCl, 0°C, 77%; f) DCC, NaOH,
pyridine/water, RT, purification on SiO2/chromatography then HCl/EtOH, 44%.
4 of 14
ACS Paragon Plus Environment

Page 5 of 14
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
The medicinal chemistry route, however, could not support the multi-kilogram
quantities of the drug substance required to support the preclinical and clinical activities.
As the target molecule progressed to clinical development and increasing quantities of drug
substance were required several alternate synthetic routes and iterations were successfully
demonstrated on kilolab and pilot plant scale. The ultimate goal was to establish an
economical and industrializable synthesis of SL65.0102-10 1. This paper summarizes the
process development of SL65.0102-10 1.
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
Results and discussion
Chiral phthalimido epoxide 2 was chosen as a starting material by the medicinal
chemistry group for the preparation of small quantity batches. However no reliable large
scale quantity manufacturer was available for this compound in the late 1990’s. The
available reactors were not equipped to handle epichlorohydrin safely, so two alternate
syntheses of this compound were evaluated for the first batches at pilot scale. Scheme 2
shows the first approach to 2 that starts from (S)-(+)-1,2-isopropylideneglycerol or (S)-(+)-
solketal 10, a widely commercially available substrate for early development. These
compounds had been successfully used to prove the compound 1 synthesis on small scale
and were readily available in multi-kilogram quantities. The objectives for the first pilot
plant campaigns were to demonstrate a scaleable synthesis of 1 and to deliver drug
substance rapidly.
Scheme 2. Early development synthesis of chiral phthalimido epoxide 2
HO
MsO
O
O
S
a
b
c
O
O
O
O
N
N
HO
OH
O
O
O
O
12
10
13
11
d
O
O
N
O
O
e
f
N
N
O
O
O
O
Br
O
O
O
14
15
2
Ph
Ph
Reagents and conditions: a) CH3SO2Cl, TEA, toluene, 93.5%; b) potassium phthalimide, DMF, TEBAC, 71.1%;
c) HCl, water, 86.2%; d) PhCHO, toluene, PPTS, 81.6%; e) NBS, dichloroethane, 87.6%; f) MeONa, toluene, 80.8%.
5 of 14
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 14
1
2
3
4
5
6
7
8
9
The first step in the synthesis of 11 involved selective mesylation of the hydroxyl
group of (S)-(+)-solketal 10 using mesyl chloride in toluene in the presence of
triethylamine. After aqueous work-up and appropriate organic phase washes, the crude
compound 11 was engaged in the following step after a solvent exchange with DMF using
vacuum distillation.
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
The standard reaction protocol commonly employed in the literature 4 was found to
be satisfactory for the reaction with potassium phthalimide. An isolation process was
chosen that minimized labor: addition of water and filtration. There were very few
impurities. The high purity product allows the crude to be used directly in the next reaction
without recrystallization.
The next step involved the hydrolysis of the dioxolane protecting group of 12 with
diluted HCl. 5 The resulting diol 13 was reacted with benzaldehyde to form acetal 14 .
Further reaction with N-bromosuccinimide allowed easy opening of the acetal ring to
afford bromo ester intermediate 15. The formation of epoxide 2 was realized with sodium
methoxide in toluene solution. 6 This sequence, without formal intermediate isolation, was
terminated with a recrystallization in ethanol to guarantee the quality for engaging epoxide
2. During this early development, the seven-step process was utilized to supply a total of
12.4 kg of epoxide 2 with 27% overall yield and no undesired enantiomer detectable by
chiral HPLC. 7
However, the long-term goal was to establish an industrializable synthesis of 1.
This implied:
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
minimum number of chemical steps;
technical scalability and good robustness of the processes;
good overall yield and process productivity (space-time-yield);
acceptable process safety and industrial hygiene;
tolerable waste generation (minimal environmental impact).
Using these criteria, the overall process to synthesize 2 via (S)-(+)-solketal 10 was
challenged with another approach depicted in scheme 3.
6 of 14
ACS Paragon Plus Environment

Page 7 of 14
Organic Process Research & Development
1
2
3
4
5
6
7
8
Scheme 3. Pilot plant synthesis of chiral phthalimido epoxide 2
O
O
Cl
R
N
a
N
b
S
OH
HO
O
HO
OH
O
O
2
16
13
Reagents and conditions: a) potassium phthalimide, DMF, TEBAC, 94.5%; b) CH3C(OCH3)3, toluene, PPTS, 50°C,
then TMSCl, at room temperature, and MeONa, 30°C, 66.5%.
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
The development of a more efficient route to epoxide 2 was a critical step in
implementing a fast and shorter synthesis for pilot scale and we relied on two main
contributions: the commercial availability of chiral (R)-(-)-3-chloro-1,2-propanediol 16
and the ability to scale up the Sharpless procedure to convert phthalimide diol 13 into
epoxide 2 in a one pot procedure. 8
The alkylation of potassium phthalimide with R-3-chloro-(1,2)-propanediol 16 led
to 2-[(2S)-2,3-dihydroxypropyl]-1,3-isoindolinedione 13. The optimization laboratory
showed that a slow addition of R-3-chloro-(1,2)-propanediol 16 to the potassium
phthalimide as a hot suspension in DMF, in the presence of a phase transfer agent, gave
better yields of the expected intermediate 13. The extrapolation of this process to the pilot
scale by extending the addition time and contact time at 100°C was very easily validated.
The recrystallization in ethyl acetate, performed in pilot run 1, was avoided for runs 2 and
3, thanks to the quality of the crude product, which did not require purification, as the
remaining phthalimide did not impact the next step.
Table 1. Scale-up of N-alkylation of potassium phthalimide using R-3-chloro-(1,2)-
propanediol 16.
Purity
(assay of
phthalimide
Reaction
time
100°C
Eq.
(potassium
phthalimide)
Scale
(mole)
Yield
(%)
Run
Solvent
) (%)
0.5
0.6
4
Laboratory
Pilot 1
Pilot 2
DMF
DMF
DMF
DMF
3h
4h20
6h
1.06
1.06
1.07
1.07
0.1
90.6
720.4
1117.2
54
50.3
59.4
94.5
Pilot 3
6h
3.5
In lab-scale campaigns, epoxidation of diol 13 was performed after drying in a
vacuum dryer. Prior to pilot plant scale, an effort was made to replace this vacuum drying
by an azeotropic removal of the residual water in the diol 13 in the next step solvent, i.e.
toluene.
7 of 14
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 14
1
2
3
4
5
6
7
8
Epoxide 2 was prepared by reacting trimethyl orthoacetate and
chlorotrimethylsilane, which led to an acetyl chlorohydrin intermediate which was cyclized
to epoxide 2 using sodium methoxide. The detailed mechanism is provided in the literature
9 and is represented in scheme 4.
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 4. Un-isolated intermediates 17 and 18 of one-pot reaction of epoxide 2
O
O
O
N
a
b
N
N
S
HO
OH
O
O
O
O
O
O
Cl
O
OMe
13
17
18
c
O
N
O
O
2
Reagents and conditions: a) CH3C(OCH3)3, toluene, PPTS, 50°C; b) TMSCl, room temperature; c) MeONa, 30°C,
66.5%.
It was determined that to obtain good quality epoxide 2 without the presence of the
intermediate acetyl chlorohydrin, it was necessary to use equimolar quantities of sodium
methoxide and chlorotrimethylsilane, i.e. 1.5 equivalents. In addition, we showed that the
epoxide 2 partially degraded during the recrystallization in ethanol. However, at the pilot
scale (30 to 60 kg), this one-pot transformation sequence was reproduced several times
with 65.3% to 74.0% yield range and quality greater than 98% as well as enantiomeric
excess superior to 99% were reproducibly achieved.
The process to prepare epoxide 2 was shown to be reliable and reasonably robust; a
total of 180 kg was prepared in the early pilot plant campaigns, most of which was used to
prepare batches of SL65.0102-10 1. This route using R-3-chloro-(1,2)-propanediol 16 as
starting material was considered significantly more efficient than the first route using
(S)(+)-solketal 10, particularly due to the reduction of the number of steps and
intermediate isolations.
The N-benzylpiperazine alkylation with epoxide 2 was performed using the same
procedure used by medicinal chemistry and the mesylation of the intermediate 4 was
8 of 14
ACS Paragon Plus Environment

Page 9 of 14
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
conducted using standard conditions as well. The remaining challenge was isolation of
quaternary ammonium salt 6 from the rather complex reaction mixture, taking into account
its high water solubility and hygroscopicity. Extensive studies were performed to find a
robust isolation process to overcome the propensity of the product to oil out of solution and
to limit yield of isolation of quaternary ammonium salt 6.
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
Thus, this quarternization step was submitted to a laboratory optimization, which
allowed demonstrating the α,α,α-trifluorotoluene as the only solvent to make both the
final reaction and the product isolation by crystallization. Indeed, the quaternary
ammonium 6 was obtained by a sequence of three operations without isolation. The
alkylation was conducted in toluene and intermediate 4 was obtained by removal of the
toluene by solvent stripping. Intermediate 4 was converted to the mesylate 5 in
dichloromethane and after washing, the solution of dichloromethane was added to the
α,α,α-trifluorotoluene at 90°C to achieve the cyclization. The dichloromethane was
distilled off as the addition progressed; the reaction was continued for several hours after
the previous addition (10 hours). The filtration of the quaternary ammonium 6 was very
slow, probably due to partial crystallization. However, compound 6 was obtained with
74% yield average (on 60 kg scale) and adequate quality to be processed to the next steps
without additional purification.
Our attention shifted to minimizing the number of steps to produce intermediate 8.
It occurred to us that the two-step deprotection of quaternary ammonium 6 was a viable
way to produce intermediate 8, and for the first batches we used the medicinal chemistry
methods based on catalytic hydrogenolysis and reaction with hydrazine hydrate as depicted
in scheme 1. Our strategy for simplifying this into a one-pot reaction was to use
hydrochloric acid as a single reagent. Additionally, the elimination of hydrazine hydrate by
replacement with less hazardous conditions was considered beneficial with regards to
safety and hygiene. Preliminary laboratory experiments demonstrated that the use of 20%
HCl was suitable to generate the desired intermediate 8.
9 of 14
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 14
1
2
3
4
Scheme 5. One-pot deprotection of quaternary ammonium 6
O
O
O
O
5
6
7
8
a
N
b
c
N
N
-
+, CH3SO3
N
N
N
O
O
HO
N
O
N
O
HN
N
O
MsO
2
6
4
N
5
N
9
3
bn
bn
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
d
N
H2N
N
, 2HCl, CH3SO3H
8
Reagents and conditions: a) toluene, reflux, no purification; b) CH3SO2Cl, TEA, DCM, 0°C, no purification. c) α,α,α-
trifluorotoluene, 90°C, 73.8%; d) HCl 20%, reflux, 48.5%.
However, debenzylation and removal of the 1,2-benzenedicarboxylic acid by-
product after removal of protecting moiety with hydrochloric acid were sluggish, even at
elevated temperatures, and required preliminary solvent stripping. It appeared that the
solvent stripping was necessary to remove the benzyl chloride or the benzyl alcohol
formed during the reaction to push the reaction toward intermediate 8. At large scale, the
captured of benzyl chloride was performed with alcoholic aqueous sodium hydroxide at the
reactor event to avoid its release in atmosphere. Even though this step needed further
optimization, the compound 8 (weight of free amine based on HPLC assay), was obtained
with 48.5% yield on 35 kg average scale and in adequate quality to be processed to the
next steps without additional purification. A final treatment in methanol allowed
intermediate 8 to be obtained with satisfactory quality to be engaged in the final coupling
with acid 9.
As the only published procedure to synthetize 8-amino-7-chloro-2,3-dihydro-1,4-
benzodioxin-5-carboxylic acid 9 required special safety equipment compatible with
chlorine gas manipulation, 10 this route was deemed impractical in our facility. Considering
our intention was to externalize this intermediate 9, no in-depth optimization work was
undertaken, thus the medicinal chemistry procedure was used according to scheme 6.
10 of 14
ACS Paragon Plus Environment

Page 11 of 14
Organic Process Research & Development
1
2
3
4
5
6
7
8
Scheme 6. Synthesis route of acid 6
COOH
COOH
COOH
CO2H
O
a
Br
Br
O
b
Br
Br
O
c
O
O
O
O
O
NO2
21
NH2
22
19
20
d
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
CO2H
COOH
e
O
O
Cl
O
O
NH2
9
NHAc
23
Reagents and conditions: a) Br2, AcOH, AcONa, 40°C, 94.1%; b) HNO3, H2SO4, AcOH, room temperature, 84%; c) H2,
Pd/C, MeOH, TEA, 60-75°C / 4.5 bars of hydrogen, not isolated; d) Ac2O, AcOH, room temperature, overnight, 70.6%
over two steps; e) NCS, AcOH, 50 to 85°C, 67.7%.
The 1,4-benzodioxan-5-carboxylic acid 19 was treated with bromine in acetic acid,
then the di-bromo intermediate 20 was submitted to nitration in sulfuric acid to afford
intermediate 21. The next step involved hydrogenation of 21 under moderate hydrogen
pressure in methanol to remove bromo substituents and reduce the nitro moiety to obtain
intermediate 22, without solid isolation. Intermediate 22 was acetylated with acetic
anhydride in acetic acid. The final operation was a chlorination of intermediate 23 using N-
chlorosuccinimide to supply acid 9.
This process, starting with the inexpensive compound 19, represents an
improvement in terms of safety compared to the procedure previously reported with the
use of free gas chlorine. Overall, the scale up of these five steps was successful and the
reaction and isolation processes proved to be robust: a total of 43.7 kg of acid 9 was
manufactured in consistent fashion in our facility, avoiding chlorine gas handling.
At the final coupling stage, for scaling-up purpose it was reasoned that this
straightforward transformation could be realized without the DCC coupling agent. This
reagent presented an important disadvantage due to the generation of by-products that
required removal by chromatography. Thus, as shown in scheme 7, we found that coupling
between this triamine 8 and the acid 9 was better performed by a mixed anhydride derived
from pivaloyl chloride in the presence of triethylamine at 0°C.
11 of 14
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 14
1
2
3
Scheme 7. Final coupling of triamine 8 and acid 6
O
O
4
5
6
N
N
a
O
N
N
H2N
N
H
H2N
O
O
7
8
Cl
, 3HCl
1
, 2HCl, H2O
O
8
OH
SL65.0102-10
9
H2N
9
Cl
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
Reagents and conditions: a) pivaloyl chloride, trimethylamine, acetone, 0°C, 67.4%, and then clarification in hot ethanol
and final crystallization in ethanol after HCl addition, 76.7%.
After the reaction, the crude mixture was filtered after 1 hour of stirring and then,
the active compound 1, as its free base, was isolated by adjusting the pH of the liquid
phase to basic with sodium hydroxide. The crude base 1 was submitted to a filtration in hot
ethanol through a 2 ꢀm filter for clarification before HCl was added. The hot filtrate was
partially concentrated and cooled to crystallize the product hydrochloride salt. Filtration of
the suspension at low temperature allowed the isolation of the active compound 1. Overall
a total of 21.56 kg of 1 was manufactured in 70% yield (as free base of active compound 1)
and 67.5 % for the final crystallization including salt formation with hydrochloric acid.
Conclusions
Efforts towards process development synthesis of SL65.0102-10 1 were reported.
The first epoxide 2 batches were prepared from (S)-(+)-solketal 10 in six chemical steps in
about 27% overall yield. Although this synthesis proved to be scalable, we changed to a
shorter synthesis route starting from (R)-(-)-3-chloro-1,2-propanediol in two chemical
steps with a greatly improved overall yield of 62.4%. Access to the quaternary ammonium
salt 6 was well-managed using optimized conditions, particularly the use of
trifluorotoluene for the quaternarization step. All deprotections were managed in a one-pot
reaction, avoiding hazardous hydrazine, to afford triamine 8. Acid 9 was manufactured in a
consistent fashion using a medicinal chemistry route. The final amide coupling was
performed with a mixed anhydride method to avoid chromatography purification.
Compared with the first generation synthesis from medicinal chemistry, key
achievements were:
ꢁ minimizing the number of steps while maintaining a good overall yield - the medicinal
chemistry route was performed in 12 chemical steps with 8 isolated steps as the
12 of 14
ACS Paragon Plus Environment

Page 13 of 14
Organic Process Research & Development
1
2
3
4
5
6
7
8
chemical process development route was minimized to only 10 chemical steps with 5
isolated steps -.
ꢁ technical scalability and good robustness improved with exclusion of purification
chromatography along the route,
9
ꢁ acceptable process safety and industrial hygiene in which the handling of toxic and
hazardous reagents were avoided,
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
and finally the development of a new access route to epoxide 2.
The chemical process development still needs to be worked, to optimize yields of each
step, and also to minimize the waste generation.
Acknowledgements
This work is published 20 years after the original patent publication of the
medicinal chemistry route.
We are grateful to the many colleagues within Sanofi who provided analytical
support.
In particular, this paper is dedicated to all colleagues of the Sanofi Porcheville
development center with thanks for their endeavor, professionalism and expertise.
Supporting Information
Supplementary materials content a detailed experimental section and 1H and 13C
NMR spectra for final compound: SL65.0102-10 1.
References
1 a) Hoyer, D.; Clarke, D.E.; Fozard, J.R.; Hartig, P.R.; Martin, G.R.; Mylecharane E.J.;
Saxena P.R.; Humphrey P.P. Pharmacol. Rev. 1994, 46 (2), 157–203.
b) Frazer, A.; Hensler, J.G Chapter 13: Serotonin Receptors". In Siegel, G.J.; Agranoff
B.W.; Albers R.W.; Fisher S.K.; Uhler M.D. editors.Basic Neurochemistry: Molecular,
Cellular, and Medical Aspects. Philadelphia: Lippincott-Raven. 263–292, 1999.
2 Frick, W.; Glombik, H.; Kramer, W.; Heuer, H.; Brummerhop, H.; Plettenburg, O. Novel
fluoroglycoside heterocyclic derivatives, pharmaceutical products containing said
compounds and the use thereof a) WO2004/052903 2004. b) WO2004/052902 2004.
3 Jegham, S.; Koenig J. J.; Lochead, A.; Nedelec, A.; Guminski, Y. N-[(1,4-
diazabicyclo[2.2.2]oct-2-yl)methyl] benzamide derivatives, their preparations and their
application in therapeutics a) FR 2756563 06/13/1995 9506951 1995. b) US 5663173
1997, Washington, DC: U.S. Patent and Trademark Office.
4 Gibson, M.S.; Bradshaw, R.W. Angewandte Chemie International Edition in English
1968, 7(12), 919-930.
5 Hough, L.; Jones, J.K.N.; Magson, M.S. J. Chem. Soc. 1952, 1525.
6 Akhrem, A.A.; Zharkov, V.V.; Zaitseva, G.V.; Mikhailopulo, LA. Tetrahedron
Lett.1973, 14(17), 1475-1478..
13 of 14
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 14
1
2
3
4
5
6
7
8
9
7 No R isomer detected by chiral HPLC for both processes (from (S)-(+)-solketal and (R)-
(-)-3-chloro-1,2-propanediol.
8 Kim, B.M.; Sharpless, K.B. Tetrahedron Lett. 1989, 30, 655.
9 Kolb, H.C.; Sharpless, K.B. Tetrahedron 1992, 48(48), 10515-10530.
10 Gaster, L.M.; Jennings, A.J.; Joiner, G.F.; King, F.D.; Mulholland, K.R.; Rahman,
S.K.;Wardle, K.A. Journal of medicinal chemistry 1993, 36(25), 4121-4123.
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
14 of 14
ACS Paragon Plus Environment