Short synthesis of a proline amide orexin receptor antagonist on the pilot plant scale

Article abstract of DOI:10.1021/op500277s

A three-step fully telescoped synthesis of an N-sulfonyl proline amide, a nonpeptide antagonist of human orexin receptors, is described. The process development from the medicinal chemistry route up to the 240 kg production of 1 is discussed with a focus

Full text of DOI:10.1021/op500277s

Subscriber access provided by GAZI UNIV
Communication
Short Synthesis of a Proline Amide Orexin
Receptor Antagonist on Pilot Plant Scale
Simone Tortoioli, Daniel Marchal, Martin Kesselgruber, Thomas Pabst, Wolfgang Skranc, and Stefan Abele
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 03 Nov 2014
Downloaded from http://pubs.acs.org on November 4, 2014
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
TOC
5
6
7
8
O
N
OH
1st generation
O
O
4 steps, 60% yield
O
$$
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
N
O
S
HN
NH2
O
O
S
1)
2)
Cl
O
MeO
MeO
ACT-462206
O
- Process Development
- Scale-up to 240 kg
- Green metrics
2nd generation
N
OH
H
3 steps, 85% yield
L-Proline
ACS Paragon Plus Environment
1

Organic Process Research & Development
Page 2 of 14
1
2
3
4
5
6
7
8
9
Short Synthesis of a Proline Amide Orexin Receptor
Antagonist on Pilot Plant Scale
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
Simone Tortoioli,* Daniel Marchal, Martin Kesselgruber, Thomas Pabst,† Wolfgang Skranc,†
and Stefan Abele
Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CHꢀ4123 Allschwil, Switzerland
† DSM Pharma Chemicals, ResCom®, Donaustaufer Strasse 378, Dꢀ93055, Regensburg,
Germany
KEYWORDS Lꢀproline, amide coupling, scaleꢀup, process mass intensity.
ABSTRACT
A three step fully telescoped synthesis of an Nꢀsulfonyl proline amide, a non peptide antagonist
of human orexin receptors is described. The process development from the Medicinal Chemistry
route up to the 240ꢀkg production of 1 is discussed with a focus on an economical and efficient
amide bond formation and identification of a new polymorph. The routes are compared using
green metrics.
Introduction
(S)ꢀ1ꢀ(4ꢀMethoxybenzenesulfonyl)ꢀpyrrolidineꢀ2ꢀcarboxylic acid (3,5ꢀdimethylphenyl)ꢀamide
(1) (ACTꢀ462206) is a nonꢀpeptide antagonist of human orexin receptors for potential use in the
treatment of sleep disorders, stressꢀrelated syndromes, addictions, cognitive dysfunctions as well
ACS Paragon Plus Environment
2

Page 3 of 14
Organic Process Research & Development
1
2
3
4
5
6
as eating or drinking disorders. This Active Pharmaceutical Ingredient (API) is currently being
studied for clinical use by Actelion.1
7
8
9
Compound 1 is a derivative of Lꢀproline by ‘simple’ functionalization of both secondary amine
and carboxylic acid functions. From discovery to scaleꢀup to the latest 240ꢀkg production,2
different routes have been evaluated resulting in significant improvements of the overall
synthetic process. In this communication we wish to describe the three main processes studied
and to compare them in terms of green metrics.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
Results and discussion
NꢀBocꢀLꢀproline 2 was the starting material employed in the medicinal chemistry route. A
sequence of coupling with 3,5ꢀdimethylaniline (3), Bocꢀremoval to afford HCl salt 5a and
sulfonamide formation with 4ꢀmethoxybenzenesulfonyl chloride (6) afforded pure API 1 after
chromatography in 74% yield (Route A, Scheme 1).
The same route was initially used by process chemistry to deliver the first 2 kg of API enabling
early pilot toxicity studies. As improvements to this route, intermediates 4 and 5b were kept in
DCM solution and Boc removal was carried out with TFA while product 1 was purified by
crystallization providing 2.1 kg of enantiopure (100% ee) API with a telescoped process in 60%
yield with one isolated intermediate (Route A’, Scheme 1).
Scheme 1. Medicinal chemistry (Route 1a) and 2ꢀkg syntheses (Route 1b).
ACS Paragon Plus Environment
3

Organic Process Research & Development
Page 4 of 14
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
For larger supply of this API it was decided to further simplify the synthesis meeting the
requirements of atomꢀeconomy and environmental friendliness. For this reason, NꢀBocꢀLꢀproline
was replaced by Lꢀproline4 and an alternative solvent for the undesirable chlorinated solvent
DCM was investigated.
Sulfamidation of Lꢀproline in aqueous base provided intermediate 7 (Scheme 2). For the amide
coupling, SOCl2 was used since it is one of the cheapest coupling reagents also on a molar basis.
Being one step shorter, this new process (Route 2a/2b) represents a significant improvement over
Route 1a/1b. Table 1 reports the study of the key amide coupling step with a focus on the acid
chloride formation.5 As soon as the acid chloride 8 was formed in high purity, the amide
coupling with amine 3 proceeded smoothly to give the API 1 which, after workꢀup, was
crystallized from iPrOAc/methylꢀcyclohexane in high yields.
ACS Paragon Plus Environment
4

Page 5 of 14
Organic Process Research & Development
1
2
3
4
Table 1. Acid chloride 8 formation with SOCl2.
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
SOCl2
(equiv)
1.5
conv.
(%)a
80b
90
time
(h)
5
entry
conditions
1
2
3
4
5
6
7
8
NMM (1.5 equiv), 0 °C to 20 °C
0 °C to 40 °C
1.3
3
DMF (0.1 equiv), rt to 45 °C
DEF (0.1 equiv), rt to 45 °C
DABCO (0.1 equiv), rt to 45 °C
DMAc (0.1 equiv), rt to 45 °C
rt to 45 °C, water wash
1.2
99
2
1.2
99
3
1.2
92
3
1.2
96
4
1.5
97c
97d
3
DMF (0.05 equiv), 45 °C
1.05
2
a
Conversion (% a/a) as calculated by LC/MS analysis (sample quenched with MeOH): [area methyl ester / (area
b
c
d
acid + area Meꢀester)] x 100. 11% a/a of anhydride observed. 37% a/a of acid 7 formed. 1 was obtained as off
white solid after crystallization.
By employing Nꢀmethylꢀmorpholine (NMM) as base, (entry 1) a slow conversion of the acid
to the chloride was observed along with the symmetrical anhydride (up to 11% a/a). Without the
base and at 40 °C the acid chloride formation was clean and fast (entry 2, 90%, 3 h), but a higher
loading of SOCl2 was required. To lower the amount of SOCl2, different catalysts were tested,
most of them forming a Vilsmeierꢀtype intermediate (entries 3ꢀ6).6 With 10 mol% of DMF or
diethylformamide (DEF) full conversion into the chloride was achieved in 2ꢀ3 h at 45 °C
respectively (entry 3 and 4) while 1,4ꢀdiazabicyclo[2.2.2]octane (DABCO) and dimethyl
ACS Paragon Plus Environment
5

Organic Process Research & Development
Page 6 of 14
1
2
3
4
5
6
acetamide (DMAc) were less efficient (entries 5 and 6). Gratifyingly, racemization of API 1 was
never observed.7
7
8
9
Having opted for DMF as catalyst, the removal of excess of SOCl2 (responsible for grey colour
in the final API) was examined. An aqueous wash of the acid chloride solution could not be used
since rapid hydrolysis to the acid was observed (entry 7, 37% of 7 formed). SOCl2 could instead
be removed by distillation, as reported on plant scale.8 In a test experiment, full conversion into
the acid chloride was obtained with 0.05 equivalents of DMF and 1.05 equivalents of SOCl2
(entry 8). Excess of thionyl chloride was removed by two distillation cycles with iPrOAc and the
acid chloride was converted in 1 h into 1 upon addition of aniline 3 in the presence of
triethylamine. The full telescoped process gave 980 g of API 1 as a pale yellow/off white solid
with 69% yield and high purity (99.6% a/a and 99.7% w/w, >99% er).
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. Routes 2a and 2b.
During the process development work, a new and more stable polymorphic form of 1 was
identified. The new polymorph displayed a higher melting point (103 °C vs 96 °C, Figure 1a vs
1b), different solubility and different crystal shape (bigger crystals instead of needles,
microscope pictures, Figure 1a vs Figure 1b). API for clinical development needed to be supplied
in the correct solid state, so additional development on the synthesis was done focusing on the
preparation of the new polymorph of the API.
ACS Paragon Plus Environment
6

Page 7 of 14
Organic Process Research & Development
1
2
3
4
Figure 1.
5
6
7
1a)
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
1b)
Fortunately, the more stable polymorph could be easily obtained by the use of seed crystals
obtained by crystallization from solutions of iPrOAc/methyl cyclohexane or heptane, resulting in
79% yield.9
ACS Paragon Plus Environment
7

Organic Process Research & Development
Page 8 of 14
1
2
3
4
5
6
7
8
9
For the amide coupling, the use of pivaloyl chloride (PivCl) and Nꢀmethyl morpholine (NMM)
as coupling reagents followed by the addition of the aniline 3 resulted in clean and efficient
conversion into 1, and it was preferred over the use of SOCl2 since the distillation to remove
excess of coupling reagent was no longer necessary. This improved process resulted into Route
2b (conditions 2b, Scheme 2) and it was used by DSM to produce 240 kg (4 batches, 85%
average yield) of GMP material to supply Phase I and Phase II studies.
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
Finally, the three routes were compared considering the number of steps, yields, the use of
classꢀ2 solvents,10 protecting groups (PG), Process Mass Intensity (PMI),3c,d Reaction Mass
Efficiency (RME)3f, and Costs (Costs of Goods normalized (%) to the most expensive route) as
parameters. Results are summarized in Table 2.
Table 2. Routes comparison.
no. steps
yield (%)
PG
1
class 2 solvents
PMIa
45
RME (%)b
20.1
Costsc (%)
100
route 1b
route 2a
route 2b
4
3
3
60
69
85
1
1
0
0
4.5
51
47.5
0
5.2
40
55.3
a PMI = Process Mass Intensity, defined as: (sum of all reagents, solvents and aqueous solutions (kg))/API produced
(kg) (ref. 3c,d). b RME = Reaction Mass Efficiency, defined as the mass of the reactants that remain in the product:
[mass of product (kg)/sum of mass of the reactants]x100 (ref. 3f). c Costs = relative costs of raw materials/kg of API
(normalized to the most expensive route at 100%).
Second generation routes 2a and 2b are superior to the Discovery Route 1b since they are
shorter with higher yields as no protecting group is employed. This is well reflected in the value
of 20.1% of Reaction Mass Efficiency (RME) for route 1b which means that 80% of the mass of
the reactants is wasted during the process and only 20% incorporated in the final product. The
value is increased to ca. 50% for second generation routes and the average of 70ꢀ74% for each of
ACS Paragon Plus Environment
8

Page 9 of 14
Organic Process Research & Development
1
2
the two chemical steps is a good score for amide and sulfamide formation reactions.3f Routes 2a
and 2b achieve also a significant cost reduction. In addition, the use of dichloromethane
(chlorinated, class 2 solvent) makes route 1b less attractive.
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
Route 2b has the highest yield, is not using any class 2 solvents (heptane instead of methyl
cyclohexane employed in the API crystallization of route 2a) and is generating the lower amount
of waste as evidenced by its low PMI (40). However, PMI also in the other two routes are quite
low compared to the average value of 100ꢀ120 for the pharmaceutical industry3c,d and this
reflects the low molecular complexity and the short synthetic sequence of this API.11 The
difference between route 2a and 2b (51 vs. 40) is due to the use of higher amounts of iPrOAc for
the removal of SOCl2 by distillation (2 cycles with 5 volumes) in route 2a.
Regarding costs, route 2a is significantly cheaper than 2b (> 10%) thanks to the use of SOCl2
instead of the more costly pivaloyl chloride. Despite route 2b scores better in all the other
parameters considered, the cost factor would play an important role at the tonꢀscale level for the
selection of the process to be used.
In conclusion, three different processes for the preparation of a novel dual orexin receptor
antagonist have been described. The racemizationꢀfree amide coupling was efficiently performed
with two very cheap coupling reagents. During the course of these optimization studies, two
polymorphic forms were also identified and characterized. Higher yield, cost reduction, lower
amount of waste produced, and greener conditions were developed for the 2nd generation
process. Route 2b was also used to produce a total of 240 kg of API for clinical supply.
Experimental Section
General
ACS Paragon Plus Environment
9

Organic Process Research & Development
Page 10 of 14
1
2
1
Compounds are characterized by H NMR (400 MHz, Bruker) or 13C NMR (100 MHz,
3
4
5
6
7
8
Bruker); internal standard for quantitative NMR was 1,4ꢀdimethoxybenzene. Details for the
HPLC and LC−MS methods are listed in the Supporting Information. Unless stated otherwise,
yields are given as is.
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
(S)-1-(4-Methoxybenzenesulfonyl)-pyrrolidine-2-carboxylic acid (3,5-dimethylphenyl)-
amide (1).
A reactor was charged with Lꢀproline (21.25 kg, 185 mol), water (195.5 kg), NaOH 50% (34.0
kg, 425 mol) at 22 °C. In a second reactor a solution of 4ꢀmethoxybenzenesulfonyl chloride
(41.96 kg, 203 mol) in THF (75.4 kg) was prepared. The latter solution of 4ꢀ
methoxybenzenesulfonyl chloride was dosed to the first reactor at 22ꢀ23 °C in 55 min and the
line rinsed with THF (7.6 kg). After ca. 1.5 h, the pH was adjusted from 12.1 to 7.7 by the
addition of 3 M HCl (9.2 kg, 26.3 mol). The solution was concentrated by distillation under
reduced pressure at 24ꢀ50 °C to ca. 250 L. iPrOAc (274.0 kg) was added and the pH was
adjusted from 7.5 to 2.1 by the addition of 3 M HCl (66.8 kg, 191 mol) and stirred for 30 min.
The organic phase was washed with water (166.5 kg) and concentrated by distillation under
reduced pressure at 20ꢀ29 °C to ca. 100 L. iPrOAc (195.5 kg) was added and the mixture was
again concentrated by distillation at 29ꢀ30 °C under reduced pressure to ca. 106 L. iPrOAc
(195.5 kg) was added (water content was 0.07% w/w by KarlꢀFisher titration). Nꢀ
methylmorpholine (19.60 kg, 194 mol) was added at 24 °C in 20 min washing the line with of
iPrOAc (8.90 kg). Pivaloyl chloride (22.30 kg, 185 mol) was added at 23ꢀ24 °C in 40 min rinsing
with iPrOAc (3.9 kg). A second reactor was charged with 3,5ꢀdimethylaniline (22.40 kg, 185
mol) and iPrOAc (164.2 kg). After ca. 2 h at 22ꢀ24 °C this solution was added to the reaction
mixture at 5 °C in 1 h and the line rinsed with iPrOAc (25.4 kg). After 2.5 h at 3ꢀ4 °C, water
ACS Paragon Plus Environment
10

Page 11 of 14
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
(85.0 kg) was added at 3ꢀ4 °C in 10 min followed by 3 M HCl (48.0 kg) in 30 min. The mixture
was stirred at 3 °C for 15 min and then stirred at 18 °C for 30 min. The organic phase was
washed with water (64.0 kg), aqueous saturated sodium bicarbonate (139.5 kg) and finally water
(64.0 kg). The organic phase was concentrated by distillation under reduced pressure to about
475 L at 21ꢀ34 °C, then transferred to a second reactor via polish filtration and the line rinsed
with iPrOAc (58.7 kg). The solution was further concentrated by distillation in vacuo to about
210 L at 26ꢀ40 °C (water content by KarlꢀFisher titration: 0.05% w/w). Heptane (43.5 kg) were
added at 22 °C. 64 g of seeds suspended in heptane (ca. 1.1 L) were added. After 2 h at 22ꢀ24 °C,
heptane (246.0 kg) were added and stirred for 30 min. The mixture was cooled to 5 °C and kept 1
h. The suspension was split on two filters for filtration. Heptane (38.0 + 38.0 kg) were charged
into the reactor followed by iPrOAc (17.0 +17.0 kg) at 2 °C. The washing solution was split into
two equal portions for washing the two filters. The products were dried under reduced pressure
under a stream of nitrogen at 30ꢀ52 °C on the two filters for approximately 15 h. A total of 59.72
kg (83%) of a white crystalline solid corresponding to proline amide 11 (ACTꢀ460206) was
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
1
obtained. Purity (HPLC): 99.3% a/ a; MS [M + 1]+ = 389.09; H NMR (CDCl3): δ 8.70 (br s, 1
H), 7.84 (m, 2 H), 7.25 (m, 2 H), 7.06 (m, 2 H), 6.80 (s, 1 H), 4.17 (dd, J = 2.5, 8.8 Hz, 1 H),
3.91 (m, 3 H), 3.63 (m, 1 H), 3.26 (td, J = 6.6, 9.6 Hz, 1 H), 2.30ꢀ2.38 (m, 7 H), 1.76ꢀ1.87 (m, 1
H), 1.66ꢀ1.73 (m, 1 H), 1.56ꢀ1.63 (m, 1 H).
ASSOCIATED CONTENT
Supporting Information. NMR spectra, HPLC analysis, MS and UV spectra for compound 1.
This information is available free of charge via the Internet at http://pubs.acs.org/.
ACS Paragon Plus Environment
11

Organic Process Research & Development
Page 12 of 14
1
2
3
4
AUTHOR INFORMATION
5
6
Corresponding Author
7
8
9
*EꢀMail: simone.tortoioli@actelion.com. Telephone: +41 61 565 82 90
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 are grateful to Dr. Markus von Raumer for solid state measurements and to Barbara Channer,
Friedrich Brandl, and Florian Schmidt for analytical support.
REFERENCES
(1) Boss, C.; Brotschi, C.; Gatfield, J.; Gude, M.; Heidmann, B.; Sifferlen, T.; Williams, J. T.
WO/2012/025877, 2012.
(2) Batch size was approximately 60 kg.
(3) (a) Li, C. J.; Anastas, P. Chem. Soc. Rev. 2012, 41, 1413. (b) Dunn, P.J., Wells, A.; Williams,
M.T. Green Chemistry in the Pharmaceutical Industry, WileyꢀVCH, 2010. (c) Manley, J. B.
Scalable Green Chemistry; Pan Stanford Publishing, 2013. p. 2ꢀ24. (d) JimenezꢀGonzalez, C.;
Ponder, C. S, Broxterman, Q. B., Manley, J. B. Org. Process Res. Dev. 2011, 15, 912ꢀ917. (e)
Andraos, J. Org. Process Res. Dev. 2005, 9, 149ꢀ163. (f) Constable D. J. C., Curzons, A. D.,
Cunningham, V. L. Green Chem. 2002, 4, 521ꢀ527.
(4) Reacting 6 with LꢀProline allowed for the least conceivable number of steps A reversal of the
order of reactions would inevitably lead to more steps. A one-pot reaction, starting with Lꢀ
Proline, Bocꢀprotection, reaction with aniline 3 was described recently: Huy, P.; Schmalz, H.ꢀG.
Synthesis 2011, 6, 954ꢀ960.
ACS Paragon Plus Environment
12

Page 13 of 14
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
(5) Despite being one of the cheapest reagent for amide couplings, to our knowledge thionyl
chloride has seldom being used in amide formation of L- (or Rꢀ) proline: (a) Itoh, T.; Matsuya,
Y.; Enomoto, Y.; Ohsawa, A. Tetrahedron 2001, 57, 7277ꢀ7289. (b) Dupont, V.; Lecoq, A.;
Mangeot, J.ꢀP.; Aubry, A.; Bussard, G.; Marraud, M. J. Am. Chem. Soc. 1993, 115, 8898ꢀ8906.
(c) Engel, W.; Trommlitz, G.; Erberlein, W.; Mihm, G.; Schmidt, G.; Hammer, R.; Giachetti, A.
US4550107A, 1985. (d) Benzotriazole formation: Katrizky, A. R.; Angrish, P.; Suzuki, K.
Synthesis 2006, 3, 411ꢀ424.
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
(6) (a) Cvetovich, R. J.; DiMichele L. Org. Process Res. Dev. 2006, 10, 944ꢀ946 (and references
contained therein). (b) Dozemann, G. J.; Fiore, P. J.; Puls, T. P.; Walker J. C. Org. Process Res.
Dev. 1997, 1, 137ꢀ148. (c) Gijsen, H. M.; Van Bakel H. C. C. K.; Zwann, W.; Hulsof L. A. Org.
Process Res. Dev. 1999, 3, 38ꢀ43 (and references therein contained).
(7) Chiral HPLC analyses of crude 1 (before crystallization) in all cases showed er of 99ꢀ100%.
Chiral purity of commercially available Lꢀproline is >98% er.
(8) Fiore P. J.; Puls, T. P.; Walker, J. C. Org. Process Res. Dev. 1998, 2, 151ꢀ156. See also ref.
6b and 6c.
(9) The crystallization process resulted from a screening of solvents and temperatures which is
not described here. Critical was seeding with the desired polymorph.
(10) ICH Q3C(R5) Impurities: Guideline for Residual Solvents. Available from:
http://www.ich.org/products/guidelines/quality/qualityꢀsingle/article/impuritiesꢀguidelineꢀforꢀ
residualꢀsolvents.html.
ACS Paragon Plus Environment
13

Organic Process Research & Development
Page 14 of 14
1
2
3
4
(11) For a correlation between molecular complexity and PMI of different drugs: Kjell, D. P.;
5
6
Watson, I. A.; Wolfe, C. N.; Spitler, J. T. Org. Process Res. Dev. 2013, 17, 169ꢀ174.
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
14