The Development of a Manufacturing Route to an MCHr1 Antagonist

Article abstract of DOI:10.1021/acs.oprd.6b00006

Process development work to provide an efficient manufacturing route to a MCHr1 antagonist is presented herewith. Features of this development work include a scalable manufacturing route to the useful 6-oxa-2-azaspiro[3.3]heptane building block and the use of a (soluble) alternative to sodium triacetoxyborohydride.

Full text of DOI:10.1021/acs.oprd.6b00006

Subscriber access provided by UNIV OF PITTSBURGH
Full Paper
The Development of a Manufacturing Route to an MCHr1 Antagonist
Michael Golden, Danny Legg, David Milne, Arun Bharadwaj M., Deepthi K, Madan Gopal, Nagaraju Dokka,
Sudhir Nambiar, Puranik Ramachandra, U. Santhosh, Parhalad Sharma, R Sridharan, Manjunatha Sulur,
Mats Linderberg, Anders Nilsson, Roger Sohlberg, John Kremers, Samuel Oliver, and Debasis Patra
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00006 • Publication Date (Web): 26 Feb 2016
Downloaded from http://pubs.acs.org on February 26, 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 23
Organic Process Research & Development
1
2
3
4
The Development of a Manufacturing Route to an MCHr1 Antagonist
5
6
7
8
Michael Golden*, Danny Legg, David Milne.
Pharmaceutical Development, AstraZeneca, Silk Road Business Park, Macclesfield, UK.
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
Arun Bharadwaj M, Deepthi K, Madan Gopal, Nagaraju Dokka, Sudhir Nambiar, Puranik
Ramachandra, U Santhosh, Parhalad Sharma, R Sridharan, Manjunatha Sulur.
Pharmaceutical Development, AstraZeneca India, Hebbal, Bellary Road, Bangalore, India.
Mats Linderberg, Anders Nilsson, Roger Sohlberg.
Process R&D AstraZeneca, S 151 85 Södertälje, Sweden.
John Kremers, Samuel Oliver.
Process R&D, Albany Molecular Research (UK) Ltd, Mostyn Road, Holywell, Flintshire, UK.
Debasis Patra.
Process R&D, Albany Molecular Research, Inc., 26 Corporate Circle, P.O. Box 15098, Albany,
NY, 12203, US.
*Corresponding author:
michael.golden@astrazeneca.com
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 23
1
2
3
4
TOC 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

Page 3 of 23
Organic Process Research & Development
1
2
3
4
5
6
Abstract
7
8
9
Process development work to provide an efficient manufacturing route to a MCHr1
antagonist is presented herewith. Features of this development work include a scalable
manufacturing route to the useful 6-oxa-2-azaspiro[3.3]heptane building block, and the use
of a (soluble) alternative to sodium triacetoxyborohydride.
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 :
6ꢀoxaꢀ2ꢀazaspiro[3.3]heptane
sodium triacetoxyborohydride
reductive amination
MCHr1 antagonist
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 23
1
2
3
4
5
6
7
8
Introduction
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
1 is a melaninꢀconcentrating hormone receptor 1 (MCHr1) antagonist, thought to be involved in
the regulation of appetite.1a MCHR1 antagonists are a class of agents that show promise for
treating obesity, that have been wellꢀvalidated in animal models.1b
1 was first manufactured using the 1st generation route (Scheme 1), which provided material for
the preꢀclinical and initial Phase I studies. However, several problems were associated with this
route. The use of mesylation to activate the alcohol 8 gave rise to a genotoxic intermediate 9 and
related (potentially genotoxic) impurities, which would be difficult to fully control if
chromatography were to be removed from the final API stage. The aldehyde 11 was impure and
required filtration through a silica plug before undertaking reductive amination, Due to the poor
solubility of the aldehyde 11, dichloromethane was found to be the only suitable solvent to
achieve this. The deprotection of the sulphonamide 4 using magnesium in methanol resulted in a
very difficult workꢀup and low yield (<35%) of the resulting 6ꢀoxaꢀ2ꢀazaspiro[3.3]heptane 5
compound. Additionally, the route was low yielding, the API 1 was isolated with low purity, and
chromatography was required for clinical use.
ACS Paragon Plus Environment

Page 5 of 23
Organic Process Research & Development
1
2
3
4
Scheme 1 – 1st generation route
5
6
7
.HCl
8
(2)
9
(6)
(7)
-
NaOH, Bu4N+ HSO4 ,
toluene, water
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
NEt3, MeOH
(8)
(3)
MsCl, DIPEA, THF
, NaOH
(4)
(9)
(10)
i) Mg, I2 (cat), MeOH
ii) Oxalic acid
Cs2CO3, DMA
(11)
(5)
i) DCM, silica filtration of (11)
ii) DIPEA, STAB, AcOH, EtOAc
iii) Chromotography
(1)
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 23
1
2
3
4
Results and Discussion
5
6
7
8
9
There is significant interest in the literature in the 6ꢀoxaꢀ2ꢀazaspiro[3.3]heptane 5 fragment,
which is incorporated into a number of drugꢀlike molecules,2 and is reported as a structural
surrogate for morpholine.3 Traditionally this molecule has been synthesised following the
methodology first described by Carreira4 via formation of a tosyl protected species 4 from
tribromopentaerythritol (2) (a commercially available flame retardant). This procedure, followed
by deprotection using magnesium/methanol was employed in the 1st generation synthesis
(Scheme 1). Whilst small scale laboratory preparation was fit for purpose, scaling the
deprotection procedure (to 100 L scale) was problematic, specifically the filtration of the
magnesium salts. Though conversion was good, much material was lost during the workꢀup, and
low yields (<35%) of poor quality material were observed. Future demands would require the
development of a more scaleable procedure. Switching to a benzyl protecting group offered a
more operable deprotection and workꢀup (Scheme 2), and ultimately this chemistry was proven
on scale, to make a total of 65 kg of 5 as the oxalate salt in two batches.
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 freebase (if required) may be conveniently liberated on laboratory scale, from the oxalate salt
by treatment with ammonia in methanol, followed by filtration of the insoluble ammonium
oxalate byꢀproduct and distillation to remove ammonia and solvent.
Differential Scanning Calorimetry (DSC), and further investigational testing in a more sensitive
calorimeter (Setaram C80), indicated that both the oxalate salt 5 (and its freebase) have relatively
low thermal stability (93oC measured in DSC (sealed gold pan at 5K/min) (oxalate salt) and 46oC
measured in C80 (at 0.5K/min) with gas evolution from 60oC (freebase)). The decomposition
noted gave significant heat release in both cases (>1000 J/g). Ensuring safe operating conditions
on appropriate scale up is imperative.
ACS Paragon Plus Environment

Page 7 of 23
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Scheme 2 – Synthesis of 6-oxa-2-azaspiro[3.3]heptane (5)
-
Aq NaOH, Bu4N+ HSO4 ,
toluene
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
(3)
(2)
i) BnNH2, aq NaOH, Bu4N+ HSO4 , toluene
ii) HCl, Dioxane, i-PrOH
-
i) NaOH, MTBE, water
ii) H2 / Pd/C, EtOH
iii) Oxalic acid
(12)
(5)
(12 - HCl salt)
(12a - freebase)
Scale up of the existing literature process5 to form the oxadiazole 7 (Scheme 3) was also
successful, ultimately producing 93 kg of material, and with scaleable routes to the key
spirocyclic oxetane 5 and oxadiazole 7 fragments in hand, different approaches to the main
branch of the synthetic pathway were explored. An alternative route producing improved quality
1, with increased yield, reduced PGI risk and without chromatography was developed (Scheme
3). The commercially available coupling partners 4ꢀfluorobenzaldehyde 20 and CBZꢀAcetidinol
13 undergo a straightforward SNAr reaction in good yield (approximately 90% solution yield).
Although the product 14 can be isolated as a solid, the kinetics of the crystallisation are very
slow, and 14 has a low melting point (<50°C), making isolation difficult. Formation of the
bisulphite adduct is also possible to achieve an isolation, but the coupling reaction is clean and
can be telescoped through to the reductive amination step more efficiently. The second step
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 23
1
2
3
4
5
6
7
8
9
proceeds via liberation of 5 as the freebase, and formation of the iminium species in situ. A slow
sodium triacetoxyborohydride addition favours reduction of the iminium species over reduction
of 14 to the alcohol. Subsequent hydrogenation to remove the CBZꢀprotecting group was found
to be trivial (though a high loading of the palladium catalyst was required to ensure completion)
with subsequent coupling with the oxadiazole species 7 proceeding after an overnight stir in
methanol. The product 1 can be crystallised on solvent swapping to ethanol, in approximately
60ꢀ65% yield, and this reaction sequence (from 20 and 13 through to 1) was proven on 100 L
scale. A two step purification procedure, using aqueous ethyl acetate recrystallisation, followed
by a hot ethanol reꢀslurry (to ensure the correct polymorph) was used to supply further
toxicological work.
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

Page 9 of 23
Organic Process Research & Development
1
2
3
4
Scheme 3 – 2nd generation route
5
6
7
8
(13)
(20)
9
KOH, DMSO
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
(5)
(14)
DIPEA, STAB, MeOH
(18)
(17)
(15)
i) NEt3, anisole
ii) SOCl2
H2 / Pd, MeOH
(7)
(16)
i) MeOH
ii) aq EtOAc, EtOH (purification)
(1)
Subsequently, in anticipation of further scale up to the pilot plant, a number of improvements
were made to this synthesis. Addition of solid sodium triacetoxyborohydride reagent into a
mixture of 5 and 14 in methanol generates a potentially hazardous environment for an operator
(hydrogen evolution during an addition of a solid) and, additionally, a large excess of solid
sodium triacetoxyborohydride (3 mol eq) is required due to the competing degradation by
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 23
1
2
3
4
5
6
7
8
9
reaction with methanol. Whilst sodium triacetoxyborohydride is insoluble in most organic
solvents, the analogous propionate 6 species 19 (Scheme 4) is soluble in a variety of solvents,
including ethyl acetate, already used in the subsequent processing step to extract the product 15.
Therefore, an approximately one molar solution of 19 in ethyl acetate was preꢀmade (using
controlled addition of propionic acid into a sodium borohydride/ethyl acetate mixture), which
could then be more controllably added into the iminium mixture as a solution. The solution of 19
can be held for at least 24 hours at ambient temperature before use. As well as the operational
advantages that this method presents, an improvement in quality was also observed; the alcohol
byꢀproduct (from reduction of 14) was suppressed, presumably by the more controlled addition
method. Replacement of methanol (with ethanol) to dissolve the iminium precursors also
reduced the molar amount of reductant required, presumably through reduced degradation of the
reductant. The amount of catalyst required for the subsequent hydrogenation was also optimised
and a 3 L trial reaction demonstrated the described modifications prior to the intended scaleꢀup.
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
Improvements to the purification procedure (formation of an oxalate salt of 1, and subsequent
liberation of the freebase) were also demonstrated in the laboratory, which gave further
improvement in the quality of the API.
ACS Paragon Plus Environment

Page 11 of 23
Organic Process Research & Development
1
2
3
4
5
Scheme 4 – Reductive amination using (soluble) propionoate anologue of sodium
triacetoxyborohydride.
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
(5)
(14)
NaBH4 (1 eq), propionic acid (3eq)
EtOAc
(19)
(~1M solution in EtOAc)
Na2CO3, EtOH
(15)
Conclusion
6ꢀoxaꢀ2ꢀazaspiro[3.3]heptanes 5 is a useful synthetic building block, which features as a key
structural motif in a number of drug molecules in the literature. An alternative more scaleable
approach to this useful synthetic building block has been proven on scale. Additionally, the use
of the propionoate analogue of sodium triacetoxyborohydride, as a means of facilitating a
solution addition of a mild reductant to replace a potentially hazardous addition of solid sodium
triacetoxyborohydride is also described as part of the development work performed to produce an
alternative, efficient synthetic route to 1.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 23
1
2
3
4
Experimental Section
5
6
7
Preparation of crude 2-benzyl-6-oxa-2-azaspiro[3.3]heptane (12a)
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
3ꢀbromoꢀ2,2ꢀbis(bromomethyl)propanꢀ1ꢀol (2) (1.80 kg, 5.54 mol, 1.0 mol eq) and
tetrabutylammonium hydrogensulfate (94.1 g, 0.27 mol, 0.05 mol eq) were charged to a 20 L
jacketed vessel, under nitrogen. Toluene (9.0 L, 5.0 rel vols) was charged with stirring and the
solution was warmed to 22°C. 50% aqueous sodium hydroxide (576 mL, 2.0 mol eq) was then
charged. The mixture was then cooled to 23°C and stirred for 23 hours. Purified water (1.8 L, 1
rel vols) was added and the reaction mixture was stirred for 30 mins. The phases were allowed to
settle for 30 mins and then separated. To this solution was charged tetrabutylammonium
hydrogensulfate (188.2 g, 0.55 mol, 0.1 mol eq) and 50% aqueous sodium hydroxide (1.44 L, 5.0
mol eq). The mixture was heated to 73°C and benzylamine (578.6 g, 5.40 mol, 1 mol eq) was
added over 10 mins by dropping funnel. The mixture was heated to 83°C and stirred for 20
hours. The batch was cooled to 20°C and purified water (3.30 L, 2.5 rel vols) was added with
stirring. The mixture was stirred for 30 mins and allowed to settle and the phases were separated.
The organic layer was extracted with 2 M acetic acid (4.62 L, 3.5 rel vols then 920 mL, 0.7 rel
vols). Toluene (6.6 L, 5 rel vols) was added to the combined aqueous layers and the batch was
basified using 50% aqueous sodium hydroxide (528 mL, 0.4 rel vols). The phases were separated
and the aqueous layer was extracted with toluene (920 mL, 0.7 rel vols). The combined organic
layers were concentrated under vacuum at 40ꢀ50°C to afford crude 2ꢀbenzylꢀ6ꢀoxaꢀ2ꢀ
azaspiro[3.3]heptane (12a) (942.7 g, 90% yield) as a pale yellow oil.
Purification of (12a) to produce 2-benzyl-6-oxa-2-azaspiro[3.3]heptane hydrochloride (12)
ACS Paragon Plus Environment

Page 13 of 23
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
A solution of 2ꢀbenzylꢀ6ꢀoxaꢀ2ꢀazaspiro[3.3]heptane (12a) (926.5 g, 4.90 mol, 1.0 mol eq) in
isopropanol (2.78 L, 3 rel vols) was charged to a 10 L jacketed vessel, under nitrogen. The
mixture was cooled to 4°C with stirring and 4 M HCl in dioxane (1.23 L, 4.90 mol, 1.0 mol eq)
was added by dropping funnel over 30 mins whilst maintaining the batch temperature below
21°C. The batch was cooled back to 0ꢀ5°C and stirred in this temperature range for 40 mins.
The slurry was filtered and the flask and filter cake were washed with methyl tertꢀbutyl ether (2 ×
927 mL, 1 rel vols). The damp solid was dried in a vacuum oven at ambient temperature to
afford 2ꢀbenzylꢀ6ꢀoxaꢀ2ꢀazaspiro[3.3]heptane hydrochloride (12) (605.6 g, 55% yield) as a white
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
1H NMR (400 MHz, D2O): 7.43ꢀ7.35 (m, 3H), 7.34ꢀ7.30 (m, 2H), 4.75 (br s, 1H), 4.69 (s, 4H),
4.27 (s, 4H), 4.20 (s, 2H). 13C NMR (100 MHz, D2O) δ ppm 37.53 (s, 1C) 57.79 (s, 2C) 61.27 (s,
2C) 78.82 (s, 1C) 80.16 (s, 1C) 129.31 (s, 1C) 129.39 (s, 2C) 129.89 (s, 2C) 130.04 (s, 1C).
Preparation of 6-oxa-2-azaspiro[3.3]heptane (5)
Step A (freebase) ꢀ 2ꢀbenzylꢀ6ꢀoxaꢀ2ꢀazaspiro[3.3]heptane hydrochloride (12) (564.2 g, 2.51 mol,
1.0 mol eq) was charged to a 10 L jacketed vessel. Purified water (1.13 L, 2 rel vols), methyl tertꢀ
butyl ether (1.97 L, 3.5 rel vols) and saturated aqueous brine solution (395 mL, 0.7 rel vols) were
added with stirring at 20ꢀ25°C and the batch was basified using 5 M aqueous sodium hydroxide
(1.09 L, 1.2 rel vols) until the pH of the reaction mixture was 13.0. The mixture was stirred for
30 mins at this pH and the phases were separated. The aqueous layer was extracted with methyl
tertꢀbutyl ether (959 mL, 1.7 rel vols). The combined organic layers were concentrated to afford
2ꢀbenzylꢀ6ꢀoxaꢀ2ꢀazaspiro[3.3]heptane (12a) (471.3 g, 99% yield from HCl salt) as a pale yellow
oil.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 23
1
2
3
4
5
6
7
8
9
Step B (hydrogenation) ꢀ 2ꢀbenzylꢀ6ꢀoxaꢀ2ꢀazaspiro[3.3]heptane (12a) (419.3 g, 2.22 mol, 1.0
mol eq), ethanol (2.93 L, 7 rel vols.) and 5% Pd/C (83.9 g, 20 wt%, Johnson Matthey Type 394)
were charged to a 7.5 L stainless steel hydrogenation vessel, which was sealed. The vessel was
purged with nitrogen then hydrogen. The reaction mixture was heated to 45°C with stirring and
the vessel was charged with 4 bar hydrogen. The reaction mixture was stirred for 16 hours, and
then vented and purged with nitrogen. The batch was filtered on a dicalite bed. The vessel was
rinsed with ethanol (839 mL, 2 rel vols) and the wash was also filtered. The filter cake was
washed with additional ethanol (839 mL, 2 rel vols). The combined organic solution was vacuum
distilled (100ꢀ135 mbar, 35ꢀ50°C) to afford 6ꢀoxaꢀ2ꢀazaspiro[3.3]heptane (5 - as the freebase)
(264.8 g, ~21.6 wt% ethanol by 1H NMR, corrected weight = 207.6 g, 94.3% yield) as a pale
yellow oil.
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
Step C (salt formation) ꢀ 6ꢀoxaꢀ2ꢀazaspiro[3.3]heptane (5) (21.86 g @ 90.0%w/w, 0.198 mol, 1.0
mol eq), isopropanol (78.7 mL, 4 rel vols) and water (19.7 mL, 1.0 rel vols) were charged to a
500 mL round bottom flask under nitrogen. The reaction mixture was cooled to 5°C with stirring
and a solution of oxalic acid (18.76 g, 0.208 mol, 1.05 mol eq) in isopropanol (98.4 mL, 5 rel
vols) was added over approx 15 mins. The reaction mixture was warmed to 20ꢀ25°C, stirred for
1 hr and filtered. The damp solid (53.7 g) was then recharged to the round bottom flask along
with IPA (167 mL, 8.5 rel vols) and water (29.5 mL, 1.5 rel vols). The white slurry was stirred at
40ꢀ45°C for 1 hr, cooled to 20ꢀ25°C and filtered. The flask and filter cake were washed with
isopropanol (2 × 39.4 mL, 2 rel vols). The filter cake was washed with additional isopropanol
(39.4 mL, 2 rel vols) and the damp solid was dried in a vacuum oven at 50°C to afford 6ꢀoxaꢀ2ꢀ
azaspiro[3.3]heptane (5 – as the oxalate salt) (33.35 g, 89% yield, 95.8% w/w by 1H NMR
assay) as a white solid.
ACS Paragon Plus Environment

Page 15 of 23
Organic Process Research & Development
1
2
3
4
5
1H NMR (400 MHz, D2O) δ: 4.28 (s, 4 H) 4.80 (s, 4 H). 13C NMR (101 MHz, D2O) δ ppm 40.11
(s, 1 C) 54.65 (s, 2 C) 80.07 (s, 2 C) 165.62 (s, 2 C).
6
7
8
9
Preparation of ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (7)
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
Anisole (650 L, 10.0 rel vols), 4ꢀmethoxybenzhydrazide (18) (65.0 kg, 1.0 mol eq) and
triethylamine (98.9 kg, 2.5 mol eq) were charged into the reactor at 25°C. Ethyl chloroxoacetate
(17) (64.7 kg, 1.2 mol eq) was slowly added into the reactor lot wise at 25°C. The mixture was
stirred at 25°C for 10 mins and then the temperature was raised to 50°C. The reaction mixture
was stirred at 50°C until reaction was complete. Thionyl chloride (55.8 kg, 1.2 mol eq) was
charged at <70°C into the reactor. The temperature was raised to 90°C and maintained at 90°C
until reaction was complete. Magnesium sulphate (32.5 kg) in water (325.0 L) was slowly added
to the reactor at 40°C. The reaction temperature was maintained at 40°C for 30 mins and then the
contents were allowed to settle for 30 min. The bottom aqueous layer was separated off and
discarded. The organic layer was washed twice with a solution of sodium carbonate (62.2 kg) in
water (325 L) at 40°C. The organic layer was concentrated to 3.0 rel vols level under vacuum
then cooled to 55°C. Nꢀheptane (325 L) was charged into the reactor and the mixture stirred for
1 hour at 55°C. The reaction mass was cooled to 10°C over a period of 4 hours and then stirred
at 10°C for 1 hour. The reaction slurry was filtered and washed the wet cake twice with nꢀheptane
(130 L, 2.0 rel vols), followed by slurry wash with ethanol (325 L, 5.0 rel vols). The product was
dried under vacuum at 40°C to yield an off white solid (7) (60.5 kg, 62%).
1H NMR (400 MHz, DMSOꢀd6) 1.38 (t, J=7.11 Hz, 3 H) 3.88 (s, 3 H) 4.46 (q, J=7.11 Hz, 2 H)
7.18 (m, J=8.73 Hz, 2 H) 8.0 (d, J=8.73 Hz, 2 H). 13C NMR (101 MHz, DMSOꢀd6) δ ppm 14.33
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 23
1
2
3
4
5
6
(s, 1 C) 56.07 (s, 1 C) 63.36 (s, 1 C) 115.15 (s, 1 C) 115.51 (s, 2 C) 129.55 (s, 2 C) 154.54 (s, 1
C) 156.51 (s, 1 C) 163.21 (s, 1 C) 165.85 (s, 1 C).
7
8
9
Preparation of [5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-[3-[4-(2-oxa-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
azaspiro[3.3]heptan-6-ylmethyl)phenoxy]azetidin-1-yl]methanone (1) on 100 L scale.
CBZ Acetidinol (13) (2.250 kg, 1.00 mol eq) and 4ꢀfluorobenzaldehyde (20) (1.32 kg, 1.00 mol
eq) were dissolved in dimethylsulphoxide (13.5 L, 6.0 rel vols) at 20°C. Potassium hydroxide
(0.625 kg, 11.1 mol, 1.05 mol eq) was charged to the solution in two lots, maintaining <28°C.
The reaction mixture was held at 20°C for 3.5 hours, before adding ethyl acetate (13.5 L, 6.0 rel
vols) and a solution of ammonium chloride (1.7 kg, 31.8 mols, 3.0 mol eq) in water (13.5L, 6.0
rel vols) whilst maintaining the temperature at ≤28°C. The layers were separated and the
aqueous layer extracted with a further portion of ethyl acetate (6.75L, 3.0 rel vols). The organic
phases were then combined and washed with a solution of sodium chloride (1.24 kg, 2.0 mol eq)
in water (11.25 L, 5.0 rel vols). The organic solution was concentrated under vacuum to a final
volume of 6.75 L (3.0 rel vols). Methanol (11.25 L, 5.0 rel vols) was added and the organic
solution was concentrated under vacuum to a final volume of 6.75 L (3.0 rel vols). Further
methanol (11.25 L, 5.0 rel vols) was added and the organic solution was again concentrated under
vacuum to a final volume of 6.75 L (3.0 rel vols). The reaction mixture was diluted with
methanol (12.4L, 5.5 rel vols), and then (5) (2.41 kg, 1.20 mol eq) and diisopropylethylamine
(7.4 L, 4.00 mol eq) were added. Sodium triacetoxyborohydride (6.75 kg, 3.00 mol eq) was then
added in five equal portions over a 2 hour period. Ethyl acetate (27 L, 12.0 rel vols) and then a
solution of 23% aqueous ammonia solution (7.5 L, 3.0 rel wt) in water (225 L, 10 rel vols), were
added maintaining <28°C. The layers were separated and the aqueous phase was extracted with
further ethyl acetate (6.75L, 3.0 rel vols). The organic phases were combined and concentrated
ACS Paragon Plus Environment

Page 17 of 23
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
under vacuum to a final volume of 6.75 L (3.0 rel vols). Methanol (11.25 L, 5.0 rel vols) was
added and the organic solution concentrated under vacuum to a final volume of 6.75 L (3.0 rel
vols). A further portion of methanol (11.25 L, 5.0 rel vols) was added and the organic solution
again concentrated under vacuum to a final volume of 6.75 L (3.0 rel vols). The reaction was
diluted with methanol (12.4L, 5.5 rel vols), and then 10% palladium on charcoal (50% wet) (1.05
kg, 0.46 rel wt) was added. The reaction mixture was thoroughly inerted with nitrogen before
being exposed to 3 barg pressure of hydrogen for 3 hours. The reaction mixture was filtered
through Celite and the catalyst residues washed with methanol (6.75 L, 3.0 rel vols). (7) (1.93
kg, 0.73 mol eq) was charged, followed by methanol (1.125 L, 0.5 rel vols) and the reaction
mixture was stirred for 18 hours. The organic solution was concentrated under vacuum to a final
volume of 6.75 L (3.0 rel vols). Ethanol (11.25 L, 5.0 rel vols) was added and the mixture
concentrated under vacuum to a final volume of 6.75 L (3.0 rel vols). Further ethanol (11.25 L,
5.0 rel vols) was added and the mixture was again concentrated under vacuum to a final volume
of 6.75 L (3.0 rel vols). The reaction mixture was diluted with ethanol (11.25 L, 5.0 rel vols) and
then cooled to 10°C before filtering, washing with ethanol (4.5 L, 2.0 rel vols) and drying at
55°C. The product was isolated as an off white solid (1) (2.93 kg, 60% yield).
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
1H NMR (500 MHz, DMSOꢀd6) δ: 3.24 (s, 4 H) 3.41 (s, 2 H) 3.87 (s, 3 H) 4.08 (dd, J=11.28,
3.61 Hz, 1 H) 4.53 (dd, J=10.72, 3.73 Hz, 1 H) ) 4.59 (s, 4 H) 4.62 (m, 1 H) 5.07 (m, 1 H) 5.13
(m, 1 H) 6.82 (d, J=8.64 Hz, 2 H) 7.16 (d, J=8.96 Hz, 2 H) 7.19 (d, J=8.61 Hz, 2 H) 8.00 (d,
J=9.08 Hz, 2 H). 13C NMR (126 MHz, DMSOꢀd6) δH 38.46 (s, 1 C) 55.61 (s, 1 C) 55.66 (s, 1 C)
60.21 (s, 1 C) 61.80 (s, 1 C) 62.75 (s, 2 C) 66.10 (s, 1 C) 80.01 (s, 2 C) 114.38 (s, 2 C) 114.88
(s,1 C) 115.05 (s, 2 C) 129.00 (s, 2 C) 129.74 (s, 2 C) 131.34 (s, 1 C) 153.12 (s, 1 C) 155.12 (s, 1
C) 157.17 (s, 1 C) 162.59 (s, 1 C) 164.45 (s, 1 C)
ACS Paragon Plus Environment

Organic Process Research & Development
Page 18 of 23
1
2
3
4
Preparation of [5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-[3-[4-(2-oxa-6-
5
6
7
8
azaspiro[3.3]heptan-6-ylmethyl)phenoxy]azetidin-1-yl]methanone (1) on 3 L scale in
preparation for pilot plant manufacture.
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
CBZ Acetidinol (13) (100 g, 1.00 mol eq) and 4ꢀfluorobenzaldehyde (20) (59.9 g, 1.00 mol eq)
were dissolved in dimethylsulphoxide (600 ml, 6.0 rel vols) at 20°C. Potassium hydroxide (31.9
g, 1.00 mol eq) was charged in two lots, maintaining <28°C. The reaction mixture was held at
20°C for 3.5 hours, before ethyl acetate (600 ml, 6.0 rel vols) and a solution of ammonium
chloride (77.4 g, 3.0 mol eq) in water (600 ml, 6.0 rel vols) were added maintaining the temp at
≤28°C. The layers were separated and the organic phase was washed twice with a solution of
sodium chloride (50 g, 0.5 rel wt) in water (500 ml, 5.0 rel vols). The organic solution was
concentrated under vacuum to a final volume of 500 ml (5.0 rel vols). Ethanol (600 ml, 6.0 rel
vols) was added and and the organic solution concentrated under vacuum to a final volume of
400 ml (4.0 rel vols). Further ethanol (600 ml, 6.0 rel vols) was added and the organic solution
concentrated under vacuum to a final volume of 400 ml (4.0 rel vols). The reaction mixture was
diluted with ethanol (450 ml, 4.5 rel vols), and then (5) (120.0 g, 1.30 mol eq) and sodium
carbonate (66.5 g, 1.3 mol eq) were added. A preꢀprepared solution of sodium borohydride (36.5
g, 2.0 mol eq), propionic acid (214 g, 6.0 mol eq) and ethyl acetate (950 ml, 9.5 rel vols) was
added over 4 hours (preparation was by addition of propionic acid to the sodium
borohydride/ethylacetate mixture over 1 hour, maintaining <20°C, followed by overnight hold at
20°C). Ethyl acetate (250 ml, 2.5 rel vols), water (700 ml, 7.0 rel vols) and then a solution of
29% aqueous ammonia solution (300 ml, 3.0 rel vols), were added maintaining <28C. The layers
were then separated by dipleg (set to remove liquid above 12.5 rel vols) retaining the upper
portion. Water (400 ml, 4.0 rel vols) was added to the lower aqueous phase and the aqueous
phase extracted with further ethyl acetate (600 ml, 6.0 rel vols), by dipleg (set to remove liquid
ACS Paragon Plus Environment

Page 19 of 23
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
above 12.5 rel vols). The organic extracts were combined and the small amount of lower
aqueous phase separated off and discarded. The organic solution was concentrated under vacuum
to a final volume of 500 ml (5.0 rel vols). Methanol (500 ml, 5.0 rel vols) was added and the
organic solution was concentrated under vacuum to a final volume of 500 ml (5.0 rel vols).
Further methanol (500 ml, 5.0 rel vols) was added and the organic solution again concentrated
under vacuum to a final volume of 500 ml (5.0 rel vols). The reaction mixture was diluted with
methanol (350 ml, 3.5 rel vols), and then 10% palladium on charcoal (50% wet) (10.0 g, 0.1 rel
wt) was added. The reaction mixture was thoroughly inerted with nitrogen, before being exposed
to 3 barg pressure of hydrogen for 3 hours. The reaction mixture was then filtered and the
catalyst residues were washed with methanol (300 ml, 3.0 rel vols). (7) (95.6 g, 0.75 mol eq) was
charged and the mixture stirred for 18 hours. The organic solution was concentrated under
vacuum to a final volume of 500 ml (5.0 rel vols). Ethanol (500 ml, 5.0 rel vols) was added and
the organic solution was concentrated under vacuum to a final volume of 500 ml (5.0 rel vols).
Further ethanol (500 ml, 5.0 rel vols) was added and the organic solution again concentrated
under vacuum to a final volume of 500 ml (5.0 rel vols). The reaction mixture was diluted with
ethanol (500 ml, 5.0 rel vols) and cooled to 20°C before filtering, washing with ethanol (4.5 L,
2.0 rel vols) and drying at 40°C. The product was isolated as an off white solid (1) (137.7 g, 62%
yield).
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
1H NMR (500 MHz, DMSOꢀd6) δ: 3.24 (s, 4 H) 3.41 (s, 2 H) 3.87 (s, 3 H) 4.08 (dd, J=11.28,
3.61 Hz, 1 H) 4.53 (dd, J=10.72, 3.73 Hz, 1 H) ) 4.59 (s, 4 H) 4.62 (m, 1 H) 5.07 (m, 1 H) 5.13
(m, 1 H) 6.82 (d, J=8.64 Hz, 2 H) 7.16 (d, J=8.96 Hz, 2 H) 7.19 (d, J=8.61 Hz, 2 H) 8.00 (d,
J=9.08 Hz, 2 H). 13C NMR (126 MHz, DMSOꢀd6) δH 38.46 (s, 1 C) 55.61 (s, 1 C) 55.66 (s, 1 C)
60.21 (s, 1 C) 61.80 (s, 1 C) 62.75 (s, 2 C) 66.10 (s, 1 C) 80.01 (s, 2 C) 114.38 (s, 2 C) 114.88
ACS Paragon Plus Environment

Organic Process Research & Development
Page 20 of 23
1
2
3
4
5
6
(s,1 C) 115.05 (s, 2 C) 129.00 (s, 2 C) 129.74 (s, 2 C) 131.34 (s, 1 C) 153.12 (s, 1 C) 155.12 (s, 1
C) 157.17 (s, 1 C) 162.59 (s, 1 C) 164.45 (s, 1 C).
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
Purification of [5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-[3-[4-(2-oxa-6-
azaspiro[3.3]heptan-6-ylmethyl)phenoxy]azetidin-1-yl]methanone (1)
[5ꢀ(4ꢀMethoxyphenyl)ꢀ1,3,4ꢀoxadiazolꢀ2ꢀyl]ꢀ[3ꢀ[4ꢀ(2ꢀoxaꢀ6ꢀazaspiro[3.3]heptanꢀ6ꢀ
ylmethyl)phenoxy]azetidinꢀ1ꢀyl]methanone (1) (2.89 kg, 1.0 mol eq), ethyl acetate (29 L, 10.0 rel
vols) and water (43.3 L, 15.0 rel vols) were added to the reaction vessel. The mixture was heated
to 60°C for 1 hour, and then cooled to 50°C before a screening filtration. The reaction solution
was cooled the reaction to 40°C and (1) was added as seed (2.5 g, 0.001 rel wt). The reaction
was cooled over 2 hours to 20°C, and held for 1 hour. The organic phase was washed with water
(4.3 L, 1.5 rel vols) and dried at 55°C. The product was then slurried with ethanol (27.4 L, 12.0
rel vols) at 60°C for 1 hour, before being filtered and washed with ethanol (3.4 L, 1.5 rel vols).
The product was dried at 55°C to yield the product as a white solid (1) (2.12 kg, 73%).
1H NMR (500 MHz, DMSOꢀd6) δ: 3.24 (s, 4 H) 3.41 (s, 2 H) 3.87 (s, 3 H) 4.08 (dd, J=11.28,
3.61 Hz, 1 H) 4.53 (dd, J=10.72, 3.73 Hz, 1 H) ) 4.59 (s, 4 H) 4.62 (m, 1 H) 5.07 (m, 1 H) 5.13
(m, 1 H) 6.82 (d, J=8.64 Hz, 2 H) 7.16 (d, J=8.96 Hz, 2 H) 7.19 (d, J=8.61 Hz, 2 H) 8.00 (d,
J=9.08 Hz, 2 H). 13C NMR (126 MHz, DMSOꢀd6) δH 38.46 (s, 1 C) 55.61 (s, 1 C) 55.66 (s, 1 C)
60.21 (s, 1 C) 61.80 (s, 1 C) 62.75 (s, 2 C) 66.10 (s, 1 C) 80.01 (s, 2 C) 114.38 (s, 2 C) 114.88
(s,1 C) 115.05 (s, 2 C) 129.00 (s, 2 C) 129.74 (s, 2 C) 131.34 (s, 1 C) 153.12 (s, 1 C) 155.12 (s, 1
C) 157.17 (s, 1 C) 162.59 (s, 1 C) 164.45 (s, 1 C). HRMS Calcd for C25H27N4O5: 463.1976;
HRMS found [M+H]+: 463.1978
ACS Paragon Plus Environment

Page 21 of 23
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Alternative purification procedure - preparation of [5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-
yl]-[3-[4-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy]azetidin-1-yl]methanone (1) (via
the oxalate 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
Step A ꢀ [5ꢀ(4ꢀMethoxyphenyl)ꢀ1,3,4ꢀoxadiazolꢀ2ꢀyl]ꢀ[3ꢀ[4ꢀ(6ꢀoxaꢀ2ꢀazaspiro[3.3]heptanꢀ2ꢀ
ylmethyl)phenoxy]azetidinꢀ1ꢀyl]methanone (1) (10.0 g) was added to dimethylsulphoxide (100
ml, 10.0 rel vols) and heated to 60°C to give a solution. The contents were then cooled to 20°C.
A solution of oxalic acid (1.84 g 1.0 mol eq) in dimethylsulphoxide (10 ml, 1.0 rel vol) was
added at 20°C. Ethanol (200 ml, 20.0 rel vol) was added and the contents stirred for 16 hours.
The precipitated solid was filtered and washed with ethanol (50 ml, 5.0 rel vol). The solid was
dried at 40°C to give the oxalate salt of (1) as an off white solid (8.58g, 76% yield)
Step B ꢀ [5ꢀ(4ꢀmethoxyphenyl)ꢀ1,3,4ꢀoxadiazolꢀ2ꢀyl]ꢀ[3ꢀ[4ꢀ(6ꢀoxaꢀ2ꢀazaspiro[3.3]heptanꢀ2ꢀ
ylmethyl)phenoxy]azetidinꢀ1ꢀyl]methanone; oxalic acid (oxalate salt of (1)) (6.0g, 1.0 mole eq)
was added to ethyl acetate (60 ml, 10.0 rel vol) at 20°C and stirred to give an off white biphasic
slurry. 15.5% aqueous ammonia (7.5 mol eq, 35.5ml) was charged over 3 minutes. The contents
were heated to 60°C, to form a biphasic solution. The solution was screened and the lower
aqueous layer separated and discarded. The organic layer was washed with water (30 ml 5.0 rel
vols) and the lower aqueous layer was separated. The organic layer was cooled to 20°C and the
slurry distilled under vacuum to 5.0 rel vols (30 ml). Ethanol (48ml, 8.0 rel vol) was added and
the mixture concentrated under vacuum to 5.0 rel vols (30ml). Further ethanol (48ml, 8.0 rel vol)
was added and the mixture again concentrated under vacuum to 5.0 rel vols (30ml). The mixture
was diluted with ethanol (18ml, 3.0 rel vol) to make up to 8.0 rel vol, cooled to 20°C and stirred
for 80 minutes. The solid was filtered and washed with ethanol (24ml, 4 rel vol), then discharged
(1) to a vacuum oven and dried at 40°C. (Yield = 4.43g, 88%).
ACS Paragon Plus Environment

Organic Process Research & Development
Page 22 of 23
1
2
3
4
5
6
7
8
9
1H NMR (500 MHz, DMSOꢀd6) δ: 3.24 (s, 4 H) 3.41 (s, 2 H) 3.87 (s, 3 H) 4.08 (dd, J=11.28,
3.61 Hz, 1 H) 4.53 (dd, J=10.72, 3.73 Hz, 1 H) ) 4.59 (s, 4 H) 4.62 (m, 1 H) 5.07 (m, 1 H) 5.13
(m, 1 H) 6.82 (d, J=8.64 Hz, 2 H) 7.16 (d, J=8.96 Hz, 2 H) 7.19 (d, J=8.61 Hz, 2 H) 8.00 (d,
J=9.08 Hz, 2 H). 13C NMR (126 MHz, DMSOꢀd6) δH 38.46 (s, 1 C) 55.61 (s, 1 C) 55.66 (s, 1 C)
60.21 (s, 1 C) 61.80 (s, 1 C) 62.75 (s, 2 C) 66.10 (s, 1 C) 80.01 (s, 2 C) 114.38 (s, 2 C) 114.88
(s,1 C) 115.05 (s, 2 C) 129.00 (s, 2 C) 129.74 (s, 2 C) 131.34 (s, 1 C) 153.12 (s, 1 C) 155.12 (s, 1
C) 157.17 (s, 1 C) 162.59 (s, 1 C) 164.45 (s, 1 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
HRMS Calcd for C25H27N4O5: 463.1976; HRMS found [M+H]+: 463.1978
References
1. (a) Johansson, A.; Löfberg, C; Antonsson, M.; von Unge, S.; Hayes, M.; Judkins, R.; Ploj,
K.; Benthem, L.; Lindén, D.; Brodin, P.; Wennerberg, M.; Fredenwall, M.; Li, L.; Persson,
J.;
Bergman, R.; Pettersen, A.; Gennemark, P.; Hogner, A.
J. Med. Chem.
http://dx.doi.org/10.1021/acs.jmedchem.5b01654 (Manuscript just accepted) (b) Luthin, D.R.;
Life Sciences Volume 81, Issue 6, (2007), Pages 423–440
2. (a) Casaubon, R.L.; Narayan, R.; Oalmann, C.; Vu, C.B.; PCT Int. Appl., 2013059587, 25
Apr 2013. (b) Burns, C.J ; PCT Int. Appl., 2014000032, 3 Jan 2014 (Phenyl amino
pyrimidine bicyclic compounds and uses thereof).
3. Wuitschik, G.; RogersꢀEvans, M; Buckl, A, Bernasconi, M.; Märki, M.; Godel T.; Fischer H.;
Wagner B.; Parrilla, I.; Schuler, F.; Schneider, J.; Alker, A.; Schweizer, W.B.; Müller, K. and
Carreira, E.M. Angew. Chem., Int. Ed. 2008, 47, 4512–4515.
4. Burkhard, J.; Carreira, E.M. Org. Lett. 2008, 16, 3525ꢀ3526.
5. Dost, J.; Heschel, M.; Stein, J. J. Prakt. Chem. (Leipzig) 1985, 327(1), 109ꢀ116.
ACS Paragon Plus Environment

Page 23 of 23
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
6. (a) McGill, J. M.; Labell, E. S.; Williams, M. A. Tetrahedron Lett. 1996, 37, 3977. (b)
McGill, J. M.; Burks, J. E.; Espinosa, L.; Labell, E. S.; Ritter, A. R.; Speakman, J. L.;
Williams, M. A.; Bradley, D. A.; Haenl, M. G.; Schmid, C. R. Org. Process Res. Dev. 1997,
1, 198.
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