Development of a large-scale asymmetric process for tert-butanesulfinamide

Article abstract of DOI:10.1021/acs.oprd.8b00399

Process development for a scalable and green synthesis of chiral tert-butanesulfinamide (TBSA) on a multikilogram scale is reported. The process is based on the identification of a chiral sulfinyl transfer agent, benzo[1,3]oxathiozin-2-one, that contains active and differentiated S?N and S?O bonds, allowing the synthesis to proceed under mild reaction conditions. This method is practical and overcomes the disadvantages of earlier methods deploying harsh reaction conditions and hazardous and toxic reagents.

Full text of DOI:10.1021/acs.oprd.8b00399

Subscriber access provided by Gothenburg University Library
Full Paper
Development of Large Scale Asymmetric Process for tert-Butanesulfinamide
Philomen DeCroos, Zhengxu S. Han, Kanwar P. Sidhu, Jon Lorenz, Larry Nummy, Denis Byrne, Bo
Qu, Yibo Xu, Ling Wu, Heewon Lee, Frank Roschangar, Jinhua J. Song, and Chris H. Senanayake
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00399 • Publication Date (Web): 22 Jan 2019
Downloaded from http://pubs.acs.org on January 23, 2019
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 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 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.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Development of Large Scale Asymmetric Process
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 tert-Butanesulfinamide
Philomen DeCroos, Zhengxu S. Han*, Kanwar Sidhu, Jon Lorenz, Larry Nummy, Denis Byrne,
Bo Qu, Yibo Xu, Ling Wu, Heewon Lee, Frank Roschangar, Jinhua J. Song, Chris H.
Senanayake*
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road,
Ridgefield, Connecticut 06877, USA
ACS Paragon Plus Environment
1

Organic Process Research & Development
Page 2 of 22
1
2
3
4
Table of Contents
5
6
7
8
9
CH3
O
S
Cl
Ts
LHMDS, THF, -10 oC
N
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NH2
O
S
. Large scale process for TBSA
. Milder reaction conditions
. Avoids use of NH3 /LiNH2
(S)-TBSA
O
toluene
-15 oC
t-BuMgCl/THF
.
Reusable template
CH3
CH3
SOCl2/pyridine
Cl
Ts
Cl
Ts
O
N
N
S
H
THF, -10 oC to -15 oC
OH
O
ACS Paragon Plus Environment
2

Page 3 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
KEYWORDS: chiral sulfinamide, large scale, S-N and S-O bond strength, lithium amide
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
ABSTRACT: Process development for a scalable and green synthesis of chiral tert-
butanesulfinamide (TBSA) on multi kilogram scale is reported. The process is based on the
identification of a chiral sulfinyl transfer agent benzo[1,3]oxathiozin-2-one that contains active
and differentiated S-N and S-O bonds, which allows the synthesis to proceed under mild reaction
conditions. This method is practical and overcomes the disadvantages of earlier methods
deploying harsh reaction conditions and hazardous and toxic reagents.
ACS Paragon Plus Environment
3

Organic Process Research & Development
Page 4 of 22
1
2
3
4
INTRODUCTION
5
6
7
8
Chiral sulfinamides are becoming powerful auxiliaries for the synthesis of chiral amines,
which are of great interest to both academic and industry.1-3 Sulfinamides have also found use as
chiral ligands for catalytic asymmetric transformations.4-6 It has become evident that bulky alkyl-
or arylsulfinamides provide higher stereoselectivities, such as Ellman’s tert-butanesulfinamide
(1a, TBSA)2a or Han-Senanayake’s triisopropylbenzenesulfinamide (1b, TIPPSA, Scheme 1).7
TBSA, in particular, is frequently used in the production of drug substance on large scale and
additional method for its production could enhance availability (Scheme 2).8 Therefore, a
practical and cost-effective process for the synthesis of hindered sulfinamides is highly desirable.
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
O
O
S
NH2
S
NH2
1b
1a
, (S)-TIPPSA
, (S)-TBSA
O
S
O
O
S
[H+]
S
NH2.HCl
[H]
or R3M
O
NH
R2
N
NH2
R
R
R
R2
R3
R1
R1
R2
R1
R1
R2
R3
Scheme 1: General synthesis of chiral amines from chiral sulfinamides
Synthesis of bulky sulfinamides in an economical way remains a challenge. The available
methods for the synthesis of TBSA include Ellman’s approach using chiral sulfinothioate 3
prepared from di-tert-butyldisulfide 2,9a,b and our method by using sulfinate 6 derived from
chiral 1,2-aminoalcohol 59c,d (Scheme 2). Our initial attempt to synthesize TBSA using Ellman’s
method encountered the release of toxic and foul-smelling gas tert-butylthiol 4. The byproduct 4
must be controlled before releasing to the environment (eq (a), Scheme 2).9f To provide an
alternative route to 1, we designed our first generation chiral sulfinyl transfer reagent 6 that was
ACS Paragon Plus Environment
4

Page 5 of 22
Organic Process Research & Development
1
2
3
4
5
6
applied in the synthesis of TBSA on kilogram scale successfully (eq (b), Scheme 2). This method
avoids the release of toxic gas and template 5 can be recycled.
7
8
9
Further scale-up investigation showed that both methods (eqs (a) and (b), Scheme 2) share one
common drawback in the synthesis of TBSA, which is the use of excess of LiNH2/NH3 (NH3/Li)
as a strong nucleophile in order to overcome the steric barriers in the cleavage of either S-S bond
or S-O bond. The NH2Li/NH3 needs to be freshly prepared in situ by portion-wise addition of a
large excess of lithium metal to anhydrous NH3 used as solvent at a reaction temperature of −78
°C.9 In the preparation of LiNH2 on large scale, a very thick slurry was formed which causes
serious agitation problems and potential safety concerns.10 Furthermore, reaction work up is by
slow evaporation of NH3 until the reactor temperature reached from −78 °C to about room
temperature. The NH3 could also be trapped to another reactor at < −40 °C or by water. The
quenching of the reaction with solid NH4Cl is very exothermic and has to be added very slowly.
Due to these drawbacks associated with the described procedure, the production of TBSA
presents safety issues on large scale. The safe handling of the reaction and the treatment of the
waste in an environmentally friendly manner are also concerns.
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
5

Organic Process Research & Development
Page 6 of 22
1
2
3
4
5
6
7
8
O
H2O2/acetone
THF/-78 oC
crys, 75%
S
SH
S
(a)
S
+
S
VO(acate)2 (cat)
Shiff base (cat)
20 h, 0 oC
2
3
)
(Ellman
4
98%, 86% ee
O
S
9
Li (metal)
NH3
(anhydrous
liquid)
[NH2Li/NH3]
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
NH2
Fe(NO3)3.9H2O (cat)
-78 oC to -45 oC
1a,
(S)-TBSA
O
S
O
NHTs
THF/-78 oC, 90%
Ph
CH3
7
THF/-45 oC
t-BuMgCl
(b)
>99% de
O
S
SOCl2/THF
HO
Py, -45 oC
Ph
O
NTs
NHTs
CH3
Ph
CH3
5
6
95%, 99% de
Scheme 2: Comparison of the two methods for the synthesis of chiral tert-butanesulfinamide
Our ultimate goal is to develop a process for the production of TBSA in a more practical and
economic means by overcoming the above mentioned obstacles. The key elements to consider
are avoiding low temperature reaction conditions and to replace NH2Li/NH3 with a milder
nucleophile, such as lithium bis(trimethylsilyl)amide (LHMDS) that is an equivalent of “NH2”
functionality.11 To achieve this, a new template with sulfinates containing an active S-O bond is
needed, which can be cleaved by LHMDS. We, therefore, designed the second generation chiral
template 8 that is based on a phenol backbone, from which optically pure chiral sulfinyl transfer
agent benzo[1,3]oxathiozin-2-one 9 can be prepared effectively (Scheme 3).12 Intermediate 9
contains S-N and S-O bonds with differentiated reactivity, so that tert-BuMgCl addition can
selectively cleave the weaker S-N bond to afford the chiral sulfinate 10 in 90% yield and >99:1
dr. Subsequent treatment of 10 with LHMDS cleaves the following S-O bond to afford the
desired (S)-TBSA in 85% yield and >99:1 er based on 100 g scale. The template 8 can be
ACS Paragon Plus Environment
6

Page 7 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
recycled in excellent yield and can be used in the next cycle.12 Most importantly, the entire
process is performed under mild reaction conditions. In the following we describe the technical
details in the process development for large scale production of TBSA.
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
CH3
LHMDS
O
S
Cl
Ts
THF/-10 oC
N
H
O
S
NH2
1a
, (S)-TBSA
10
O
toluene
-15 oC
t-BuMgCl/THF
CH3
CH3
Cl
Ts
SOCl2/Py
Cl
Ts
O
N
H
OH
N
S
THF, -10 oC to -15 oC
O
8
9
Scheme 3: New method for the synthesis of TBSA under mild reaction conditions
Process Development
Production of chiral benzo[1,3]oxathiozin-2-one 9. Our first task was to develop a scalable
process for the synthesis of 9 in good yield and high stereoselectivity, and to identify a reaction
media for 9 that can facilitate the following tert-butylmagnesium chloride (t-BuMgCl) reaction
in the synthesis of 10 without isolation of 9. The established procedure11 was first investigated
on scale, in which 8 was treated with 1.3 equiv of thionyl chloride (SOCl2) and 2.7 equiv of
o
pyridine at 25 C in THF, and the reaction afforded 9 in 98:2 dr and >95% yield. Upon
completion, the reaction mixture was diluted with EtOAc and sodium bicarbonate (NaHCO3)
aqueous solution was added to quench the reaction. It turned out that this protocol suffers from a
few issues. First, the quenching process is exothermic and produces large amount of gases from
the reaction of NaHCO3 with the excess SOCl2. Second, the pH of the quenched mixture is about
6 and pyridine could not be efficiently removed from the organic phase with aqueous wash. The
ACS Paragon Plus Environment
7

Organic Process Research & Development
Page 8 of 22
1
2
3
4
5
6
7
8
9
presence of pyridine reduces the efficiency of product recovery. Third, concentration of the
resulting organic phase by azeotrope distillation at 40 oC under vacuum to remove residue water
causes 5-10% racemization of the title compound 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
Further optimization of reaction conditions led to the reduction of the stoichiometries of SOCl2
and pyridine to 1.02 equiv and 2.3 equiv, respectively. The reaction was also conducted at milder
o
o
temperature of 10 C to 15 C by slow addition of pyridine in 1 h to afford the product in a
similar diastereoselectivity and yield. Under this condition, the reaction could be quenched with
water instead of NaHCO3. The resulting mixture has a pH of 3 to 4, which facilitates pyridine
removal from the organic phase. The following organic phase concentration by distillation
avoided the racemization of 9, but decomposition of 9 to 8 occurred in this process. This issue
was then solved by introducing 5% of sodium hydrogen phosphate (Na2HPO4) aqueous wash
followed by another water wash, which gave a final pH of about 7. Under this condition, both the
hydrolysis and racemization of 9 were found minimal during the distillation process.
Evaluation of solvent effect on the overall process found that toluene as co-solvent benefits the
efficiency of solvent switching and the removing of water in the organic phase during the
azeotrope distillation process. The selectivity and yield are not affected in the presence of
toluene. Moreover, toluene can be used as solvent of 9 for next step reaction. Therefore, the
optimal process was conducted by addition of SOCl2 in toluene solution to a mixture of 8 in THF
o
o
o
and pyridine at 10 C to 15 C. Upon work-up, the organic phase was distilled around 20 C
under vacuum to reach a KF below 0.03% affording a stable solution of 9 in a toluene solution.
Three batches were carried out and the reactions in the synthesis of 9 gave a yield of up to 94%
and 97.6:2.4 dr (Table 1).
Table 1: Scale up results in the production 9 and 10
ACS Paragon Plus Environment
8

Page 9 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Batch Scale of 8
#
Yield of 9 in
Yield of 10b (dr)
isolated quantity
87.0% (98.97:1.03)
12.73 kg
Purity of 10 Yield in 2 steps
toluenea (dr)
1
15.0 kg
15.0 kg
16.5 kg
73.9%c (97.5:2.5)
99.7A%
99.7A%
99.8A%
64.3%
81.3%
75.1%
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
2
3
94.0% (97.5:2.5)
87.9% (97.6:2.4)
86.5% (98.39:1.61)
16.1 kg
85.4% (98.8:1.2)
16.35 kg
a Assay yield based on HPLC analysis of product in toluene solution. b isolated yield based on
c
the reaction from 9 to 10. Lower yield resulted from the first trial with low pH of quenched
reaction mixture
Ring opening reaction for the synthesis of chiral sulfinate 10. Studies showed that the
optimal temperature for the reaction of t-BuMgCl with 9 in toluene is around 15 °C. Initially,
the reaction was performed by slow addition of 1.1 equiv of 1.0 M t-BuMgCl in THF to a
toluene solution of 9. The reaction completed within 10-20 min after addition as monitored by
HPLC analysis. But compound 8 was found in the reaction mixture in more than 6%, which was
resulted from the further addition of the extra Grignard to the product 10 by cleaving the S-O
bond. To minimize this side reaction, the end point of Grignard addition was, therefore,
determined by applying in situ React-IR to monitor the reaction.13a This monitoring method was
found successful by avoiding overcharge of the Grignard reagents. The required amount of
Grignard reagents is only 1.05 equiv, with which a clean reaction was observed with minimal
formation of starting template 8.
The quenching of the reaction is also important for a successful process. When NaHCO3
solution was used to quench the reaction; it resulted in the deposition of a large mass of
magnesium salts that cannot be conveniently filtered. Use of 50% aqueous ammonium acetate
ACS Paragon Plus Environment
9

Organic Process Research & Development
Page 10 of 22
1
2
3
4
5
6
7
8
9
was briefly evaluated; however, the pH of the quenched mixture remained at about pH 10, which
caused a significantly racemization of 10 to form the undesired diastereomers of 10’ (Figure 1) at
up to 18%. In order to control the pH to neutral, large amount of ammonium acetate solution was
required, which significantly decreased batch volume efficiency. Alternatively, quenching with
20% of citric acid was found to provide clean phase separation, and the optimal condition was
identified using 0.4 equiv of citric acid to achieve a final pH of around 6. Then the organic phase
was washed with 5% of Na2HPO4 solution to reach the final pH to neutral, which suppressed the
racemization and hydrolysis of the title product 10.
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
CH3
Cl
Ts
N
H
O
S
O
10'
Figure 1: Structure of undesired diastereomer 10’
Product 10 is a crystalline solid and isolation by crystallization was attempted. Heptane was
found the optimal anti-solvent for the recrystallization. Therefore, the THF was first distilled off
at about 40 °C to 45 °C, and the residual water was also removed under azeotrope. The
crystallization of 10 in toluene was first generated by stirring the mixture for 2 h to form a slurry.
To increase the yield, heptane was added. The crystallization was completed by first stirring the
mixture at about 40 °C for 2 h, then cooled to 10 °C to 15 °C, and agitated for 2 h. Product 10
was collected as a white solid in 85% average yield from the Grignard reaction and up to 99: 1
dr, and >99% purity based on the results of the three executed batches (Table 1). The overall
yield for the two-step reaction in the synthesis of 10 from 8 was also listed in Table 1.
Synthesis and isolation of TBSA and recovery of the template 8 (Scheme 4)
ACS Paragon Plus Environment
10

Page 11 of 22
Organic Process Research & Development
1
2
3
4
5
6
CH3
O
CH3
Cl
Ts
1) LiHMDS/THF
N
H
S
Cl
Ts
-10 oC
NH2
N
H
+
O
S
7
8
9
2) Water
OH
1a
, (S)-TBSA
O
8
10
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) water
2) distillation
3) H3PO4 solution
(pH 7-8)
CH3
Cl
Ts
O
O
N
1) extract w/ MeOAc
S
H
S
NH2
NH2
OH
2) switch to heptane
cryst.
8
8
(crude solid)
61%
96% ee
(combined)
(S)-TBSA in water
91-94% assay yield
91-98% ee
from toluene
recryst.,80%
Batch Scale of 10
Weight of
(S)-TBSA
(S)-TBSA
Yield (er)
#
(S)-TBSA aq solution assay Wt.% assay weight
1
14.50 kg
61.90 kg
60.40 kg
76.35 kg
6.21 %
6.27 %
5.38 %
3.84 kg
3.79 kg
4.11 kg
93.9% (98.8:1.2)
94.3 (95.5:4.5)
91.1% (95.6:4.4)
2
14.24 kg
3
16.00 kg
Scheme 4: Synthesis of (S)-TBSA and recovery of template 8
The synthesis of (S)-TBSA, its isolation, and the recovery of the template 8 is shown in
Scheme 4. In contrast to earlier methods, the reaction of 10 with LHMDS was performed under
mild conditions at ‒10 °C in THF. The reaction completed in 20-30 min after addition of
LHDMS due to the active S-O bond of 10. The reaction could be quenched by addition of water
while keeping the internal temperature around ‒5 °C to give a reaction mixture of (S)-TBSA and
the template 8.13b Initial solubility study found that both compounds are soluble to some degree
in most of organic solvents, and use of organic solvents cannot separate them efficiently. It
turned out that (S)-TBSA has good solubility in water, but 8 is not.13c For better separation, both
THF and trimethylsilanol formed from LHDMS need to be removed by distillation and it was
ACS Paragon Plus Environment
11

Organic Process Research & Development
Page 12 of 22
1
2
3
4
5
6
7
8
9
achieved at about 55 °C at 10-20 mmHg vacuums. The optimal crystallization condition was
then found by adjusting the pH of the mixture at 7 to 8 by adding 25% phosphoric acid at about
10 °C, from which crude 8 was crystallized out as a nice slurry and collected by filtration. (S)-
TBSA was collected as an aqueous solution in the filtrate in 91% to 94% assay yield and 91% to
98% ee (Scheme 4).
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)-TBSA is very soluble in water and its recovery from aqueous solution was investigated.
Initially, dichloromethane (DCM) was used as the extraction solvent. The aqueous phase was
saturated with NaCl for efficient extraction. The recovery yield is about 75% after four
extractions with equal volume of DCM to aqueous solution. Methyl acetate (MeOAc), however,
was found as more efficient extraction solvent, and four extractions yielded a >98% recovery
yield. For large scale production, this was accomplished by continuous extraction. The extracts
was then distilled and switched to heptane, and (S)-TBSA was crystallized out from heptane.
The above three batches of (S)-TBSA in aqueous solution was combined and partial of it was
extracted with MeOAc to give 137 kg extracts with 6.0 wt% of (S)-TBSA (8.21 kg in 93% ee).13d
After switching the solvent to heptane, (S)-TBSA was isolated by crystallization in 61.4% yield
(5.04 kg based on assayed amount of TBSA in MeOAc) and 96.2% ee.12 One more
recrystallization from MTBE/heptane (5.04 kg) furnishes (S)-TBSA (4.24 kg) in 84% yield and
99.2% ee.13d
The recovery of the template is straightforward. Crude 8 was first dissolved in THF and
filtered to remove the inorganic salts followed by switching the solvent to toluene. The desired
template 8 was recrystallized from toluene in more than 80% recovery yield and 99% ee, which
was successfully used in the next cycle for the production of TBSA.
Conclusion
ACS Paragon Plus Environment
12

Page 13 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
We have successfully developed a practical, safe and environmentally friendly process for the
synthesis of enantiomerically pure tert-butanesulfinamide on 15 kg scale of chiral template 8.
The three-step process was conducted under mild reaction conditions in the pilot plant. Chiral
TBSA was provided in about 40% overall yield and 99% ee starting from 8. The modest overall
yield is affected by the isolation of enantiomerically pure TBSA from MeOAc extract and the
recrystallization, which is under further optimization. The template was recovered in 80% yield.
The process employs environmentally friendly raw materials and eliminates the use of hazardous
or toxic chemicals, such as liquid ammonia and lithium metal. The process is also performed
under milder temperature. The current process generates about 187 kg waste/kg TBSA or 22.7 kg
waste/mole of TBSA (cEF value).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental
Synthesis of (2S,4R)-6-chloro-4-methyl-3-tosyl-3,4-dihydrobenzo[e][1,2,3]-oxathiazine 2-
oxide 9. To a jacket reactor equipped with a nitrogen inlet and temperature probe was charged 8
(15.0 kg, 46.0 mol) under nitrogen followed by anhydrous THF (26.67 kg) and stirred to get a
homogeneous solution. Pyridine (8.57 kg, 108.34 mol, 2.35 equiv) was added in one portion.
After the solution was cooled to 10 °C to 15 °C, SOCl2 (5.80 kg, 48.76 mol, 1.05 equiv) in
toluene (54 kg ) was added over 1 h while keeping the internal temperature below 10 °C. The
reaction mixture was stirred at 10 °C to 15 °C for 30 min to complete the reaction. Water (30
kg) was added slowly while keeping the internal temperature around 0 °C. After phase
separation, the aqueous layer was removed and the organic phase was washed with 5% sodium
hydrogen phosphate (30 kg) followed by water (30 kg). The organic phase was concentrated by
distillation under vacuum to get about 60.9 kg of product in toluene with a KF of 0.03%. The
ACS Paragon Plus Environment
13

Organic Process Research & Development
Page 14 of 22
1
2
3
4
5
6
7
8
9
content was assayed by HPLC analysis to give 16.08 kg of product in 94% yield and 97.5:2.5 dr.
The mixture was then stored at 0 °C to 5 °C and used directly for next step reaction (product may
precipitate out during storage).
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
Synthesis
of
4-chloro-2-((S)-1-((4-methylphenyl)sulfonamido)ethyl)phenyl
(S)-2-
methylpropane-2-sulfinate 10. To the slurry of 9 (16.08 kg, 43.24 mol) in toluene from last
step was added THF (20.8 kg), stirred to get a homogenous solution at ambient temperature. The
mixture was cooled to ‒10 °C to ‒15 °C and t-BuMgCl (45.98 kg, 45.40 mol, 1.05 equiv) was
added over 1.5 h while maintaining the internal temperature below ‒10 °C and stirred for 10-20
min to complete the reaction as monitored by in-situ React-IR. Toluene (13.5 kg) was added
followed by 10% of aqueous citric acid solution (43.0 kg) over 30 min maintaining the internal
o
temperature below ‒5 C and then warmed to ambient temperature after addition. The phases
were separated and the aqueous phase was removed. After washing with 5% of Na2HPO4
solution (33 kg) and water (32 kg), the organic phase was distilled under vacuum (10 to 20 mm
Hg) until the internal temperature reached to about 40 °C to 45 °C to leave about 40 L of residue
and stirred for 2 h to form a slurry. Heptane (13 kg) was added over 30 min and stirred for 2 h at
about 40 °C. The mixture was cooled to 10 °C to 15 °C and stirred for 2 h and filtered. The wet
cake was washed with toluene/heptane mixture (1:1, v/v) (13 kg) and dried to give the desired
product 10 (16.10 kg) in 86.5% yield and 98.4:1.6 dr.
Synthesis of (S)-tert-butanesulfinamide (S)-TBSA. To a THF solution of LHMDS solution
(55.10 kg, 1.3 M in THF, 77.56 mol, 2.30 equiv) at ‒10 °C was added 10 (14.5 kg, 33.72 mol) in
THF (25.7 kg) slowly maintaining the internal temperature below ‒5 °C and stirred for 20 to 30
o
min to complete the reaction. Water (14.5 kg) was added at around ‒5 C and then the reaction
mixture was warmed to 20 °C to 30 °C. The content was distilled under vacuum (10-20 mm Hg)
ACS Paragon Plus Environment
14

Page 15 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
until the internal temperature reached to about 55 °C to about 40 L left. Cooled the mixture to
around 10 °C and 25% of phosphoric acid solution (4.35 kg) was added over 30 min. The
mixture was warmed to 30 °C to 35 °C and stirred 2 h to form a slurry. Cooled the mixture to 20
°C and added 25 % of phosphoric acid solution (6.7 kg) until the pH of the solution was 7-8.
The mixture was stirred 2 to 3 h and filtered and the wet cake was washed with water (14.5 kg)
to give 61.9 kg of filtrate with 3.84 kg (6.21 wt%) of crude (S)-TBSA in 93.9% yield and
98.8:1.2 er. The wet cake was dried at 55 °C under vacuum to give 13.9 kg of crude 8 that was
saved for later recovery process.
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
Recovery of (S)-TBSA from aqueous solution. An aqueous solution of (S)-TBSA (140 kg from
combined three batches with 8.38 kg of (S)-TBSA based on assay (some aqueous solution was
used for process development) was added 35 kg of NaCl and dissolved followed by extraction
with methyl acetate (about 130 kg) to yield a solution of (S)-TBSA in methyl acetate (137 kg
with about 8.21 kg of (S)-TBSA based on assay in 98% recovery yield and 93 % ee (Note: one
batch of TBSA has low ee, which is produced during the process study). The content was
distilled at about 60 °C to leave about 22 L of residue. Heptane (50 kg) was added and the
mixture was continuously distilled until the internal temperature reached to about 85 °C to 90 °C
to reach a volume of about 35 L. The mixture was cooled to 40 °C and stirred 2 h to form a
slurry, and then cooled to 10 °C and stirred for 2 h. The slurry was filtered and the wet cake was
dried at 30 °C under vacuum to give the product (6.57 kg crude with 5.04 kg of pure (S)-TBSA
based on assay)14 in 61.4% yield and 96.2 % ee (in one particular trial run, the ee of the resulting
TBSA was only 93%. Normally, the process would provide >95% ee of (S)-TBSA and one
crystallization is enough to get the product in >99% ee).
ACS Paragon Plus Environment
15

Organic Process Research & Development
Page 16 of 22
1
2
3
4
5
6
7
8
9
Recrystallization of (S)-TBSA if the optical purity is less than 99% ee. A reactor was charged
(S)-TBSA (6.57 kg, 76.7wt%, 96% ee) and MTBE (24.31 kg) and the mixture was stirred at 35-
45 °C to dissolve the product. Cooled the mixture to room temperature and the content was
filtered and washed with MTBE (2 kg). The filtrate was concentrated to about 20 L and 8.51 kg
of heptane was added while maintaining the internal temperature above 50 °C. The mixture was
seeded with (S)-TBSA in >99% ee and cooled the content to 40 °C around 10 min and stirred at
40 °C for 2 h. The mixture was cooled to 10 °C, stirred for 1 h and filtered. The wet cake was
washed with cooled heptane and dried at 30 °C to 35 °C overnight under vacuum to give (S)-
TBSA as a white solid (4.26 kg) in 84.5% yield and 99.7% ee.
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
Recovery of template 8. To the crude template 8 (15.8 kg, 73.6%) was charged THF (25.84 kg)
and stirred at 20 °C to 30 °C for about 30 min. The slurry was filtered and the cake was washed
with THF (14.54 kg). The filtrate was distilled to about 26 L and toluene (41.87 kg) was added.
The mixture was further distilled at about 60 °C to about 33 L and cooled to around 50 °C. The
product was allowed to crystallize over 1 to 2 h. Cooled the slurry to 20 °C over 2 h and filtered
and the wet cake was washed with toluene (60 mL) and dried at 60 °C for over 3 h under vacuum
to give 8 (9.1 kg) in 78% recovery yield.
Supporting Information: Analytics for reaction monitoring and the analysis of enantiomeric
purity.
Corresponding Authors: email: steve.han@boehringer-ingelheim.com
Notes:
Vendor’s information for supplying of 8: Astatach (Chengdu) BioPhatmaceutical Corp.; 488
West Kelin Rdoad, Wenjiang Dist., Chengdu, Sichuan, 611130, P. R. China
Phone: +86-28-82666873; Fax: +86-28-82666739; Emai: sales@astatech.com.cn
ACS Paragon Plus Environment
16

Page 17 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
REFERENCES
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. a) Senanayake, C. H.; Han, Z.; Krishnamurthy, D. in “Organosulfur Chemistry in Asymmetric
Synthesis”, 2008, (Eds. T. Toru, C. Bolm) Wiley-VCH: Weinheim, p 234; b) Senanayake, C.
H.; Krishnamurthy, D.; Lu, Z.-H.; Han, Z. ; Gallou, I. Enantiopure Sulfoxides and Sulfinamides:
Recent Developments in Their Stereoselective Synthesis of Applications to Asymmetric
Synthesis, Aldrichim Acta, 2005, 38, 93-104; c) Han, Z.; Reeves, D. C.; Krishnamurthy, D.;
Senanayake, C.H. in Comprehensive Chirality (Eds. E.M. Carreira, H. Yamamoto), 2012, 3, 560-
-600, Amsterdam Elsevier.
2. a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Synthesis and Applications of tert-
Butanesulfinamide, Chem. Rev. 2010, 110, 3600-3740.; b) Kimmel, K. L.; Weaver, J. D.; Lee,
M.; Ellman, J. A. Catalytic Enantioselective Protonation of Nitronates Utilizing an
Organocatalyst Chiral Only at Sulfur, J. Am. Chem. Soc. 2012, 134, 9058-9061.
3. a) Zhou, P.; Chen, B.-C.; Davis, F. A. Recent Advances in Asymmetric Reactions Using
Sulfinimines (N-Sulfinyl Imines), Tetrahedron, 2004, 60, 8003-8030; b) Davis, F. A.; Friedman,
A. J.; Kluger, E. W. Chemistry of the Sulfur-nitrogen Bond. VIII. N-Alkylidenesulfinamides, J.
Am. Chem. Soc. 1974, 96, 5000-5001.
4. Zhu, T.-S.; Jin, S.-S.; Xu, M.-H. Rhodium-Catalyzed, Highly Enantioselective 1,2-Addition of
Aryl Boronic Acids to α-Ketoesters and α-Diketones Using Simple, Chiral Sulfur-Olefin
Ligands, Angew. Chem. Int. Ed. 2011, 50, 780-783.
ACS Paragon Plus Environment
17

Organic Process Research & Development
Page 18 of 22
1
2
3
4
5
6
7
8
9
5. Wang, Y.; Feng, X.; Du, H. Kinetic Resolution of Hindered Morita-Baylis-Hillman Adducts
by Rh(I)-Catalyzed Asymmetric 1,4-Addition/β-Hydroxyelimination, Org. Lett. 2011, 13, 4954-
4957.
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. Cogan, D. A.; Liu, G.; Ellman, J. A. Asymmetric Synthesis of Chiral Amines by Highly
Diastereoselective 1,2-Additions of Organometallic Reagents to N-tert-Butanesulfinyl Imines,
Tetrahedron 1999, 55, 8883-8904.
7. a) Han, Z.; Krishnamurthy, D.; Grover, P.; Fan, K. Q; Plum, D.; Senanayake, C. H. Effective
Tuning of the Arene and Alkanesulfinamides for Highly Enantioselective Synthesis of (S)-4-
Chlorophenylphenylmethylamine, A Key Intermediate for Antihistamic (S)-Cetirizine,
Tetrahedron Lett, 2003, 44, 4195-4197; b) Han, Z.; Busch, R.; Fandrick, K. R.; Meyer, A.; Xu,
Y.; Krishnamurthy, D. K.; Senanayake, C. H. Asymmetric Synthesis of Diverse α, α-
Diarylmethylamines
via
Aryl
Grignard
Additions
to
Chiral
N-2,4,6-
Triisopropylbenzenesulfinylimines, Tetrahedron 2011, 67, 7035-7041; c) Reeves, J.; Tan, Z;
Herbage, A. M; Han, Z.; Marsini, A. M; Li, Z; Li, G; Xu, Y; Fandrick, R. K; Gonnella, N.; Scot,
C.; Ma, S.; Grinberg, N.; Lee, H.; Lu, B.; Senanayake, C. H. Carbamoyl Anion Addition to N-
Sulfinyl Imines: Highly Diastereoselective Synthesis of ɑ-Amino Amides, J. Am. Chem. Soc.
2013, 135, 5565-5568; d) Kong, J.-R.; Cho, C.-W.; Krische, M. J. Hydrogen-Mediated
Reductive Coupling of Conjugated Alkynes with Ethyl (N-Sulfinyl) iminoacetates: Synthesis of
Unnatural α-Amino Acids via Rhodium-Catalyzed C-C Bond Forming Hydrogenation, J. Am.
Chem. Soc. 2005, 127, 11269-11270; e) Kimmel, K. L.; Robak, A. T.; Ellman, J. A.
Enantioselective Addition of Thioacetic Acid to Nitroalkenes via N-Sulfinyl Urea
Organocatalysis, J. Am. Chem. Soc. 2009, 131, 8754-8755; f) Davis, F. A.; Song, M.; Qiu, H.;
ACS Paragon Plus Environment
18

Page 19 of 22
Organic Process Research & Development
1
2
3
4
5
6
Chai, J. Total Synthesis of (5R,6R,8R,9S)-(-)-5,9-Z-Indolizidine 221T Using Sulfinimine-
Derived N-Sulfinyl β–Amino Ketones, Org. Biomol. Chem. 2009, 7, 5067-5073.
7
8
9
8. a) Thaisrivongs, D. A.; Naber, J. R.; Rogus, N. J.; Spencer, G. Development of and
Organometallic Flow Chemistry Reaction at Pilot-Plant Scale for the Manufacture of
Verubecestat, Org. Process Res. Dev. 2018, 22, 403-408; b) Zhang, W.-Y.; Hogan, P. C.; Chen,
C.-L.; Niu, J.; Wang, Z.; Lafrance, D.; Gilicky, O.; Dunwoody, N.; Ronn, M. Process Research
and Development of an Enantiomerically Enriched Allylic Amine, One of the Key Intermediates
for the Manufacture of Synthetic Tetracyclines, Org. Process Res. Dev. 2015, 19, 1784-1795; c)
Han, Z.; Koenig, S. G.; Zhao, H.; Su, X.; Singh, S. P.; Bakale, R. P. Development of a large-
Scale Stereoselective Process for (1R,4S)-4-(3.4-Dichlorophenyl)-1,2,3,4-tetrahydroanphthalen-
1-amine Hydrochloride, Org. Process. Res. Dev. 2007, 11, 726-730; d) for recycling of TBSA:
Wakayama, M.; Ellman, J. A. Recycling of tert-Butanesulfinyl Group in the Synthesis of Amines
Using tert-Butanefinamide, J. Org. Chem. 2009, 74, 2646-2650.
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
9. a) Weix, D. J.; Ellman, J. A. Improved Synthesis of tert-Butanesulfinamide Suitable for
Large-Scale Production, Org. Lett. 2003, 5, 1317-1320; b) Liu, G. Liu.; Cogan, D. A.; Ellman,
J.A. Catalytic Asymmetric Synthesis of tert-Butanesulfinamide: Application to the Asymmetric
Synthesis of Amines, J. Am. Chem. Soc. 1997, 119, 9913-9914; c) Cogan, D. A.; Liu, G.; Kim,
K.; Backes, B. J.; Ellman, J. A. Catalytic Asymmetric Oxidation of tert-Butyl Disulfide.
Synthesis of tert-Butanesulfinamides, tert-Butyl Sulfoxides, and tert-Butanesulfinimines, J. Am.
Chem. Soc. 1998, 120, 8011-8019; d) Han, Z.; Krishmurthy, D.; Grover, P.; Fang, Q. K.;
Senanayake, C. H. Properly Designed Modular Asymmetric Synthesis of Enantiopure
Sulfinamides Auxiliaries from N-Sulfonyl-1,2,3-oxathiazolidine-2-oxide Agents, J. Am. Chem.
Soc. 2002, 124, 7880-7881; e) Han, Z.; Krishmurthy, D.; Grover, P.; Fnag, Q. K.; Su, X.;
ACS Paragon Plus Environment
19

Organic Process Research & Development
Page 20 of 22
1
2
3
4
5
6
7
8
9
Wilkinson, H. S.; Lu,, Z. H.; Magiera, D.; Senanayake, C. H. Practical and Highly
Stereoselective Technology for Preparation of Enantiopure Sulfoxides and Sulfinamides
Utilizing Activated and Functionally Differentiated N-Sulfonyl-1,2,3-oxathiazolidine-2-oxide
Derivatives, Tetrahedron, 2005, 61, 6386-6408; f) Capture and Removal of tert-Butylthiol was
Reported, Weix, D. J.; Ellman, J. A. (R)-(+)-2-Methyl-2-propanesulfinamide, Org. Synth. 2005,
82, 157-165.
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
10. The synthesis of NH2Li on large scale is a very tedious process that needs a long time to
condense the ammonia under low temperature. The following addition of lithium metal is
operated by slowly addition to avoid the reaction mixture heating up. The initiation for the
formation of NH2Li under Fe(NO3)3 catalyst is not consistent depending on the dryness of the
ammonia solvent because ammonia tents to absorb moisture easily. With continuous addition of
lithium, a very think slurry would suddenly form and lead to difficult agitation.
11. A similar strategy was report by Chelouan, A.; Recio, R.; Alcudia, A.; Khiar, N.; Fernandez,
I. DMPA-Catalysed Sulfinylation of Diacetone-D-Glucose: Improved Method for the Synthesis
of Enantiopure tert-Butyl Sulfoxides and tert-Butanesulfinamides, Eur. J. Org. Chem. 2014, 31,
6935-6944.
12. a) Han, S. Z.; Herbage, M. A.; Mangunuru, H. P. R.; Xu, Y.; Zhang, Li.; Reeves, J. T.;
Sieber, J. D.; Li, Z.; Decroos, P.; Zhang, Y.; Li, G.; L, N.; Ma, S.; Gringerg, N.; Wang, X.;
Goyak, N.; Krishnamurthy, D.; Lu, B. L.; Wang, G.; Senanayake, C. H. Design and Synthesis of
Chiral Oxathiozinone Scaffolds: Efficient Synthesis of Hindered Enantiopure Sulfinamides and
Sulfinyl Ketimines, Angew. Chem. Int. Ed. 2013, 52, 6713–6717; b) Both enantiomers are
ACS Paragon Plus Environment
20

Page 21 of 22
Organic Process Research & Development
1
2
3
4
commercially available and 8 is also available on large scale from the vendor and the process is
5
6
to be published in due course (see note for vendor’s information).
7
8
9
13. a) Refer Figure S3 for React-IR time-course spectrum; b) Refer Supporting Information for
the calorimetry of the process progress. c) The solubility study was performed by dissolving a
mixture of template 8 and TBSA in different solvents and then monitoring the content of them in
the solution; d) Refer experimental procedures for detailed operation.
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. The crude TBSA contains some NaCl which resulted from the carry-over water from the
aqueous extraction with MeOAc.
ACS Paragon Plus Environment
21

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