Nucleophilic Aromatic Substitutions of 2-Halo-5-(sulfamoyl)benzoic Acids and N, O-Bis-alkylation via Phase Transfer Catalysis: Synthesis of RoRγInverse Agonist GSK2981278A

Article abstract of DOI:10.1021/acs.oprd.9b00147

GSK2981278A (1) is a RORγinverse agonist used as a potential topical nonsteroidal therapy for psoriasis. New synthesis of 1 was developed based on a S_NAr reaction of (tetrahydro-2H-pyran-4-yl)methanol with an aryl halide intermediate, prepared from 2-halobenzoic acids. The dianion underwent in situ N,O-bis-isobutylation, followed by a reduction to provide 1. The new route eliminated a genotoxic tosylate of (tetrahydro-2H-pyran-4-yl)methanol and a difficult reductive amination from the original synthesis starting from methyl salicylate. A primary version of the route has been scaled up to deliver 125 kg of 1. However, the heating of a strong base in DMSO for an extended period during the bis-alkylation was found to be a safety concern for manufacturing. A safer and greener process was then developed utilizing a facile N,O-bis-alkylation, which was conducted under phase transfer conditions with mild bases such as potassium carbonate and in green solvents such as water. The concise four stage sequence from 2-halobenzoic acids to GSK2981278A (1) had an overall yield of 41%.

Full text of DOI:10.1021/acs.oprd.9b00147

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Full Paper
Nucleophilic Aromatic Substitutions of 2-Halo-5-(sulfamoyl)benzoic
Acids and N,O-Bis-alkylation via Phase Transfer Catalysis:
Synthesis of RoR# Inverse Agonist GSK2981278A
Gregg A. Barcan, Jose J Conde, Mohamed K Mokhallalati, Mark G. Nilson, Shiping Xie, C. Liana
Allen, Yemane W. Andemichael, Nicholas A. Calandra, David C. Leitch, Ling Li, and Michael J. Morris
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00147 • Publication Date (Web): 03 Jun 2019
Downloaded from http://pubs.acs.org on June 3, 2019
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Nucleophilic Aromatic Substitutions of 2-Halo-5-
(sulfamoyl)benzoic Acids and N,O-Bis-alkylation via
Phase Transfer Catalysis: Synthesis of RoR Inverse
Agonist GSK2981278A
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Gregg A. Barcan,† Jose J. Conde,† Mohamed K. Mokhallalati,† Mark G. Nilson,† Shiping Xie,†,*
C. Liana Allen,‡ Yemane W. Andemichael,† Nicholas A. Calandra,§ David C. Leitch,|| Ling Li,†
and Michael, J. Morris†
†Product Development and Supply, GlaxoSmithKline, 1250 South Collegeville Road,
Collegeville, Pennsylvania 19426, United States.
‡Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210.
§H3 Biomedicine, 300 Technology Square, Cambridge, Massachusetts 02139.
||University of Victoria, P.O. Box 3065, Victoria, British Columbia, Canada V8W 3V6.
shiping.x.xie@gsk.com
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Table of Contents (TOC) graphic:
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O
OH
HO
O
OH
OH
O
O
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X
O
O
O
O
O
Br
S
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O
O
O
S
Red-Al
79%
HN
HN
O
S
S
O
base
SNAr
N
N
O
O
K2CO3, water or MeCN
phase transfer catalysis
N,O-bisisobutylation
92%
O
O
O
86%
for X = F
X = Br, Cl and F
from 2-halobenzoic acid
65% for X = F
GSK2981278A (1)
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ABSTRACT
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O
OH
HO
O
OH
OH
O
O
X
O
O
O
O
O
Br
S
O
O
O
S
Red-Al
79%
HN
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HN
O
S
S
O
base
SNAr
N
N
O
O
K2CO3, water or MeCN
phase transfer catalysis
N,O-bisisobutylation
92%
O
O
O
86%
for X = F
X = Br, Cl and F
from 2-halobenzoic acid
65% for X = F
GSK2981278A (1)
GSK2981278A (1) is a ROR inverse agonist as a potential topical non-steroidal therapy for
psoriasis. New synthesis of 1 was developed based on a SNAr reaction of (tetrahydro-2H-pyran-4-
yl)methanol with an aryl halide intermediate, prepared from 2-halobenzoic acids. The dianion
underwent in situ N,O-bis-isobutylated, followed by a reduction to provide 1. The new route
eliminated a genotoxic tosylate of (tetrahydro-2H-pyran-4-yl)methanol and a difficult reductive
amination from the original synthesis starting from methyl salicylate. A primary version of the
route has been scaled up to deliver 125 kg of 1. However, the heating of a strong base in DMSO
for an extended period during the bis-alkylation was found to be a safety concern for
manufacturing. A safer and greener process was then developed utilizing a facile N,O-bis-
alkylation, which was conducted under phase transfer conditions with mild bases such as
potassium carbonate and in green solvents such as water. The concise four stage sequence from 2-
halobenzoic acids to GSK2981278A (1) had an overall yield of 41%.
Key words: ROR SNAr, N,O-bisalkylations, phase transfer catalysis.
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Introduction
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Psoriasis vulgaris is a chronic autoimmune inflammatory skin condition resulting from an
interaction of genetic, environmental and systemic factors and it affects 2–3% of the Caucasian
population.1 IL-17-targeting biologics have been successful in reducing the disease burden of
psoriasis patients with moderate-to-severe disease.2,3 Unfortunately, the stratum corneum prevents
penetration of proteins with large molecule weights, including monoclonal antibodies. For most of
psoriasis patients ineligible for systemic treatments, a small molecule targeting RORγ, the master
regulator of IL-17 family cytokines, may represent an alternative topical medicine with biologic-
like efficacy.4 GSK2981278A (1), shown in Figure 1, is a potent ROR inverse agonist. The
program required a very large quantity of the drug substance to support development of a topical
formulation and clinical studies. The synthetic target can be viewed as 2-(hydroxymethyl)phenol
(salicylic alcohol), with the phenol capped as the (tetrahydro-2H-pyran-4-yl)methyl ether and the
para position functionalized as the sulfonamide with 4-ethyl-N-isobutylaniline.
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OH
O
O
S
N
O
O
1
GSK2981278A ( )
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Figure 1. Structure of ROR inverse agonist GSK2981278A (1).
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The original synthesis of 1 is shown in Scheme 1. The synthesis started with the p-
chlorosulfonylation of methyl salicylate to give aryl sulfonyl chloride 2, which reacted with 4-
ethyl-N-isobutylaniline 3 to provide sulfonamide 4. Alkylation of the phenol with tosylate 5,
derived from (tetrahydro-2H-pyran-4-yl)methyl alcohol, led to ether 6. Finally, reduction of the
methyl ester followed by recrystallization gave 1. While the overall yield of the synthesis was high,
chromatography had to be employed at the end of the synthesis in the delivery of 25 kg of 1 to
remove an amine impurity derived from the reductive amination of butyraldehyde and 4-
ethylaniline in the preparation of the 4-ethyl-N-isobutylaniline 3. The reductive amination could
not be cleaned up readily on scale, so the crude product in ~80% assayed yield was used directly.
Additionally, compounds 2 and 5 were Ames positive and were subject to strict control in the
analytical release of the drug substance based on the predicted treatment dose and duration.
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Scheme 1. Original Synthesis of GSK2981278A (1)
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HO
4
5
6
O
O
+
NH2
TsCl, TEA, DCM
94%
7
8
9
H2, 30-40 MPa
Pd/C
i-PrOH,toluene
80% assayed yield
TsO
O
O
OH
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O
O
NH
O
O
O
SOCl2, ClSO3H,
DCM
O
5
OH
S
3
N
OH
O
O
Ames positive
S
pyridine, DCM
85%
85%
K2CO3, DMF
88%
Cl
O
2
methyl salicylate
Ames positive
4
OH
O
O
O
O
O
O
1. Dibal-H, THF
93%
S
S
O
N
N
O
2. recrystallization
EtOAc, heptane
3. silica gel purification
O
O
~80%
1
GSK2981278A ( )
6
Two new routes to 1 were explored as shown in Figure 2. The first approach would need the
selective mono -hydroxymethylation via a phenol formaldehyde reaction. The phenol substrate
would be prepared from commercially available sodium 4-hydroxybenzenesulfonate or the less
stable 4-hydroxybenzenesulfonyl chloride. The other approach would introduce the (tetrahydro-
2H-pyran-4-yl)methyl ether via a nucleophilic aromatic substitution (SNAr) on an aryl halide.
Palladium catalyzed C-O bond formation would be another possibility for this substrate. 2-
Halobenzoic acids are readily available for this approach.
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R3O
O
OH
X
5
6
7
8
O
S
R1
O
S
R1
N
O
R2
O
N
HO
R2
-hydroxymethylation via
phenol formaldehyde reactions
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SNAr or Pd catalyzed ether
formation with (tetrahydro-2H-
pyran-4-yl)methyl alcohol
O
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O
S
O
N
O
1
GSK2981278A ( )
Figure 2. New approaches to 1 based on phenol formaldehyde reactions or SNAr reactions.
We herein report our findings in the execution of the new synthetic strategies, which led to a
significantly improved synthesis. Over 125 kg of 1 was delivered with the new route utilizing the
efficient SNAr reactions of 2-halo-5-(sulfamoyl)benzoic acids. The synthesis was further
optimized with the principles of process safety and green chemistry to provide an even more
practical solution with phase transfer catalysis to enable a N,O-bis-alkylation under very mild
conditions.
Results and Discussion
To avoid the byproduct formations and the conditions under high pressure in the preparation of
4-ethyl-N-isobutylaniline (3) from isobutyraldehyde and 4-ethylaniline, we sought alternative
approach shown in Scheme 2. Reductive amination with borane pyridine complex was reported to
be generally very rapid.5 Over alkylation to 7 occurred to some degree. Fortunately, amine 7 was
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not reactive for the next step, so the crude product containing up to 8% of 7 could be used without
chromatographic purification. Transfer hydrogenation worked well to avoid the use of hydrogen.6
Free base 3 was converted to the HCl salt 3a as a solid for higher purity and easier handling. To
solve the problem of over-alkylation, a borrowing hydrogen approach was tested with isobutyl
alcohol and 4-ethylaniline.7 Under the condition shown with 2.5 mol% of the Ru catalyst, the
reaction was clean without over-alkylation to tertiary amine 7, but conversion was only 60%.
Addition of extra catalyst or longer heating time was able to achieve higher conversion of 80%,
albeit with a less clean reaction profile. Ultimately, the optimization was not carried out for the
borrowing hydrogen method.
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Scheme 2. Preparation of 4-Ethyl-N-isobutylaniline 3 by Reductive Amination with
Isobutyraldehyde and Borrowing Hydrogen Methodology with Isobutyl Alcohol
BH3.pyridine (0.8 equiv)
EtOH, 0 oC to rt, 2 h
or Pd/C (2.5 mol%)
N
O
HCO2NH4 (6 equiv), rt, 2 h
N
+
NH2
+
H
3:
free base (crude ~90%)
3a:
HCl
HCl salt (crystallized)
7
76% from 4-ethylaniline
Ru[(p-cymene)Cl2]2 (2.5 mol%)
dppf (5 mol%)
HO
NH2
+
3
toluene, 110 oC, 22 h
60-80% conversion
The -hydroxymethylation of a phenol via Friedel-Crafts reaction (Figure 2) was very attractive
to us as it would only take three steps from the readily available 4-hydroxybenzenesulfonyl
chloride to obtain target 1. The synthesis of salicylic alcohol templates from a phenol via this
approach is reported.8 Our result from this effort is shown in Scheme 3. Sulfonamide 8 was
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prepared from amine 3 and 4-hydroxybenzenesulfonyl chloride prepared in situ from the reaction
of the sodium salt precursor and SOCl2 with a catalytic amount of DMF. Caution is warranted due
to the potential formation of carcinogenic N,N-dimethyl carbamoyl chloride (DMCC) from the use
of DMF with SOCl2.9 Reaction of 8 with paraformaldehyde, catalyzed by sodium metaborate,
provided an 8:1 mixture of the desired mono-hydroxymethylated product 9 and the bis-
hydroxymethylated side product 10 in only 46% conversion. Optimization for higher conversion
led to even more of 10 from the bis-hydroxymethylation. Alternatively, phenol 8 was reacted with
tosylate 5 in 85% yield to give ether 11. Hydroxymethylation of 11 did not proceed to yield product
1.
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Scheme 3. -Hydroxymethylation Approach via Friedel-Crafts Reactions
OH
OH
OH
OH
paraformaldehyde (6 equiv)
1. SOCl2 (6 equiv)
DMF (0.1 equiv)
70 oC, 5 h
OH
OH
O
OH
S
O
O
O
NaBO2·4H2O (8 equiv)
N
S
S
O
+
N
N
3
2. , pyridine (6 equiv),
O
O
S
water (15 vol)
80 oC, 42 h
NaO
DCM, rt
60%
O
46% conversion
8
10
9
OTs
9 10
/
= 8 : 1
O
(1 equiv)
5
K2CO3 (1.7 equiv)
2-Me-THF, 80 oC, 10 h
86%
O
O
S
O
paraformaldehyde (6 equiv)
NaBO2·4H2O (8 equiv)
N
O
1
water (15 vol), 80 o
C
11
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We next explored the SNAr approach shown in Figure 2 to install the ether moiety through
reaction of an aryl halide with (tetrahydro-2H-pyran-4-yl)methanol as the nucleophile.10
Genotoxic tosylate 5, utilized in the original synthesis, should be avoided. The aryl sulfonyl
chlorides 12a-c are commercially available in small quantities, and they could be readily prepared
from the corresponding 2-halobenzoic acids and chlorosulfonic acid.11
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The sulfonamide formation between 4-ethyl-N-isobutylaniline 3 or its HCl salt 3a and 5-
(chlorosulfonyl)-2-halobenzoic acids 12a-c proved more challenging than anticipated as shown in
Scheme 4. In addition to the desired sulfonamide 13a-c, the reaction yielded amide byproducts 14
and 15 in significant quantities, requiring careful purifications. These byproducts likely derived
from mixed anhydrides formed from the starting carboxylic acid and sulfonyl chloride in 12. The
mixed anhydrides reacted with the amine 3 to generate 14 and 15. Significant efforts including use
of Design of Experiments (DOE) tool were not able to minimize the formation of 14 and 15 to a
level suitable for isolation by crystallization on scale. Bases such as pyridine, ethyl nicotinate and
sodium bicarbonate favored the generation of the desired sulfonamide 13, while tertiary amine
bases such as triethylamine and Hünig’s base led to mostly the byproducts. The SNAr reactions of
13a-c with (tetrahydro-2H-pyran-4-yl)methanol with potassium t-pentoxide were clean. The ether
product was converted to 1 by ester formation (MeOH and HCl) and reduction of the methyl ester
by LiBH4 as shown in Scheme 4. However, the difficulty in preparation and purification of 13a-c
led us to pursue an alternative sequence shown in Scheme 5. It is worth mentioning that the
chloride 13b was also successful for use in coupling with (tetrahydro-2H-pyran-4-yl)methanol
through Pd-catalyzed ether formation, as an alternative to the SNAr reaction.
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Scheme 4. Unexpected Byproduct Formation in Preparation of Arylsulfonamide 13a-c
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N
HO
O
O
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X
X
HO
O
NH
.HCl
O
O
N
O
pyridine (4-6 equiv)
X
S
S
N
N
+
+
+
O
O
O
X
2-MeTHF (10 vol)
rt, 18 h
S
O
Cl
O
S
HO
O
60-80%
12a
12b
12c
, X = Br
, X = Cl
, X = F
3a
14a
14b
14c
, X = Br
, X = Cl
, X = F
15a
15b
15c
, X = Br
, X = Cl
, X = F
13a
13b
13c
, X = Br
, X = Cl
, X = F
~2%
(~8%)
1. KOt-Pent (2.5 equiv)
toluene or DMSO, 90 oC, 20 h
OH
O
(1.1 equiv)
2. MeOH, HCl
3. LiBH4, THF
1
GSK2981278A ( )
We were interested in compounds such as 16 shown in Scheme 5 as a substrate for the SNAr
reaction. Several potential benefits were envisioned with this sequence: elimination of the need for
reductive amination to prepare secondary amine 3, sulfonamide formation with less basic 4-
ethylaniline to avoid the formation of the corresponding byproducts similar to 14 and 15, and one-
pot preparation of 18 by sequential ether formation to 17 via the SNAr reaction and in situ N,O-
bis-isobutylation of the dianion of 17. The new route turned out to be successful with all three
compounds 13a-c, and all the anticipated benefits were realized. The sequence starting with 2-
fluorobenzoic acid shown in Scheme 5 was selected for successful scale up to deliver >125 kg of
GSK2981278A (1). This decision was made before a much milder process for the bis-alkylation
via phase transfer catalysis was developed and became available, due to the urgent need of a large
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quantity of drug substance 1 to support the program. Aryl fluoride 16c was preferred because of
the slightly lower temperature and shorter reaction time required relative to the bromide 16a and
chloride 16b for the SNAr reactions.
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Scheme 5. Synthesis of 1 on Scale and with Conditions and Yields Shown for the Fluoro
Series
HO
O
NH2
X
HO
O
OH
(1.05 equiv)
HO
O
O
O
X
(1.03 equiv)
NaHCO3 (2.2 equiv)
ClSO3H (4 equiv)
S
HN
X
O
O
LiOtBu (4 equiv)
DMSO (10 vol)
71 °C, 24 h
S
MTBE (7 vol), 40 °C
24 h; aq. HCl
88%
74%
by assay analysis
Cl
O
X = Br, Cl or F
12a
12b
12c
, X =Br
, X =Cl
, X =F
66 kg scale
65 kg scale
16a
16b
16c
, X =Br
, X =Cl
, X =F
HO
O
O
O
O
Br
O
S
O
HN
O
Red-Al (1.2 equiv)
(4 equiv)
O
S
1
GSK2981278A ( )
O
N
toluene (4 vol)
0-25 °C, 4 h
79%
71 °C, 24 h
57-71%
O
O
100 kg scale
17
used in situ as a dianion
18
silica gel treatment and
recrystallization required
5-(Chlorosulfonyl)-2-fluorobenzoic acid 12c was commercially available but the relatively low
stability and the high cost made it more practical to prepare from 2-fluorobenzoic acid for the large
campaign to supply >100 kg of 1. The solution of crude 12c in MTBE was used directly in the
amide formation with 4-ethylaniline to form sulfonamide 16c in 88% yield. As expected, the
reaction with 4-ethylaniline was cleaner than the analogous reaction with 4-ethyl-N-isobutylaniline
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3. The ether 17 was successfully installed via the key SNAr reaction of the aryl fluoride 16c with
the lithium salt of (tetrahydro-2H-pyran-4-yl)methanol. However, DMSO and elevated
temperature (>90 °C) had to be used in the presence of a large amount (4 equiv) of a strong base
to achieve a clean and complete SNAr reaction for yields ranging 90-95%. The strong condition
was needed likely due to decreased activity of the Ar-X, as a dianion derived from 17 by the
deprotonation, towards the SNAr reaction. This step was telescoped with a double N-, O-alkylation
with isobutyl bromide to provide ester 18, which was isolated by filtration after addition of water
to the reaction mixture. Process safety test showed that the combination of DMSO and lithium t-
butoxide was a significant safety risk at 90 °C for an extended period. Thus, only up to 71 °C was
allowed for this reaction in the scaleup in the plant as shown in Scheme 5. This led to incomplete
reaction and byproduct formation derived from the degradation during the long heating including
formation of methylpropene. Rework of intermediate 18 by treatment with silica gel, followed by
recrystallization, was needed. This ultimately led to lower yield of 18 in the scaleup (57-71% for
the three runs in the plant). Ester 18 was readily reduced with Red-Al (sodium bis(2-
methoxyethoxy)aluminum hydride) to give the API GSK2981278A (1) in 79% yield. The Red-Al
was much more economical and practical than the Dibal-H in the original reduction of the same
substrate. The overall yield for the sequence shown in Scheme 5 was 29-37%. This route was
short but the safety concern of heating lithium t-butoxide and DMSO over a prolonged period
prevented us from designating this route as the manufacturing route. The degradation of isobutyl
bromide in the heated t-butoxide was also a major concern.
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To reduce the amount of time DMSO was exposed to a strong base with heating (up to two days
from 16 to 18, see Scheme 5), we divided the one-pot process from 16 to 18 into two discreet
stages, with isolation of 17 as shown in Scheme 6. This would be followed by bis-isobutylation
in another solvent such as THF and MeCN, safer than an aprotic polar solvent like DMSO in the
presence of a strong base.12
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The SNAr process on 16, as shown in Scheme 6, provided 17 smoothly as a crystalline solid in
81% and 86% yield, resepctively from 16b and 16c. Aryl fluoride 16c was again preferred for the
process to provide 17 as an isolated intermediate at 75 oC. Analogous chemistry with aryl chloride
16b required 90 oC and 14 hours longer. The safety issue of heating DMSO in the presence of a
strong base is well known.13 Use of the lowest temperature and heating time is warranted, when a
strong base cannot be avoided as in our SNAr reactions. For the subsequent bis-alkylation, contrary
to our expectation, we found that there was no product observed even with 8 equivalents of isobutyl
bromide and 3 equivalents of lithium t-butoxide in 2-MeTHF or MeCN. It appeared that the
dianion from reaction of a strong base and 17 precipitated out unless an aprotic polar solvent like
DMSO or DMF was used. This likely inhibited the alkylations in solvents other than DMSO and
DMF.
Scheme 6. Two-stage Approach from 16 to 18 with 17 Isolated
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O
OH
O
OH
O
O
O
X
OH
Br
O
O
O
O
(8 equiv)
S
S
HN
(1.1 equiv)
LiOt-Bu (3 equiv), 90 oC, 4 h
HN
O
O
O
O
S
16b
16c
: KOt-Pent (3.2 equiv)
2-Me-THF, 90 oC, 17 h
81%
N
O
2-MeTHF or MeCN
O
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: KOt-Bu (3.5 equiv)
DMSO, 75 oC, 3 h
86%
17
16b
16c
, X = Cl
, X = F
18
not observed
It was postulated that a phase transfer catalysis (PTC) would be suitable for alkylation or bis-
alkylation of the dianion of 17.14 As a proof of concept (Scheme 7), 17 was dissolved in THF (15
vol) and treated with a stoichiometric amount of tetrabutylammonium bromide (TBAB) and
isobutyl bromide (6 equiv) in two reactions with K2CO3 and KOH, respectively. Gratifyingly, the
bis-isobutylated product 18 was detected by HPLC after just 30 min at ambient temperature. The
reaction with K2CO3 was complete and very clean after 10 h at 70 oC, while the reaction with KOH
afforded 45% of the targeted N,O-bis-isobutylation product 18, along with 55% of the N-isobutyl
product 19 (Scheme 7). The mono-alkylated product in aqueous KOH was probably caused by the
competitive ester hydrolysis. While KOH may have been adopted with optimization of the aqueous
pH in the manner described by King and co-authors,15 we chose K2CO3 for the next phase of
optimization. In contrast, there was no alkylated product in the absence of TBAB. In a test run
with 0.4 equivalent of TBAB and 50 wt% aqueous K2CO3 (2 vol) in 2-MeTHF (9 vol) at 70 oC,
product 18 was isolated in 88% yield without chromatography as shown in Scheme 7. The mild
conditions contrasted with the harsh and failed conditions in Schemes 5 and 6 for the bis-alkylation
with lithium t-butoxide at up to 90 oC.
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Scheme 7. Proof of Concept for Green N,O-Bis-isobutylation of 17 by Phase Transfer
5
6
Catalysis (PTC)
7
8
9
O
OH
O
OH
O
O
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Br
O
O
O
O
n-Bu4NBr (0 to 1 equiv)
O
O
S
O
HN
S
+
S
N
N
O
K2CO3 or KOH
O
O
O
O
water and organic solvent
70 o
C
no reaction without TBAB;
18
17
19
18
isolated in 88% yield with TBAB
without chromatography.
observed when
aq. KOH used
A solvent screening was then carried out with K2CO3 as the base as shown by the area under
curve (AUC%) of product 18 in Figure 3. With a 9:1 v/v mixture of an organic solvent and water,
the reaction was fastest with THF and MIBK, but slower in toluene. All reactions reached
completion after just 22 h. Screening on single solvents was then carried out as shown on the
bottom chart of Figure 3 All reactions were clean with the reaction in MeCN slightly faster than
the three other solvents. The reaction in water was worked up by acidification and direct filtration
to give 18 as a crystalline solid of 100% purity. No product was detected in the aqueous mother
liquor by HPLC analysis, indicating a clean reaction and excellent recovery with water as the
solvent.
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N,O-bis-isobutylation of 17 to prepare 18
in mixed solvents
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9
120
100
80
60
40
20
0
Toluene-water
2-MeTHF-water
MIBK-water
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THF-water
40 min
14 h
22 h
Reaction time
N,O-bis-isobutylation of 17 to prepare 18
in single solvents
120
100
80
60
40
20
0
Water
MeCN
MIBK
THF
20 min
15 h
Reaction time
Figure 3. Solvent screening for PTC: TBAB (0.2 equiv), i-BuBr (4 equiv), K2CO3 (4 equiv), 70
oC. Top chart: mixed organic solvents and water. Bottom chart: single solvents.
In the scaleup with water as a single solvent, it was noted that isobutyl bromide (bp 90-92 oC)
was partially lost to evaporation due to its high volatility. The poor immiscibility with water was
another factor, leaving isobutyl bromide on top of the reaction mixture when not well agitated.
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This led to incomplete reaction, unless a closed system was used as in the screening in tubes
equipped with a screw cap. It was predicted that MeCN as the single solvent should not have this
issue as MeCN is fully miscible with isobutyl bromide. This proved to be the case as shown in
Figure 4. The reaction kinetics in MeCN were compared for two reactions: one in a round bottle
flask connected to a nitrogen line and the other in a sealed tube. Clearly the sealed reaction was
faster at the 4th hour. After 17 h, both reactions reached completion and was very clean as shown
by the amount of product 18 by HPLC.
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Open reaction
Sealed reaction
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0
i-BuBr (4 equiv)
n-Bu4NBr (0.2 equiv)
17
18
K2CO3 (4 equiv)
MeCN (11 vol)
70 oC, 17 h
92% isolated
yield from the
"open" reaction
"open" vs. sealed reactions
15 min
4 h
16 h
Reaction time
Figure 4. N,O-Bis-isobutylation of 17 to 18, sealed tube vs. flask “open” to nitrogen line.
The conditions shown in Figure 4 were run in 2 g scale in a regular round bottle flask (10 vol of
MeCN, 70 oC, 15 h) to provide 92% isolated yield of product 18 in 100% purity by HPLC, avoiding
the need of silica gel chromatographic purification in the previous bis-alkylation with lithium t-
butoxide in DMSO as shown in Scheme 5. The workup consisted of a simple addition of water to
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dissolve K2CO3 for discharge as a concentrated homogeneous aqueous solution in the bottom
layer. The top MeCN layer was partially concentrated to provide crystalline 18 for direct filtration.
For water to be the single solvent for the bis-isobutylation, a closed vessel had to be used and the
isolated yield of 18 was 87% without optimization.
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The PTC reaction worked equally well for the related 2-halo-5-(sulfamoyl)benzoic substrates
16b and 16c, indicating some substrate scope for the PTC catalyzed N, O-bis-alkylation.
Intermediate 18 from the safe PTC process was converted to GSK2981278A (1) under the
same reduction conditions with Red-Al as shown in Scheme 5. Although the PTC process has not
been scaled up in the plant, it has demonstrated consistency from milligram scale in screening in
tubes to gram scale in flasks for both reaction profile and purity of isolated product. Ultimately,
we expect to use water as the solvent on scale for this reaction with easier containment of the
volatile i-BuBr in a plant setting and truly achieve “green” status for the alkylation. This route was
expected to be designated as the manufacturing route for the much safer and cleaner N,O-bis-
isobutylation. The overall yield from 2-fluorobenzoic acid was 41% (65% for
sulfonylation/sulfonamidation from 2-F-PhCO2H to 16, 86% for SNAr from 16 to 17, 92% for the
PTC bis-alkylation from 17 to 18, and 79% for reduction of 18 to 1). Despite being one stage
longer for the isolation of 17, the overall yield for the new route including the PTC bis-alkylation
was higher than the 29-37% yield for the 3-stage sequence shown in Scheme 5, which required
lengthy heating of lithium t-butoxide in DMSO and purification with silica gel and
recrystallization.
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Conclusion
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8
GSK2981278A (1) was synthesized in four stages by the new route starting from 2-halobenzoic
acids in ~41% overall yield. The high efficiency was attributed to the well-chosen nucleophile (4-
ethylaniline) for the formation of the 2-halo-5-(sulfamoyl)benzoic acids, the dianions of which
were excellent substrates for SNAr reactions with (tetrahydro-2H-pyran-4-yl)methanol. Mild and
efficient N,O-bis-isobutylation via phase transfer catalysis was successfully developed for the N,O-
bis-alkylations of the SNAr products. Compared to the original synthesis starting from methyl
salicylate, the new synthesis eliminated a reductive amination for amine 3, a genotoxic tosylate
intermediate (5) and chromatographic purifications. A version of the new route has been utilized
to deliver >125 kg of GSK2981278A (1) in the plant, with one example of the SNAr reactions
scaled up to 60-70 kg three times. The facile SNAr reactions and the mild N,O-bis-alkylations
should find applications in a wider scope of substrates.
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Experimental Section
General Procedures. All reactions were run under nitrogen. Unless otherwise specified,
concentration by rotary evaporation or distillation was carried out under house vacuum of 12-50
torr. Melting points were measured in Mettler Toledo MP 90 Melting Point System at 3 °C/min
ramp, and the results were not corrected. All NMR spectra were acquired at ambient temperature
on a Bruker 400 MHz spectrometer. Solvents and frequencies for specific data acquisitions are
noted for each case in the following sections. Chemical shifts were calibrated relative to residual
protio solvent (1H and 13C). Data were processed using ACD Spectrus. HPLC analysis was
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performed on Agilent 1260 or 1290 series instruments with diode array detectors, though analysis
was typically done with traces from a single wavelength. Two HPLC methods were utilized during
this work: Method A: Column: Zorbax SB-C18, 1.8 μm, 3 mm x 50 mm; column temperature: 60
°C; flow rate: 1.5 mL/min; solvent gradient: ACN (0.05% TFA v/v) / H2O (0.05% TFA v/v), from
100/0 to 5/95 over 2.7 min; detection wavelength: 220 nm. Method B: Column: Phenomenex Luna
C18(2), 3.0 μm, 5 mm x 20 mm; column temperature: 40 °C; flow rate: 1.0 mL/min; solvent
gradient: ACN (0.05% TFA v/v) / H2O (0.05% TFA v/v), from 100/0 to 5/95 over 8 min; detection
wavelength: 220 nm. HRMS (m/z) was measured using an Exactive Plus (Thermo) orbitrap mass
spectrometer equipped with a heated electrospray ionization (HESI) ion source.
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4-Ethyl-N-isobutylaniline and the Hydrochloride Salt (3/3a). A. Through Reductive
Amination of Isobutyraldehyde with Borane Pyridine Complex. To a 500 mL flask was added
12.0 g (99 mmol) of 4-ethylaniline and 10.7 g (149 mmol) of isobutyraldehyde. The mixture was
stirred for 10 min with visible solids from the formation of the imine, followed by addition of 60
mL of EtOH. The mixture was cooled to 20 oC, and 7.36 g (79.2 mmol) of pyridine borane complex
was added over about 10 min. At the end of the addition, generic HPLC Method A showed 94%
of product 3a at retention time of 1.9 min and 1.9% of the over-alkylated 7 at retention time of 2.4
min. However, the amounts of 3 and 7 changed to 88% and 8%, respectively after stirring for 2 h
at ambient temperature. The reaction was quenched with 40 mL of water, treated with 20 mL of 1
N HCl and stirred for 10 min.16 The mixture was extracted with 100 mL of DCM, and the organic
layer was successively washed with 50 mL each of 0.5 N HCl, saturated NaHCO3 and 25 wt%
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NaCl, dried over anhydrous Na2SO4 and evaporated to 18.7 g of crude 3, which was used directly
for the next step as a free base or further purified as the HCl salt 3a as shown in method B below.
B. Through Reductive Amination of Isobutyraldehyde by Transfer Hydrogenation. To a 500
mL 3-neck flask fitted with a magnetic stir bar and an immersion thermometer was charged 180
mL of isopropanol, followed by 20 mL of water. The flask was sealed except for the middle neck
and flushed through with nitrogen for 5 min. To the mixture was added 8.78 g (4.15 mmol) of 5
wt% Pd/C, followed by portion-wise addition of 62.4 g (990 mmol) of ammonium formate. After
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o
being cooled to 16 C, the mixture was treated with 20.5 mL (165 mmol) of 4-ethylaniline,
followed by 19.6 mL (215 mmol) of isobutyraldehyde in one portion. The flask was sealed under
nitrogen and stirred at ambient temperature for 1.5 h, at that point the reaction was deemed
complete by complete consumption of the starting aniline by HPLC Method A (1.52 min). The
reaction was filtered over Celite, and the flask was successively rinsed with 40 mL of toluene, 40
mL of water and 360 mL of toluene until no product was observed in the effluent by HPLC Method
A (2.01 min). The biphasic solution was transferred to a separatory funnel and washed with 2 x
200 mL of water. The layers were split, and the organic layer was washed with 2x70 mL of
saturated brine, dried over anhydrous MgSO4, filtered and concentrated on a rotovap to give free
base 3 as an oil.
An anhydrous solution of HCl in EtOAc was prepared by addition of 14.1 mL (198 mmol) of
acetyl chloride to 10.0 mL (248 mmol) of methanol in 110 mL of ethyl acetate. The free base 3
prepared above was dissolved in 70 mL of EtOAc, followed by the slow addition of the above
anhydrous HCl solution. The reaction darkened immediately, and a white precipitate formed about
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half way through the addition. Addition of 50 mL of MeOH and heating to near reflux dissolved
the solids. After being cooled to ambient temperature, the mixture was seeded with granules of 4-
ethyl-N-isobutylaniline hydrochloride (3a). Crystallization was so rapid that 50 mL of 1:1 solution
of EtOAc and heptane was added to aid the stirring. After being cooled to 0 oC, the mixture was
treated with 30 mL of heptane, filtered, washed with 100 mL of 1:1 EtOAc-heptane and dried at
40 ˚C to give 26.83 g (76%) of the title compound 3a as an off-white solid: mp. 147.9 oC. 1H NMR
(400 MHz, CDCl3): δ 11.2 (br s, 2 H), 7.52 (d, J = 7.5 Hz, 2 H), 7.18 (d, J = 7.7 Hz, 2 H), 3.05 (d,
J = 7.1 Hz, 2 H), 2.62 (q, J = 7.6 Hz, 2 H), 2.12 (dquin, J = 13.5, 6.8 Hz, 1 H), 1.20 (t, J = 7.6 Hz,
3 H) 1.02 (d, J = 6.9 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ 145.4, 133.4, 129.2, 123.4, 60.4,
28.5, 25.3, 20.4, 15.4. HRMS (ESI) m/z calcd for C12H20N (MH+ for free base 3) 178.1590, found
178.1589.
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C. Through Amination of Isobutyl Alcohol by Hydrogen Borrowing Method. To a 50 mL tube
was successively added 253 mg (0.413 mmol) of [Ru(p-cymene)Cl2]2, 457 mg (0.825 mmol) of
dppf, 2.06 ml (16.5 mmol) of 4-ethylaniline, 3.06 ml (33.0 mmol) of isobutyl alcohol, and 16.5
o
mL of degassed toluene. The mixture was stirred under nitrogen at 110 C for 22 h. After being
cooled to ambient temperature, the reaction was analyzed by generic HPLC Method A which
showed 60% conversion based on the ratio of 3 (2.01 min) to 4-ethylaniline (1.52 min). Additional
126 mg (0.206 mmol) of the [Ru(p-cymene)Cl2]2 and 230 mg (0.415 mmol) of dppf was added
and the reaction was stirred under nitrogen for additional 22 h at 110 oC. The reaction was cooled
and sampled for analysis by generic HPLC Method A, which showed 80% conversion. This
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reaction was run as a part of the screening of conditions for the hydrogen borrowing reaction and
it was not worked up for product isolation.
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(Tetrahydro-2H-pyran-4-yl)methyl 4-Methylbenzenesulfonate (5). To a 500 mL flask was
added 14.0 g (121 mmol) of (tetrahydro-2H-pyran-4-yl)methanol, 112 mL of DCM and 25.2 mL
(181 mmol) of triethylamine, followed by 29.9 g (157 mmol) of p-toluenesulfonyl chloride at room
temperature. The reaction was slightly exothermic. After being stirred for 20 h at room
temperature, the mixture was cooled with an ice batch and quenched with 120 mL of water. The
layers were split, and the aqueous layer was back extracted with 50 mL of DCM. The combined
organic layer was successively washed with 120 mL of water and 125 mL of 13 wt% NaCl and
evaporated to 120 mL. Crystallization was occurred during the evaporation, and 40 mL of heptane
was added for further crystallization. The mixture was cooled for 1 h, filtered, washed with 3x10
mL of heptane and dried at 60 oC to give 26.9 g (83 %) of 5 as a white crystalline solid: mp. 99.8
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oC. H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 7.7 Hz, 2 H), 7.26 (d, J = 7.7 Hz, 2 H), 6.74 (m, 4
H), 3.78 (m, 2 H), 3.76 (d, J = 6.4 Hz, 2 H), 3.23 (td, J = 11.9, 2.2 Hz, 2 H), 2.35 (s, 3 H), 1.83 (m,
1 H), 1.48 (m, 2 H), 1.17 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ 144.9, 132.9, 129.9, 127.8,
74.2, 67.1, 34.6, 28.9, 21.6. HRMS (ESI) m/z calcd for C13H19O4S (MH+) 271.0999, found
271.0997.
N-(4-Ethylphenyl)-4-hydroxy-N-isobutylbenzenesulfonamide (8). To a 100 mL flask was
added 9.80 g (45.8 mmol) of 4-hydroxybenzenesulfonic acid sodium salt hydrate and 0.35 ml (4.58
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mixture was heated to 60-70 C and stirred for 5 h. Excess thionyl chloride was removed by
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evaporation under vacuum (~15 torr) at 45 oC to produce a gel-like residue. After addition of 50
mL of toluene, the mixture was further evaporated under vacuum at 50 oC, followed by addition
of 40 mL of DCM. Further evaporation gave a yellow oil, which was diluted with 30 mL of DCM
to make a white slurry for direct use in the next step as 4-hydroxybenzenesulfonyl chloride.
To a 500 mL flask was successively added 9.91 g (50.3 mmol) of crude 3, 30 mL of DCM and
21.7 g (275 mmol) of pyridine. After being stirred for 2 min at room temperature, 4-
hydroxybenzenesulfonyl chloride in DCM as prepared above was added. The mixture was stirred
for 30 min, cooled with an ice batch and quenched with 50 mL of 1 N HCl. The layers were split,
and the DCM layer was successively washed with 50 mL of 1 N HCl and 50 mL saturated NaHCO3
and 25 wt% NaCl, dried over anhydrous Na2SO4 and evaporated to give an oil. Crystallization was
achieved by slow addition of about 30 mL each of DCM and heptane over 3 h and stirring
overnight. The mixture was filtered, and the cake was washed with 3x5 mL of 3:1 heptane/DCM
and dried at 65 oC to give 9.10 g (60 %) of 8 as a white crystalline solid: mp. 142.3 oC. 1H NMR
(400 MHz, CDCl3): δ 7.27 (d, J = 8.0 Hz, 2 H), 6.96 (d, J = 7.2 Hz, 2 H), 6.74 (m, 4 H), 3.10 (d, J
= 7.3 Hz, 2 H), 2.47 (q, J = 7.6 Hz, 2 H), 1.39 (m, 1 H), 1.07 (t, J = 7.7 Hz, 3 H) 0.74 (d, J = 6.9
Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ 159.9, 144.1, 136.7, 129.9, 129.4, 128.5, 128.4, 115.6,
58.0, 28.4, 26.7, 19.9, 15.3. HRMS (ESI) m/z calcd for C18H24NO3S (MH+) 334.1468, found
334.1468.
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N-(4-Ethylphenyl)-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
(11): To a 100 mL flask was successively added 2.00 g (6.00 mmol) of phenol 8, 1.62 g (6.00
mmol) of tosylate 5, 16.0 mL of DMF and 1.33 g (9.60 mmol) of potassium carbonate. The mixture
was heated at 100 oC for 18 h. After being cooled to room temperature, the reaction was quenched
with 28 mL of water. The resultant white solids were filtered, washed with 3x10 mL of water and
dried at 70 oC to give 2.22 g (86%) of 11 as an off-white crystalline solid: mp. 146.4 oC. 1H NMR
(400 MHz, CDCl3): δ 7.48 (d, J = 8.0 Hz, 2 H), 7.11 (m, 2 H), 6.92 (m, 4 H), 4.03 (dd, J = 11.3,
3.2 Hz, 2 H), 3.84 (d, J = 6.4 Hz, 2 H), 3.45 (td, J = 11.8, 2.1 Hz, 2 H), 3.25 (d, J = 7.3 Hz, 2 H),
2.63 (q, J = 7.6 Hz, 2 H), 2.08 (m, 1 H), 1.76 (br dd, J = 13.0, 2.0 Hz, 2 H), 1.51 (m, 3 H), 1.22 (t,
J = 7.7 Hz, 3 H), 0.90 (d, J = 6.9 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ 162.1, 143.8, 137.0,
130.2, 129.8, 128.5, 128.3, 114.2, 72.8, 67.6, 57.9, 35.1, 29.6, 28.4, 26.7, 19.9, 15.3. HRMS (ESI)
m/z calcd for C24H34NO4S (MH+) 432.2203, found 432.2203.
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2-Bromo-5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)benzoic Acid (13a). To a 50 mL flask was
added 1.30 g (4.34 mmol) of 12a and 11 mL of DCM. The solution was cooled with a water bath
of 20 oC, followed by addition of 1.03 g (5.21 mmol) of crude 3 as a solution in 3 mL DCM and
2.11 mL (26.0 mmol) of pyridine over about 3 min. After being stirred at room temperature for 1
h, the reaction was quenched by 20 mL water, diluted with 20 mL DCM and further treated with
30 mL of 1 N HCl (pH ~4). Layers were split, and the DCM layer was successively washed with
50 mL of 1 N HCl and 50 mL of 25 wt% NaCl, dried over anhydrous Na2SO4, filtered and
evaporated under 40 torr at 40 oC to about 30 mL. Crystallization was initiated after about 15 mL
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of heptane was added. After being stirred for 30 min, the mixture was filtered, washed with 2x5
mL of 3:1 heptane/DCM and dried at 70 oC under vacuum to give 1.20 g (63%) of 13a as a white
crystalline solid: mp. 176.5 oC. 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 2.0 Hz, 1 H), 7.80 (d,
J = 8.3 Hz, 1 H), 7.50 (dd, J = 8.3, 2.2 Hz, 1 H), 7.16 (m, 2 H), 6.97 (m, 2 H), 3.33 (d, J = 7.3 Hz,
2 H), 2.66 (q, J = 7.6 Hz, 2 H), 1.11 (m, 1 H), 1.24 (t, J = 7.6 Hz, 3 H), 0.93 (d, J = 6.9 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ 169.2, 144.5, 138.1, 136.1, 135.4, 131.9, 131.2, 131.0, 128.7,
128.3, 127.3, 58.2, 28.4, 26.8, 19.8, 15.3. HRMS (ESI) m/z calcd for C19H23BrNO4S (MH+)
440.0526, found 440.0529.
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2-Chloro-5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)benzoic Acid (13b). To a 100 mL flask
was successively added 2.64 g (12.4 mmol) of 3a, 9 mL of DCM and 3.80 mL (47.0 mmol) of
pyridine at room temperature, followed by addition of 3.00 g (11.8 mmol) of 12b as a solution in
20 mL of DCM over about 15 min. After being stirred for 25 min, the reaction was sampled and
analyzed by HPLC Method B which showed 13b (6.16 min), 14b (5.05 min) and 15b (8.09 min)
in normalized AUC of 92.4%, 1.8% and 5.8%, respectively. After being stirred for additional 30
min, the reaction was quenched with 50 mL of 1 N HCl. Layers were split, and the aqueous layer
was extracted with 30 mL of DCM. The combined DCM layers were successively washed with 30
mL of 1 N HCl and 30 mL of 25 wt% NaCl and evaporated under 170 torr at 30 oC. Crystallization
began when the volume was reduced to ~30 mL. After addition of 30 mL of hexanes, the mixture
was stirred for 30 min, filtered, washed with 2x15 mL of hexanes and dried at 75 oC to give 3.69
g (79%) of 13b as a crystalline solid: mp. 162.9 oC. 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J =
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2.2 Hz, 1 H), 7.59 (m, 2 H), 7.16 (m, 2 H), 6.97 (m, 2 H), 3.33 (d, J = 7.6 Hz, 2 H), 2.66 (q, J =
7.6 Hz, 2 H), 1.61 (dquin, J = 13.6, 6.9 Hz, 1 H), 1.24 (t, J = 7.7 Hz, 3 H), 0.93 (d, J = 6.6 Hz, 6
H). 13C NMR (100 MHz, CDCl3): δ 168.7, 144.5, 139.1, 137.5, 136.1, 132.1, 132.0, 131.4, 129.0,
128.7, 128.3, 58.2, 28.4, 26.8, 19.8, 15.3. HRMS (ESI) m/z calcd for C19H23ClNO4S (MH+)
396.1031, found 396.1031.
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2-Chloro-5-(N-(4-ethylphenyl)sulfamoyl)benzoic Acid (16b). To a 100 mL flask was
successively added 1.57 g (12.9 mmol) of 4-ethylaniline, 2.85 mL (35.3 mmol) of pyridine and 30
mL of dichloromethane. The mixture was cooled to 0 oC, and 3.00 g (11.8 mmol) of 12b was added
in 5 portions over 5 min. The mixture was warmed to room temperature and stirred for about 30
min. The reaction was quenched with 50 mL 1N HCl, vigorously stirred for 10 min, filtered,
washed with 2x30 mL of water and dried at 60 oC to give 3.20 g (80%) of 16b as a white solid:
mp. 205.7 oC. 1H NMR (400 MHz, DMSO-d6): δ 13.9 (br s, 1 H), 10.3 (s, 1 H), 8.12 (d, J = 2.2
Hz, 1 H), 7.77 (m, 2 H), 7.09 (m, 2 H), 6.99 (m, 2 H), 2.46 (q, J = 7.7 Hz, 2 H), 1.09 (t, J = 7.7
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Hz, 3 H). C NMR (100 MHz, DMSO-d6): δ 165.2, 140.4, 138.5, 136.4, 134.6, 132.0, 131.9,
130.3, 129.1, 128.5, 121.3, 27.4, 15.4; HRMS (ESI) m/z calcd for C15H15ClNO4S (MH+) 340.0400,
found 340.0399.
2-Fluoro-5-(N-(4-ethylphenyl)sulfamoyl)benzoic Acid (16c). To a reactor was added 66.0 kg
(471 mol) of 2-fluorobenzoic acid and 275 kg (1943 mol) of chlorosulfonic acid under nitrogen.
The mixture was heated to 75-85 oC and stirred for 14 h. After being cooled to 15 oC, the reaction
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was transferred slowly to 528 L of water, which was pre-cooled to 0 C in another reactor,
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maintaining the temperature below 10 C throughout the quench. The mixture was filtered and
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was washed with 66 L of saturated NH4Cl at 10 C and then concentrated to about 198 L.
Additional 462 L of MTBE was added, and the solution was again concentrated to about 200 L.
About 300 L of MTBE was added to make 479 kg of the solution of 12c in MTBE for use in the
next transformation. Assay analysis showed 17.4 w/w% of 12c. This corresponded to 83.4 kg
(74%) of 12c with purity of 99% by HPLC and water content of 0.09% by KF method.
To a separate reactor was successively added 44.0 kg (363 mol) of 4-ethylaniline, 580 L of
MTBE and 64.1 kg (763 mol) of NaHCO3 under nitrogen. The mixture was heated and stirred at
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40 C, then 82.8 kg (347 mol) of 12c, as the 17.4 w/w% solution in MTBE above, was added
slowly over 1.5 h to minimize the risk of sudden gas evolution. The mixture was stirred for 24 h
at 40 oC. After being cooled to 15 oC, the reaction was quenched with 414 L of water. The pH was
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adjusted to 1-2 with concentrated HCl at 15 C, and the mixture was stirred for 30 min. Layers
were separated, and the organic layer was treated with 828 L of water. The pH was adjusted to
about 10 with solid KOH and the mixture was stirred for 30 min. Layers were separated, and the
aqueous layer was transferred to another reactor, and the pH was adjusted to 1-2 with 2 N HCl.
The resultant slurry was stirred for 3 h, filtered, washed with water and dried at 50 oC to give 99.1
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kg (88%) of 16c as a white crystalline solid: mp. 191.9 C. HPLC retention times for reaction
monitoring by Method A: 16c, 2.18 min; 4-ethylaniline, 1.56 min; 12c, 1.97 min. 1H NMR (400
MHz, DMSO-d6): δ 13.75 (br s, 1 H), 10.24 (s, 1 H), 8.27 (dd, J = 6.9, 2.5 Hz, 1 H), 7.90 (m, 1
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