Synthesis of deuterated 4, 4′-diaminodiphenylsulfone (Dapsone) and related analogs

Article abstract of DOI:10.1002/jlcr.649

A general scheme tor the synthesis ot 4,4′-diaminodiphenylsulfone-d₅ (Dapsone) from aniline-d₅ is described. The method may have general application and the preparation of the related analogs, 4,4′-dimethylaminodiphenyl sulfone from aniline-d₅ and 4,4′-dimethoxydiphenyl sulfone from phenol-d₅, is also described. Copyright

Full text of DOI:10.1002/jlcr.649

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 107–114.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.649
Research Article
Synthesis of deuterated 4,
40-diaminodiphenylsulfone (Dapsone)
and related analogs
Peter M. Gannett*, Edward M. Johnson II, Michael A. Grimes,
Alan L. Myers, Robert E. Deavers III and Timothy S. Tracy
Department of Basic Pharmaceutical Sciences, School of Pharmacy,
West Virginia University, PO Box 9530, Morgantown, WV 26506-9530, USA
Summary
A general scheme for the synthesis of 4; 40-diaminodiphenylsulfone-d5
(Dapsone) from aniline-d5 is described. The method may have general
application and the preparation of the related analogs, 4; 40-dimethylamino-
diphenyl sulfone from aniline-d5 and 4; 40-dimethoxydiphenyl sulfone from
phenol-d5, is also described. Copyright # 2002 John Wiley & Sons, Ltd.
Key Words: 4; 40-diaminophenyl sulfone; Dapsone; deuterated; synthesis
Introduction
4; 40-Diaminodiphenyl sulfone (Dapsone, 1a, Figure 1) was originally
marketed as an anti-leprosy agent, but has seen a resurgence in use in
the last few years as it has become widely used in the treatment of
Pneumocystis carinii pneumonia in AIDS patients. At therapeutic
concentrations, 1a is metabolized by cytochrome P450 2C9 to a
hydroxylamine metabolite (1d).1 Recent work in our laboratory has also
*Correspondence to: P. M. Gannett, Department of Basic Pharmaceutical Sciences, School of
Pharmacy, West Virginia University, PO Box 9530, Morgantown, WV 26506-9530, USA.
E-mail: pgannett@hsc.wvu.edu.
Contract/grant sponsor: National Institutes of Health; contract/grant number: GM63215-01
Copyright # 2002 John Wiley & Sons, Ltd.
Received 28 May 2002
Revised 29 July 2002
Accepted 6 August 2002

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P. M. GANNETT ET AL.
Figure 1. Structure of Dapsone (1a), analogs prepared (1a–c), and analogs of
biochemical interest
demonstrated that 1a can ‘activate’ the metabolism of other CYP2C9
substrates such as flurbiprofen and naproxen.2; 3 Co-incubation of either
flurbiprofen or naproxen with 1a results in a simultaneous increase in
Vmax and decrease in Km for the metabolism of flurbiprofen or
naproxen. In addition, several related compounds including diphenyl
sulfone (1e) and 4; 40-dimethyldiphenyl sulfone (1f) have the same affect.
Interestingly, 4-amino-40-nitrodiphenyl sulfone (1g), a close analog of
1a, has just the opposite affect and inhibits the metabolism of
flurbiprofen.
These findings have led to the hypothesis that both 1a and another
substrate (e.g. flurbiprofen or naproxen) can be present simultaneously
in the enzyme active site.3 This simultaneous binding of 1a and
flurbiprofen to the active site increases the likelihood that binding will
be productive due to steric constraints imposed by 1a, and the active site
itself, on flurbiprofen. To test this hypothesis we need to be able to
prepare 1a analogs with the non-exchangeable protons replaced by
deuterium. The resulting protio and deuterio compounds 1 are to be
used for an isotope edited NMR experiment,4 the success of which
depends on the isotopic purity of 1.
Results and discussion
Initially, we examined noble metal catalyzed exchange between 1a and
deuterium gas5 D2O and various catalysts6; 7 or DCl.8 These efforts
were met with limited success. Under some of these conditions, partial
exchange was observed but we were unable to achieve the high level of
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SYNTHESIS OF LABELED DAPSONE
109
Figure 2. Generalized synthetic scheme used to prepare either protio or deutero
Dapsone and analogs (1a–c)
isotopic purity we required. Therefore, we explored an alternative
approach based on commercially available deuterated materials such as
aniline-d5.
In the case of 1a, the synthetic scheme shown in Figure 2 was
followed.9 Thus, aniline or aniline-d5 was acetylated to protect the
amino group (2a) and then treated with SOCl2 and AlCl3 in carbon
disulfide to give the sulfoxide 3a which was then oxidized with 30%
H2O2 in acetic acid to give the sulfone 4a. Finally, 4a was deprotected in
hydrochloric acid (deuterium chloride for deuterium labeled com-
pounds) to give 1a. The isotopic purity of each of the intermediates and
products were determined by mass spectrometry and this indicated that
there was little or no H–D exchange in any of the reactions used to
prepare 1a (1% or less). H–D exchange was possible due to the acidic
nature of all of the reaction conditions used to convert aniline
(aniline-d5) to 1a.
The generality of the scheme used here was examined by preparing
two additional analogs of 1a, the N-methylamino derivative 1b and the
methoxy derivative 1c. Compound 1b requires the preparation of
deuterated N-methylaniline 2b, which can be obtained by methylation
of deuterated aniline. Compound 1c requires the preparation of
deuterated anisole 2c, which can be obtained from methylation of
phenol-d5. These intermediates were successfully coupled to form the
sulfoxide (3b and 3c) and oxidized to the corresponding sulfone
(4b and 1c).
Compounds 4a and 4b were then hydrolyzed to remove the acetyl
protecting group and yielded 1a and 1b, respectively. Depending on the
substrate, some modification of the reaction conditions for the coupling
step was required. In particular, due to the greater reactivity of the
starting material for 2c, the amount of AlCl3 used, reaction time and
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P. M. GANNETT ET AL.
temperature had to be significantly decreased. However, other than this
problem, the approach presented here provides a general route to these
compounds and will aid both metabolic and NMR investigations.
Experimental
Unless otherwise noted, solvents and reagents were used as received
(Aldrich Chem. Co.). Acetic anhydride and acetic acid were distilled
prior to use. A Varian Gemini 2000, 300 MHz broadband spectrometer
was used to measure NMR spectra, IR were measured on a Perkin-
Elmer 782 spectrophotometer, UV were measured on a Beckman DU
1
640 spectrophotometer, and MS on a Micromass ZMD. H; 2H NMR
and 13C NMR data were recorded. However, multiplicities, coupling
constants and chemical shifts are reported for the 1H product only as, in
all cases the chemical shift data for the protio and deutero derivatives
were identical. All procedures described apply to either unlabeled
substrates or to deuterium containing substrates. All reactions were
monitored by TLC (silica gel, MeOH=CH2Cl2).
N-acetylaniline 2a
Aniline ð1 g; 10:8 mmolÞ or aniline-d5 was added to acetic anhydride
ð2:5 mlÞ and the mixture heated at reflux ð30 minÞ. After cooling to
room temperature (r.t.), water ð3 mlÞ was added and heated at reflux
ð10 minÞ, cooled to r.t., diluted with water to precipitate the product
which was filtered, washed with water, recrystallized from water and
dried to yield 2a ð1:14 g; 85%Þ. mp 112–1148C; IR ðKBrÞ cmꢀ1 3300;
3170; 3090; 1665; 1430; 1320; 1H NMR (dmso-d6) d ppm 2:06 ð3H; sÞ;
7:10 ð1H; t; J ¼7:2 HzÞ 7:26 ð2H; t; J ¼7:2 HzÞ 7:64 ð2H; d; J ¼ 7:2 HzÞ;
9:929 ð1H; bsÞ; 13C NMR (dmso-d6) d ppm 24:63; 119:6; 123:6; 129:3;
140:0; 168:9; UV (MeOH) lmax ðlog eÞ 241 (3.80); MS m=z (intensity) 136
(100), 94 (80). 2a-d5: mp 114–1168C; MS m=z (intensity) 141 (100), 99
(67); isotopic purity 99%.
4; 40-Di-N-acetylaminodiphenyl sulfoxide 3a
To a suspension of 2a ð0:59 g; 4:37 mmolÞ in CS2 ð6 mlÞ was added
SOCl2 ð0:24 g; 2:02 mmolÞ, and AlCl3 ð1:1 g; 8:24 mmolÞ. After the
initial reaction subsided, the mixture was heated at reflux ð6 hÞ, cooled
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SYNTHESIS OF LABELED DAPSONE
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to r.t. and quenched by the addition of ammonium chloride
ð10%; 10 mlÞ. The mixture was filtered, the filter cake was then washed
with water. The filter cake was then dissolved in THF, filtered, and the
filtrate concentrated in vacuo to yield 3a ð480 mg; 70%Þ. mp 281–2838C;
IR ðKBrÞ cmꢀ1 3305; 3250; 3160; 3080; 1670; 1515; 1400; 1300; 1280; 1050;
1H NMR (dmso-d6) d ppm 2:04 ð6H; sÞ; 7:57 ð4H; d; J ¼ 8:7 HzÞ;
7:71 ð4H; d; J ¼ 8:7 HzÞ; 10:21 ð2H; bsÞ; 13C NMR (dmso-d6) d ppm
24:20; 119:3; 125:0; 139:1; 141:6; 168:7; UV (MeOH) lmax ðlog eÞ 271
ð3:95Þ; 254 ðsÞ ð3:88Þ; MS m=z (intensity) 317 (40), 303 (20), 136
(100). 3a-d8: mp 289–2918C; MS m=z (intensity) 325 (19), 139 (100);
isotopic purity 99%.
4; 40-Di-N-acetylaminodiphenyl sulfone 4a
To a suspension of 3a ð400 mg; 1:27 mmolÞ in glacial acetic acid ð5 mlÞ
was added H2O2 ð30%; 0:5 mlÞ and the mixture was allowed to stand for
3 h at r.t., heated at 508C for 2 h and then at reflux until the mixture was
homogenous. The mixture was then cooled to r.t., H2O2 ð30%; 0:3 mlÞ
added, stored overnight at 48C and the mixture concentrated in vacuo to
yield 4a ð294 mg; 70%Þ. mp 275–2788C; IR ðKBrÞ cmꢀ13335; 3250; 3100;
1682; 1585; 1525; 1405; 1315; 1294; 1150; 1H NMR (dmso-d6) d ppm
2:06 ð6H; sÞ; 7:76 ð4H; d; J ¼ 8:8 HzÞ; 7:84 ð4H; d; J ¼ 8:8 HzÞ; 10:38
ð2H; bsÞ; 13C NMR (dmso-d6) d ppm 22:4; 117:1; 126:6; 133:3; 141:8;
167:3; UV (MeOH) lmax ðlog eÞ 283 (4.19), 255 (4.05); MS m=z
(intensity) 333 (12), 291 (100), 259 (21), 198 (22), 156 (24), 124 (23).
4a-d8 mp 280–2838C; MS m=z (intensity) 341 (15), 299 (100); isotopic
purity 98%.
4; 40-Diaminodiphenyl sulfone (Dapsone) 1a
A suspension of 4a ð200 mg; 0:6 mmolÞ in 10% HCl ð2 mlÞ or DCl with
4a-d8, was heated at reflux ð1:5 hÞ, decolorizing carbon added, then
heated at reflux an additional 1 h, filtered while still hot and cooled to
r.t. Sodium hydroxide (10%) was then added to adjust the pH to 14 and
the resulting precipitate isolated by filtration, recrystallized from water/
MeOH, and dried in vacuo to yield 1a ð120 mg; 80%Þ. mp 174–68C (lit
175–68C); IR ðKBrÞ cmꢀ1 3480; 3300; 3275; 1630; 1570; 1275; 1213; 1135;
1H NMR (dmso-d6) d ppm 5:97 ð4H; bsÞ; 6:57 ð4H; d; J ¼ 8:4 HzÞ; 7:
44 ð4H; d; J¼ 8:4 HzÞ;13 C NMR (dmso-d6) d ppm 113:5; 128:8; 129:2;
153:4; UV (MeOH) lmax ðlog eÞ 295 (4.67), 260 (4.45); MS m=z
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P. M. GANNETT ET AL.
(intensity) 249 (100), 156 (50), 149 (32). 1a-d8 mp 196–1988C; MS m=z
(intensity) 257 (100), 160 (73); isotopic purity 98%.
N-acetyl-N-methylaniline 2b
N-methylaniline ð1 g; 9:35 mmolÞ was treated exactly as described for 2a
to give 2b ð1:24 g; 89%Þ. mp 97–998C; IR ðKBrÞ cmꢀ1 3050; 2940; 1640;
1600; 1500; 1420; 1385; 1140; 1H NMR (dmso-d6) d ppm 1:75 ð3H; sÞ;
3:33 ð3H; sÞ; 7:32 ð2H; d; J¼7:8 HzÞ; 7:44 ð3H; mÞ; 13C NMR (dmso-
d6) d ppm 22:85; 37:18; 127:7; 128:0; 130:2; 145:0; 169:7; UV (MeOH)
lmax ðlog eÞ 228 (3.85); MS m=z (intensity) 150 (100), 108 (5). 2b-d5
mp 96–988C; MS m=z (intensity) 155 (100), 113 (6); isotopic purity 99%.
4; 40-Di-(N-acetyl-N-methylamino)diphenyl sulfoxide 3b
Compound 2b ð0:65 g; 4:4 mmolÞ was treated as described for 2a to
yield 3b ð550 mg; 77%Þ. mp 269–2718C; IR ðKBrÞ cmꢀ1 3160,
1
3080,1672,1515,1405,1310, 1285,1050; H NMR (dmso-d6) d ppm 1:75
ð6H; sÞ; 2:03 ð6H; sÞ; 7:50 ð4H; d; J ¼ 8:7 HzÞ; 7:72 ð4H; d; J ¼ 8:7 HzÞ;
10:11 ð2H; bsÞ; 13C NMR (dmso-d6) d ppm 23:00; 38:20; 120:6; 126:5;
141:1; 143:2; 169:5; UV (MeOH) lmax ðlog eÞ 270 (4.00), 254 (s) (3.90);
MS m=z (intensity) 345 (30), 330 (25), 149 (100). 3b-d8 mp 276–2788C;
MS m=z (intensity) 353 (35) 338 (20), 153 (100); isotopic purity 99%.
4; 40-Di-(N-acetyl-N-methylamino)diphenyl sulfone 4b
A suspension of 3b ð500 mg; 1:45 mmol) was treated as described for 3a
to yield 4b ð390 mg; 75%Þ. mp 265–2668C; IR ðKBrÞ cmꢀ1
1
3106,1690,1585,1400,1305,1290,1145; H NMR (dmso-d6) d ppm 2:05
ð6H; sÞ; 7:77 ð4H; d; J ¼8:8 HzÞ; 7:86 ð4H; d; J ¼8:8 HzÞ; 10:30 ð2H; bs
Þ; 13C NMR (dmso-d6) d ppm 18:4; 23:3; 118:4; 128:0; 135:1; 142:8;
169:1; UV (MeOH) lmax ðlog eÞ 285 (4.20), 259 (4.15); MS m=z
(intensity) 361 (12), 319 (100), 198 (22), 134 (23). 3b-d8 mp
271–2748C; MS m=z (intensity) 369 (10), 327 (100), 174 (60); isotopic
purity 98%.
4; 40-Diaminomethyldiphenyl sulfone 1b
A suspension of 4b ð200 mg; 0:55 mmolÞ as described for 4a to yield
1b ð115 mg; 75%Þ. mp 162–1648C; IR ðKBrÞ cmꢀ1 3470,3320, 3075,
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SYNTHESIS OF LABELED DAPSONE
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1625,1575,1250,1145; 1H NMR (dmso-d6) d ppm 3:01 ð6H; sÞ; 5:90
ð4H; bsÞ; 6:65 ð4H; d; J ¼ 8:4 HzÞ; 7:34 ð4H; d; J ¼ 8:4 HzÞ; 13C NMR
(dmso-d6) d ppm 38:02; 114:0; 130:1; 129:9; 151:3; UV (MeOH) lmax
ðlog eÞ 295 (4.70), 263 (4.50); MS m=z (intensity) 277 (100), 170 (50), 163
(32). 1b-d8 mp 190–1928C; MS m=z (intensity) 285 (100), 171 (20);
isotopic purity 98%.
4; 40-Dimethoxydiphenyl sulfoxide 3c
To a solution of 2c ð1 g; 9:26 mmolÞ in CS2 ð12 mlÞ was added SOCl2
ð0:55 g; 4:63 mmolÞ and AlCl3 ð1:36 g; 10:2 mmolÞ. The mixture was
stirred at r.t. ð1 hÞ and quenched by the addition of ammonium chloride
ð10%; 30 mlÞ. The reaction mixture was then extracted with
CH2Cl2 ð3 ꢁ 30 mlÞ, the combined extracts dried over MgSO4, filtered,
and concentrated in vacuo to yield 3c as a light yellow oil ð0:97 g; 80%Þ.
IR ðneatÞ cmꢀ1 2995,2980,2890,1590,1495,1261, 1178,1065,1030; 1H
NMR (dmso-d6) d ppm 3:80 ð6H; sÞ; 7:23 ð4H; d; J ¼ 8:7 HzÞ; 7:64
ð4H; d; J ¼ 8:7 HzÞ; 13C
NMR
(dmso-d6)
d ppm 56:72; 117:8;
133:4; 134:0; 163:5; UV (MeOH) lmax ðlog eÞ 258 (3.82); MS m=z
(intensity) 263 (12), 246 (44), 232 (40), 231 (38), 85 (100). 3c-d8, light
yellow oil; MS m=z (intensity) 271 (10), 254 (35), 240 (47), 111 (100);
isotopic purity 98%.
4; 40-Dimethoxydiphenyl sulfone 1c
Compound 3c ð0:90 g; 3:7 mmolÞ was treated as described for 3a to
yield 1c ð0:88 g; 85%Þ as a viscous oil. IR ðKBrÞ cmꢀ1 3300, 3105,3063,
1
2980,2845,1595,1500,1255,1145,1020; H NMR (dmso-d6) d ppm 3:74
ð6H; sÞ; 7:04 ð4H; d; J ¼ 8:4 HzÞ; 7:77 ð4H; d; J ¼ 8:4Þ; 13C
NMR
(dmso-d6) d ppm 56:38; 115:5; 129:9; 132:3; 163:5; UV (MeOH) lmax
ðlog eÞ 259 (5.01), 234 (5.00); MS m=z (intensity) 279 (100), 171 (6), 87
(3). 1c-d8, viscous oil; MS m=z (intensity) 287 (100), 175 (10); isotopic
purity 97%.
Conclusions
A method for the preparation of deuterated 4; 40-diaminodiphenyl
sulfone (1a, Dapsone) has been devised. The method is based on using
commercially available deuterated materials such as aniline-d5 and
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phenol-d5 which can be obtained inexpensively (according to the catalog
of the Cambridge Isotope Laboratories, Inc., the cost of 1 g of aniline
(ring-D5; 99%) is 45 dollars and 1 g of phenol (ring-D5; 98%) is 85
dollars). Using the method described, virtually no loss in isotopic purity
is observed (1% or less). The method will likely have broader
applicability as two additional analogs of 1a, 4; 40-N-methylaminophenyl
sulfone and 4; 40-methoxyphenyl sulfone, were readily prepared with
only minor changes in the reaction conditions. Finally, the high isotopic
purity of 1 will permit the use of this material in isotope edited NMR
experiments and may find additional uses in metabolism studies.
Acknowledgements
We thank the National Institutes of Health for their financial support of
the work (GM63215-01).
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