Preparation of labeled bis-amino acid hydroxyethylamino sulfonamide HIV protease inhibitors

Article abstract of DOI:10.1002/jlcr.676

Preparation of radiolabeled sulfonamide HIV protease inhibitors, DMP852 and DMP853 is described. The C-14 labeling of DMP852 was accomplished by acylation of the intermediate amine with [1-¹⁴C]-chloroacetic anhydride followed by the treatment of the chloroacetyl derivative with methylamine. Due to the rapid loss of the methylglycine moiety during metabolism studies, a route that involved an oxidation-reduction sequence was employed to prepare tritium labeled DMP852. Similar methodology was utilized to prepare tritium labeled DMP853. Copyright

Full text of DOI:10.1002/jlcr.676

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 353–363.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.676
Research Article
Preparation of labeled bis-amino acid
Hydroxyethylamino sulfonamide HIV
protease inhibitors
Kai Cao*,y, Shiang-Yuan Chen and Shimoga R. Prakashz
Radiochemistry, Discovery Chemistry, Pharmaceutical Research Institute,
Bristol-Myers Squibb Company, New Brunswick, NJ 08903,USA
Summary
Preparation of radiolabeled sulfonamide HIV protease inhibitors, DMP852
and DMP853 is described. The C-14 labeling of DMP852 was accomplished by
acylation of the intermediate amine with [1-14C]-chloroacetic anhydride
followed by the treatment of the chloroacetyl derivative with methylamine.
Due to the rapid loss of the methylglycine moiety during metabolism studies, a
route that involved an oxidation-reduction sequence was employed to prepare
tritium labeled DMP852. Similar methodology was utilized to prepare tritium
labeled DMP853. Copyright # 2003 John Wiley & Sons, Ltd.
Key Words: [1-14c]-chloroacetic anhydride; Sodium borotritide; Retroviral
protease inhibitors
y This work was completed at Stine-Haskell Research Center, Drug Metabolism and Pharmaco-
kinetics Department, prior to acquisition of DuPont Pharmaceuticals Company by Bristol-Myers
Squibb Company.
*Correspondence to: K. Cao, Radiochemistry, Discovery Chemistry, Pharmaceutical Research
Institute, Bristol-Myers Squibb Company, New Brunswick, NJ, 08903, USA. E-mail: kai.-
cao@bms.com.
z Present address: Radiochemistry/Process Chemistry, Millenium Pharmaceuticals, Inc., 38 Sidney
Street, Cambridge, MA 02139, USA.
Copyright # 2003 John Wiley & Sons, Ltd.
Received 8 May 2002
Revised 25 September 2002
Accepted 17 October 2002

354
K. CAO ET AL.
Introduction
O
O
O
R
HN
S
O
O
N
H
N
H
N
O
OH
R = methyl, DMP852 1
R = cyclopropyl, DMP853 2
DMP852 1 and DMP853 2 are two potent HIV protease inhibitors
discovered by Searle scientists.1 These compounds belong to a class of
bis-amino acid hydroxyethylamino sulfonamide derivatives, and were
in-licensed from Searle. In order to study their metabolism and
pharmacokinetic behavior, radiolabeled versions of the two compounds
were required. Selection of a labeling site with peptides like DMP852
and DMP853 presents challenges as one has to consider several factors
or may even have to attempt several versions before settling on one that
is most appropriate. Preliminary metabolism investigations revealed
that incorporation of the label at the terminal amide carbon of DMP852
would be adequate for the purpose.
The C-14 labeled version of DMP852 was prepared by a two-step
sequence utilizing [1-14C]-chloroacetic anhydride as the precursor.
Detailed metabolism investigations precluded the use of this labeled
version due to the loss of the methylglycine portion. An attractive
alternative to C-14 labeling appeared to be utilization of an oxidation–
reduction sequence to yield tritium labeled DMP852. It was also
anticipated that reduction of the ketone obtained by oxidation of
DMP852 with sodium borotritide would yield a mixture of diaster-
eomers containing the desired product. This strategy was successfully
employed to prepare tritium labeled DMP852 and was later extended to
preparation of labeled DMP853.
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LABELED HIV PROTEASE INHIBITORS
355
Results and discussion
[14C]-DMP852 1a
To generate the labeled compound in a timely manner, we resorted to
procedures and conditions that were used to prepare the unlabeled
compound (Scheme 1).1 Chloroacetic anhydride was employed in the
original synthesis (Scheme 1), and we used the analogous [1-14C] reagent
rather than [1-14C]-chloroacetic chloride because of its lower volatility.
Reaction of amine 3 with 1.1 equivalent of labeled chloroacetic
anhydride provided the labeled chloroacetyl derivative, which was used
in the next step without further purification. Treatment of 4 with excess
methylamine followed by crystallization of the hydrochloride salt
yielded pure 1a.
[3H]-DMP852 1b
The oxidation–reduction strategy useful in rapid preparation of tritium
labeled compounds containing a secondary alcohol group appeared to
be ideally suited to preparation of tritium labeled versions of DMP852
and DMP853 (Scheme 2). Swern oxidation2,3 of BOC protected
DMP852 provided the ketone in excellent yield, and sodium borotritide
reduction of the ketone gave a mixture of diastereomeric products,
which were separated using HPLC methods.
As shown in Scheme 3, in the case of DMP852 the diastereoselectivity
during reduction was around 70% in favor of the desired isomer A.
O
*
*
Cl
Cl
O
O
O
O
O
O
O
O
HN
S
H N
S
O
O
O
O
2
*
O
Cl
N
H
N
N
H
N
OH
OH
N
4
3
O
O
O
CH NH
3
2
HN
S
O
O
*
N
H
N
H
N
O
OH
[14C]-DMP852, 1a
Scheme 1.
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356
K. CAO ET AL.
O
O
O
H
O
H
O
N
O
O
BOC-ON
R
N
S
N
S
O
O
O
O
N
N
N
N
R
N
O
H
H
H
O
OH
O
OH
TEA, dioxane, water
1 R = Methyl
5 R = Methyl
6 R = cyclopropyl
2 R = Cyclopropyl
O
O
H
(COCl) , DMSO
2
O
O
NaBT
4
N
S
O
N
R
N
N
O
CH Cl
2
H
2
O
EtOH
O
O
7 R = Methyl
8 R = Cyclopropyl
O
O
O
H
O
N
H
O
N
O
O
TFA
N
S
R
N
S
O
O
O
N
N
H
N
N
T
H
H
T
O
OH
R
O
OH
O
CH Cl
2 2
O
3
1b R = Methyl, [ H]-DMP852
3
9
R = Methyl
10 R = cyclopropyl
2b R = Cyclopropyl, [ H]-DMP853
Scheme 2.
O
O
O
O
O
O
S
S
N
N
N
N
H
T
H
HO
OH
T
B
A
A: 70 %
B: 27 %
O
O
O
O
N
O
O
S
S
N
H
N
N
H
HO
T
OH
T
C
D
C + D : 3 %
Scheme 3.
Diastereomer B was formed to an extent of 27% and the remainder
could be attributed to other two diastereomers (C, D) resulting perhaps
from enolization of the ketone before tritiation. Only the desired isomer
was separated by HPLC on a reversed-phase column and deprotection
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LABELED HIV PROTEASE INHIBITORS
357
of the isolated compound, followed by further purification, yielded [3H]-
DMP852 1b, the structure of which was confirmed by 1H-NMR and 3H-
NMR analyses, and by mass spectrometry. The specific activity of 1b
was 2.5 Ci/mmol. Similar methodology was used for the synthesis of
[3H]-DMP853 2b, specific activity 2.8 Ci/mmol.
Two batches of sodium borotritide were used, with specific activity
11.8 Ci/mmol for DMP852 and 14 Ci/mmol for DMP853, respectively.
The expected specific activity of the products should have been 2.95 Ci/
mmol for DMP852 and 3.5 Ci/mmol for DMP853. Even with an
intentional excess of sodium borotritide to mitigate its consumption by
moisture, the tritium–proton exchange due to moisture still caused a
lowering of specific activity (2.5 Ci/mmol for DMP852 and 2.8 Ci/mmol
for DMP853).
In summary, we have described a simple method for the preparation
of tritium labeled bis-amino acid hydroxyethylamino sulfonamide HIV
protease inhibitors. The majority of highly active compounds in this
series have the central unit bearing the hydroxyl group.1 This labeling
methodology is therefore expected to be generally applicable to any
other compounds chosen for further progression.
Experimental
3
1H-NMR and H-NMR spectra were obtained from a Bruker 500
spectrometer at 500 and 533 mHz, respectively. Mass spectral analyses
were conducted on a Finnigan TSQ-70 or a LCQ spectrometer.
Radioactivity determinations were carried out with a Packard liquid
scintillation counter, using external standard methods and Ultima Gold
as the scintillation fluid. HPLC analyses were performed using a Waters
Alliance or HP1100 LC system with a Radiomatic model Flo-One/Beta
CR radioactivity detector. The mobile phase consisted of solvent A:
0.05% (v/v) TFA in water, B: 0.05% TFA in acetonitrile. Column:
Zorbax RX-C18, 4.6 mm ꢀ 25 cm, flow: 1 ml/min, linear gradient
elution from 30% B to 90% B in 30 min. TLC was carried out on silica
gel 60 F254 plates (Merck). [1–14C]-Chloroacetic anhydride was
obtained from ChemSyn Science Laboratories and sodium borotritide
was obtained from NEN Life Science Products. Identities of labeled
compounds were established by co-chromatography with pure unla-
beled compounds.
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2 S-N-{(1S,2R)-3-[(1,3-Benzodioxol-5-ylsulfonyl)(isobutyl)amino]-1-
benzyl-2-hydroxypropyl}-3,3-dimethyl-2-[(2-chloro-[1-14C]acetyl)
amino]butanamide 4
To a stirring solution of 3 (257 mg, 0.45 mmol), diisopropylethylamine
(200 mL) in tetrahydrofuran (THF, 3 mL) at 48C was added dropwise a
solution of [1-14C]-chloroacetic anhydride (60 mCi, 0.53 mmol, radio-
chemical purity 90%) in THF (1 ml). The temperature of the reaction
mixture was maintained at 4 – 58C with continued stirring for another
3 h. The reaction mixture was diluted with ethyl acetate (EtOAc, 10 ml),
washed with water (saturated sodium bicarbonate, 5 ml ꢀ 2), 5% citric
acid in water (5 ml ꢀ 2), and brine (5 mL ꢀ 2) consecutively. HPLC
and TLC (50% EtOAc in heptane v/v) analysis of the EtOAc extract
indicated the presence of 75% of the chloroacetyl product. This solution
was evaporated to dryness and the residue was used directly in the next
step without further purification.
2 S-N-{(1S,2R)-3-[(1,3-Benzodioxol-5-ylsulfonyl)(isobutyl)amino]-1-
benzyl-2-hydroxypropyl}-3,3-dimethyl-2-{[2-(methylamino)-
[1-14C]acetyl]amino}butanamide 1a
To the residue 4 in THF (5 ml) at 58C was added methylamine (40% in
water, 1 ml) and the mixture was stirred for 6 h. The reaction mixture
was diluted with EtOAc (10 ml), washed with saturated sodium
bicarbonate in water (5 ml ꢀ 2) and brine (5 ml ꢀ 2). The EtOAc
extract was acidified with concentrated HCl (37%, 0.2 ml) and
evaporated to dryness. The residue was crystallized from ethanol
(1 ml) and ethyl ether (1 ml) to yield the title product (14.6 mCi, yield
49%). Radiochemical purity, >99.5% by HPLC.
tert-Butyl 2-{(1S)-1-[({(1S,2R)-3-[(1, 3-benzodioxol-5-ylsulfonyl)
(isobutyl)amino]-1-benzyl-2-hydroxypropyl}amino)carbonyl]-2,2-di-
methylpropyl}amino-2-oxoethyl(methyl) carbamate 5
To a stirred mixture of 1 (320 mg, 0.50 mmol) in water (1 ml) and 1,
4-dioxane (1 ml) was added triethylamine (TEA, 105 ml) and
2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON, 136 mg,
0.55 mmol). After stirring at room temperature for 3 h, water (2 ml) was
added, the mixture was extracted with ether (3 ꢀ 5 ml). The ethereal
extract was dried over MgSO4 and filtered. The residue obtained on
evaporation was purified by preparative TLC (5:4 v/v hexane:EtOAc) to
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LABELED HIV PROTEASE INHIBITORS
359
give 5 (339 mg, 96%), which was shown by HPLC to be > 99% pure.
Mass spectrum (ES+): 704.9 [M+H]+, 648.9 [M+H}t-Bu]+, 605.2
[M+H}t-BuOCO]+, and 421.0 (fragment containing the hydroxyl
group from cleavage of the center amide bond).
tert-Butyl 2-{(1S)-1-[({(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(iso-
butyl)amino]-1-benzyl-2-oxopropyl}amino)carbonyl]-2,2-dimethylpro-
pyl}amino-2-oxoethyl(methyl) carbamate 7
Oxalyl chloride (43 ml, 0.49 mmol) in CH2Cl2 (1 ml) was placed in a 5 ml
flask at –788C, DMSO (70 ml, 0.98 mmol) in CH2Cl2 (0.5 mL) was added
dropwise, and stirring was continued for 2 more minutes. Upon
addition of 5 (289 mg, 0.28 mmol) in CH2Cl2 (1 mL) over 5 minutes, a
slurry was formed. The reaction mixture was stirred at ꢁ788C for 15
more minutes, triethylamine (279 mL, 2 mmol) was added and stirring
was continued at ꢁ788C for a further 5 min. The reaction mixture was
allowed to warm to room temperature, water (2 ml) was added, the
CH2Cl2 layer was separated, and the aqueous layer was extracted with
CH2Cl2 (3 ꢀ 2 ml). The CH2Cl2 extracts were combined and washed
with 0.2% HCl (2 ml), 5% NaHCO3 (2 ml), water (2 ml), dried over
MgSO4, filtered and evaporated to give a solid 7 (260 mg, 90%, >99%
pure by HPLC). Mass spectrum (ES+): 702.8 [M+H]+, 685.1
[M+H}H2O]+, 646.9 [M+H}t-Bu]+, 603.2 [M+H}t-BuOCO]+,
and 419.1(fragment containing the keto group from cleavage of the
center amide bond). 1H-NMR (DMSO-d6): d (ppm) 7.20 (m, 7 H), 7.02
(d, 1 H), 6.15 (s, 2 H), 4.55 (m, 1 H), 4.28 (m, 2 H), 3.60-4.00 (m, 3 H),
3.05 (m, 2 H), 2.89 (m, 1 H), 2.73 (m, 4 H), 1.60 (m, 1 H), 1.31 (s, 9 H),
0.85 (s, 9 H), 0.71 (m, 6 H).
Reduction of 7 by NaBH4
To a stirred solution of 7 (112 mg, 0.16 mmol) in ethanol (4 mL), was
added dropwise a solution of 0.04 M NaBH4 in ethanol (0.04 mmol,
1 mL). The reaction mixture was stirred at room temperature overnight.
HPLC analysis of an aliquot of the reaction mixture showed complete
consumption of 7 and formation of BOC-DMP852 and its diaster-
eomers. Ethanol was removed by distillation under vacuum. The residue
was redissolved in 50% B, any excess of NaBH4 was quenched. The
crude was purified on a Zorbax RX C18 (9.4 mm x 25 cm, flow rate:
4 ml/min, 254 nm, mobile phase: 50% B). Compound 5 eluted at
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14.5 min and was baseline separated from other diastereomers.
Lyophilization of the pooled fractions containing 5 provided pure
compound, 75 mg, yield 66%.
Deprotection of 5
To 5 from the previous reaction (10 mg, 0.014 mmol) was added 30%
TFA in CH2Cl2 (1 ml), and the solution was stirred at room temperature
for 4 hours. HPLC analysis showed completion of the reaction. The
solvent was evaporated via vacuum distillation. The residue was purified
on a semi-preparative column to give 1, 5.3 mg, 65%. (Zorbax RX C18,
9.4 mm ꢀ 25 cm, flow rate: 4 ml/min, 254 nm, gradient elution in 30 min
from 10% B to 90% B, tR of 1, 8 min).
tert-Butyl 2-{(1S)-1-[({(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(iso-
butyl)amino]-1-benzyl-2-hydroxy-2-[3H]-propyl}amino)carbonyl]-2,2-
dimethylpropyl}amino-2-oxoethyl (methyl) carbamate 9 (Reduction of 7
by NaB[3H]4)
To 7 (10 mg) in a reaction vial was added NaB[3H]4 (100 mCi) in
absolute ethanol (2 ml), the vial was then sealed and stirred at room
temperature for 4 h. HPLC showed formation of BOC protected [3H]-
DMP852 and three other diastereomers (see Results and Discussion).
Ethanol was removed via vacuum distillation. The residue was dissolved
in 50% B (6 ml), and purified on a Zorbax RX C18 column (9.4 mm ꢀ
25 cm, flow rate: 4 ml/min, 254 nm, mobile phase: 50% B). Fractions
containing pure BOC protected [3H]-DMP852 (tR 14.5 min) were
combined and utilized in the next step without further processing.
Total activity was 16.4 mCi.
(2S)-N-{(1S,2R)-3-[(1,3-Benzodioxol-5-ylsulfonyl)(isobutyl)amino]
-1-benzyl-2-hydroxy-2-[3H]-propyl}-3,3-dimethyl-2-{[2-(methylamino)
acetyl]amino}butanamide 1b
The pooled fractions containing 9 were concentrated by vacuum
distillation, followed by addition of 30% TFA in CH2Cl2 (1 mL). After
2 hours, the solvent was removed by evaporation with a gentle stream of
N2. The residue obtained was redissolved in 30% acetonitrile (2 mL),
and chromatographed on a Zorbax RX C18 column (9.4 mm ꢀ 25 cm,
flow rate: 4 ml/min, 254 nm, linear gradient elution from 10% B to 90%
B in 30 min). Radiochemical purity of the combined fractions was 96%.
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The combined fractions were then lyophilized and rechromatographed
on the same semi-preparative column (flow rate: 4 ml/min, 254 nm,
gradient elution from 10% B, to 70% B in 30 min, tR 11.4 min).
Fractions collected were lyophilized again to give 1a (5 mCi, radio-
chemical purity, >99.5%), which was stored in absolute ethanol (5 ml).
Radiochemical yield 5% (from NaB[3H]4, reflected higher losses during
purification). Specific activity as determined by HPLC/UV assay was
2.5 Ci/mmol. 3H-NMR (proton decoupled, DMSO-d6): singlet at
4.0 ppm.
tert-Butyl 2-{(1S)-1-[({(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(iso-
butyl)amino]-1-benzyl-2-hydroxypropyl}amino)carbonyl]-2,2-dimethyl-
propyl}amino-2-oxoethyl (cyclopropyl) carbamate 6
To the free base generated from 2 (HCl salt, 513 mg, 0.77 mmol) was
added water (2 ml), dioxane (2.5 mL), triethylamine (162 ml), followed
by the addition of 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile
(BOC-ON, 208 mg, 0.85 mmol). After stirring at room temperature for
4 h, water (5 ml) was added, the aqueous solution was extracted with
EtOAc and the EtOAc extract was dried over MgSO4. The crude
product obtained by evaporation of EtOAc was purified by preparative
TLC (1:2 v/v EtOAc:hexane), to afford >98% pure 6 (477 mg, 85%).
1H-NMR (DMSO-d6): d 7.32 (d, 1 H), 7.27 (s, 1 H), 7.15 (m, 5 H), 7.05
(d, 1 H), 6.15 (s, 2 H), 4.95 (d, 1 H), 4.17 (d, 1 H), 4.00 (m, 1 H), 3.75 (bs,
1 H), 3.58 (m, 1 H), 3.25 (m, 1 H), 2.95 (m, 3 H), 2.80 (m, 1 H), 2.53 (m,
1 H), 1.92 (m, 1 H), 1.30 (s, 9 H), 0.8 (m, 15 H), 0.55 (m, 4 H). Mass
spectrum (ES+), m/z: 753.3 [M+Na]+, 697.1 [M+Na - t-Bu]+, 653.4
[M+Na - t-BuOCO]+.
tert-Butyl 2-({(1S)-1-[({(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)
(isobutyl)amino]-1-benzyl-2-oxopropyl}amino)carbonyl]-2,2-dimethyl-
propyl}amino-2-oxoethyl (cyclopropyl) carbamate 8
Following the procedure described for the preparation of 7, 8 was
synthesized in 90% yield. Mass spectrum (ES+), m/z: 751.3 [M+Na]+,
695.1 [M+H}t-Bu]+, 651.3 [M+H}t-BuOCO]+.
Reduction of 8 by NaBH4
By analogy with sodium borohydride reduction of 7, 8 yielded BOC
protected DMP853 (69%), another major diastereomer (28%) and a
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K. CAO ET AL.
pair of other diastereomers (4%). Deprotection of the mixture
with TFA in CH2Cl2 followed by preparative HPLC purification
yielded 2 (Vydac protein peptide C18, 9.4 mm ꢀ 25 cm, flow rate:
4 ml/min, 254 nm, mobile phase: 40% acetonitrile in 0.2% aqueous
TFA).
tert-Butyl 2-{(1S)-1-[({(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(iso-
butyl)amino]-1-benzyl-2-hydroxy-2-[3H]-propyl}amino)carbonyl]-2,2-
dimethylpropyl}amino-2-oxoethyl (cyclopropyl) carbamate 10 (Reduc-
tion of 8 by NaB[3H]4)
Following the same reaction conditions for reduction of 7 by NaB[3H]4
(100 mCi), HPLC assay showed formation of BOC protected [3H]-
DMP853 (68%), another major diastereomer (28%) and a pair of other
diastereomers (4%). Ethanol was removed via vacuum distillation to
give 10 (28.2 mCi). Compound 10 was used directly in the next step
without further purification.
(2S)-N-{(1S,2R)-3-[(1,3-Benzodioxol-5-ylsulfonyl)(isobutyl)amino]
-1-benzyl-2-hydroxy-2-[3H]-propyl}-3,3-dimethyl-2-{[2-(cyclopropyl-
amino)acetyl]amino} butanamide 2b
A solution of 30% TFA in CH2Cl2 (1 ml) was added to 10 (28.2 mCi)
and stirred at room temperature for 2 h. HPLC assay showed
completion of the reaction. Dichloromethane was removed via vacuum
distillation, the residue was redissolved in 40% acetonitrile in 0.2%
aqueous TFA (5 ml), chromatographed on a Vydac protein peptide C18
column (9.4 mm ꢀ 25 cm, flow rate: 4 ml/min, 254 nm, mobile phase:
40% acetonitrile in 0.2% aqueous TFA, tR, 5 min). Combined fractions
were lyophilized to give 2b (10 mCi, 10% from NaB[3H]4), which was
stored in absolute ethanol (10 mL). Specific activity was determined by
HPLC/UV assay to be 2.8 Ci/mmol. 3H-NMR (proton decoupled,
DMSO-d6): singlet at 4.0 ppm.
Acknowledgements
The authors thank Gregory Harris for providing DMP852 and
DMP853 samples, Abdul Mutlib, John Shockcor and Hao Chen for
mass spectral data and NMR spectral data.
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References
1. Getman DP, Descrescenzo GA, Freskos JN, et al. (GDS Searle & Co.,
USA). PCT Int. Appl., 255 pp. CODEN: PIXXD2. WO 9628464 A1
960919. Application: WO 96-US2685 960307. Priority: US 95-402450
950310; US95-479071 950607 CAN 126: 8710.
2. Mancuso AJ, Brownfain DS, Swern D. J Org Chem 1979; 44: 4148-4150.
3. Swern oxidation of DMP852 without protection of the amino group
resulted in a mixture of N-dimethyl sulfonium salts.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 353–363