close

Вход

Забыли?

вход по аккаунту

?

Synthesis of 4-Methylthio Analogues of FLT and AZT and their Evaluation against HIV.

код для вставкиСкачать
4-Methylthio Analogues of FLT and AZT
67
Synthesis of 4-Methylthio Analogues of FLT and AZT and their
Evaluation against HIV
Adel A.-H. Abdel-Rahman”),Hamed M. Abdel-Bary”),Erik B. Pedersena)*,and Claus Nielsenb)
a)
b,
Department of Chemistry, Odense University, DK-5230 Odense M, Denmark
Retrovirus Laboratory, Department of Virology, Statens Seruminstitut, Artillerivej 5, DK-2300 Copenhagen, Denmark
Received May 25, 1994
Synthese von 4-Methylthioanalogen des FLT und AZT und ihre
Priifung auf Anti-HIV-Wirkung
Silylated 4-methylthiouracil and 4-methylthiothymine were condensed in
Silyliertes 4-Methylthiouracil und 4-Methylthiothymin wurden in
the presence of TMS triflate with methyl 2,3-dideoxy-3-fluoro-5-0-(4- Gegenwart von TMS-Triflat mit Methyl-2,3-didesoxy-3-fluoro-5-0-(4phenylbenzoy1)-o-eryrhro-pentofuranoside(3) and methyl 3-azido-5-0phenylbenzoy1)-D-erythro-pentofuranosid(3) und Methyl-3-azido-5-0(8), respec(tert-butyldiphenylsilyl)-2,3-dideoxy-~-eryrhr~-pento~roside
(8) zu den
(tert-butyldiphenylsilyl)-2,3-didesoxy-D-e~thr~-pentof~~osid
tively, to give the corresponding nucleosides which were deprotected. The
entspr. Nukleosiden kondensiert. Anschlieknd wurden die Schutzgruppen
3’-azido nucleoside was reduced with triphenylphosphine to the correentfernt. Das 3-Azidonukleosid wurde mit Triphenylphosphin zum entspr.
sponding 3’-amino nucleoside. The 3’-amino nucleoside was also obtained
3-Aminonukleosid reduziert, das auch durch Kondensation von
by condensation of 4-methylthiothymidine with a 3-phthalimido sugar 14 4-Methylthiothymidin mit dem 3-Phthalimido-Zucker 14 und Abspaltung
followed by deprotection. The 4-methylthio analogue 11 of AZT showed der Schutzgruppen erhalten wurde. - Das 4-Methylthio-Analogen 11 des
moderate activity against HIV.
AZT ist gegen HIV schwach wirksam.
In a recent publication it was reported by Czernecki era/.’)that 3’-azido2’,3’-dideoxy-4-methylthiouridine
showed activity against human immunodeficiency virus (HIV) in CEM-Cl13 cells. This type of compounds
were synthesized in a linear route’) from the corresponding natural nucleosides by thionation of the protected nucleoside with Lawesson’s reagent
followed by a modified Honvitz’) route and subsequent S-methylation.
methyldisilazane (HMDS) was carried out according to
Vorbriiggen el a l l 3 )by refluxing the nucleobase in HMDS
in the presence of catalytic amounts of ammonium sulphate.
Coupling of the sugars with the nucleobases was carried out
We thought it advantageous to use a convergent route in
which the 4-methylthiouracil is condensed with the appropriate sugar to give the 3’-azido-2’,3’-dideoxy-4-methylthiHC,
ouridines. In a similar way, it would also be possible to syn1
thesize the corresponding 3’-fluoro analogues as base modified analogues of 3’-fluoro-3’-deoxythymidine(FLT).
Although more toxic3),FLT is in fact a more potent inhibitor of HIV than 3’-azido-3’-deoxythymidine(AZT)4).
Moreover, other 3’-flUOrO analogues demonstrate a selectiv3
ity against HIV that is quite comparable to that of their 3’Me,SiO
azido counterpart^^-^). We also considered it interesting to
synthesize the 4-methylthio analogues of 3-amino-3’deoxythymidine because it has been reported by Cheng et
~ 1 .that
~ ) the triphosphate of 3-amino-3’-deoxythymidine
is
a potent inhibitor of isolated reverse transcriptase.
2-Deoxy-D-ribose (1) was treated with HC1 in methanol to
afford the methyl furanoside which was selectively 5 - 0
protected with 4-phenylbenzoyl chloride in pyridine to give
NHfleOH
methyl 2,3-dideoxy-5-0-(4-phenylbenzoyl)-~-~-erythro- L
pentofuranoside (2)9).Methyl 3-fluoro-2,3-dideoxy-5-0(4-phenylbenzoyl)-~-D-erythro-pentofuranoside
(3) was
formed upon treatment of 2 with diethylaminosulfur trifluoride (DAST) in 1 : l O molar ratio in dry CH2Cl2I0).4-Methylthiouracils 4 and 9 were synthesized according to Brown
R 4-PhCeH4CO
et ul.”) by heating 4-thio~racils’~)
with methyliodide in the
presence of NaOH. Silylation of the nucleobase with hexa- Scheme 1
b
HC,
3
2
TMS
triflate
MeCN
-
N5
4
Ro$
F5
+
SMe
6
7
t
Arch. Pharm. (Weinheim)328,67-70 (1995)
0 VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1995
0366-6233/95/0101-0067 $5.00+ ,2510
68
Pedersen and coworkers
under the Vorbruggen condition^'^). The condensation of
the fluoro sugar 3 and the silylated 4-methylthiouracil 4
was performed in dry acetonitrile, using trimethylsilyl trifluoromethanesulfonate(TMS triflate) as a catalyst, producing 5 in 79% yield with p/a ratio 2:l. The anomeric mixture 5 was deprotected with a saturated N H w e O H giving
an anomeric mixture of 6 and 7 which was separated by
chromatography in 45% and 20% yield, respectively.
The condensation of the azido sugar 815)and the silylated
4-methylthiothymidine 9 by the TMS triflate method of
Vorbriiggen et al.I3)in dry acetonitrile afforded the anomeric mixture 10 with a@ ratio 3:2. After chromatographic
purification, treatment of 10 with tetrabutylammonium fluoride (Bu4NF) in tetrahydrofuran (THF) resulted in complete deprotection of the hydroxy group and the resulting
anomeric mixture was separated by chromatography to give
11 and 12 in 27% and 53% yield, respectively.
Mungall et a1.I6)reported on the utility of the azido group
as a synthon for a terminal amino group in an oligonucleotide. Among the methods available for converting azides to
amines, the most promising one for application in the
nucleotide field appeared to be utilizing triphenylphosphine, first described by Staudinger and Hauser17). Thus,
9
the amino nucleoside 13 was obtained in 71% yield by the
reduction of the azido nucleoside 11 using triphenylphosphine in pyridine.
Amino nucleosides can be obtained by coupling of
silylated bases with a 3-phthalimido sugar"): the silylated
base 9 was condensed with the phthalimido sugar 14 in dry
acetonitrile using TMS triflate as a catalyst, as described by
Vorbriiggen et ~ 1 . ' ~After
) . chromatographic workup, the
p-anomer 15 was obtained in 54% yield and the a-anomer
16 in 8% yield. During deprotection of the nucleoside 15
with 33% methylamine in absol. ethanol at reflux temp., the
methylthio group in the 4-position of the pyrimidine moiety
was very susceptible to a nucleophilic substitution reaction
and the N4-methylcytidine derivative 17 was isolated in
30% yield together with the 4-methylthio nucleoside 13 in
51% yield. The 'H-NMR- and 13C-NMR-spectra of the
compound which still has the 4-methylthio group are
identical to the spectra of 13 obtained by reduction of the
azido group. The attempt of deprotection of 16 with
methylamine in ethanol resulted in a complex mixture of
products which was not separated.
The assignment of the anomeric configurations was based
on 'H-NMR spectra: The resonance of 4'-H in the
a-anomer appears downfield from that observed for the
p-anomer, and the resonance of 5'-H of the a-anomer
appears upfield from that observed for the p - a n ~ m e r ' ~ - ~ ' ) .
The 2a-H resonance of 7 exhibited a dd due to a large
geminal coupling and a coupling to fluorine. No couplings
were observed to 1-H and 3-H, trans to 2a-H. In
conformity with a-configuration of 7 we also observed a
small coupling constant (3.71 Hz) of C-6 which was
ascribed to through-space coupling to fluorine. Through-
h3
10
SMe
+
HoY
I
PhthN
15
SMe
fJ3
16
12
11
NHMe
1
Ph3P/Pyridine
15
SMe
33% MeNH-JEtOH* 1 3 +
A
0
HOV
AH,
17
-
[Si] = f BuPbSi
13
Scheme 2
Scheme 3
Arch. Pharm. (Weinheim)328,67-70 (1995)
4-Methylthio Analogues of FLT and AZT
space 13C-19Fcouplings are known for adenine derivatives**). For compound 7, the through-space l3C-I9F
coupling also indicates anti conformation around the glycosidic bond to the nucleobase.
A moderate activity was found against HIV-1 for compound 11. The effective dose (EDs0) of achieving 50%
reduction of HIV anti-gene production in cultures of MT-4
cells was 31 pM which was considerably higher than the
one found for AZT in a control experiment (EDs0 = 0.05
pM). Compound 11 is non-toxic at 100 pM which was the
highest concentration tested. Compounds 6, 7, 12, 13, and
17 did not show any significant activity against HIV-1.
Experimental Part
Anhydrous MeCN was distilled from P205 followed by distillation from
CaH2. All other solvents were used after distillation.- Analytical TLC
plates 60 F, and silica gel (230-400 mesh) were purchased from Merck.‘H- and I3C-NMR-spectra:Bruker AC 250 W NMR Spectrometer at 250
MHz for ‘H-NMR and 62.9 MHz for 13C-NMR.- EI-mass spectra: Varian
MAT 31 1A Spectrometer.
1-[2,3-Dideoxy-3-fluoro-5-0-(4-phenylbenzoyl-ff,~~-erythro-
pentofuranosyl]-4-methylthiopyrimidin-2(1H)-one
(5)
A mixture of 4-methylthiouracil 4 (0.85 g, 6 mmol) and hexamethyldisilazane (30 ml) was refluxed for 1 h (clear solution after 0.5 h) and the
solvent was removed in vacuo. The residue was dissolved in dry MeCN
(30 ml) and the fluoro sugar 3 (1.0 g, 3 mmol) was added. The reaction
mixture was stirred and cooled to -30°C. A solution of TMS triflate (1.3
ml, 6.5 mmol) in dry MeCN ( 5 ml) was added dropwise. The reaction
mixture was stirred for 0.5 h at -25°C. then at room temp. for 0.5 h. The
mixture was diluted with CH2C12 (150 ml) was washed with a cold sat. aq.
NaHC03 (250 ml) and water (3 x 150 ml). The org. phase was dried over
Na2S04.After evaporation in vacuo, the residue was chromatographed on
a silica gel column using 0-1% MeOH in CHCI3 to afford 5 (1.05 g,
79%).- ‘H-NMR (CDC13): 6 (ppm) = 2.13 (2 x m,J2,F = 36.8 Hz, IH, 2’H(p)), 2.49 (s, 3H, SCH3),2.55 (s, 3H, SCH3),2.68 (m, lH, 2’-H(a)), 2.88
(m,lH, 2’-H(a)), 3.13 (ddd, J = 27.7; 21.3; 5.5 Hz, lH, 2’-H(P)), 4.374.77 (m, 5-H, 4’-H(P)), 4.97 (dt, J = 23.6,4.5 Hz, IH, 4’-H(cr)), 5.32 (dt, J
= 53.0, 3.5 Hz, IH, 3’-H), 6.1 1 (d, J = 7.0 Hz, IH, 5-H), 6.25 (d, J = 7.3
Hz, IH, I’-H(p)), 6.32 (d, J = 6.6 Hz, lH, l’-H(a)), 7.27-8.09 (m,10 H,
Ar-H, 6-H).- I3C-NMR (CDCI3): 6 (ppm) = 12.61 (SCH3), 39.47 (d, J =
20.5 Hz, C-2’U), 39.39 (d, J = 21.6 HZ, C-2p), 63.30 (d, J = 11.5 Hz, C5’a),63.66 (d, J = 10.4 Hz, C-S’P), 83.52 (d, J = 26.5 Hz,C-4’p). 85.41
(d, J = 24.7 Hz, C-4’a). 87.84 (C-l’p), 88.52 (C-l’a), 93.61 (d, J = 180.3
Hz, C-3’a.p). 103.32 (C-5), 127.08, 127.14, 128.20, 128.26, 129.79,
130.01, 139.41, 146.32 (biphenyl), 138.01 (C-6), 153.55 (C-2), 165.61
(C=O), 178.04 (C-4).- FAB MS (CDC13 + 1% AcOH + 3-nitrobenzyl
alcohol): m/z: 441 (M + H+).
I-(2,3-Dideoxy-3-fluoro-/%D-erythro-pentofuranosy1)-4methylthiopyrimidin-2(1H)-one (6)and its a-anomer 7
Satd. NH$vleOH (40 ml)was added dropwise with stirring to a solution
of the anomeric mixture 5 (2 mmol) in methanol (20 ml) at 0°C. The
reaction mixture was stirred at room temp. for 5 h. The solvent was
Arch. Pharm.(Weinheirn)328.67-70 (1995)
69
removed in vacuo and the residue was chromatographed on a silica gel
column using 3% MeOH in CHCll to afford 6 (265 mg, 45%) and 7 (120
mg, 20%).
6 (p-anomer): ‘H-NMR (CD30D): 6 (ppm) = 2.21 (2 x m, J = 38.5 Hz,
lH, 2’-H), 2.52 (s, 3H, SCH3), 2.77 (ddd, J = 20.8; 14.6 5.3 Hz,lH, 2’H), 3.76 (d, J = 2.8 Hz, 2H, 5’-H), 4.35 (d, J = 26.2 Hz, lH, 4’-H), 4.76 (s,
lH, OH), 5.26 (dd, J = 53.7; 4.4 HZ, IH, 3’-H), 6.23 (t. J = 6.1 Hz, lH, 1’H), 6.46 (d, J = 6.4 Hz, lH, 5-H), 8.13 (d, J = 6.8 Hz, lH, 6-H).- I3C-NMR
(CD30D): 6 (ppm) = 13.19 (SCH3),41.02 (d, J = 11.4 Hz, C-2’), 62.83 (d,
J = l0.8H~,C-5’),88.16(d,J=23.7H~,C-4’),89.15(C-l’),96.19(d,J=
176.3 Hz, C-3’), 105.40 (C-5), 141.83 (C-6). 156.39 (C-2), 180.85 (C-4).MS (70 eV): m/z (%) = 260 (33, M+*).
7 (a-anomer): ‘H-NMR (CD30D): 6 (ppm) = 2.44 (dd, J = 22.6; 16.3
Hz, IH, 2’-H), 2.52 (s, 3H, SCH3), 2.74 (2 x m, J = 42.7 Hz, IH, 2’-H),
3.65 (m, 2H, 5’-H), 4.60-4.80 (m, 2H, 4’-H and OH), 5.24 (dd, J = 53.4;
4.6 Hz, lH, 3’-H), 6.16 (d, J = 6.9 Hz, IH, 5-H), 6.46 (d, J = 7.4 Hz,lH,
l’-H), 7.86 (d, J = 7.1 Hz, lH, 6-H).- I3C-NMR (CD,OD): 6 (ppm) =
13.17 (SCH,), 41.16 (d, J = 20.3 Hz, C-2’). 63.04 (d, J = 11.5 Hz,C-5’).
90.46 (d, J = 22.7 Hz, C-4’). 90.74 (C-1’). 95.87 (d, J = 174.4 Hz, C-3’),
104.91 (C-5). 141.51 (d, J = 3.7 Hz,C-6), 156.58 (C-2). 180.65 (C-4).- MS
(70 eV): m/z (%) = 260 (22, M+’).
I -(3-Azido-5-O-tert-butyldiphenylsilyl-2j-dideoxy-a,~-~-erythropentofuranosyl)-S-methyl-4-methylthiopyrimidin-2(lH)-one
(10)
A mixture of 4-methylthiothymine 9 (1.25 g, 8 mmol) and HMDS
(50 ml) was refluxed for 1 h and the solvent was removed in vacuo. The
residue was dissolved in dry MeCN (20 ml) and the azido sugar 8 (2.05 g,
5 mmol) was added. The reaction mixture was stirred and cooled to -30°C.
A solution of TMS triflate (1.3 ml, 6.5 mmol) in dry MeCN (5 ml) was
added dropwise. The reaction mixture was stirred for 0.5 h at -25°C. The
temp. was raised to room temp. and the mixture was stirred for 0.5 h. Then
it was diluted with CH2CI2(200 ml), washed with a cold satd. aq. NaHC03
(350 ml), water (3 x 200 ml) and dried (Na2S04). The solvent was
removed in vacuo and the residue was chromatographed on a silica gel
column using 1% MeOH in CHCl, to give the anomeric mixture 10 (2.3 g,
86%) which was directly deprotected.
I -(3-Azido-2,3-dideoxy-/%D-erythro-pentofuranosyl)-5-methyl-4methylthiopyrimidin-2(IH)-one(11) and its a-anomer (12)
Tetrabutylammonium fluoride (5 ml, 1M solution in THF) was added
slowly with stirring to the cold solution of the anomeric mixture 10
(5 mmol) in THF (50 ml) at 0°C for 0.5 h. The mixture was stirred at room
temp. for 1 h. The solvent was removed in vacuo and the residue was
separated on a silica gel column with 1-3% MeOH in CHC13 to give 11
(330 mg, 27%) and 12 (650 mg, 53%).
11 (p-anomer): ‘H-NMR (CDCI3): 6 (ppm) = 2.03 (s, 3H, CH3), 2.53
(m, 5H, 2’-H and SCH3), 3.80-4.10 (m,3H, 5’-H and 4’-H), 4.38 (q, J =
5.8 Hz, IH, 3’-H), 6.05 (t, J = 5.9 Hz, lH, l’-H), 7.80 (s, lH, 6-H).- I3CNMR (CDCI3):6 (ppm) = 12.85 (CH,), 13.96 (SCH,), 38.06 (C-2’). 59.36
(C-3’), 61.34 (C-5’). 85.25, 87.87 (C-1’ and C-4’). 112.20 (C-5). 137.86
(C-6). 153.77 (C-2), 178.92 (C-4).- MS (70 eV): m/z (%) = 297 (5, M+’).
12 (a-anomer): ‘H-NMR (CDC13): 6 (ppm) = 2.07 (s, 3H, CH3), 2.20
(m, IH, 2’-H), 2.56 (s, 3H, SCH3), 3.02 (m, lH, 2’-H), 3.74-3.84 (m, 2H,
5’-H), 4.31-4.37 (m,2H, 3’-H and 4’-H), 6.19 (dd, J = 6.6; 2.9 Hz, lH, 1’H), 7.43 (s, lH, 6-H).- I3C-NhlR (CDCI3):6 (ppm) = 12.90 (CH,), 14.19
(SCH3). 38.73 (C-2’). 61.12 (C-3’), 62.60 (C-5’), 86.99, 87.88 (C-I’ and
C-4’). 111.84 (C-5), 136.19 (C-6), 153.91 (C-2). 178.71 (C-4).- MS (70
eV): d z (%) = 297 (4, M+*).
70
1-(3-Amino-23-dideoxy-~-erythro-penrofurunosyl)-5-methyl-4methylthiopyrimidin-2(lH)-one(13)
The azido derivative 11 (18.7 mmol) and triphenylphosphine (30.5
mmol) were dissolved in 15 ml of pyridine and kept at room temp. for 1 h.
Conc. NH, in water was added and the solution was allowed to stand for
an additional 3 h. Pyridine was removed in vacuo and the residue was
chromatographed on a silica gel column with 5.10% MeOH in CHC13 to
remove impurities and then with 20-25% MeOH in CHCI, to give 13 (97
mg, 71%).- ‘H-NMR ([D,]DMSO): 6 (ppm) = 1.96 ( s , 3H, CH,), 2.032.34 (m, 2H, 2’-H), 2.45 (s, 3H, SCH,), 3.36 (m, IH, 3’-H), 3.58-3.70 (m,
3H, 4’-H and 5’-H). 5.10 ( s , lH, OH), 5.98 (dd, IH, J = 6.3: 3.7 Hz, 1’-H),
8.13 (s, lH, 6-H).- ‘,C-NMR ([D6]DMSO): 6 (ppm) = 12.08 (CH3), 13.45
(SCH,), 41.60 (C-2’). 49.47 (C-3’). 59.79 (C-5’). 85.21, 88.02 (C-1’ and
C-4’), 109.88 (C-5). 138.49 (C-6). 152.41 (C-2). 176.31 (C-4): MS (70
eV): m/z (%) = 271 (0.7, M+).
Pedersen and coworkers
The reaction mixture was refluxed for 2 h and then cooled to Mom temp.
The solvent was removed in vacuo and the residue was chromatographed
on a silica gel column with 510% MeOH in CHCI, to remove impurities
and then with 15-20% MeOH in CHCI, to give 13 in 51% yield and 17 in
30% yield, respectively.
17: ’H-NMR ([D,]DMSO): 6 (ppm) = 1.83 (s, 3H, 5-CH3). 1.94 (m, 2H,
2’-H), 2.78 (d, J = 4.0 Hz, NH-CH,), 3.30-3.70 (m,4H, 3’-H, 4’-H and 5’H), 4.96 ( s , IH, OH), 6.06 (t, J = 5.6 Hz, IH, 1’-H), 7.10 (9, J = 4.1 Hz,
lH, NH),7.64 (s, lH, 6-H).- I3C-Nh4R ([D6]DMSO): 6 (ppm) = 12.92 (5CH,), 27.44 (NH-CH,), 41.33 (C-2’), 50.43 (C-3’). 60.63 (C-5’). 83.96 (C1’). 87.35 (C-4’). 101.06 (C-5). 136.96 (C-6). 154.92 (C-2), 163.07 (C-4).MS (70 eV): m/z (%) = 254 (1, M+’).
References
1-(5-O-Acetyl-3-phrhalimido-2
3-dideoxy-~-~-erythro-pentofuranosyl)-5- 1
rnethyl-4-methylthio-pyrimidin-2(IH)-one
(15) and its a-anomer 16
2
3
A solution of TMS triflate ( I .3 ml, 6.5 mmol) in dry MeCN (5 ml) was
added dropwise to a stirred mixture of the phthalimido sugar 14 (1.24 g, 5
4
mmol) and the silylated 4methylthiothymine 9 (0.89 g, 8 mmol) in dry
MeCN (30 ml) at -30°C. The temp. was raised to room temp. The reaction
mixture was stirred for 1 h. The solution was diluted with CHzClz (200
5
ml). washed with a cold satd. aq. NaHCO, (350 ml), cold water (3 x 200
6
ml) and dried (NazSO,). The solvent was removed in vucuo and the residue was chromatographed on a silica gel column with ethyl acetate/petro7
leum ether (64, v/v) to give 15 (860 mg, 54%) and 16 (120 mg, 8%).
15 (p-anomer): ‘H-NMR ([D6]DMSO): 6 (ppm) = 2.01 (s. 6H, CH, and
8
CH,CO), 2.38 (m, lH, 2’-H), 2.47 (s, 3H, SCH,), 2.88 (m, IH, 2’-H), 4.27
(d, J = 4.2 Hz, 2H, 5’-H), 4.52 (m, lH, 4’-H), 4.87 (m, lH, 3’-H), 6.42 (t. J
9
= 6.3 Hz, lH, 1’-H), 7.87 (m, 5H, Ar-H and 6-H).- ‘,C-NMR
10
([D6]DMSO): 6 (ppm) = 12.18 (CH3), 13.34 (SCH,), 20.36 (CH,CO),
11
34.61 (C-2’), 48.79 (C-3’). 63.74 (C-5’), 78.40 (C-4’), 86.33 (C-1’).
110.70 (C-5). 122.94 (phth), 131.44 (phth), 134.31 (phth), 138.56 (C-6),
152.21 (C-2). 167-38 ( G O ) , 169.94 (CH,CO), 177.36 (C-4).- FAB MS
12
(DMSO + AcOH + 3-nitrobenzyl alcohol): m/z: 444 (M + H+).
13
16 (a-anomer): ’H-NMR ([D,]DMSO): 6 (ppm) = 2.01 (s, 3H, CH,),
2.06 (s, 3H, CH,CO), 2.48 (s, 3H, SCH,), 2.65 (m, lH, 2’-H), 2.87 (m, lH,
14
2’-H), 4.22 (m, 2H, 5’-H), 4.86 (m, 2H. 3’-H and 4’-H), 6.20 (dd, J = 6.7;
15
5.3 Hz, IH, 1’-H), 7.86 (m,4H, Ar-H), 7.93 (s, IH, 6-H).- ‘,C-NMR
16
([D,]DMSO): 6 (ppm) = 12.18 (CH,), 13.57 (SCH,), 20.57 (CH,CO),
17
34.31 (C-2’). 48.77 (C-3’), 63.39 (C-5’), 76.91 (C-4’). 85.90 (C-I,),
18
110.71 (C-5), 122.95 (phth), 131.37 (phth), 134.33 (phth), 137.35 (C-6),
152.34 (C-2). 167.41 ( G O ) , 169.89 (CH&O), 177.14 (C-4).- FAB MS
19
(DMSO + 1% AcOH + 3-nitrobenzylalcohol): m/z: 444 (M + H+).
20
Preparation of 13 and 1-(3-amino-2.3-dideoxy-~-erythropentofuranosyl)-5-methyl-4-methylaminopyrimidin-2(1H)-one
(17)
A 33% solution of MeNHz in absol. EtOH (60 ml) was added to a stirred
solution of compound 15 (4 mmol) in 99.9% EtOH (30 ml) at room temp.
S. Czernecki, T. Le Diguarher, J.M. ValCry, Nucleosides & Nucleo-
rides 1993.12.369-380.
J.P. Honvitz, J. Chua, M. Noel, J. Org. Chem. 1964,29,2076-2078.
H. Hartmann, M.W. Vogt, A.G. Dumo, M.S. Hirsch, G. Hunsmann, F.
Eckstein, AIDS Res. Human Retrovir. 1987,4,457-466.
H. Mitsuya, K.J. Weinhold, P.A. Furman, M.H. Saint-Clair, S. Nusinoff Lehrmann, R.C. Gallo, D. Bolognesi, D.W. Barry, S. Broder,
Proc. Natl. Acad. Sci. USA 1985.82.7096-7100.
J. Balzarini, M. Baba, R. Pauwels, P. Herdewijn, E. De Clercq, Biochem. Pharmucol. 1988,37,2847-2858.
J. Balzarini, M. Baba, R. Pauwels, P. Herdewijn, S.G. Wood, M.J.
Robins, E. De Clercq, Mol. Pharmacol. 1988.33.243-249.
E. De Clercq, A.V. Aerschot, P. Herdewijn, M. Baba, R. Pauwels. J.
Balzarini, Nucieosides and Nucleotides 1989,s. 659-67 1.
Y.-C. Cheng, G.E. Dutschmann, K.F. Bastow, M.G. Sarnyadharan,
R.Y.C. Ting, J . Biol. Chem. 1987.262.2 187-2189.
M.S. Motawia, E.B. Pedersen, Liebigs Ann. Chem. 1990,599-602.
H.M. Abdel-Bary, A.A. El-Barbary, A.I. Khodair, A.E.-S. AbdelMegied, E.B. Pedersen, C. Nielsen, Bull. Soc. Cim. Fr., submitted.
T.H. Brown, R.C. Blakemove, G.J. Durant, J.C. Emmett, C. Robin
Ganellin, M.E. Parsons, D.A. Anthony Rawlings, T.F.J. Walker, J .
Med. Chem. 1988,23,53-62.
J.J. Fox, D.V. Praag, J. Am. Chem. Soc. 1960,82,486-489.
H. Vorbriiggen, K.Krolikiewicz, B. Bennua, Chem. Ber. 1981, 114,
1234-1255.
U. Niedballa, H. Vorbriiggen, J . Org. Chem. 1974.39.3654-3660.
P. Hansen, E.B. Pedersen, Acta. Chem. Scand. 1990,44,522-523.
W.S. Mungall, G.L. Greene, G.A. Heavner, R.L. Letsinger, J . Org.
Chem. 1975,40, 1659-1882.
H. Staudinger, E. Hauser, Helv. Chim. Acta 1921,4,21-23.
M.S. Motawia, .I.
Wengel, A.E.-S. Abdel-Megied, E.B. Pedersen. Synthesis 1989, 384-387.
M.S. Motawia, E.B. Pedersen, Liebigs Ann. Chem. 1990, 1137-1 139.
P. Nuhn, A. Zschunke, 0. Heller, G. Wagner, Tetrahedron 1969.25,
2139-2144.
21 G.W.J. Fleet, J. Son, A.E. Derome, Tetrahedron 1988,44,625-636.
22 M.S. Motawia, A.M. El-Torgoman, E.B. Pedersen, Liebigs Ann.
Chem. 1991,879-883.
[Ph254]
Arch. Pharm. (Weinheim) 328,67-70 (1995)
Документ
Категория
Без категории
Просмотров
2
Размер файла
392 Кб
Теги
hiv, synthesis, azt, flt, evaluation, methylthio, analogues
1/--страниц
Пожаловаться на содержимое документа