CAS No.......518048-05-0 (free acid)
871038-72-1 (monopotassium salt)IUPAC Name:-
N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)
Organic Process Research and Development, 2011 , vol. 15, 1 pg. 73 - 83,
143 - 144.1 °C(free acid)
MW: 444.42
..........................................................
K SALT
C
20H
20FN
6O
5*K, 482.513
MP..275 - 277 °C
European Journal of Medicinal Chemistry,
2012 , vol. 50, pG. 361 - 369
Drug
information:- Raltegravir is an Anti-microbial drug further classified
as anti-viral agent of the class integrase inhibitor. It is used either
signally or in combination with other drugs for the treatment of human
immunodeficiency virus (HIV) and further clinical trials are in process.
RALTEGRAVIR
CAS NO. 518048-05-0, Raltegravir H-NMR spectral analysis
k salt
............
http://www.google.com/patents/WO2011123754A1?cl=en
Raltegravir, also referred to as Raltegravir free
hydroxy, N-(2-(4-(4- fluorobenzylcarbamoyl)-5 -hydroxy- 1 -methyl-6-oxo-
1 , 6-dihydropyrimidin-2-yl)propan-2- yl)
-5-methyl-l,3,4-oxadiazole-2-carboxamide, having the following formula;
is an antiretroviral drug used to treat HIV
infection. Raltegravir targets integrase, an HIV enzyme that integrates
the viral genetic material into human chromosomes, a critical step in
the pathogenesis of HIV. Raltegravir potassium salt is marketed under
the trade name ISENTRESS™ by Merck & Co.
Raltegravir and its preparation are described in US
Patent No. 7,169,780. US Publication No. US 2006/0122205, WO 2010/140156
and WO 2011/024192 describe potassium salt of Raltegravir including
amorphous and crystalline forms I, II, III and HI as well as amorphous
and crystalline forms of Raltegravir free-hydroxy.
The present invention relates to salts of Raltegravir, as well as solid
state forms of Raltegravir and Raltegravir salts. These properties can
be influenced by controlling the conditions under which Raltegravir
potassium, Raltegravir sodium, Raltegravir calcium, Raltegravir
tert-butyl amine, Raltegravir lithium, Raltegravir diethylamine,
Raltegravir diisopropylamine, Raltegravir meglumine and Raltegravir free
hydroxy, are obtained in solid form.
Polymorphism, the occurrence of different crystal
forms, is a property of some molecules and molecular complexes. A single
molecule may give rise to a variety of polymorphs having distinct
crystal structures and physical properties like melting point, thermal
behaviors (e.g. measured by thermogravimetric analysis - "TGA", or
differential scanning calorimetry - "DSC"), X-ray diffraction pattern,
infrared absorption fingerprint, and solid state NMR spectrum. One or
more of these techniques may be used to distinguish different
polymorphic forms of a compound.
http://www.google.com/patents/WO2012103105A1?cl=en
U.S. Patent No. 7, 169,780 discloses Raltegravir and preparation thereof, as described in the following reaction scheme:
Scheme 1
J. Med. Chem. 2008, 51 , 5843-5855 discloses another
process for preparing Raltegravir as described in the following
reaction scheme:
RLT K-salt
Scheme 2
U.S. Publication No. US 2006/0122205 describes an alternative process
for preparing Raltegravir, in which the alkylation step does not include
a step for protecting the 5-hydroxy group. The process is described in
the following reaction scheme:
Scheme 3
Provided herein is an industrially applicable
process for preparing RLT-7', RLT-8, RLT-9 and RLT-9-OP, intermediates
in the synthesis of Raltegravir, as well as processes for preparing
Raltegravir and crystalline forms thereof.
US Publication No. US 2006/0122205, WO 2010/1401 56 and WO 201 1 /
024192 describe the potassium salt of Raltegravir,
including amorphous and crystalline forms I, II, III and H I , as well
as amorphous and crystalline forms of Raltegravir free- hydroxy. PCT
publication No. WO 201 1/123754 describes certain Raltegravir salts and
polymorphs, including form V of Raltegravir potassium.
Example 9: Preparation of Raltegravir
To a 0.5 liter reactor was added acetonitrile ( 15
vol), N-methylpyrrolidinone ( 1 vol) and N-methylmorpholine (0.5 g). The
resulting solution was cooled to about 0°C and then methyl oxadiazole-
potassium (8g) was added. Pivaloyl chloride (7.22 ml) was then added
dropwise (over 10 min). The resulting mixture was stirred for about 6 h.
N-Methylmorpholine (5.9 g) and RLT-9 were then
added. The resulting mixture was then heated to 20°C and stirred for
16h. The solvent was then evaporated to provide a residue. Water (75 ml)
and isopropyl alcohol (25 ml) were added to the residue. The resulting
solution was stirred overnight at RT. A precipitate formed and was
filtered and
washed with water (10 ml) and IPA (20 ml). The product was dried under
vacuum at 60°C overnight to give 8.76g Raltegravir (85.7% assay, 77%
yield). The obtained crude product was purified by slurry in MeOH/Water
mixture
https://web.stlawu.edu/library/system/files/course_readings/Discovery%20of%20Raltegravir,%20a%20Potent,%20Selective%20Orally%20Bioavailable.pdf
Journal of Medicinal Chemistry, 2008, Vol.51 no 18 pg 5854
free base
NMR (DMSO-d6)δ
12.19 (s, 1 H), 9.83 (s, 1 H), 9.25-8.90 (bs,1 H), 7.39 (dd,J)8.5, 5.6 Hz, 2 H), 7.16 (app. t,J)8.8 Hz, 2H), 4.51 (d,J)6.4 Hz, 2 H), 3.48 (s, 3 H), 2.56 (s, 3 H), 1.74 (s,6 H). MSm/z445 (M+H)+. HRMS calcd for C20H22O5N6F(M+H)+
: 445.16302. Found: 445.16278. Melting point 216°C.
k salt
1H NMR (DMSO-d6) 11.70-11.20 (bs, 1 H), 9.75 (s, 1H), 7.33 (dd,J)8.8, 5.8 Hz, 2 H), 7.12 (app. t,J)
8.8 Hz, 2 H),4.44 (d,J)5.8 Hz, 2 H), 3.40 (s, 3 H), 2.56 (s, 3 H), 1.70 (s, 6H). Melting point 282°C
..............................................
nmr
Imp roved synthesis of raltegravir
GUO D i2liang et al
Department ofM edicinal Chem istry, China PharmaceuticalUniversity, N anjing 210009;
Journal of China Pharmaceutical University 2009, 40 (4) : 297 - 301
http://star.sgst.cn/upload/attach/attach20091230100028d4masjzgcv.pdf
1H NMR (CD3OD) δ: 7.40 (m, 2H) , 7.04 (m , 2H) ,
4.56 (s, 2H ) , 3.46 ( s, 3H ) , 2.65 (s, 3H ) , 1.83 (s,
6H);
13C NMR (CD3OD ) δ: 168.4, 164.8, 163.2,
162.0, 161.9, 160.1, 155.3, 145.8, 136.0, 134.9,
131.0, 116.7, 116.6, 60.2, 43.8, 41.3, 34.8, 27.6,
11.4;
ESI2MS m /z 443 (M )-; LR2MS (EI) m /z 444(M )+; HR2MS ( E I) m /z C20 H21 FN6O5(M )+
calcd444, 155, 7, found 444, 154, 2
second set
WO2009088729 ,
US20100280244
lH NMR (399.87 MHz
5 CDCI3) δ 12.04 (s, IH), 8.45 (s, IH), 7.94 (t, J = 6.2 Hz, IH), 7.41-736 (m, 2H), 7.08-7.02 (m, 2H)
5 4.61 (d, J - 6.2 Hz, 2H), 3.68 (s, 3H), 2.63 (s, 3H), 1.87 (s, 6H).
13C NMR (100.55 MHz, CDCI3) δ 168.3, 166.7, 162.6 (d, JCF=245.7 Hz), 159.6, 159.1, 152.O
5 150.4, 147.2, 133.4 (d, JCP=3.2 Hz)
5 129.9 (d, JcF=8.0 Hz), 124.1, 115.9 (d, JcF=21.7 Hz), 58.0, 42.7, 33.5, 26.7, 11.4.
.........................
IR
WO2011024192,
WO2011024192A3
absorption bandsKBR (cm
"1) at 832, 1017, 1248, 1350, 1510, 1682, 2995, and 3374
...................
K SALT
Org. Process Res. Dev., 2011, 15 (1), pp 73–83
DOI: 10.1021/op100257r
http://pubs.acs.org/doi/full/10.1021/op100257r
mp 274.2−275.2 °C.
1H NMR (500 MHz, DMSO-
d6) δ: 11.65 (t,
J = 6.0 Hz, 1 H), 9.75 (s, 1 H), 7.36 (dd,
J = 8.6, 5.7 Hz, 2 H), 7.14 (app. t,
J = 8.6 Hz, 2 H), 4.48 (d,
J = 6.0 Hz, 2 H), 3.43 (s, 3 H), 2.58 (s, 3 H), 1.73 (s, 6 H);
13C NMR (125 MHz, DMSO-
d6) δ: 168.7, 167.0, 166.6, 162.1 (d,
JCF = 243 Hz), 159.7, 158.3, 153.1, 139.6, 138.0 (d,
JCF = 3 Hz), 130.2 (d,
JCF = 8 Hz), 123.7, 116.0 (d,
JCF = 22), 58.4, 42.1, 33.3, 28.1 (2 C), 11.7.
.................................
.........
China
Pharmaceutical University (CPU), located in the "ancient capital city of
six dynasties" - Nanjing, is one of the "211 project" key universities
...
DHAKA BANGLADESH
.
Steamers and ferries in Sadarghat Port
Kawran Bazar
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Dry fish sellers at the Karwan Dry Fish Market (Bazar), Dhaka, Bangladesh.