Vol. 29, No. 5 (2017)
A Novel Process for Synthesis of Rosuvastatin 1019
2-{methyl(methylsulfonyl)amino}-5-pyrimidinyl)methyl]
triphenylphosphonium bromide (100 g) and tert-butyl (4R-
cis)-6-formaldehyde-2,2-dimethyl-1,3-dioxane-4-acetate
(45.66 g) in DMSO (350 mL) at 25-30 °C was added potassium
carbonate (50 g) under N2 atmosphere at 25-30 °C. Stir the
reaction mass at 65-70 °C for 4 h. Reaction monitored by TLC,
after completion of reaction add toluene (600 mL) at 50-55 °C
and cool to 25-30 °C. Filter the reaction mass and washed
with 200 mL toluene. Cooled the filtrate to 0-5 °C and slowly
added 600 mL water, separated the organic layer and washed
with water, distilled off solvent completely under vacuum at
65-70 °C to get the solid. Charged methanol (300 mL) stirred
the separated solid for 1 h at 25-30 °C. Filtered the solid and
washed with methanol (100 mL). Dried the material under
vacuum at 50 °C to get compound-V.
and twice washed with purified water (100 mL). Distilled the
solvent completely under reduced pressure at 50 °C and co-
distilled with toluene (120 mL) at 50 °C. Residue dissolved in
toluene (480 mL) at 60 °C. Slowly cooled to 25 °C and left
for 3 h. Filtered the solid and washed with toluene (120 mL)
to yield N-(4-bromophenyl)-2-((4R,6S)-6-((E)-2-(4-(4-fluoro-
phenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)-
pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)aceta-
mide (compound-III).Yield 73 % and HPLC purity 97.6 %.
Compound-III was confirmed by analytical data.
Off-white crystalline solid; m.p.: 124-126 °C and DSC:
1
126.19 °C. GC-MS (m/z): 677 [M+1]; H NMR (400 MHz,
CDCl3) δ (ppm): 8.3 (1H, s), 7.6 (2H, m), 7.4 (4H, m), 7 (2H,
t), 6.57 (1H, d), 5.4 (1H, dd), 4.4 (1H, bd), 4.3 (1H, m), 3.57
(3H, d), 3.51 (3H, s), 3.3 (1H, m), 2.5 (2H, d), 1.5 (6H, d), 1.3
(1H, s), 1.2 (6H, m); XRPD with specific peaks 2θ: 5.7, 9.3,
10.0, 11.4, 12.4, 13.4, 14.1, 14.4, 14.8, 16.6, 17.6, 19.3, 19.6,
20.2, 20.6, 21.0, 21.3, 22.0, 22.7, 23.7, 24.2, 24.6, 24.9, 25.5,
26.6, 27.1, 27.9, 28.6, 29.8, 31.3, 32.5, 33.5, 34.6 and 36.8.
FT-IR (KBr, cm–1): 3382, 2966, 1677, 1596, 1151, 504.
Few of the related compounds are prepared and confirmed
by 1H NMR and Mass data.
Preparation of 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-
6-isopropyl-2-(N-methyl methyl sulfonamido)pyrimidin-5-
yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetic acid (Compound
IV): In a 2 L 4-necked round bottom flask was taken tert-
butyl-6-[(1E)-2-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-
[methyl(methylsulfonyl)amino]-5-pyrimidinyl]ethenyl]-2,2-
dimethyl-1,3-dioxane-4-acetate (compound-V, 100 g) and
water (50 mL) to this methanolic sodium hydroxide solution
(24.26 g in 1 L) was added at a temperature in the range of 25-
30 °C under stirring. The reaction mixture was heated to 50-
55 °C and stirred for 15 h. Reaction monitored by HPLC, after
completion of the reaction distilled off solvent completely under
reduced pressure. After distillation, 300 mL of dichlorome-
thane and purified water (300 mL) were added and pH adjusted
to 7.0-7.5 using 40 % acetic acid at 20 °C. The mixture was
allowed to settle for about 10 min resulting in two layers,
organic layer washed with 5 % aq. sodium chloride solution
and dried over anhydrous sodium sulphate. To organic layer
was added cyclohexane (1200 mL) precipitate forms which is
heated to 40 °C for 30 min and cooled to 20 °C and stirred for
12 h. Filter the solid and wash with cyclohexane (200 mL) to
obtain compound-IV in 80 % yield with HPLC purity 98.50 %.
Compound was confirmed by analytical data such as IR (KBr,
cm–1) 3482, 2967, 1698, 1605, 1155. GC-MS (m/z): [M+1]
522.2 (m.w.: 521.6). 1H NMR (400 MHz, CD3OD) δ (ppm):
7.7-7.6 (2H, dd), 7.18-7.14 (2H, dd), 6.63-6.58 (1H, d), 5.5-
5.4 (1H, dd), 4.55-4.50 (1H, m), 4.38-4.32 (1H, m), 3.4 (3H,
s), 3.5 (3H, s), 3.2 (1H, m), 1.28 (6H, s), 1.26 (6H, s).
1
R: CH3 (methyl): Mass value: 535.3 [M+1]; H NMR
(400 MHz, CDCl3) δ (ppm): 7.7-7.6, (2H, dd), 7.18-7.14 (2H,
dd), 6.5-6.4 (1H, d), 6 (1H, bd), 5.5-5.4 (1H, dd), 4.55-4.50
(1H, m), 4.38-4.32 (1H, m), 3.57 (3H, s), 3.51 (3H, s), 3.3
(1H, m), 2.8 (3H, d), 2.4 (2H, m), 1.6 (1H, s), 1.5 (3H, bs), 1.2
(3H, bs), 1.26 (6H, s), 1.19 (1H, m).
1
R: C6H5 (phenyl): Mass value: 597.3 [M+1]; H NMR
(400 MHz, CD3OD) δ (ppm): 8.2 (1H, s), 7.7-7.6, (2H, dd),
7.5 (2H, d) 7.3 (2H, t), 7.1 (1H, t) 7.0 (2H, t), 6.5 (1H, dd), 5.5
(1H, dd), 4.4 (1H, m), 4.3 (1H, m), 3.5 (3H, s), 3.39 (3H, s),
3.35 (1H, m), 2.5 (2H, d), 1.6 (1H, m), 1.5 (6H, s), 1.3 (1H, s),
1.2 (6H, m).
R: C6H4-F (4-fluoro phenyl): Mass value: 615.2 [M+1];
1H NMR (400 MHz, CDCl3) δ (ppm): 8.2 (1H, s), 7.7-7.6 (2H,
dd), 7.5 (2H, d), 7.3 (1H, m), 7.1 (4H, m) 6.80 (1H, t), 6.7
(1H, m), 6.5 (1H, dd), 5.4 (1H, dd), 4.4 (1H, m), 4.3 (1H, m),
4.3 (3H, t) 3.9 (4H, m), 3.5 (3H, s), 3.4 (3H, s), 3.3 (4H, m),
2.9 (3H, bt), 2.8 (5H, s), 2.5 (2H, d), 2 (1H, s), 1.5 (3H, s),
1.50 (3H, s) 1.27 (1H, s), 1.26 (6H, s), 0.9 (3H, s), 0.85 (1H, m).
Preparation of (3R,5S,E)-N-(4-bromophenyl)-7-(4-(4-
fluorophenyl)-6-isopropyl-2-(N-methyl methylsulfonyl-
amido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enamide
(compound II): N-(4-bromophenyl)-2-((4R,6S)-6-((E)-2-(4-
(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfona-
mido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-
yl)acetamide (1 mole eq, compound III) is treated with dilute
hydrochloric acid (1 eq, 1.5 molar dilution in water) at 25-
30 °C and stirred for 6 h. Reaction monitored by TLC. After
completion of reaction diolanilide (compound II) is isolated
by distillation of acetonitrile at 45 °C under vacuum.
Preparation of N-(4-bromophenyl)-2-((4R,6S)-6-((E)-
2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsul-
fonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-
4-yl)acetamide (compound III): In a 1 L 4-necked round
bottom flask taken 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-
6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-
yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid (compound-
IV) (60 g) and dichloromethane (480 mL), added N-methyl
morpholine and isobutyl chloroformate at 0-5 °C under
nitrogen atmosphere and stirred for 2 h. The resulting reaction
mixture was added to a mixture of 4-bromo aniline and
dichloromethane (120 mL) at 25-30 °C and stirred for 2 h.
Reaction monitored by TLC, after completion of the reaction
purified water (180 mL) was added and stirred for 10 to 15
min and allowed to settle the layers, separated the organic layer
GC-MS: 636 [M+1]; DSC: 132.91 °C; XRPD with
specific peaks 2θ: 3.2, 4.3, 9.1, 13.2, 13.7, 14.6, 16.9, 17.4,
18.4, 19.0, 19.7, 20.1, 20.8, 22.5, 23.7, 24.7, 25.8, 26.7 and
29.8. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.1 (1H, S), 7.6
(2H, m), 7.4 (3H, m), 7.3 (1H, s), 7.1 (2H, m), 6.6 (1H, d), 5.5
(1H, d), 4.5 (1H, m), 4.3 (1H, m), 3.6 (3H, s), 3.5 (3H, s), 3.3