U.S. patent application number 10/576774 was filed with the patent office on 2007-11-01 for process for the manufacture of the calcium salt of rosuvastatin (e)-7-'4-(4-fluorophenyl)-6-isopropyl-2-'methyl (methylsulfonyl) amino ! pyrmidin -5-yl! (3r, 5s)-3,5-dihydroxyhept-6-enoic acid and crystalline intermediates thereof.
Invention is credited to John Horbury, David Dermot Patrick Laffan, Tetsuo Okada.
Application Number | 20070255060 10/576774 |
Document ID | / |
Family ID | 29595716 |
Filed Date | 2007-11-01 |
United States Patent
Application |
20070255060 |
Kind Code |
A1 |
Okada; Tetsuo ; et
al. |
November 1, 2007 |
Process for the Manufacture of the Calcium Salt of Rosuvastatin
(E)-7-'4-(4-Fluorophenyl)-6-Isopropyl-2-'Methyl (Methylsulfonyl)
Amino ! Pyrmidin -5-Yl! (3R, 5S)-3,5-Dihydroxyhept-6-Enoic Acid and
Crystalline Intermediates Thereof
Abstract
A process for the manufacture of the calcium salt of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl](3R,5S)3,5-dihydroxyhept-6-enoic acid, useful as an
HMGCoA reductase inhibitor, from a compound of the formula (7)
wherein A is an acetal or ketal protecting group and R is alkyl,
via isolated crystalline compounds of the formula (8) or of formula
(10) is described. Crystalline intermediates of formulae 7, 8 and
10 are also described. ##STR1##
Inventors: |
Okada; Tetsuo; (Osaka,
JP) ; Horbury; John; (Bristol, GB) ; Laffan;
David Dermot Patrick; (Cheshire, GB) |
Correspondence
Address: |
MORGAN LEWIS & BOCKIUS LLP
1111 PENNSYLVANIA AVENUE NW
WASHINGTON
DC
20004
US
|
Family ID: |
29595716 |
Appl. No.: |
10/576774 |
Filed: |
October 22, 2004 |
PCT Filed: |
October 22, 2004 |
PCT NO: |
PCT/GB04/04481 |
371 Date: |
March 16, 2007 |
Current U.S.
Class: |
544/297 |
Current CPC
Class: |
C07D 405/06 20130101;
Y02P 20/55 20151101; A61P 9/10 20180101; A61P 3/06 20180101; A61P
43/00 20180101; C07D 239/42 20130101 |
Class at
Publication: |
544/297 |
International
Class: |
C07D 405/06 20060101
C07D405/06; C07D 239/42 20060101 C07D239/42 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 24, 2003 |
GB |
0324791.3 |
Claims
1. A process for the manufacture of the calcium salt of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, comprising: a)
acid hydrolysis of an acetal protecting group in a compound of the
formula (7) ##STR21## wherein A is an acetal or ketal protecting
group and R is (1-6C)alkyl, and isolation of a resulting
crystalline compound of the formula (8); ##STR22## b) optional
recrystallisation of the compound of the formula (8); c) hydrolysis
of the ester group in the compound (8) to give a dihydroxy
carboxylate derivative (9) (wherein M is hydrogen or a metal
counterion other than calcium) or a compound of the formula (1);
and ##STR23## d) where necessary, conversion of a compound of the
formula (9) into a compound of the formula (1).
2. A process as claimed in claim 1 wherein the compound of the
formula (7) is a compound of the formula (7a). ##STR24##
3. A process for the manufacture of the calcium salt of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, from a
crystalline compound of formula (8) as claimed in steps c) and d)
of claim 1.
4. A process as claimed in claim 1 or claim 2 or claim 3 wherein R
is methyl, ethyl, iso-propyl, tert-butyl or hexyl.
5. A process as claimed in any one of claims 1 to 4 wherein R is
ethyl, iso-propyl or tert-butyl.
6. A crystalline compound of the formula 7 as defined in claim 1,
which crystalline compound is
methyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-
amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
having an X-ray powder diffraction pattern with peaks at
2-theta=9.5, 13.6 and 17.5.
7. A crystalline compound of the formula 7 as defined in claim 1,
which crystalline compound is
ethyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)a-
mino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
having an X-ray powder diffraction pattern with peaks at
2-theta=15.9, 18.4 and 19.5.
8. A crystalline compound of the formula 7 as defined in claim 1,
which crystalline compound is
iso-propyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfo-
nyl)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetat-
e having an X-ray powder diffraction pattern with peaks at
2-theta=7.8, 11.6 and 15.5.
9. A crystalline compound of the formula 7 as defined in claim 1,
which crystalline compound is
n-hexyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
having an X-ray powder diffraction pattern with peaks at
2-theta=5.3, 7.1 and 18.9.
10. A crystalline compound of the formula 8 as defined in claim 1,
which crystalline compound is
ethyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amin-
o]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an X-ray
powder diffraction pattern with peaks at 2-theta=8.1, 11.3 and
19.9.
11. A crystalline compound of the formula 8 as defined in claim 1,
which crystalline compound is
iso-propyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an
X-ray powder diffraction pattern with peaks at 2-theta=9.8, 17.3
and 21.1.
12. A crystalline compound of the formula 8 as defined in claim 1,
which crystalline compound is
tert-butyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an
X-ray powder diffraction pattern with peaks at 2-theta=18.2, 19.9
and 20.8.
13. A process for the manufacture of the calcium salt of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, comprising: a)
acid hydrolysis of an acetal protecting group in a compound of the
formula (7) ##STR25## wherein A is an acetal or ketal protecting
group and R is (1-6C)alkyl, and isolation of the resulting
crystalline compound of the formula (10); ##STR26## b) optional
recrystallisation of the compound of the formula (10); c)
hydrolysis of the compound of formula (10) to give a dihydroxy
carboxylate derivative (9) (wherein M is a metal counterion other
than calcium) or a compound of the formula (1); and ##STR27## d)
where necessary, conversion of a compound of the formula (9) into a
compound of the formula (1).
14. A process as claimed in claim 13 wherein the compound of the
formula (7) is a compound of the formula (7a). ##STR28##
15. A process for the manufacture of the calcium salt of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, from a
crystalline compound of formula (10) as claimed in steps b) and c)
of claim 13.
16.
Crystalline(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulf-
onyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic
acid-(3,6)-lactone having an X-ray powder diffraction pattern with
peaks at 2-theta=7.9, 11.9, 15.9, 20.3, 21.7 and 22.5.
17. A process for formation of amorphous
bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-
pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt
comprising isolation of a crystalline compound as claimed in claim
16 from a solution and subsequent conversion to the amorphous form
of
bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-
pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium
salt.
18. The use of a compound as claimed in claim 16 as a processing
aid for isolation of amorphous
bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-
pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium
salt.
19. The use of a compound as claimed in claim 16 as a processing
aid for recovery of amorphous
bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-
pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt
from waste solutions.
20. The use of a compound as claimed in claim 16 as an intermediate
in the manufacture of amorphous
bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-
pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt.
Description
[0001] This invention concerns improvements to a chemical process,
particularly a chemical process for manufacture of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt (1)
(illustrated below), which is useful for the production of a
pharmaceutical useful in the treatment of, inter alia,
hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
This invention also concerns crystalline intermediates useful in
the chemical process. ##STR2##
[0002] The sodium salt (3) and calcium salt (1) of the compound
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid (hereinafter
referred to as the `Agent`) were disclosed in European Patent
0521471. This patent also describes a process for the synthesis of
the calcium salt (1), via the dihydroxy ester (2) and the sodium
salt (3), as shown in Scheme 1 below. The calcium salt thus formed
is then collected and dried and may be processed further as
required. ##STR3##
[0003] Our International Patent Application WO 00/49014 describes
an alternative route to the calcium salt (1), also via the sodium
salt (3), from the compound tert-butyl
(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-
pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
(BEM) (4), which is exemplified as shown in Scheme 2 below:
##STR4##
[0004] As described in WO 00/49014, the transformation from BEM (4)
to the calcium salt (1) may be carried out via the methylamine salt
(5) as shown in Scheme 2. Isolation of this intermediate
crystalline methylamine salt allows purification by
recrystallisation before final formation of the (amorphous) calcium
salt. However formation of the methylamine salt introduces an extra
step into the process, which is generally undesirable for
manufacture (for example because of additional cost and the
potential for introduction of additional impurities).
[0005] The transformation from BEM (4) to the sodium salt (3) in
Scheme 2 takes place in two steps as shown below in Scheme 3.
##STR5##
[0006] Treatment with hydrochloric acid hydrolyses the acetal to
the diol (6) (referred to herein as BED), then treatment with
sodium hydroxide hydrolyses the ester to give the sodium salt (3)
of the parent carboxylic acid. The intermediate compound BED (6) is
not isolated in the process described in WO 00/49014. The analogous
methyl ester (2) was described in European Patent 0521471 as a
syrup and therefore, by analogy, isolation of BED (6) would not be
expected to provide any advantages to the process.
[0007] However we have surprisingly found that BED and other
(1-6C)alkyl ester analogues are generally crystalline compounds
which may advantageously be isolated and recrystallised, thus
removing the need for isolation of an intermediate salt such as the
methylamine salt in order for purification to be carried out.
[0008] Therefore the present invention provides a process for the
manufacture of the calcium salt of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl](3R,5S)-3,5dihydroxyhept-6-enoic acid, comprising:
[0009] a) acid hydrolysis of an acetal protecting group in a
compound of the formula (7) ##STR6## wherein A is an acetal or
ketal protecting group and R is (1-6C)alkyl, and isolation of the
resulting crystalline compound of the formula (8); ##STR7## [0010]
b) optional recrystallisation of the compound of the formula (8);
[0011] c) hydrolysis of the ester group in the compound (8) to give
a dihydroxy carboxylate derivative (9) (wherein M is hydrogen or a
metal counterion other than calcium) or a compound of the formula
(1); and ##STR8## [0012] d) where necessary, conversion of a
compound of the formula (9) into a compound of the formula (1).
[0013] In a further aspect of the invention there is provided
crystalline compounds of the formula (8).
[0014] Furthermore, we have found that some compounds of the
formula (7), which are analogues of BEM (4) are also crystalline
and are themselves useful intermediates which may be recrystallised
if necessary to improve the quality of the material. These
crystalline compounds are novel and each independently provides a
further aspect of the invention.
[0015] Thus in a further aspect of the invention is provided
crystalline
methyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-
amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
having an X-ray powder diffraction pattern with peaks at
2-theta=9.5, 13.6 and 17.5.
[0016] In a further aspect of the invention is provided crystalline
methyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-
amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2dimethyl[1,3]dioxan-4-yl)acetate
having an X-ray powder diffraction pattern with peaks at
2-theta=5.7, 9.5, 13.6, 17.5, 19.9 and 22.4.
[0017] In a further aspect of the invention is provided crystalline
methyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-
amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
having an X-ray powder diffraction pattern with peaks at
2-theta=5.7, 8.7, 9.5, 13.6, 17.5, 19.0, 19.9, 20.8, 21.8 and
22.4.
[0018] In a further aspect of the invention is provided crystalline
methyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-
amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
having an X-ray powder diffraction pattern substantially as shown
in FIG. 1.
[0019] In a further aspect of the invention is provided crystalline
ethyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)a-
mino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
having an X-ray powder diffraction pattern with peaks at
2-theta=15.9, 18.4 and 19.5.
[0020] In a further aspect of the invention is provided crystalline
ethyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)a-
mino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
having an X-ray powder diffraction pattern with peaks at
2-theta=15.9, 18.4, 19.5, 23.0, 24.3 and 25.0.
[0021] In a further aspect of the invention is provided crystalline
ethyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)a-
mino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
having an X-ray powder diffraction pattern with peaks at
2-theta=5.9, 8.0, 12.2, 15.9, 18.4, 19.5, 19.7, 23.0, 24.3 and
25.0.
[0022] In a further aspect of the invention is provided crystalline
ethyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)a-
mino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
having an X-ray powder diffraction pattern substantially as shown
in FIG. 2.
[0023] In a further aspect of the invention is provided crystalline
iso-propyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfo-
nyl)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetat-
e having an X-ray powder diffraction pattern with peaks at
2-theta=7.8, 11.6 and 15.5.
[0024] In a further aspect of the invention is provided crystalline
iso-propyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfo-
nyl)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetat-
e having an X-ray powder diffraction pattern with peaks at
2-theta=6.9, 7.0, 7.8, 8.7, 11.6 and 15.5.
[0025] In a further aspect of the invention is provided crystalline
iso-propyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfo-
nyl)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetat-
e having an X-ray powder diffraction pattern with peaks at
2-theta=6.9, 7.0, 7.8, 8.7, 10.4, 11.6, 13.0, 14.7, 15.5 and
20.2.
[0026] In a further aspect of the invention is provided crystalline
iso-propyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfo-
nyl)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetat-
e having an X-ray powder diffraction pattern substantially as shown
in FIG. 3.
[0027] In a further aspect of the invention is provided crystalline
n-hexyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
having an X-ray powder diffraction pattern with peaks at
2-theta=5.3, 7.1 and 18.9.
[0028] In a further aspect of the invention is provided crystalline
n-hexyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
having an X-ray powder diffraction pattern with peaks at
2-theta=5.3, 7.1, 14.2, 14.8, 18.9 and 21.4.
[0029] In a further aspect of the invention is provided crystalline
n-hexyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
having an X-ray powder diffraction pattern with peaks at
2-theta=5.3, 7.1, 11.4, 14.2, 14.8, 18.9, 20.1, 20.4 and 21.4.
[0030] In a further aspect of the invention is provided crystalline
n-hexyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
having an X-ray powder diffraction pattern substantially as shown
in FIG. 4.
[0031] In a further aspect of the invention is provided crystalline
ethyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amin-
o]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an X-ray
powder diffraction pattern with peaks at 2-theta=8.1, 11.3 and
19.9.
[0032] In a further aspect of the invention is provided crystalline
ethyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amin-
o]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an X-ray
powder diffraction pattern with peaks at 2-theta=8.1, 11.3, 12.4,
19.9, 21.0 and 22.1.
[0033] In a further aspect of the invention is provided crystalline
ethyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amin-
o]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an X-ray
powder diffraction pattern with peaks at 2-theta=4.3, 8.1, 11.3,
12.4, 15.1, 19.9, 21.0, 21.7, 22.1 and 23.5.
[0034] In a further aspect of the invention is provided crystalline
ethyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amin-
o]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an X-ray
powder diffraction pattern substantially as shown in FIG. 5.
[0035] In a further aspect of the invention is provided crystalline
iso-propyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an
X-ray powder diffraction pattern with peaks at 2-theta=9.8, 17.3
and 21.1.
[0036] In a further aspect of the invention is provided crystalline
iso-propyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl](3R,5S)-3 ,5-dihydroxyhept-6-enoate having an
X-ray powder diffraction pattern with peaks at 2-theta=9.8, 12.2,
17.3, 19.6, 20.1 and 21.1.
[0037] In a further aspect of the invention is provided crystalline
iso-propyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an
X-ray powder diffraction pattern with peaks at 2-theta=9.8, 12.2,
13.6, 17.3, 18.5, 19.6, 20.1, 21.1, 22.4 and 23.3.
[0038] In a further aspect of the invention is provided crystalline
iso-propyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an
X-ray powder diffraction pattern substantially as shown in FIG.
6.
[0039] In a further aspect of the invention is provided crystalline
tert-butyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an
X-ray powder diffraction pattern with peaks at 2-theta=18.2, 19.9
and 20.8.
[0040] In a further aspect of the invention is provided crystalline
tert-butyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an
X-ray powder diffraction pattern with peaks at 2-theta=9.8, 18.2,
19.9, 20.6, 20.8 and 26.3.
[0041] In a further aspect of the invention is provided crystalline
tert-butyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an
X-ray powder diffraction pattern with peaks at 2-theta=9.8, 17.4,
18.2, 19.4, 19.9, 20.6, 20.8, 22.1, 25.1 and 26.3.
[0042] In a further aspect of the invention is provided crystalline
tert-butyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an
X-ray powder diffraction pattern substantially as shown in FIG.
7.
[0043] A crystalline polymorph of BEM (4) is provided as a further
aspect of the invention.
[0044] The X-ray powder diffraction spectra were determined by
mounting a sample of the crystalline form on Siemans single silicon
crystal (SSC) wafer mounts and spreading out the sample into a thin
layer with the aid of a microscope slide. The sample was spun at 30
revolutions per minute (to improve counting statistics) and
irradiated with X-rays generated by a copper long-fine focus tube
operated at 40 kV and 40 mA with a wavelength of 1.5406 angstroms.
The collimated x-ray source was passed through an automatic
variable divergence slit set at V20 (20 mm path length) and the
reflected radiation directed through a 2 mm antiscatter slit and a
0.2 mm detector slit. The sample was exposed for 4 seconds per 0.02
degree 2-theta increment (continuous scan mode) over the range 2
degrees to 40 degrees 2-theta in theta-theta mode. The running time
was 2 hours 6 minutes and 40 seconds. The instrument was equipped
with a scintillation counter as detector. Control and data capture
was by means of a DECpc LPv 433sx personal computer running with
Diffrac AT (Socabim) software.
[0045] It will be understood that the 2-theta values of an X-ray
powder diffraction pattern may vary slightly from one machine to
another or from one sample to another, and so the values quoted are
not to be construed as absolute. It will also be understood that
the relative intensities of peaks may vary according to the
orientation of the sample under test so that the intensities in the
XRD traces included herein are illustrative and not intended to be
used for absolute comparison.
[0046] The crystalline forms obtained according to the present
invention are substantially free from other crystal and non-crystal
forms of each compound of the formula 7 or 8. The term
"substantially free from other crystal and non-crystal forms" shall
be understood to mean that the desired crystal form contains less
than 50%, preferably less than 10%, more preferably less than 5% of
any other form of the compound.
[0047] Suitable values for the acetal protecting group A are as
described in EP0319847. A preferred value for A is iso-propylidene
such that the compound of the formula (7) is a compound of the
formula (7a). ##STR9##
[0048] Conveniently, in compounds of the formulae 7, 7a and 8, R is
(2-6C)alkyl. More conveniently, R is (2-5C)alkyl.
[0049] Suitably R is selected from methyl, ethyl, propyl,
iso-propyl, butyl, tert-butyl, pentyl and n-hexyl.
[0050] Preferably R is selected from methyl, ethyl, iso-propyl,
tert-butyl and n-hexyl.
[0051] More preferably R is selected from ethyl, iso-propyl and
tert-butyl.
[0052] In a further aspect of the invention there is provided a
process for the manufacture of the calcium salt of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl](3R,5S)-3 ,5-dihydroxyhept-6-enoic acid, comprising:
[0053] a) acid hydrolysis of an acetal protecting group in a
compound of the formula (7a) ##STR10## wherein R is ethyl,
iso-propyl or tert-butyl, and isolation of the resulting
crystalline compound of the formula (8); ##STR11## [0054] b)
optional recrystallisation of the compound of the formula (8);
[0055] c) hydrolysis of the ester group in the compound (8) to give
a dihydroxy carboxylate derivative (9) (wherein M is hydrogen or a
metal counterion other than calcium) or a compound of the formula
(1); and ##STR12## [0056] d) where necessary, conversion of a
compound of the formula (9) into a compound of the formula (1).
[0057] In a further aspect of the invention there is provided a
process for the manufacture of the calcium salt of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, comprising:
##STR13## [0058] a) hydrolysis of the ester group in a crystalline
compound of the formula (8) (where R is as hereinbefore defined) to
give a dihydroxy carboxylate derivative (9) (wherein M is hydrogen
or a metal counterion other than calcium) or a compound of the
formula (1); and ##STR14## [0059] b) where necessary, conversion of
a compound of the formula (9) into a compound of the formula
(1).
[0060] The compound of the formula (8) in this aspect of the
invention may be made by any convenient method such as those
described and referenced hereinbefore.
[0061] In a further aspect of the invention, there is provided the
use of a crystalline compound of formula (7a) as an intermediate in
the manufacture of amorphous
bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-
pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium
salt.
[0062] In a further aspect of the invention, there is provided the
use of a crystalline compound of formula (8) as an intermediate in
the manufacture of amorphous
bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-
pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium
salt.
[0063] Under some conditions for the hydrolysis of the acetal group
A in a compound of formula (7), the group R may also simultaneously
be hydrolysed which may result in formation of the crystalline
lactone (10)
[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyr-
imidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid-(3,6)-lactone;
also described as
N-(4-(4-fluorophenyl)-5-{(E)-2-[{2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyra-
n-2-yl]ethenyl}-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide].
This compound is hereinafter described as "lactone". ##STR15##
[0064] Suitable conditions for conversion of compounds of formula
(7), for example (7a), into a compound of formula (10) are, for
example, treatment with aqueous acid (such as hydrochloric acid)
and removal of water by azeotropic distillation of toluene or MTBE
(methyl tert-butyl ether). The crystalline lactone (10) may be
isolated instead of the compound (8) and then converted into a
compound of the formula (9) or formula (1) by hydrolysis in aqueous
base.
[0065] Therefore in a further aspect of the invention there is
provided a process for the manufacture of the calcium salt of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, comprising:
[0066] a) acid hydrolysis of an acetal protecting group in a
compound of the formula (7) ##STR16## wherein A is an acetal or
ketal protecting group and R is (1-6C)alkyl, and isolation of the
resulting crystalline compound of the formula (10); ##STR17##
[0067] b) optional recrystallisation of the compound of the formula
(10); [0068] c) hydrolysis of the compound of formula (10) to give
a dihydroxy carboxylate derivative (9) (wherein M is a metal
counterion other than calcium) or a compound of the formula (1);
and ##STR18## [0069] d) where necessary, conversion of a compound
of the formula (9) into a compound of the formula (1).
[0070] Preferably step c) is carried out by hydrolysis in aqueous
base, such as alkali metal bases, for example sodium hydroxide (M
is Na), or potassium hydroxide (M is K).
[0071] In a further aspect of the invention there is provided a
process for the manufacture of the calcium salt of
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, comprising:
##STR19## [0072] a) hydrolysis of the ester group in a crystalline
compound of the formula (10) to give a dihydroxy carboxylate
derivative (9) (wherein M is a metal counterion other than calcium)
or a compound of the formula (1); and ##STR20## [0073] b) where
necessary, conversion of a compound of the formula (9) into a
compound of the formula (1).
[0074] In a further aspect of the invention is provided
crystalline(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic
acid-(3,6)-lactone having an X-ray powder diffraction pattern with
peaks at 2-theta=7.9, 15.9 and 20.3.
[0075] In a further aspect of the invention is provided
crystalline(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic
acid-(3,6)-lactone having an X-ray powder diffraction pattern with
peaks at 2-theta=7.9, 11.9, 15.9, 20.3, 21.7 and 22.5.
[0076] In a further aspect of the invention is provided
crystalline(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic
acid-(3,6)-lactone having an X-ray powder diffraction pattern
substantially as shown in FIG. 8.
[0077] It will be appreciated that the process described in WO
00/49014 for isolation of the amorphous calcium salt of the Agent,
or the process described in WO2004/014872, for precipitation of the
amorphous form of the calcium salt of the Agent from a
(substantially) aqueous solution of a different salt form, will
generally lead to a proportion of residual calcium salt of the
Agent in waste solutions such as the mother liquors remaining after
the precipitated salt has been filtered off. Even a very small
proportion of such residue may represent significant financial loss
if the process is carried out repeatedly on a commercial
manufacturing scale. Any reduction in such residue also potentially
provides environmental benefits, reducing the amount of treatment
that effluent requires before it can be disposed of.
[0078] We have found that this loss may be avoided by treatment of
said waste solutions (such as mother liquors) such that the residue
calcium salt of the Agent may be isolated as crystalline lactone,
optionally re-crystallised and then re-treated to form the desired
calcium salt of the Agent. Thus lactone has value as a processing
aid for isolation of the amorphous form of the Agent.
[0079] Therefore in a further aspect of the invention, there is
provided a process for formation of amorphous
bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-
pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt
comprising isolation of
crystalline(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic
acid-(3,6)-lactone from a solution and subsequent conversion to the
amorphous form of
bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-
pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium
salt.
[0080] In a further aspect of the invention, there is provided the
use of lactone (as hereinbefore defined) as a processing aid for
isolation of amorphous
bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfo-
nyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic
acid]calcium salt.
[0081] In a further aspect of the invention, there is provided the
use of lactone (as hereinbefore defined) as a processing aid for
recovery of amorphous
bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfo-
nyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic
acid]calcium salt from waste solutions.
[0082] In a further aspect of the invention, there is provided the
use of lactone (as hereinbefore defined) as an intermediate in the
manufacture of amorphous
bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-
pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium
salt.
[0083] MTBE may be used to isolate crystalline lactone from waste
solutions such as mother liquors. MTBE is also a suitable
recrystallisation solvent for lactone.
[0084] The utility of the compound of the formula (I) formed by the
process of the invention may be demonstrated by standard tests and
clinical studies, including those described in EPA 521471.
[0085] A further aspect of the invention comprises a compound of
the formula (I) obtained by the process of the invention as
hereinbefore described.
[0086] A further aspect of the invention comprises a compound of
the formula (I) obtainable by the process of the invention as
hereinbefore described.
[0087] According to a further feature of the invention is a method
of treating a disease condition wherein inhibition of HMG CoA
reductase is beneficial which comprises administering to a
warm-blooded mammal an effective amount of a compound of the
formula (I) formed by the process of the invention. The invention
also relates to the use of compounds of the formula (I) formed by
the process of the invention in the manufacture of a medicament for
use in a disease condition.
[0088] The compound of the invention may be administered to a
warm-blooded animal, particularly a human, in need thereof for
treatment of a disease in which HMG CoA reductase is implicated, in
the form of a conventional pharmaceutical composition. Therefore in
another aspect of the invention, there is provided a pharmaceutical
composition comprising a compound of the formula (I) formed by the
process of the invention in admixture with a pharmaceutically
acceptable carrier.
[0089] Such compositions may be administered in standard manner for
the disease condition that it is desired to treat, for example by
oral, topical, parenteral, buccal, nasal, vaginal or rectal
administration or by inhalation. For these purposes the compound of
the formula (I) may be formulated by means known in the art into
the form of, for example, tablets, capsules, aqueous or oily
solutions, suspensions, emulsions, creams, ointments, gels, nasal
sprays, suppositories, finely divided powders or aerosols for
inhalation, and for parenteral use (including intravenous,
intramuscular or infusion) sterile aqueous or oily solution or
suspensions or sterile emulsions. A preferred route of
administration is oral. The compound of the formula (I) will be
administered to humans at a daily dose in, for example, the ranges
set out in EPA 521471. The daily doses may be given in divided
doses as necessary, the precise amount received and the route of
administration depending on the weight, age and sex of the patient
being treated and on the particular disease condition being treated
according to principles known in the art.
[0090] According to a further feature of the invention, there is
provided a process for the manufacture of a pharmaceutical
composition containing the compound of the formula (I) as active
ingredient, which comprises admixing the compound of the formula
(I) together with a pharmaceutically acceptable carrier.
[0091] The invention will now be illustrated by the following
examples. .sup.1H NMR were analysed using a Bruker DPX400 operating
at a field strength of 400 MHz, and unless otherwise stated were
run in deuterochloroform. Chemical shifts are given in parts per
million relative to tetramethylsilane. Peak multiplicities are
shown as: s=singlet, d=doublet, sept=septet, q=quartet, t=triplet,
dd=doublet of doublets, dt=doublet of triplets, m=multiplet It will
be appreciated that the crystalline compounds of formulae (7) and
(8), and crystalline lactone, may additionally be characterised by
other methods known in the art.
General Procedure for Synthesis of a Compound of Formula (7):
Example for R=iso-propyl:
iso-Propyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfo-
nyl)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetat-
e
[0092] Sodium bis(trimethylsilyl)amide (80.47 mL, 1.0 M in
tetrahydrofuran (THF)) was added dropwise to a cooled solution of
diphenyl[4-(4-fluoropheny)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyr-
imidin-5-ylmethyl]phosphine oxide (40.43 g, 75 mmol) in THF (477.1
mL) at -65.degree. C. over 30 minutes, maintaining the temperature
at -65.degree. C.
Isopropyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl}acetate
in toluene (21.68 g) was added dropwise to the solution over 35
minutes, maintaining the temperature at -65.degree. C. The contents
of the vessel were kept at -65.degree. C. for 15 minutes, then
allowed to warm evenly to 10.degree. C. over 80 minutes. Water
(40.4 mL) followed by acetic acid (6.87 g, 114 mmol) were added to
give a two phase light yellow solution. The batch was then
distilled at atmospheric pressure to remove .about.485 mL of
distillates. This solution was washed sequentially with water (84
mL), 7.0% w/w sodium bicarbonate (92.6 g), 1.8% w/w sodium
bicarbonate (91.1 g) and water (63.5 mL). The resulting organic
phase was distilled under vacuum at 270 mbar to leave .about.95 mL
of solution in the distillation flask (removing .about.229mL of
distillates). Methanol (202 mL) at 50.degree. C. was charged to the
flask and the solution distilled at atmospheric pressure, removing
.about.134 mL of distillates. A further portion of methanol (229
mL) at 50.degree. C. was added to the solution and the batch cooled
to 40.degree. C. over 30 minutes. The batch was cooled to
25.degree. C. over 30 minutes, 0-5.degree. C. over 30 minutes, then
chilled to -8.degree. C. over 20 minutes and kept at this
temperature for 30 minutes. The solid was collected by vacuum
filtration, washed with 2 portions of cooled (-8.degree. C.)
methanol (2.times.80.6 mL) then dried in a vacuum oven at
50.degree. C., 200 mbar, yield=28.9 g (68.3%).
[0093] Analogues with different ester groups R may be made as above
using the appropriate starting materials, with the following
exceptions:
[0094] For the ethyl derivative: after the acetic acid quench the
mixture was evaporated to dryness onto silica gel (Merck, 230-400
mesh) and added to a short plug of silica Elution was performed
with 25-27.5% ethyl acetate in iso-hexane. The isolated product was
then crystallised from methanol (150 mL) as described in the method
above.
[0095] For the methyl derivative, the crude product was evaporated
to dryness onto silica after the first sodium bicarbonate
treatment. Purification was performed on silica gel as for the
ethyl derivative (eluting with 14, 16 and 20% ethyl acetate in
iso-hexane). The product was crystallised from methanol.
Procedure for Compound of Formula 7 where R=n-hexyl:
[0096] Sodium hydride (141 mg, 60% dispersion in mineral oil, 3.5
mmol) was added in one portion to n-hexanol (15 mL) at ambient
temperature. After the resulting effervescence had stopped the
clear solution was agitated for 30 minutes.
N-Ethyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl-
)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
(2 g, 3.6 mmol) was added to the solution in one portion. After 90
minutes, acetic acid (263 mg, 3.6 mmol) was added to the reaction
mixture and the solution left at ambient temperature for 16 hours.
The solvent was removed on the rotary evaporater (oil pump) and
then dissolved in ethyl acetate. The solution was evaporated to
dryness onto silica and purified on silica eluting with 20% ethyl
acetate in iso-hexane. The resulting pale yellow oil was
crystallised from methanol as described above.
Analytical Data: for
R-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amin-
o]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
[0097] TABLE-US-00001 R .sup.1H NMR(ppm) Iso-propyl 1.15(q, 1H),
1.24(dd, 6H), 1.27(dd, 6H), 1.40(s, 3H), 1.49(s, 3H), 1.55(dt, 1H),
2.34(dd, 1H), 2.50(dd, 1H), 3.38(spt, 1H), 3.51(s, 3H), 3.57(s,
3H), 4.32(m, 1H), 4.43(m, 1H), 5.04(sptt, 1H), 5.47(dd, 1H),
6.52(d, 1H), 7.08(t, 2H), 7.65(dd, 2H) Ethyl 1.14(q, 1H),
1.25-1.29(m, 9H), 1.40(s, 3H), 1.49(s, 3H), 1.56(dt, 1H), 2.37(dd,
1H), 2.55(dd, 1H), 3.38(spt, 1H), 3.51(s, 3H), 3.57(s, 3H),
4.21-4.12(m, 2H), 4.37-4.30(m, 1H), 4.46-4.41(m, 1H), 5.47(dd, 1H),
6.53(d, 1H), 7.08(t, 2H), 7.65(dd, 2H) Methyl 1.14(q, 1H), 1.27(dd,
6H), 1.40(s, 3H), 1.49(s, 3H), 1.56(dt, 1H), 2.38(dd, 1H), 2.57(dd,
1H), 3.37(spt, 1H), 3.51(s, 3H), 3.57(s, 3H), 3.70(s, 3H),
4.37-4.30(m, 1H), 4.46-4.41(m, 1H), 5.47(dd, 1H), 6.52(d, 1H),
7.08(t, 2H), 7.65(dd, 2H) n-Hexyl 0.89(t, 3H), 1.15(q, 1H),
1.27(dd, 6H), 1.37-1.29(m, 7H), 1.40(s, 3H), 1.49(s, 3H),
1.66-1.57(m, 2H), 2.38(dd, 1H), 2.55(dd, 1H), 3.37(spt, 1H),
3.51(s, 3H), 3.57(s, 3H), 4.10(t, 2H), 4.36-4.29(m, 1H),
4.46-4.41(m, 1H), 5.47(dd, 1H), 6.52(d, 1H), 7.08(t, 2H), 7.65(dd,
2H)
General Procedure for Compounds of Formula (8):
Example for iso-propyl analogue
[0098] Hydrochloric acid (17.24 mL, 0.02M) was added dropwise over
100 minutes to a warm solution of iso-propyl
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate (10 g, 17 mmol) in
acetonitrile (69 mL) at 35.degree. C. The mixture was agitated for
a further 80 minutes then allowed to cool to 25.degree. C. over 30
minutes. Sodium chloride (9.26 g) in water (23 mL) was added to the
mixture, which was agitated for 15 minutes then allowed to settle
for 16 hours. The organic layer was separated off and the aqueous
layer extracted with acetonitrile (15 mL). The combined organic
layers were evaporated to dryness and the residue recrystallised
from toluene (40 mL). The solid was dried in a vacuum oven at
40.degree. C., 620 mbar, yield=7.06 g (79.3%).
[0099] Analogues with different ester groups R may be made as above
with the following exceptions: for the ethyl derivative, the
product did not crystallise from toluene: this solution was
evaporated to dryness and purified on silica to afford an oily
solid which was then treated with a 1:1 mixture of
iso-hexane:toluene and filtered by vacuum filtration.
Analytical Data: for
R-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]py-
rimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate
[0100] TABLE-US-00002 R .sup.1H NMR(ppm) t-Butyl 1.27(d, 6H),
1.42(dt, 1H), 1.47(s, 9H), 1.58-1.50(m, 1H), 2.38(d, 2H), 3.37(spt,
1H), 3.51(s, 3H), 3.57(s, 3H), 3.65(bs, 1H), 3.80(bs, 1H),
4.18-4.15(m, 1H), 4.48-4.44(m, 1H), 5.46(dd, 1H), 6.64(d, 1H),
7.09(t, 2H), 7.65(dd, 2H) Iso-propyl 1.27-1.25(m, 12H), 1.45(dt,
1H), 1.60-1.51(m, 1H), 2.43(d, 2H), 3.37(spt, 1H), 3.51(s, 3H),
3.57(s, 3H), 3.57(bs, 1H), 3.73(bs, 1H), 4.21-4.19(m, 1H),
4.47-4.44(m, 1H), 5.06(spt, 1H), 5.46(dd, 1H), 6.64(d, 1H), 7.09(t,
2H), 7.65(dd, 2H) Ethyl 1.30-1.24(m, 9H), 1.45(dt, 1H),
1.60-1.52(m, 1H), 2.46(d, 2H), 3.37(spt, 1H), 3.51(s, 3H), 3.51(bs,
1H), 3.57(s, 3H), 3.70(bs, 1H), 4.19(q, 2H), 4.23-4.17(m, 1H),
4.47-4.45(m, 1H), 5.46(dd, 1H), 6.64(d, 1H), 7.09(t, 2H), 7.65(dd,
2H)
Procedure for Formation of Lactone (3R, 5S) (a)
[0101]
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)ami-
no]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium
salt (30.0 g) was dissolved in acetonitrile (300 mL) and saturated
brine (50 mL) was added. The solution was then chilled to
0-5.degree. C. The pH was adjusted to 4.0 with a mixture of 4N HCl
(15 mL) and saturated brine (35 mL). An extra portion of water (15
mL) was added to dissolve the solid, resulting in two clear phases.
The aqueous layer was separated off (112 mL) and the organic phase
dried with magnesium sulphate. The solution was distilled at
atmospheric pressure until .about.100 mL of acetonitrile had been
removed, then toluene (250 mL) was added gradually to maintain the
distillation flask volume at 200 mL . This resulted in collecting
.about.390 mL of distillates at a final head temperature of
106.degree. C. The solution was allowed to stir at ambient
temperature overnight and was then heated to reflux for two hours.
The mixture was cooled to 0-5.degree. C. and the resulting solid
was filtered, washed with toluene (2.times.20 mL) and dried at
35.degree. C. under vacuum.
[0102] .sup.1H NMR .delta.: 1.28-1.26 (m, 6H), 1.69-1.62 (m, 1H),
1.94-1.88 (m, 1H), 2.66-2.60 (m, 1H), 2.72 (dd, 1H), 3.33 (septet,
1H), 3.51 (s, 3H), 3.57 (s, 3H), 4.34-4.30 (m, 1H), 5.26-5.21 (m,
1H), 5.49 (dd, 1H), 6.72 (d, 1H), 7.11 (t, 2H), 7.62 (dd, 2H).
Procedure for Formation of Lactone (3R, 5S) (b)
[0103]
Tertiary-butyl(6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(-
methylsulfonyl)amino]pyrimidin-5-yl]ethenyl}(4R,6S)-2,2-dimethyl-1,3-dioxa-
n-4-yl)acetate (20.0 g) was dissolved in acetonitrile (140 mL) at
40.degree. C., then cooled to 35.degree. C. before gradual addition
of hydrochloric acid (0.02M, 35 mL) at 35.degree. C. The resulting
solution was stirred at 35.degree. C. until the reaction was
complete then cooled to 25.degree. C. Acetonitrile (8 mL) and
sodium hydroxide (1.0M, 38 mL) was added at 25.degree. C. and the
resulting mixture stirred at this temperature until the reaction
was complete. Sodium chloride (18.8 g) was added and the mixture
cooled to 0.degree. C. Sodium chloride saturated hydrochloric acid
(1 M) was then added to the stirred reaction mixture at 0.degree.
C. until a pH of 4 was achieved. The two phase system was allowed
to settle at 0.degree. C. and the lower aqueous phase was removed
to waste. Toluene (250 mL) was added to the organic phase and
mixture was distilled at atmospheric temperature until the mixture
reached a temperature of 105.degree. C. was achieved. The solution
was then heated under azeotropic conditions for a further 6 hours
at 105.degree. C. The mixture was allowed to cool to ambient
temperature before isolating the crystalline lactone. The material
was washed with methyl t butyl ether (100 mL) before drying in a
vacuum oven at 22.degree. C. under nitrogen to yield 12.8 g of dry
lactone.
[0104] .sup.1H NMR (500 MHz, DMSO d6), .delta.: 1.23 (d+d, 6H),
1.64 (m, 1H), 1.76 (m, 1H), 2.40 (ddd, 1H), 2.66 (dd, 1H), 3.36
(spt, 1H)*, 3.46 (s, 3H), 3.56 (s, 3H), 4.08 (m, 1H), 5.16 (m, 1H),
5.26 (d, 1H), 5.57 (dd, 1H), 6.76 (dd, 1H), 7.31 (t, 2H), 7.70 (dd,
2H).
*Partially obscured
Procedure for Conversion of Lactone to Calcium Salt (1)
[0105] Aqueous sodium hydroxide (4% w/w, 38 ml) was added to a
stirred solution of N-(4-(4-fluorophenyl)-5-{(E)-2-[{2S,
4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethenyl}-6-isopropylpyrimidin-
-2-yl)-N-methylmethanesulfonamide (16 g) in acetonitrile (148 mL)
at 20.degree. C. The reaction held at 25.degree. C. for 2.5 hour
with stirring. Aqueous hydrochloric acid (29 mL, 0.1M) was added to
adjust the pH of the solution to approximately pH10.5. Water (71
mL) was added so that the combined charge of water and hydrochloric
acid (0.1 M) (from the previous pH adjustment step) was 100 mL.
Toluene (125 ml) was then added and the mixture stirred at
40.degree. C. for 30 minutes before it was allowed to settle for 1
hour at 40.degree. C. The aqueous phase was then separated from the
organic phase at 40.degree. C. The aqueous phase was then distilled
under reduced pressure (53 mBar, .ltoreq.40.degree. C.) until the
volume was reduced to 135 mL. Water (35 mL) was added to bring the
total volume to 170 mL. The solution was heated to 40.degree. C.
before addition of a solution of calcium chloride di-hydrate (3.05
g) in water (29.5 mL) over 20 min, maintaining the reaction mixture
at 38-41.degree. C.
[0106] The reaction mixture was stirred for a further 15 min at
40.degree. C., then cooled to 20.degree. C. and stirred at this
temperature for a further 15 min. The resulting suspension was
filtered, washed with water (3.times.53 mL) and dried to give
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt
(17.13 g).
Synthesis of Starting Materials
Isopropyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl}acetate
[0107] Chlorine gas (2469.6 mL, 118 mmol) was charged to toluene
(373.3 mL) at -60.degree. C. Dimethyl sulphide (11.67 mL, 121 mmol)
was then added dropwise to the cooled solution over 30 minutes,
keeping the contents at -60.degree. C. After 30 minutes at this
temperature, isopropyl
2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl}acetate (24.56 g,
95 mmol) in toluene (46.7 mL) was added dropwise to the vessel over
30 minutes, maintaining the internal temperature at -60.degree. C.
The reaction mixture was agitated at -60.degree. C. for 30 minutes
followed by the dropwise addition of triethylamine (26.36 g, 261
mmol) over 30 minutes, allowing the internal temperature to rise to
-50.degree. C. The reaction mixture was then allowed to warm to
25.degree. C. evenly over 75 minutes. The resulting slurry was
stirred at 25.degree. C. for 30 minutes, then water (77 mL) was
added and the mixture agitated for 30 minutes. The aqueous layer
was separated and the pH checked (pH should be between 7.5 and
8.5). The resulting organic portion was washed with water (23.3 mL)
and the organic portion separated for vacuum distillation at 150
mbar. Distillation was continued until .about.350 mL of toluene had
been removed. Toluene (350 mL) was added to the flask and the
vacuum distillation repeated at 150 mbar to remove .about.350 mL of
toluene. The resulting solution was transferred to a flask
containing activated 4 angstrom molecular sieves and left at
ambient temperature overnight. This solution was used directly for
the coupling stage.
[0108] Analogues with different ester groups R may be made as above
with the following exceptions: for the methyl analogue, the
distillations were performed at much higher vacuum (and therefore
at lower temperatures).
Iso-propyl2-[(4R,6S)-6-formyl-2,2-dimethy-1,3-dioxan-4-yl}acetate
[0109] This compound may be made using the procedures described in
EP0319847. Analogues with different ester groups R may be made by a
similar method.
Diphenyl[4-(4-fluoropheny)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyri-
midin-5-ylmethyl]phosphine oxide
[0110] This compound can be made as described in Patent Application
WO00/49014 TABLE-US-00003 2-theta d-spacing Relative Intensities
5.7 15.4 51 8.7 10.1 25 9.5 9.3 100 13.6 6.5 54 17.5 5.1 58 19.0
4.7 41 19.9 4.5 53 20.8 4.3 29 21.8 4.1 34 22.4 4.0 41
[0111] TABLE-US-00004 2-theta d-spacing Relative Intensities 5.9
15.0 23 8.0 11.0 33 12.2 7.3 21 15.9 5.6 100 18.4 4.8 65 19.5 4.6
82 19.7 4.5 45 23.0 3.9 53 24.3 3.7 37 25.0 3.6 29
[0112] TABLE-US-00005 2-theta d-spacing Relative Intensities 6.0
14.7 35 7.0 12.6 41 7.8 11.3 90 8.7 10.1 37 10.4 8.5 27 11.6 7.6
100 13.0 6.8 20 14.7 6.0 19 15.5 5.7 56 20.2 4.4 53
[0113] TABLE-US-00006 2-theta d-spacing Relative Intensities 5.3
16.8 18 7.1 12.4 100 11.4 7.8 10 14.2 6.2 19 14.8 6.0 14 18.9 5.7
27 20.1 4.4 10 20.4 4.4 5 21.4 4.1 12
[0114] TABLE-US-00007 2-theta d-spacing Relative Intensities 4.3
20.4 13 8.1 11.0 100 11.3 7.8 48 12.4 7.1 21 15.1 5.9 18 19.9 4.5
56 21.0 4.2 41 21.7 4.1 18 22.1 4.0 26 23.5 3.8 15
[0115] TABLE-US-00008 2-theta d-spacing Relative Intensities 9.8
9.0 88 12.2 7.3 24 13.6 6.5 20 17.3 5.1 57 18.5 4.8 18 19.6 4.5 24
20.1 4.4 53 21.1 4.2 100 22.4 4.0 20 23.3 3.8 16
[0116] TABLE-US-00009 2-theta d-spacing Relative Intensities 9.8
9.1 31 17.2 5.2 13 18.2 4.9 35 19.4 4.6 15 19.9 4.5 50 20.6 4.3 33
20.8 4.3 100 22.1 4.0 12 25.1 3.5 10 26.3 3.4 18
[0117] TABLE-US-00010 2-theta d-spacing Relative Intensities 7.9
11.1 76 11.9 7.4 25 15.9 5.6 69 20.3 4.4 100 21.7 4.1 59 22.5 3.9
31
* * * * *