U.S. patent application number 13/145783 was filed with the patent office on 2012-01-26 for key intermediates for the synthesis of rosuvastatin or pharmaceutically acceptable salts thereof.
This patent application is currently assigned to LEK PHARMACEUTICALS D.D.. Invention is credited to Zdenko Casar, Janez Kosmrlj.
Application Number | 20120022091 13/145783 |
Document ID | / |
Family ID | 40589996 |
Filed Date | 2012-01-26 |
United States Patent
Application |
20120022091 |
Kind Code |
A1 |
Casar; Zdenko ; et
al. |
January 26, 2012 |
KEY INTERMEDIATES FOR THE SYNTHESIS OF ROSUVASTATIN OR
PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
Abstract
The present invention relates in general to the field of organic
chemistry and in particular to the preparation of
N-(4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methylmethane-
sulfonamide (I),
N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methyl-
methanesulfonamide (II) and
N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-meth-
ylmethanesulfonamide (III), key intermediates in preparation of
Rosuvastatin.
Inventors: |
Casar; Zdenko; (Ljubljana,
SI) ; Kosmrlj; Janez; (Ljubljana, SI) |
Assignee: |
LEK PHARMACEUTICALS D.D.
Ljubljana
SI
|
Family ID: |
40589996 |
Appl. No.: |
13/145783 |
Filed: |
February 1, 2010 |
PCT Filed: |
February 1, 2010 |
PCT NO: |
PCT/EP2010/051163 |
371 Date: |
October 3, 2011 |
Current U.S.
Class: |
514/275 ;
204/157.72; 544/297 |
Current CPC
Class: |
A61P 3/06 20180101; C07F
9/54 20130101; C07F 9/535 20130101; C07D 405/06 20130101; A61K
31/506 20130101; C07D 239/42 20130101; A61K 31/505 20130101 |
Class at
Publication: |
514/275 ;
544/297; 204/157.72 |
International
Class: |
A61K 31/505 20060101
A61K031/505; C07D 239/42 20060101 C07D239/42 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 2, 2009 |
EP |
091518811 |
Claims
1. A process for preparing the compound of formula II ##STR00030##
comprising the steps of: providing a compound of formula I:
##STR00031## and converting the compound of formula I by
bromination into the compound of formula II.
2. The process according to claim 1, wherein said bromination is
performed with an N-bromoamide as a brominating agent, wherein said
N-bromoamide is selected from the group consisting of
N-bromoacetamide, N,N-dibromobenzene sulfonamides,
N-bromosuccinimide, N-bromophthalimide, N-bromoglutarimide,
3-bromo-hydantoin and 1,3-dibromo-5,5-dimethylhydantoin.
3. The process according to claim 2, wherein the initial amount of
brominating agent is from about 1 to about 3 times the molar
stoichiometric amount based on compound I.
4. The process according to claim 1, wherein the bromination
reaction is performed in an organic solvent selected from the group
consisting of acetone, ethyl acetate, hydrocarbons, aromatic
hydrocarbons, acetonitrile and a mixture thereof.
5. The process according to claim 1 avoiding use of HBr and
PBr.sub.3.
6. The process according to claim 1, which is performed under
treatment of ultraviolet radiation, wherein said ultraviolet
radiation has a wavelength of about 200 to 400 nm.
7. The process according to claim 1, wherein the bromination is
carried out at a temperature between 0 to 90.degree. C.
8. The process according to claim 1, further comprising a step of
purifying of the compound of formula II.
9. A process for preparing a compound of formula I ##STR00032##
comprising a step of reacting a compound of formula IX or IX'
##STR00033## wherein P.sub.1 and P.sub.2 respectively denote same
or different hydroxy protecting groups and R is selected from alkyl
or aryl; with a compound of formula X or X' ##STR00034## wherein Z
is selected from the group consisting of: ##STR00035## and wherein
Rx, Ry, and Rz, are the same or different and are selected from
optionally substituted C.sub.1-C.sub.8 alkyl or C.sub.3-C.sub.6
cycloalkyl or C.sub.1-C.sub.8 alkenyl or C.sub.5-C.sub.6
cycloalkenyl or aryl, and X.sup..theta. is an anion; wherein in
said reaction the compound of formula X or X' is used in molar
excess over the compound of formula IX or IX', and/or wherein the
reaction takes place in the presence of water or other protic
molecules, to obtain the compound of formula I.
10. The process according to claim 9, wherein the compound of
formula I is obtained as a product besides a compound selected from
formulas XI or XI' ##STR00036## wherein P.sub.1 and P.sub.2
respectively denote same or different hydroxy protecting groups;
wherein the obtained compound selected from formulas XI and XI' is
used to be subsequently converted to Rosuvastatin or its salt.
11. A process for preparing rosuvastatin, comprising: (a) reacting
a compound of formula IX or IX' ##STR00037## wherein P.sub.1 and
P.sub.2 respectively denote same or different hydroxy protecting
groups and R is selected from alkyl or aryl; with a compound of
formula X or X' ##STR00038## wherein Z is selected from the group
consisting of: ##STR00039## and wherein Rx, Ry, and Rz, are the
same or different and are selected from optionally substituted
C.sub.1-C.sub.8 alkyl or C.sub.3-C.sub.6 cycloalkyl or
C.sub.1-C.sub.8 alkenyl or C.sub.5-C.sub.6 cycloalkenyl or aryl and
X.sup..theta. is an anion; (b) obtaining reaction products of a
compound of formula I ##STR00040## and a compound selected from
formulas XI or XI' ##STR00041## wherein P.sub.1 and P.sub.2 are as
defined above; (c) using the obtained compound selected from
formulas XI and XI' for conversion into Rosuvastatin or its salt;
and (d) using the obtained compound of formula I for providing said
compound in a process according to claim 1 in a recycling process
for producing rosuvastatin.
12. The process according to claim 11, wherein in step (b) the
obtained reaction products are respectively separated into the
compound of formula I and the compound selected from formulas XI or
XI', prior to the respective use in step (d).
13. A process for preparing a compound of formula III ##STR00042##
comprising the step of converting the compound of formula II
##STR00043## by hydrolysis into the compound of formula III.
14. The process according to claim 13, wherein hydrolysis is
performed in the presence of an inorganic base.
15. A one-pot process for preparing the compound of formula III
##STR00044## comprising converting a compound of formula I
##STR00045## by reaction via non-isolated compound of formula II
##STR00046## into the compound of formula III.
16. The process according to claim 13, further comprising the step
of purifying compound of formula III.
17. A process for the preparation of Rosuvastatin or
pharmaceutically acceptable salt of Rosuvastatin, comprising the
steps of: a) carrying out a process for preparing the compound of
formula I according to claim 9, carrying out a process for
preparing the compound of formula II by converting the compound of
formula I by bromination into the compound of formula II or
carrying out a process for preparing the compound of formula III by
converting the compound of formula II by hydrolysis into the
compound of formula III, and b) subjecting the compound of formula
I, II or III respectively to further synthesis steps to yield
Rosuvastatin or pharmaceutically acceptable salts thereof.
18. A process for the preparation of a pharmaceutical composition
comprising Rosuvastatin as active ingredient, comprising the steps
of: a) preparing Rosuvastatin or pharmaceutically acceptable salts
thereof according to the process according to claim 17, and b)
admixing the thus prepared Rosuvastatin or pharmaceutically
acceptable salt thereof with at least one pharmaceutically
acceptable excipient.
19. A process for the preparation of a pharmaceutical composition
comprising Rosuvastatin as active ingredient, comprising the steps
of: a) preparing Rosuvastatin or pharmaceutically acceptable salts
thereof according to the process according claim 10, b) admixing
the thus prepared Rosuvastatin or pharmaceutically acceptable salt
thereof with at least one pharmaceutically acceptable
excipient.
20. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a process for the
preparation of
N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methyl-
methanesulfonamide,
N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-meth-
ylmethanesulfonamide and
N-(4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methylmethane-
sulfonamide, useful as key intermediates for the preparation of
Rosuvastatin or pharmaceutically acceptable salts thereof. The
present invention further relates to a process wherein the above
mentioned compounds are used as intermediates.
BACKGROUND OF THE INVENTION
[0002]
(N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-
-methylmethanesulfonamide),
(N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-met-
hylmethanesulfonamide) and
N-(4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methylmethane-
sulfonamide are possible intermediates in the synthesis of
Rosuvastatin and its pharmaceutically acceptable salts.
Rosuvastatin calcium, chemically described as
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, is a synthetic lipid-lowering agent that acts as an inhibitor
of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase
(HMG-CoA Reductase inhibitor). HMG-CoA reductase inhibitors are
commonly referred to as "statins." Statins are therapeutically
effective drugs used for reducing low density lipoprotein (LDL)
particle concentration in the blood stream of patients at risk for
cardiovascular disease. Therefore, Rosuvastatin calcium is used in
the treatment of hypercholesterolemia and mixed dyslipidemia.
[0003] The EP 521471 A1 discloses Rosuvastatin and a process for
its preparation, among others by a process comprising a step of
preparing
N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-meth-
ylmethanesulfonamide by reduction of a suitable ester derivative
thereof with diisobutylaluminium hydride (DIBAL-H) as a reduction
reagent. Furthermore, WO2008/059519 A2 also describes the
preparation of Rosuvastatin via
N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-meth-
ylmethanesulfonamide as intermediate obtained by reduction of a
suitable ester thereof by means of DIBAL-H.
[0004] International patent application WO2007/017117 A1 describes
the preparation of Rosuvastatin via
N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methyl-
methanesulfonamide as the intermediate. This intermediate is
prepared by nucleophilic substitution of
N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-meth-
ylmethanesulfonamide by means of HBr as the source of
nucleophile.
[0005] The object of the present invention is to provide an
improved process for preparing
N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methyl-
methanesulfonamide,
N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-meth-
ylmethanesulfonamide and
N-(4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methylmethane-
sulfonamide, so as to provide valuable intermediates for the
preparation of Rosuvastatin and pharmaceutically acceptable salts
thereof.
SUMMARY OF THE INVENTION
[0006] The object is solved by processes for the preparation of
N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methyl-
methanesulfonamide,
N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-meth-
ylmethanesulfonamide and
N-(4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methylmethane-
sulfonamide according to claims 1, 9, 13 and 15, a process for the
preparation of Rosuvastatin or pharmaceutically acceptable salts
thereof according to claims 11 and 17, a preparation of a
pharmaceutical composition according to claims 18 and 19 and a use
of
N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methyl-
methanesulfonamide,
N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-meth-
ylmethanesulfonamide and
N-(4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methylmethane-
sulfonamide for the preparation of Rosuvastatin or pharmaceutically
acceptable salts thereof according to claim 20 respectively.
Preferred embodiments are set forth below and in the subclaims.
[0007] According to the present invention, it has been surprisingly
found that a more efficient and easier to handle synthesis of
N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methyl-
methanesulfonamide and
N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-meth-
ylmethanesulfonamide respectively can be carried out by selecting
suitable starting materials which can be converted to the desired
product without the necessity of aggressive, difficult to handle
and/or expensive reagents. Moreover, the process for the
preparation is more efficient as it allows beneficial reaction
conditions providing for less by products and thus higher purity of
the products and higher yields, and/or less necessary reaction
steps. Furthermore, the process according to the present invention
enables to use mild reactants, further contributing to an easier
handling in terms of less necessary precautions concerning
application and storage, and less precautions concerning the
requirement of special reaction conditions such as protective gas
atmosphere and/or anhydrous solvent. Furthermore an efficient
process for recovering of
N-(4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methylmethane-
sulfonamide is disclosed that has an favorable impact on the
efficiency of the overall process of the rosuvastatin
synthesis.
[0008] As a result, desirable key intermediates for the preparation
of Rosuvastatin or pharmaceutically acceptable salts thereof are
provided by a significantly improved process.
[0009] Various aspects, advantageous features and preferred
embodiments of the present invention, which respectively alone and
in combination particularly contribute to solving the object of the
invention are summarized in the following items: [0010] (1) A
process for preparing the compound of formula II
[0010] ##STR00001## [0011] comprising the steps of: [0012]
providing a compound of formula I:
[0012] ##STR00002## [0013] and converting the compound of formula I
by bromination into the compound of formula II. [0014] (2) The
process according to item (1), wherein bromination proceeds by
radical reaction [0015] (3) The process according to item (1) or
(2), wherein said bromination is performed with an N-bromoamide as
a brominating agent, preferably an N-bromoamide selected from the
group consisting of N-bromoacetamide, N,N-dibromobenzene
sulfonamides, N-bromosuccinimide, N-bromophthalimide,
N-bromoglutarimide, 3-bromo-hydantoin and
1,3-dibromo-5,5-dimethylhydantoin, more preferably
N-bromosuccinimide. [0016] (4) The process according to item (3),
wherein the initial amount of brominating agent is from about 1 to
about 3 times the molar stoichiometric amount based on compound I,
preferably about 1.2 to about 2.5 times, more preferably about 1.4
to about 2.2 times, and in particular about 2 times. [0017] (5) The
process according to any one of items (1) to (4) avoiding use of
HBr and PBr.sub.3. [0018] (6) The process according to any one of
the preceding items, wherein the bromination reaction is performed
in an organic solvent selected from the group consisting of
acetone, ethyl acetate, hydrocarbons, aromatic hydrocarbons and
acetonitrile or a mixture thereof, preferably the organic solvent
is acetonitrile. [0019] (7) The process according to items (1) to
(6), wherein the bromination is performed under a treatment of
ultraviolet radiation. [0020] (8) The process according to item
(7), wherein said ultraviolet radiation has a wavelength of about
200-400 nm, preferably about 310 nm. [0021] (9) The process
according to item (7) or (8), wherein said ultraviolet radiation is
performed for 2 to 10 hours, preferably for about 4 hours. [0022]
(10) The process according to any one of items (1) to (9), wherein
the bromination is carried out at a temperature between 0 to
90.degree. C., preferably between 10 to 65.degree. C., more
preferably between 15 to 35.degree. C. and in particular between 19
to 25.degree. C. [0023] (11) The process according to any one of
the preceding items, wherein no radical former is applied. [0024]
(12) The process according to any one of items (1) to (10), wherein
a radical former is applied, wherein the radical former is
preferably an organic peroxide, an organic peracid, an organic
hydroperoxide or an organic azo compound, more preferably the
radical former is benzoyl peroxide or azoisobutyronitrile. [0025]
(13) The process according to item (12), wherein the initial amount
of radical former is between about 0 to 0.5 molar stoichiometric
amount based on compound I, preferably about 0 to 0.07 molar
stoichiometric amount based on compound I, and more preferably no
radical former is applied. [0026] (14) The process according to any
one of the preceding items, further comprising a step of purifying
of the compound of formula II, preferably by crystallization.
[0027] (15) The process according to item (14), wherein
crystallisation is performed with an MTBE/hexane mixture,
preferably with an MTBE/hexane mixture, wherein the volume ratio of
MTBE to hexane is 2 to 1, preferably 1 to 1 and more preferably 2
to 3. [0028] (16) A process for preparing a compound of formula
I
[0028] ##STR00003## [0029] comprising a step of reacting a compound
of formula IX or IX'
[0029] ##STR00004## [0030] wherein P.sub.1 and P.sub.2 respectively
denote same or different hydroxy protecting groups and R is
selected from alkyl or aryl; [0031] with a compound of formula X or
X'
[0031] ##STR00005## [0032] wherein Z is selected from the group
consisting of:
[0032] ##STR00006## [0033] and wherein Rx, Ry, and Rz, are the same
or different and are selected from optionally substituted
C.sub.1-C.sub.8 alkyl or C.sub.3-C.sub.6 cycloalkyl or
C.sub.1-C.sub.8 alkenyl or C.sub.5-C.sub.6 cycloalkenyl or aryl,
preferably phenyl, and X.sup..theta. is an anion, preferably a
halogen or carboxylate anion, more preferably chloride, bromide or
trifluoroacetate; [0034] wherein in said reaction the compound of
formula X or X' is used in molar excess over the compound of
formula IX or IX', and/or wherein the reaction takes place in the
presence of water or other protic molecules, [0035] to obtain the
compound of formula I. [0036] (17) The process according to item
(16), wherein the compound of formula I is obtained as a product
besides a compound selected from formulas XI or XI'
[0036] ##STR00007## [0037] wherein P.sub.1 and P.sub.2 are as
defined above; [0038] wherein said compound selected from formulas
XI and XI' is subsequently used for conversion into Rosuvastatin or
its salt, and wherein the compound of formula I is used to provide
said compound in a process according to claim 1. [0039] In this
way, the compound of formula I can be efficiently recycled to
perform a further synthesis route for the preparation of
Rosuvastatin or its salt. [0040] (18) A process for preparing
rosuvastatin, comprising: [0041] (a) reacting a compound of formula
IX or IX'
[0041] ##STR00008## [0042] wherein P.sub.1 and P.sub.2 respectively
denote same or different hydroxy protecting groups and R is
selected from alkyl or aryl; [0043] with a compound of formula X or
X'
[0043] ##STR00009## [0044] wherein Z is selected from the group
consisting of:
[0044] ##STR00010## [0045] and wherein Rx, Ry, and Rz, are the same
or different and are selected from optionally substituted
C.sub.1-C.sub.8 alkyl or C.sub.3-C.sub.6 cycloalkyl or
C.sub.1-C.sub.8 alkenyl or C.sub.5-C.sub.6 cycloalkenyl or aryl,
preferably phenyl, and X.sup..theta. is an anion, preferably a
halogen or carboxylate anion, more preferably chloride, bromide or
trifluoroacetate; [0046] (b) obtaining reaction products of [0047]
a compound of formula I
[0047] ##STR00011## [0048] and [0049] a compound selected from
formulas XI or XI'
[0049] ##STR00012## [0050] wherein P.sub.1 and P.sub.2 are as
defined above; [0051] (c) using the obtained compound selected from
formulas XI and XI' for conversion into Rosuvastatin or its salt;
and [0052] (d) using the obtained compound of formula I for
providing said compound in a process according to item (1) in a
recycling process for producing rosuvastatin. [0053] (19) The
process according to item (18), wherein in step (b) the obtained
reaction products are respectively separated into the compound of
formula I and the compound selected from formulas XI or XI', prior
to the respective use in step (d).
[0054] In the manner defined by items (18) and (19), an
advantageous and generally applicable recycling process is provided
for improving the overall yield of Rosuvastatin or its salt. [0055]
(20) A process for preparing a compound of formula III
[0055] ##STR00013## [0056] comprising the step of converting the
compound of formula II
[0056] ##STR00014## [0057] by hydrolysis into the compound of
formula III. [0058] (21) The process according to item (20),
wherein hydrolysis is performed in the presence of an inorganic
base, preferably an alkaline or alkaline earth carbonate or
hydrogencarbonate, more preferably NaHCO.sub.3. [0059] (22) The
process according to item (21), wherein the inorganic base is added
to the reaction mixture in the form of a saturated aqueous
solution. [0060] (23) The process according to any one of items
(21)-(22), wherein the initial amount of inorganic base is between
about 1 to 10 times the molar stoichiometric amount based on
compound II, preferably about 3 to 7 and more preferably 5 to 6
times. [0061] (24) A one-pot process for preparing the compound of
formula III
[0061] ##STR00015## [0062] comprising converting compound of
formula I
[0062] ##STR00016## [0063] by reaction via non-isolated compound of
formula II
[0063] ##STR00017## [0064] into the compound of formula III. [0065]
(25) The process according to item (24), wherein conversion of the
compound of formula I into the compound of formula II is carried
out by the process of any one of items (1) to (13). [0066] (26) The
process according to item (24) or (25), wherein conversion of the
compound of formula II into the compound of formula III is carried
out by the process of any one of items (20) to (23) [0067] (27) The
process according to any one of items (24) to (26), wherein a
reaction batch after converting compound of formula I into compound
of formula II is diluted with a solvent as defined under item (6).
[0068] (28) The process according to any one of items (20) to (27),
further comprising the step of purifying compound of formula III,
preferably by crystallization. [0069] (29) The process according to
item (28), wherein crystallisation is performed with an MTBE/hexane
mixture, preferably with an MTBE/hexane mixture wherein the volume
ratio of MTBE to hexane is 2 to 1, preferably 1 to 1 and more
preferably 2 to 3. [0070] (30) A process for the preparation of
Rosuvastatin or pharmaceutically acceptable salt of Rosuvastatin,
comprising the steps of: [0071] a) carrying out a process for
preparing the compound of formula I according to item (16), and
[0072] b) subjecting the compound of formula I to further synthesis
steps to yield Rosuvastatin or pharmaceutically acceptable salts
thereof. [0073] (31) A process for the preparation of Rosuvastatin
or pharmaceutically acceptable salt of Rosuvastatin, comprising the
steps of: [0074] a) carrying out a process for preparing the
compound of formula II according to any one of items (1) to (15),
and [0075] b) subjecting the compound of formula II to further
synthesis steps to yield Rosuvastatin or pharmaceutically
acceptable salts thereof. [0076] (32) A process for the preparation
of Rosuvastatin or pharmaceutically acceptable salt of
Rosuvastatin, comprising the steps of: [0077] a) carrying out a
process for preparing the compound of formula III according to any
one of items (20) to (29), and [0078] b) subjecting the compound of
formula III to further synthesis steps to yield Rosuvastatin or
pharmaceutically acceptable salts thereof. [0079] (33) A process
for the preparation of a pharmaceutical composition comprising
Rosuvastatin as active ingredient, comprising the steps of: [0080]
a) preparing Rosuvastatin or pharmaceutically acceptable salts
thereof according to the process according to item (31) or (32),
and [0081] b) admixing the thus prepared Rosuvastatin or
pharmaceutically acceptable salt thereof with at least one
pharmaceutically acceptable excipient. [0082] (34) A process for
the preparation of a pharmaceutical composition comprising
Rosuvastatin as active ingredient, comprising the steps of: [0083]
a) preparing Rosuvastatin or pharmaceutically acceptable salts
thereof according to the process according to any one of items (17)
to (19), [0084] b) admixing the thus prepared Rosuvastatin or
pharmaceutically acceptable salt thereof with at least one
pharmaceutically acceptable excipient. [0085] (35) Use of compound
of formula II prepared according to the process of any one of items
(1) to (15) for the preparation of Rosuvastatin or pharmaceutically
acceptable salts thereof. [0086] (36) Use of compound of formula
III prepared according to the process of any one of items (20) to
(29) for the preparation of Rosuvastatin or pharmaceutically
acceptable salts thereof. [0087] (37) Use of the compound of
formula I prepared according to any one of the processes of items
(16) to (19) for the preparation of Rosuvastatin or
pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0088] The present invention is now described in more detail by
referring to further preferred and further advantageous embodiments
and examples, which are however presented for illustrative purposes
only and shall not be understood as limiting the scope of the
present invention.
[0089] In order to improve a process for the preparation of a
compound of formula II
(N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methy-
lmethanesulfonamide) and a compound of formula III
(N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-met-
hylmethanesulfonamide), extensive test series were carried out by
the inventors to find critical factors that are particularly suited
to increase the product yields and to decrease byproducts, while
significantly simplifying preparation due to beneficial reaction
conditions and/or less necessary reaction steps.
[0090] Conventionally, the compound of formula III was prepared by
reduction of a suitable ester derivative of the formula IV (wherein
R preferably denotes a methyl or ethyl residue) by means of a
suitable reducing agent in a late or last step of a multi step
synthesis procedure, as illustrated on the following scheme:
##STR00018##
[0091] However, this type of reduction has significant procedural
drawbacks. Most commonly, reduction is carried out by
diisobutylaluminium hydride (DIBAL-H) as the reducing agent, and
therefore the reduction must be carried out at temperatures around
or below 0.degree. C. (preferably up to -70.degree. C.) under
dry/anhydrous conditions. A further drawback of the reduction with
DIBAL-H is that the complex hydride DIBAL-His an expensive and
hazardous reagent. Less common, the reduction is carried out with
KBH.sub.4/ZnCl.sub.2 as the reducing agent, which also requires
dry/anhydrous conditions. Moreover, there is the problem of
unreacted starting material and generation of byproducts which are
hardly removed in the subsequent Rosuvastatin synthesis steps if
dry/anhydrous conditions are not employed and reaction does't go to
completion.
[0092] As shown on the following scheme, conventionally, the
compound of formula III was then converted into the compound of
formula II by a nucleophilic substitution reaction using HBr or
PBr.sub.3 in order to introduce bromine:
##STR00019##
[0093] Said nucleophilic substitution reaction has significant
drawbacks, inter alia since HBr is a very corrosive and aggressive
reagent, and the alternative reactant PBr.sub.3 is toxic, evolves
corrosive HBr, and reacts violently with water and alcohols which
makes it difficult to handle.
[0094] In conclusion, it can be said that the above described
conventional preparation of the compound of formula III, or the
conventional preparation of the compound of formula II via the
compound of formula IV requires reactants which are difficult to
handle, dangerous and/or expensive. Furthermore, several reaction
steps are necessary in order to obtain the compound of formula II,
and the conventional processes suffer from drawbacks of critical
generation of byproducts which affects further synthesis of
Rosuvastatin.
[0095] According to one aspect of the present invention,
nucleophilic substitution reaction for introduction of bromine with
HBr or PBr.sub.3 is not used but the compound of formula II is
prepared by converting a compound of formula I by bromination into
the compound of formula II as presented on the following
scheme:
##STR00020##
[0096] Since the compound of the formula I
(N-(4-(4-fluorophenyl)-5-methyl-6-isopropylpyrimidin-2-yl)-N-methylmethan-
esulfonamide) is used as the starting material, compound II
(N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methy-
lmethanesulfonamide) can be obtained in only one step by
bromination. The reaction can be carried out most efficiently by
radical bromination reaction, optionally assisted by UV irridation
and/or use of radical formers.
[0097] The above described bromination, notably when proceeding
with radical reaction, significantly differs from the introduction
of bromine by means of a nucleophilic substitution reaction (e.g.
wherein compound of the formula III is converted into compound of
the formula II). A nucleophilic substitution reaction requires a
leaving group such as for example --OH of the compound of the
formula III. In contrast to that, the compound of the formula I
does not require such a leaving group.
[0098] In the above described bromination reaction of the present
invention bromination agents such as N-bromoamides are preferably
used. Advantageously, N-bromoamides provide for a constant, low
concentration of bromine in the reaction mixture during reaction.
More preferably, said N-bromoamides are selected from the group
consisting of N-bromoacetamide, N,N-dibromobenzene sulfonamides;
the N-bromoimides, such as N-bromosuccinimide, N-bromophthalimide,
N-bromoglutarimide, 3-bromo-hydantoin, and
1,3-dibromo-5,5-dimethylhydantoin. N-bromosuccinimide is the most
preferred brominating agent, since it is readily commercially
availably and economically priced. Advantageously, the
aforementioned bromination agents provide for mild reaction
conditions resulting in less byproducts. HBr and PBr.sub.3, which
are aggressive and difficult to handle reactants which would
negatively affect purity and yield of the compound of formula II,
can be avoided.
[0099] The initial amount of said brominating agents is from about
0.1 to about 3 times the molar stoichiometric amount based on
compound I, preferably about 0.9 to about 2.5 times, more
preferably about 1.4 to about 2.2 times, and in particular about 2
times. In this way, efficient bromination resulting in high yields
of compound II is provided, while economical amounts of brominating
agent are used.
[0100] The above mentioned bromination reaction is suitably
performed in organic solvent, preferably selected from the group
consisting of acetone, ethyl acetate, hydrocarbons, aromatic
hydrocarbons and acetonitrile. Most preferably, acetonitrile is
used as organic solvent. The aforementioned organic solvents
provide for suitable solubilisation of the reactants and
advantageous reaction rates. Furthermore, these organic solvents
are largely less toxic than carbon tetrachloride or chlorobenzene,
which have been typically used in radical bromination of
hydrocarbon side chains of aromatic substrates.
[0101] Preferably, the step of reacting a compound of formula I
with brominating agent to give the compound of formula II is
performed under a treatment of ultraviolet radiation, wherein said
ultraviolet radiation has preferably a wavelength of about 200 to
400 nm, more preferably about 310 nm. Said ultraviolet radiation is
preferably performed for 2 to 10 hours, more preferably for about 4
hours.
[0102] In a particular preferred embodiment of the invention, the
bromination reaction is carried out at suitable temperature,
preferably at a temperature between 0 to 90.degree. C., more
preferably between 10 to 65.degree. C., even more preferably
between 15 to 35.degree. C. and in particular at an ambient
temperature between 19 to 25.degree. C. In this way, beneficial
mild reaction conditions can be set, which further contributes to
form less byproducts compared to a nuclephilic substitution
reaction for introducing bromine wherein elevated reaction
temperatures are used. Higher yields are obtained, purification
will be facilitated, and further synthesis steps to obtain
Rosuvastatin are less affected by critical byproducts.
[0103] Surprisingly, when using compound of formula I as starting
compound, the above described radical bromination proceeds within
relatively short reaction times and high yields, even if no radical
former is applied. The absence of a radical former is advantageous,
since the reaction becomes more safe in view of operational safety,
because radical formers are quite reactive and therefore dangerous
to handle compounds. Furthermore, the costs for a radical former
can be saved. Therefore, it is preferred to perform the bromination
without a radical former. In addition, significantly less
impurities are formed during the reaction if no radical former is
used.
[0104] Nevertheless, if one wishes to further accelerate the
bromination reaction, a radical former may be applied. If used, the
radical former is preferably an organic peroxide, an organic
peracid, an organic hydroperoxide or an organic azo compound. These
radical performers are suitable for accelerating/supporting radical
reactions. More preferably, the radical former is selected from
benzoyl peroxide or azoisobutyronitrile, since these radical
performers are readily commercially available and inexpensive.
[0105] If a radical former is applied in the bromination reaction,
the initial amount of radical former is between about 0 to 0.5
molar stoichiometric amount based on compound I, preferably about 0
to 0.07 molar stoichiometric amount based on compound I, and more
preferably no radical former is applied. The aforementioned amounts
of radical former provide for an advantageous acceleration of the
reaction, while still providing a stable and safe reaction.
[0106] According to one embodiment, the compound of formula II is
isolated and purified, preferably by crystallization. In this way,
a simple and effective purification method is applied, compared to
labor, time and material intensive column chromatography. Since the
bromination reaction is performed under mild conditions, there are
less byproducts, and therefore, crystallisation will be sufficient
in order to provide an advantageously pure product. Furthermore, it
was found by that crystallisation performed with an MTBE/hexane
mixture, and in particular with an MTBE/hexane mixture wherein the
volume ratio of MTBE to hexane is 2 to 1, preferably 1 to 1 and
more preferably 2 to 3 is particularly advantageous.
[0107] The compound of formula I can be obtained by a targeted
synthesis. Or, according to a preferred embodiment, the compound of
formula I is obtained as a side product in the preparation of
rosuvastatin intermediates where the compound of formula I is
formed in a Wittig reaction between a phosphonium salt, phosphine
oxide or phosphonate (compound of formula X) of a corresponding
rosuvastatin heterocycle--or their converted reagents in the
corresponding ylide or phosphorane form (for phosphonium salt) or
corresponding carbanion (for phosphine oxide or phosphonate)
(compound of formula X')--and a chiral statin side chain. An
illustrative reaction system can be depicted from Scheme 1
below.
[0108] In Scheme 1, Z in the compound of formula X and X' is
selected from the group consisting of phosphonium salt moiety,
phosphine oxide moiety or phosphonate moiety:
##STR00021##
wherein Rx, Ry, Rz are the same or different and are selected from
optionally substituted C.sub.1-C.sub.8 alkyl or C.sub.3-C.sub.6
cycloalkyl or C.sub.1-C.sub.8 alkenyl or C.sub.5-C.sub.6
cycloalkenyl or aryl, preferably phenyl, and X.sup..theta. is an
anion, preferably a halogen or carboxylate anion, more preferably
chloride, bromide or trifluoroacetate;
[0109] Further in Scheme 1, P.sub.1 and P.sub.2 independently
denote conventional hydroxyl protecting groups. The protecting
group P.sub.1 and P.sub.2 may be any conventionally used protecting
group for hydroxyl groups, for example selected independently from
the group consisting of alkyl, branched alkyl, acyl, silyl or
similar group, more particularly selected from acetonide, acetyl
(Ac), pivaloyl (Piv), p-toluenesulfonyl (TOS),
.beta.-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM),
p-methoxybenzyl ether (PMB), methylthiomethyl ether, t-butyl,
tetrahydropyranyl (THP), benzyl (Bn), diphenylmethyl or
triphenylmethyl group, preferably silyl protecting group which can
be represented by a formula SiR.sub.1'R.sub.2'R.sub.3' in which
R.sub.1', R.sub.2', R.sub.3' are independently selected from alkyl
(preferably C.sub.1-C.sub.6) or aryl (preferably C.sub.5-C.sub.10),
such as SiMe.sub.3 (TMS), SiMe.sub.2.sup.tBu (TBDMS),
Si(i-Pr).sub.3 (TIPS), SiPh.sub.2.sup.tBu, SiMe.sub.2Ph.
[0110] Hence, as illustrated in Scheme 1, the protected final
rosuvastatin intermediate can be used to proceed with the final
synthesis steps for obtaining rosuvastatin or its salts, while
alternatively or in addition the compound of formula I can be
utilized by being recycled into another (same or different)
rosuvastatin synthesis route.
[0111] Prior to the respective further use, the reaction products
obtained in the Wittig reaction can be respectively separated by
appropriate and known methods into the compound of formula I and
the compound selected from formulas XI or XI'.
##STR00022##
[0112] Advantageously and surprisingly, the compound of formula I
is more substantially formed when the Wittig reaction is performed
with excess of the phosphonium salt (or its ylide or phosphorane),
phosphine oxide (or its carbanion) or phosphonate (or its
carbanion) Wittig reagent (e.g. a molar excess of compound X or X'
over compound IX or IX' of suitably 5% or more, preferably 10% or
more, and particularly 15% or more), more effectively after
quenching with protic solvent, and/or when the Wittig reaction is
performed in the presence of water or other protic molecules such
as alcohols (e.g. methanol, ethanol, propanol, isopropanol butanol
and phenols), etc. The presence of water or other protic molecules
may be accomplished by addition of water or typically known protic
solvent types such as alcohols, but alternatively it is preferred
and sufficient if e.g. undried or wet, or insufficiently dried
solvent(s) introduced into the Wittig reaction is (are) used.
According to another efficient embodiment, the starting compound of
formula IX can obtained from its hydrate form in an appropriate
solvent but without removal of the released water molecules, as
shown in the following reaction scheme,
##STR00023##
and is then directly (i.e. without removal of water) introduced
into the Wittig reaction. An appropriate solvent for the following
reaction is tetrahydrofuran (THF), for example.
[0113] The provision and the utilization of the compound of formula
I has a significant favorable impact on the efficiency of the
overall process of the rosuvastatin synthesis. Since the
heterocyclic part of the molecule is prepared in many laborious
synthetic steps as disclosed e.g. in EP 521471, it is highly
advantageous to recover the valuable compound of formula I and
render it utilizable by specifically converting it into compounds
of formula II or III, which in turn are capable of being
beneficially used further, for example by converting them again
into a phosphonium salt, phosphine oxide or phosphonate
representing a further starting material for the preparation of
rosuvastatin intermediates via Wittig reaction (as exemplified for
example in Scheme 1 above). The compound of formula II can be
directly transformed to phosphonium salt derivative, phosphine
oxide or phosphonate (see e.g. US2005/0124639). Alternatively, the
compound of formula I can be transformed to the compound of formula
III, which can be converted to phosphonium salt derivative,
phosphine oxide or phosphonate (see e.g. WO2007/017117). Although
the compound of formula II can be prepared by prior art processes
(see e.g. WO2007/017117), this process cannot be applied for the
recovery of compound I to phosphonium salt derivative, phosphine
oxide or phosphonate. Similarly, prior-art processes for the
preparation of compound III as disclosed in the EP521471 cannot be
used for recovery of the compound of formula I to phosphonium salt
derivative, phosphine oxide or phosphonate.
[0114] Therefore, the provision of compound of formula I, besides
being useful of its own, can contribute to a markedly improved
overall yield of a rosuvastatin synthesis.
[0115] According to another aspect of the invention, a compound of
formula III is prepared by a process comprising the step of
converting a compound of formula II by hydrolysis into the compound
of formula III, as depicted in the following scheme:
##STR00024##
[0116] According to a preferred embodiment, the above mentioned
conversion is performed in the presence of an inorganic base,
preferably an alkaline or alkaline earth carbonate or
hydrogencarbonate, more preferably NaHCO.sub.3 is used as the
inorganic base. Besides, it is preferred to add said inorganic base
to the reaction mixture in the form of a saturated aqueous
solution.
[0117] Preferably, the initial amount of inorganic base is between
about 1 to 10 times the molar stoichiometric amount based on
compound II, preferably about 3 to 7 times and more preferably 5 to
6 times.
[0118] According to another aspect of the present invention, the
compound of formula III is prepared by a one-pot synthesis
converting compound of formula I via non-isolated compound of
formula II into the compound of formula ill as depicted in the
following scheme.
##STR00025##
[0119] It was found feasible to yield compound of formula III
without isolating and purifying the intermediate compound of
formula II. Therefore, the number of process steps can be reduced,
which makes the whole synthesis route substantially more
efficient.
[0120] Preferably, the aforementioned one-pot synthesis is carried
out by converting compound of formula I into compound of formula II
by the above described bromination according to the present
invention, or/and converting compound of formula II into compound
of formula III by the above described hydrolysis according to the
invention.
[0121] Furthermore, it is preferred to add a solvent to the
resulting reaction batch after conversion of compound of formula I
into compound of formula II is performed, in order to dilute the
reaction batch. Conversion of compound of formula I into compound
of formula II may e.g. be monitored by thin layer chromatography or
high pressure liquid chromatography (HPLC). Preferably, said
solvent for dilution is selected from the group of solvents
described for the above mentioned bromination reaction, and more
preferably it is the same solvent as used in the bromination
reaction. Thereby, an advantageous degree of dissolution of the
compound of the formula II is obtained, which in turn provides for
a smooth hydrolysis giving rise to high yields.
[0122] According to a further embodiment, the process for preparing
the compound of the formula III further comprises the step of
purifying compound of formula III, preferably by crystallization.
In this way, a simple and effective purification method is applied,
compared to labor, time and material intensive column
chromatography. Since the hydrolysis reaction provides for a full
conversion of compound of the formula II into compound of the
formula III, crystallisation will be sufficient in order to provide
an advantageously pure product. Furthermore, it was found by that
crystallisation performed with an MTBE/hexane mixture, and in
particular with an MTBE/hexane mixture wherein the volume ratio of
MTBE to hexane is 2 to 1, preferably 1 to 1 and more preferably 2
to 3 is particularly advantageous.
[0123] The key intermediate compounds of formula II and III can
then be subjected to further synthesis steps in order to yield
Rosuvastatin or pharmaceutically acceptable salts thereof by
synthesis routes known to or readily devisable by a person skilled
in the art. As shown in the scheme below, following synthesis
routes may be applied:
##STR00026##
[0124] For preparing a pharmaceutical composition comprising
Rosuvastatin or pharmaceutically acceptable salts thereof as active
ingredient, first Rosuvastatin or pharmaceutically acceptable salts
thereof is provided by the process as described above.
[0125] Then, the thus prepared Rosuvastatin or pharmaceutically
acceptable salts thereof is suitably admixed with at least one
suitable pharmaceutically acceptable excipient. Pharmaceutically
acceptable excipients may be selected from the group consisting of
binders, diluents, disintegrating agents, stabilizing agents,
preservatives, lubricants, fragrances, flavoring agents, sweeteners
and other excipients known in the field of the pharmaceutical
technology.
[0126] Preferably, excipients may be selected from the group
consisting of lactose, microcrystalline cellulose, cellulose
derivatives, e.g. hydroxypropylcellulose, polyacrylates, calcium
carbonate, starch, colloidal silicone dioxide, sodium starch
glycolate, talc, magnesium stearate, polyvinylpyrrolidone,
polyethylene glycol and other excipients known in the field of the
pharmaceutical technology.
EXPERIMENTAL PROCEDURES
Example 1
Preparation of
N-(4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methyl-methan-
esulfonamide (I)
##STR00027##
[0128] To a cold (-42.degree. C.), stirred suspension of
((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-
-yl)methyl)triphenylphosphonium bromide (814 mg, 1.20 mmol) in
tetrahydrofuran (25 mL) is added sodium hexamethyldisilazane in THE
(1.2 mL of 1.0 M, 1.20 mmol). The reaction mixture is stirred for
45 min at -42.degree. C., cooled to -82.degree. C., and treated
with a solution of
(2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-carbal-
dehyde (266 mg, 1.03 mmol) obtained by dissolution of its hydrate
(284 mg, 1.03 mmol) in 15 mL of tetrahydrofurane without removal of
released water. After 30 min of stirring, the solution is warmed to
-53 to -58.degree. C. and stirred further for 6 hours. Then, the
mixture is allowed to warm to ambient temperature in 100 min and
treated with saturated ammonium chloride solution (40 mL). After
stirring for 10 min at 10.degree. C. the aqueous phase is treated
with 20 mL of water and 40 mL of saturated solution of brine. The
product is extracted with t-BuMeO (50 mL+4.times.30 mL). The
combined organic layers dried (MgSO.sub.4) and concentrated under
reduced pressure (11 mbar) at 40.degree. C. to give white solid.
The residue is purified by silica gel chromatography (elution with
hexane/AcOEt=3:1 mixture) to give 170 mg (42%) of
N-(4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methylmethane-
sulfonamide (I). R.sub.f (hexane/AcOEt=3:1)=0.42. White solid m.p.
113-114.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3, 25.degree.
C.): .delta.=7.56 (m, 2H), 7.14 (m, 2H), 3.55 (s, 3H), 3.51 (s,
3H), 3.31 (sept, .sup.3J=6.7 Hz, 1H), 2.28 (s, 3H), 1.30 (d,
.sup.3J=6.7 Hz, 6H) ppm. .sup.13C NMR (75 MHz, CDCl.sub.3,
25.degree. C.): .delta.=175.3, 164.6, 163.8 (d, J.sub.C-F=249 Hz),
156.7, 134.7 (d, J.sub.C-F=3.4 Hz), 131.1 (d, J.sub.C-F=8.3 Hz),
118.6, 115.1 (d, J.sub.C-F=21.5 Hz), 42.2, 33.0, 31.8, 21.2, 14.1
ppm. MS (ESI+) m/z (%): 338 (MH.sup.+, 100). Anal. Calcd for
C.sub.16H.sub.20FN.sub.3C.sub.2S: C, 56.95; H, 5.97; N, 12.45.
Found: C, 56.95; H, 5.85; N, 12.45.
Example 2
##STR00028##
[0130]
N-(4-(4-fluorophenyl)-5-methyl-6-isopropylpyrimidin-2-yl)-N-methylm-
ethanesulfonamide (112.5 mg, 0.33 mmol, 1 equiv.) and
N-bromosuccinimide (NBS) (126 mg, 0.72 mmol, 2.1 equiv.) were
dissolved in 2 mL of acetonitrile. The mixture was irradiated with
light of a wavelength .lamda.=310 nm for 4 hours at ambient
temperature (about 20.degree. C.). Then, water (10 mL) was added
and the mixture was extracted with CH.sub.2Cl.sub.2 (3.times.10
mL). The combined organic phases were washed with 10 mL of brine,
and the obtained solution was dried with Na.sub.2SO.sub.4. Solvent
was removed under the reduced pressure to give 138.6 mg of crude
N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methyl-
methanesulfonamide (II), which contained 93% of
N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methyl-
methanesulfonamide (II) as determined by .sup.1H-NMR integral. This
product can be further purified by crystallization from MTBE/hexane
mixture to afford pure material.
Example 3
##STR00029##
[0132]
N-(4-(4-fluorophenyl)-5-methyl-6-isopropylpyrimidin-2-yl)-N-methylm-
ethanesulfonamide (112.5 mg, 0.33 mmol, 1 equiv.) and
N-bromosuccinimide (NBS) (118.7 mg, 0.66 mmol, 2 equiv.) were
dissolved in 2 mL of acetonitrile. The mixture was irradiated with
light of a wavelength .lamda.=310 nm for 4 hours at ambient
temperature (about 20.degree. C.). The obtained yellow solution was
diluted with 1 mL of acetonitrile. After 2 mL of saturated
NaHCO.sub.3 solution was added, the obtained mixture was further
stirred under reflux for 4 hours. Then the mixture was cooled to
room temperature, water (10 mL) was added and the mixture was
extracted with CH.sub.2Cl.sub.2 (3.times.10 mL). The combined
organic phases were washed with 10 mL of brine, and the obtained
solution was dried with Na.sub.2SO.sub.4. Solvent was removed under
the reduced pressure to give 110.8 mg (95%) of crude
N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-meth-
ylmethanesulfonamide (III) which contained 77% of
N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-meth-
ylmethanesulfonamide (III) as determined by .sup.1H-NMR integral.
This product can be further purified by crystallization from
MTBE/hexane mixture to afford pure material (HPLC area %=99.6) with
T.sub.m=140-141.degree. C.
* * * * *