U.S. patent application number 12/220259 was filed with the patent office on 2008-12-18 for process for the manufacture of hmg-coa reductase inhibitory mevalonic acid derivatives.
Invention is credited to Christian Mathes, Gottfried Sedelmeier.
Application Number | 20080312462 12/220259 |
Document ID | / |
Family ID | 9931523 |
Filed Date | 2008-12-18 |
United States Patent
Application |
20080312462 |
Kind Code |
A1 |
Sedelmeier; Gottfried ; et
al. |
December 18, 2008 |
Process for the manufacture of HMG-CoA reductase inhibitory
mevalonic acid derivatives
Abstract
The invention relates to a process for the manufacture of a
compound of formula: (Formula I); or a salt, especially a
pharmaceutically acceptable salt with a base, thereof or a lactone
thereof wherein the element (a) represents --CH.sub.2--CH.sub.2
CH-- or --CH.dbd.CH-- and R represents a cyclic radical.
##STR00001##
Inventors: |
Sedelmeier; Gottfried;
(Schallstadt, DE) ; Mathes; Christian; (Offenburg,
DE) |
Correspondence
Address: |
NOVARTIS;CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
9931523 |
Appl. No.: |
12/220259 |
Filed: |
July 23, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11684134 |
Mar 9, 2007 |
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12220259 |
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10504655 |
Aug 13, 2004 |
7208623 |
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PCT/EP03/01738 |
Feb 20, 2003 |
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11684134 |
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Current U.S.
Class: |
556/137 |
Current CPC
Class: |
C07F 9/5352 20130101;
A61P 9/10 20180101; C07D 309/30 20130101; C07F 15/0053 20130101;
A61P 3/06 20180101; C07F 15/025 20130101; C07C 59/42 20130101; C07F
15/065 20130101; C07F 15/045 20130101; C07F 15/008 20130101; A61P
43/00 20180101; C07F 15/004 20130101; C07C 51/09 20130101 |
Class at
Publication: |
556/137 |
International
Class: |
C07F 15/00 20060101
C07F015/00 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 21, 2002 |
GB |
0204129.1 |
Claims
1-7. (canceled)
8. A compound of formula (II d), ##STR00036## wherein L.sub.1 is
hydrogen and L.sub.2 represents phenyl or phenyl substituted by
one, two, three, four or five alkyl residues, and R.sub.5
represents a residue selected from the group consisting of 2- or 3-
or 4-pyridyl, 4-chloro-4-phenoxy-phenyl, 4-phenoxy-phenyl,
5-di(m)ethylamino-1-naphthyl, 5-nitro-1-naphthyl, 2-, 3-,
4-nitrophenyl, 4-vinylphenyl, 4-biphenylyl, 9-anthracenyl, 2,3-,
4-hydroxyphenyl, tolyl, phenanthryl, benzo[1,3]-dioxole,
dimethyl(naphthalene-1-yl)-amine, mono to
tristrifluoromethylphenyl, chrysenyl, perylenyl and pyrenyl or
2-phenylethene; M is Ru, Rh, or Ir; and R.sup.8 and R.sup.9 is each
independently phenyl or cyclohexyl or substituted phenyl.
9. The compound of claim 4 wherein L.sub.2 is phenyl or phenyl
substituted by isopropyl.
10. The compound of claim 8 wherein L.sub.2 is
4-isopropyl-phenyl.
11. The compound of claim 4 wherein R.sup.8 is phenyl and R.sup.9
is phenyl.
12. The compound of claim 4 wherein M is Ru.
Description
[0001] The invention relates to a process for the manufacture of
HMG-CoA reductase inhibitors, to process steps, to novel
intermediates and to novel catalysts.
[0002] HMG-CoA reductase inhibitors (also called
.beta.-hydroxy-.beta.-methylglutaryl-co-enzyme-A reductase
inhibitors and also called statins) are understood to be those
active agents which may be preferably used to lower the lipid
levels including cholesterol in blood and can be used e.g. for the
prevention or treatment of hyperlipidemia and
artheriosclerosis.
[0003] The class of HMG-CO-A reductase inhibitors comprises
compounds having differing structural features. For example,
mention may be made of the compounds which are selected from the
group consisting of atorvastatin, cerivastatin, fluvastatin,
lovastatin, pitavastatin (formerly itavastatin), pravastatin,
rosuvastatin, and simvastatin, or, in each case, a pharmaceutically
acceptable salt thereof.
[0004] Preferred HMG-Co-A reductase inhibitors are those agents
which have been marketed, most preferred is fluvastatin,
atorvastatin, pitavastatin, especially the Calcium salt thereof, or
simvastatin or a pharmaceutically acceptable salt thereof.
[0005] Atorvastatin of formula
##STR00002##
is disclosed and claimed in U.S. Pat. No. 5,273,995.
[0006] Cerivastatin of formula
##STR00003##
is disclosed and claimed in U.S. Pat. No. 5,177,080.
[0007] (+)-(5S,3R)-Form of fluvastatin of formula
##STR00004##
is disclosed and claimed in U.S. Pat. No. 5,345,772.
[0008] Lovastatin of formula
##STR00005##
is disclosed and claimed in U.S. Pat. No. 4,231,938.
[0009] Pitavastatin of formula
##STR00006##
is disclosed and claimed in U.S. Pat. No. 5,856,336.
[0010] Pravastatin of formula
##STR00007##
is disclosed and claimed in U.S. Pat. No. 4,410,629.
[0011] Rosuvastatin of formula
##STR00008##
is disclosed and claimed in U.S. Pat. No. 5,260,440.
[0012] Simvastatin of formula
##STR00009##
is disclosed and claimed in U.S. Pat. No. 4,444,784.
[0013] The structure of the active agents identified hereinbefore
or hereinafter by generic or tradenames may be taken from the
actual edition of the standard compendium "The Merck Index" or from
databases, e.g. Patents International or LifeCycle Patents
International, respectively, (e.g. IMS World Publications). The
corresponding content thereof is hereby incorporated by reference.
Any person skilled in the art is fully enabled to identify the
active agents and, based on these references, and is likewise
enabled to manufacture and test the pharmaceutical indications and
properties in standard test models, both in vitro and in vivo.
[0014] Acidic representatives of HMG-Co-A reductase inhibitors have
been launched are being developed as salts, for example,
fluvastatin as sodium salt and pitavastatin as calcium salt.
[0015] The corresponding active ingredients or a pharmaceutically
acceptable salts thereof may also be used in form of a solvate,
such as a hydrate or including other solvents, used for
crystallization.
[0016] Essentially, statins comprise a cyclic core element and a
side chain element of formula
##STR00010##
(a 3,5dihydroxy-hept-6-enoic acid moiety) that might form a
corresponding lactone partial structure of formula
##STR00011##
(a 3,5-dihydroxy-heptanoic acid derivative) that might form a
corresponding lactone partial structure of formula
##STR00012##
[0017] In said side chain elements (A) or (C), respectively, the
3,5-syn diol structure and the R-configuration at C-3 are essential
features, as corresponding statins with this specific element
exhibit the highest biological activity.
[0018] The objective of the present invention is to provide an
enantioselective synthesis of compounds of formula (I) resulting in
high yields and moreover guaranteeing a minimization of the
ecological pollution of the environment, being economically
attractive, e.g. by using less reaction steps in the reaction
sequence for the manufacture of compounds of formula I, and leading
to largely enantiomerically pure target products and to products of
high crystallisability. Furthermore, another objective of the
present invention is to provide a process that can be carried out
in a larger scale and can thus be used for a corresponding
production process. Furthermore, there is a need to avoid any
separation of any stereoisomers.
[0019] Surprisingly, the process of the present invention clearly
meets the above objectives. The process relates to an
enantioselective synthesis by using essentially the so-called
transfer hydrogenation approach. For example, an enantiomer excess
(ee) of a compound of formula (I) of .gtoreq.95%, preferably
.gtoreq.98% and most preferably .gtoreq.99% can be achieved.
[0020] The invention relates to a process for the manufacture of a
HMG-CoA reductase inhibitory mevalonic acid derivative of formula
(I a)
##STR00013##
or a salt, especially a pharmaceutically acceptable salt with a
base, thereof or a lactone thereof wherein the element represents
--CH.sub.2--CH.sub.2-- or --CH.dbd.CH-- and R represents a cyclic
residue.
[0021] A salt of a compound of formula (I) is, for example, a salt
with a base, preferably a corresponding pharmaceutically acceptable
salt thereof.
[0022] A lactone of a compound of formula (I) is represented by
formulae (I a) and (I b)
##STR00014##
[0023] Corresponding cyclic residue R comprises a cyclic residue
selected from the group consisting of
##STR00015##
[0024] Extensive experimental evaluations surprisingly resulted in
a process sequence for the manufacture that meets the above
criteria showing the indicated advantages.
[0025] The process as disclosed in Bioorganic & Medicinal
Chemistry Letters 9 (1999) 2977-2982 for the manufacture of
pitavastatin (NK 104) requires the formation of a racemic
erythro-.beta.,.delta.-dihydroxyester that is hydrolysed to form
the corresponding acid. With .alpha.-methylbenzylamine a
diastereomeric mixture of resulting salts are formed that need to
be resolved into the different diastereomeric salts. The clear
disadvantage of this approach is that half of the material needs to
be destroyed. Accordingly, the process of the present invention can
be carried out without such a diastereomeric resolution
procedure.
[0026] The process for the manufacture of a compound of formula
##STR00016##
or a salt thereof or a lactone thereof, wherein the element
represents --CH.sub.2--CH.sub.2-- or --CH.dbd.CH-- and R represents
a cyclic residue, according to the present inventions is
characterized by (a) reacting a compound of formula (II a)
##STR00017##
wherein R.sup.1, R.sup.2 and R.sup.3, independently of one another,
represents phenyl that is unsubstituted or substituted by one or
more substituents selected from the group consisting of
C.sub.1-C.sub.7alkyl, hydroxy, C.sub.1-C.sub.7alkoxy,
C.sub.2-C.sub.8alkanoyl-oxy, halogen, nitro, cyano, and CF.sub.3,
and R.sup.4 is an aliphatic, cycloaliphatic, araliphatic or
aromatic residue; with a compound of formula R--CH(.dbd.O) (II b)
wherein R represents a cyclic residue; and (b) reducing a resulting
compound of formula (II c)
##STR00018##
wherein R and R.sup.4 have the meanings as defined above; in the
presence of a reducing agent selected from the group consisting of
a compound of formulae (II d), (II d'), (II d''), (II d'''), (II
d''''), (II d'''''), (II d''''''), and (II d''''''')
##STR00019## ##STR00020##
wherein [0027] M is Ru, Rh, Ir, Fe, Co or Ni; [0028] L.sub.1 is
hydrogen; [0029] L.sub.2 represents an aryl or aryl-aliphatic
residue; [0030] Hal is halogen; [0031] R.sup.5 is an aliphatic,
cycloaliphatic, cycloaliphatic-aliphatic, aryl or aryl-aliphatic
residue, which, in each case, may be linked to a polymer; [0032]
each of R.sup.6 and R.sup.7, independently, is an aliphatic,
cycloaliphatic, cycloaliphatic-aliphatic, aryl or aryl-aliphatic
residue; [0033] each of R.sup.8 and R.sup.9 is phenyl or R.sup.8
and R.sup.9 form together with the carbon atom to which they are
attached a cyclohexane or cyclopentane ring; and [0034] R.sup.15 is
H, halogen, amino, nitro or C.sub.1-C.sub.7alkoxy; wherein any
aromatic residue of a compound of formula (IId), (IId'), (IId''),
(IId'''), (IId'''), (IId'''''), (IId'''''') or (IID''''''') is
unsubstituted or substituted; wherein for compounds of formula
(IId''), (IId'''), (IId''''), (IId'''''), (IId'''''') or
(IID''''''') also combinations with (R)- or (S)-BINAP are possible;
and (c) condensing a resulting compound of formula (II e)
##STR00021##
[0034] wherein R and R.sup.4 have the meanings as defined above,
with a compound of formula (II f)
##STR00022##
wherein R.sup.16 represents an aliphatic residue, and (d) reducing
a resulting compound of formula (II g)
##STR00023##
wherein R and R.sup.16 have the meanings as defined above, and (e)
hydrolysing a resulting compound of formula (II h)
##STR00024##
wherein R and R.sup.16 have the meanings as defined above, and (f)
isolating a resulting compound of formula (I) or a salt thereof;
and, if desired, converting a resulting free acid of formula (I)
into a salt thereof or into a lactone of formula (I a) or (I b),
respectively, or converting a resulting lactone of a formula (I a)
or (I b) into an acid of formula (I) or a salt thereof, or
converting a resulting compound of formula (I) wherein the element
represents --CH.dbd.CH-- into a compound of formula (I) wherein the
element represents --CH.sub.2--CH.sub.2--.
[0035] The general terms used hereinbefore and hereinafter have the
following meanings, unless defined otherwise.
[0036] C.sub.1-C.sub.7Alkyl is for example methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or a
corresponding pentyl, hexyl or heptyl residue.
C.sub.1-C.sub.4alkyl, especially methyl or tert-butyl is
preferred.
[0037] C.sub.1-C.sub.7Alkoxy is for example methoxy, ethoxy,
n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy,
tert-butyloxy or a corresponding pentyloxy, hexyloxy, or heptyloxy
residue. C.sub.1-C.sub.4alkoxy is preferred. Especially preferred
is methoxy and tert-butoxy.
[0038] C.sub.2-C.sub.8Alkanoyl in C.sub.2-C.sub.8alkanoyl-oxy is in
particular acetyl, propionyl, butyryl, isobutyryl or pivaloyl.
C.sub.2-C.sub.5Alkanoyl is preferred.
[0039] Halogen is in particular halogen with an atomic number up to
and including 35, i.e. fluorine, chlorine or bromine, and in a
broader sense includes iodine. Fluorine or chlorine is
preferred.
[0040] An aliphatic hydrocarbon residue is, for example,
C.sub.1-C.sub.7alkyl, C.sub.2-C.sub.7alkenyl or secondarily
C.sub.2-C.sub.7alkynyl.
[0041] C.sub.2-C.sub.7Alkenyl is in particular
C.sub.3-C.sub.7alkenyl and is, for example, 2-propenyl or 1-, 2- or
3-butenyl. C.sub.3-C.sub.5alkenyl is preferred.
[0042] C.sub.2-C.sub.7-Alkynyl is in particular
C.sub.3-C.sub.7alkynyl and is preferably propargyl.
[0043] A cycloaliphatic residue is, for example, a
C.sub.3-C.sub.8cycloalkyl or, secondarily,
C.sub.3-C.sub.8cycloalkenyl.
[0044] C.sub.3-C.sub.8Cycloalkyl is, for example, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopentyl
and cyclohexyl are preferred.
[0045] C.sub.3-C.sub.8Cycloalkenyl is in particular
C.sub.3-C.sub.7cycloalkenyl and is preferably cyclopent-2-en-yl and
cyclopent-3-enyl, or cyclohex-2-en-yl and cyclohex-3-en-yl.
[0046] A cycloaliphatic-aliphatic residue is, for example,
C.sub.3-C.sub.8cycloalkyl-C.sub.1-C.sub.7alkyl, preferably
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4alkyl. Preferred is
cyclopropylmethyl.
[0047] An araliphatic residue is in particular
phenyl-C.sub.1-C.sub.7alkyl, also phenyl-C.sub.2-C.sub.7alkenyl or
phenyl-C.sub.2-C.sub.7alkynyl.
[0048] An aromatic residue is, for example, a carbocyclic or
heterocyclic aromatic residue, in particular phenyl or in
particular an appropriate 5- or 6-membered and monocyclic residue
which has up to four identical or different hetero atoms, such as
nitrogen, oxygen or sulfur atoms, preferably one, two, three or
four nitrogen atoms, an oxygen atom or a sulfur atom. Appropriate
5-membered heteroaryl residues are, for example, monoaza-, diaza-,
triaza-, tetraaza-, monooxa- or monothia-cyclic aryl radicals, such
as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl
and thienyl, while suitable appropriate 6-membered residues are in
particular pyridyl.
[0049] Pyrrolyl is, for example, 2- or 3-pyrrolyl. Pyrazolyl is 3-
or 4-pyrazolyl. Imidazolyl is 2- or 4-imidazolyl. Triazolyl is, for
example, 1,3,5-1H-triazol-2-yl or 1,3,4-triazol-2-yl. Tetrazolyl
is, for example, 1,2,3,4-tetrazol-5-yl, furyl is 2- or 3-furyl and
thienyl is 2- or 3-thienyl, while suitable pyridyl is 2-, 3 or
4-pyridyl.
[0050] Appropriate multicyclic residues are anthracenyl,
phenanthryl, benzo[1,3]-dioxole or pyrenyl. An aryl residue may be
mono-substituted by e.g. NH.sub.2, OH, SO.sub.3H, CHO, or
di-substituted by OH or CHO and SO.sub.3H.
[0051] Any aromatic residue is preferably unsubstituted or
substituted, for example, by one or more, e.g. two or three,
residues e.g. those selected from the group consisting of
C.sub.1-C.sub.7alkyl, hydroxy, C.sub.1-C.sub.7alkoxy,
C.sub.2-C.sub.8alkanoyl-oxy, halogen, nitro, cyano, and
CF.sub.3.
[0052] Polymers may be polystyrene (PS), cross-linked PS (J),
polyethylene glycol (PEG) or a silica gel residue (Si). Examples
are NH--R.sup.15 wherein R.sup.15 is C(O)(CH.sub.2).sub.n--PS or
C(O)NH(CH.sub.2).sub.n--PS; and
--O--Si(R.sup.14).sub.2(CH.sub.2).sub.nR.sup.16 wherein n is 1 to
7, R.sup.14 is C.sub.1-C.sub.6alkyl, e.g. ethyl, and R.sup.16 is a
PS, J, PEG or Si (obtainable by Aldrich, Switzerland).
[0053] In formula formula (IId), (IId'), (IId''), (IId'''),
(IId''''), (IId'''''), (IId'''''') or (IID''''''') the following
significances are preferred independently, collectively or in any
combination or sub-combination: [0054] M is Ru, Rh, Ir, preferably
Ru. [0055] L.sub.2 is isopropylmethylbenzene, benzene,
hexamethylbenzene, mesitylene, preferred is isopropylmethylbenzene.
[0056] R.sup.5 is 2- or 3- or 4-pyridyl, 4-chloro-4-phenoxy-phenyl,
4-phenoxy-phenyl, 5-di(m)ethylamino-1-naphthyl, 5-nitro-1-naphthyl,
2-, 3-, 4-nitrophenyl, 4-vinylphenyl, 4-biphenylyl, 9-anthracenyl,
2,3 or 4 hydroxyphenyl, tolyl, phenanthryl, benzo[1,3]-dioxole,
dimethyl(naphthalene-1-yl)-amine, mono to
tristrifluoromethylphenyl, chrysenyl, perylenyl or pyrenyl or
2-phenylethene. [0057] Each of R.sup.6 and R.sup.7, independently,
are phenyl, 4-methylphenyl or 3,5-dimethylphenyl, preferred is
phenyl. [0058] Each of R.sup.8 and R.sup.9 is phenyl or cyclohexyl
or substituted phenyl, preferably is phenyl. [0059] Preferred Hal
is chloro. [0060] Preferred R.sub.15 is H. [0061] L.sub.1 is as
defined above.
[0062] In a preferred aspect, the invention provides a process for
the production of a compound of formula I'a or I'b
[0063] The reactions described above and below in the variants are
carried out, for example in the absence or, customarily, in the
presence of a suitable solvent or diluent or a mixture thereof, the
reaction, as required, being carried out with cooling, at room
temperature or with warming, for example in a temperature range
from about -80.degree. C. up to the boiling point of the reaction
medium, preferably from about -10.degree. to about +200.degree. C.,
and, if necessary, in a closed vessel, under pressure, in an inert
gas atmosphere and/or under anhydrous conditions.
[0064] Preferably, in the process according to the present
invention compounds of formulae (II a), (II c), (II e), (II f), (II
g) and (II h) are used, wherein R.sup.4 or R.sup.16, respectively,
represent C.sub.1-C.sub.4alkyl, especially methyl or ethyl or most
preferably tert-butyl.
Step (a):
[0065] In reaction Step (a), the reaction of a compound of formula
(II a) with a compound of formula (II b) is carried out in a
suitable inert solvent, such as a nitrile, especially acetonitrile
or propionitrile, and in a temperature range from, for example,
from -78.degree. C., to the boiling point of the solvent,
preferably at the boiling point of the solvent.
Step (b):
[0066] Reaction Step (b) is an asymmetric transfer hydrogenation,
especially when using a chiral Ru(II) catalyst of formula (II d)
and a hydrogen donor.
[0067] Step (b) is carried out in a suitable inert solvent, such as
an ether, e.g. tetrahydrofuran, an ester, such as ethylacetate, an
nitrile, especially acetonitrile, a formamide, especially
dimethylformamide, and in a temperature range from, for example,
from -78.degree. C., to the boiling point of the solvent,
preferably at room temperature.
[0068] Preferred catalysts are following compounds
##STR00025##
wherein L.sub.1 is hydrogen and L.sub.2 represents an aliphatic,
cycloaliphatic, cycloaliphatic-aliphatic, aryl or araliphatic
residue; Hal is halogen; R.sup.5, R.sup.6 and R.sup.7,
independently of one another, represents an aliphatic,
cycloaliphatic, cycloaliphatic-aliphatic, aryl or araliphatic
residue; wherein, in each case, any aromatic residue of a compound
of formulae (II d), (II d') and (II d'') is unsubstituted or
substituted;
[0069] Preferred Ru (II) catalysts of formula (II d) are those
wherein L.sub.1 is hydrogen and L.sub.2 is isopropylphenyl, R.sup.5
is tolyl.
[0070] A preferred hydrogen donor is, for example,
NEt.sub.3/H.sub.3PO.sub.2/H.sub.2O, diphenylsilan/MeOH or a system
comprising 2-propanol, 3-pentanol, or most preferably HOOCH in the
presence of an amine, such as triethylamine, DBU or other tertiary
amines. The hydrogen donor may also be used as inert solvent,
especially 2-propanol and most preferably HCOOH. An alternative
hydrogen donor is 2-propanol in the presence of various catalysts
and base, e.g.
Ru[(1S,2S)-p-TsNCH(C.sub.6H.sub.5)CH(C.sub.6H.sub.5)NH](.eta..sup.6-p-cym-
ene) and base or "in situ" [Ru(.eta..sup.6-p-cymene)Cl.sub.2].sub.2
with chiral ligand (R,R- or S,S-TsDPEN, amino-alcohol) and base.
The preferred bases are: t-BuOK, KOH or i-PrOK.
[0071] A preferred hydrogen donor is, for example, a system
comprising HOOCH in the presence of an amine, such as
triethylamine, or most preferably 2-propanol. The hydrogen donor
may also be used as inert solvent, especially HCOOH and most
preferably 2-propanol.
[0072] Step (b) can also be carried out by hydrogenating with
hydrogen in the presence of a catalyst of formula (II d') or (II
d''), (IId''), (IId'''), (IId''''), (IId'''''), (IId'''''') or
(IID'''''''), respectively. A suitable inert solvent is e.g. an
ether, such as tetrahydrofuran, an ester, such as ethylacetate, or
an alcohol, such as a C.sub.1-C.sub.4alkanol, for example,
isopropanol.
[0073] Preferred Hal is chloro.
Step (c):
[0074] Condensation Step (c) is carried out in the presence of a
condensation system and in a suitable inert solvent, such as an
ether, especially tetrahydrofuran or tert-butyl-ethyl ether, and in
a temperature range from, for example, from -78.degree. C., to the
boiling point of the solvent, preferably at room temperature.
[0075] A suitable condensating system is, for example, a base, such
as an alkane alkalimetal, especially butyl lithium, or a hydride,
e.g. sodium hydride, or a mixture thereof. Especially preferred is
the use of the condensation system butyl lithium in the presence of
diisopropylamine.
Step (d):
[0076] A preferred reduction agent is, for example, a hydride, for
example, an alkalimetal borohydrid, especially sodium borohydride,
preferably in the presence of a
di-C.sub.1-C.sub.7alkyl-C.sub.1-C.sub.7alkoxy-borane, most
preferably diethyl-methoxy-borane.
[0077] The reduction is carried out in an inert solvent, such as an
ether, preferably tetrahydrofuran, and at low temperatures, for
example, from -78.degree. to 0.degree. C., preferably at
-78.degree. C. To split a corresponding boronic ester the reaction
mixture is then oxidized with an oxidizing agent, such as a
peroxide, especially, hydrogen peroxide. The oxidation is carried
out in an inert solvent, such as an ether, preferably
tetrahydrofuran, and in a temperature range from, for example, from
0.degree. C., to the boiling point of the solvent, preferably in a
range of 0.degree. to 20.degree. C.
Step (e):
[0078] The saponification Step (e) is carried out, for example, by
treating the ester of formula (II h) with a strong base, such as an
alkali metal hydroxide, preferably NaOH, or with Ca(OH).sub.2 and
acidifying the resulting reaction mixture.
Step (f):
[0079] The isolation Step (f) of a compound of formula (I) is
carried out according to conventional isolation methods, such as by
crystallizing the resulting compound of formula (I) from the
reaction mixture or by chromatography of the reaction mixture.
[0080] Inert solvents are those that do not react with the
corresponding reactants.
[0081] The present invention likewise relates to a novel compound
of formula (II c). Especially preferred are compounds of formula
(II c), wherein R is a group of formula
##STR00026##
the element represents --CH.dbd.CH--, and R.sub.4 is
C.sub.1-C.sub.4alkoxy, especially methoxy or ethoxy or
tert-butoxy.
[0082] The present invention likewise relates to a novel compound
of formula (II c). Especially preferred are compounds of formula
(II c), wherein R is a group of formula
##STR00027##
the element represents --CH.dbd.CH--, and R.sup.4 is
C.sub.1-C.sub.4alkoxy, especially methoxy or ethoxy or
tert-butoxy.
[0083] It is known from the art that asymmetric transfer
hydrogenation using a Ru (II) catalyst (esp. a Noyori catalyst) is
carried out in the absence of water and under inert gas conditions.
Surprisingly, the transfer hydrogenation step according to the
present invention can be run in a water containing solvent system
and in the absence of an inert gas. This means that the reaction is
successful even though the solvent used comprised water (e.g. 3% by
Karl-Fischer).
[0084] Furthermore, the compound of formula (II c) could--in view
of the esterified carboxy group--be a ligand of the Ru (II)
catalyst as well. Surprisingly, it has been proven that a compound
of formula (II c) does not form a ligand to the Ru catalyst.
[0085] It is known that quinoline moieties are desactivating the
hydrogenation catalysts. Especially, in case of the manufacture of
compound of (I) being pitavastatin, the person skilled in the art
would expect that the quinoline group desactivates the Ru catalyst.
Surprisingly, the asymmetric transfer hydrogenation step according
to the present invention is successfully carried out without that
the catalyst of formulae (II d), (II d'), (II d''), (IId'''),
(IId''''), (IId'''''), (IId'''''') or (IId''''''') is being
desactivated.
[0086] Accordingly, the present invention also relates to reaction
step (b), especially when using a Ru(II) catalyst of formulae (II
d), (II d') or (II d''), respectively.
##STR00028## [0087] wherein M, L.sub.1, L.sub.2, R.sup.8 and
R.sup.9 are as defined above and R.sup.5 is a group of formula
##STR00029##
[0087] wherein [0088] n is 0, 1, 2, 3,4, 5, 6 or 7; [0089] X is O
or S; [0090] R.sup.10 is polystyrol; [0091] R.sup.11 is silica gel;
[0092] R.sup.12 is cross-linked polystyrol; [0093] R.sup.13 is
polyethylene-glycol; [0094] R.sup.14 is C.sub.1-C.sub.6alkyl; and
[0095] m is 1, 2 or 3.
[0096] The following compounds of formula (IId), (IId'), (IId''''')
or (IId'''''') wherein L.sub.1, L.sub.2 and R.sup.5 are as defined
above, are preferred:
##STR00030##
[0097] Compounds of formula (IId), (IId'), (IId'''''') or
(IId'''''') may be prepared by reacting a compound of formula
VII
##STR00031##
wherein R.sup.5, R.sup.8 and R.sup.9 are as defined above, with
[MCl.sub.2(p-cymene)].sub.2 in conventional manner. The
hydrogenation may be carried out in a suitable inert solvent, such
as an ether, e.g. tetrahydrofuran, an ester, such as ethylacetate,
a halogenated solvent, such as methylenchloride, supercritical
CO.sub.2, ionic liquids, a nitrile, especially acetonitrile, an
amide, such as dimethylformamide or dimethylacetamide and in a
temperature range from, for example, from -78.degree. C., to the
boiling point of the solvent, preferably at room temperature.
[0098] Preferred catalysts of formula (II d) are those, wherein
L.sub.1 is hydrogen and L.sub.2 represents phenyl or phenyl
substituted by one, two, three, four or five alkyl residues,
especially by once by isopropyl such as 4-isopropyl-phenyl, and
R.sup.5 represents phenyl or phenyl substituted by one, two, three,
four or five alkyl residues, especially phenyl, tolyl,
3,5-dimethylphenyl, or 2,3,4,5,6pentamethyl-phenyl. Especially
preferred is the catalyst of formula (II d) or (Id'), wherein
L.sub.1 is hydrogen, L.sub.2 is isopropylphenyl, and R.sup.5 is
tolyl.
[0099] The present invention likewise relates to preferred
catalysts of formula (II d) being those, wherein L.sub.1 is
hydrogen and L.sub.2 represents phenyl or phenyl substituted by
one, two, three, four or five alkyl residues, especially by once by
isopropyl such as isopropyl-phenyl, and R.sub.5 represents a
residue selected from the group consisting of 2- or 3- or
4-pyridyl, 4-chloro-4-phenoxy-phenyl, 4-phenoxy-phenyl,
5di(m)ethylamino-1-naphthyl, 5nitro-1-naphthyl, 2-,
3-,4-nitrophenyl, 4-vinylphenyl, 4-biphenylyl, 2-phenyl-ethen and
9-anthracenyl.
[0100] Especially preferred are those catalysts of formula (IId),
wherein the ligands L.sub.1 and L.sub.2 have the S or R
configuration and/or wherein the corresponding phenyl rings
attached to the 1,2-diaminoethyl moiety are in the
R,R-configuration or S,S-configuration.
[0101] Preferred catalysts of formula (II d') and (IId''') are
those, wherein Hal is each case is chloro; R.sup.6 and R.sup.7, in
each case, represents phenyl or phenyl substituted by one or more
C.sub.1-C.sub.7alkyl, especially 3,5-dimethylphenyl. The present
invention likewise relates to corresponding compounds of formula
(II d'). Especially preferred are those catalysts of formula (II
d'), wherein the BINAP moiety has the R- or S-configuration.
[0102] Preferred catalysts of formula (II d'') and (IId'''') are
those, wherein Hal, in each case, is chloro; R.sup.6 and R.sup.7,
in each case, represents phenyl or phenyl substituted by one or
more C.sub.1-C.sub.7alkyl, especially 3,5-dimethylphenyl. The
present invention likewise relates to corresponding compounds of
formula (II d'''') and (IId'''''). Especially preferred are those
catalysts of formula (II d'''') and (IId'''''), wherein the BINAP
moiety has the R- or S-configuration. Most preferred are
corresponding compounds of formula (II d''''') and (IId''''').
[0103] Likewise preferred are compounds of formula
##STR00032##
[0104] The present invention likewise relates to the novel
compounds, e.g. starting materials or intermediates, respectively,
as described in the Working Examples part.
[0105] The present invention likewise relates to the concrete
products directly obtained by the process sequence or by the single
process steps, especially the corresponding products that are in an
essentially enantiomerically pure form.
[0106] The conversion of an acid of formula (I) into a salt is
carried out in a manner known per se.
[0107] Thus, for example, a salt with a base of compounds of the
formula I is obtained by treating with a base. Salts can be
converted into the free compounds in a customary manner, and salts
with a base can be converted, for example, by treating with a
suitable acid agent to the free acid.
[0108] The conversion of an acid of formula (I) into a
corresponding lactone of formula (I a) or (I b), respectively, is
carried out in the presence of an acid, preferably a mineral acid,
in a suitable, e.g. protic or aproctic, solvent, such as ethanol or
acetonitrile. Depending on the acid, the conversion is carried out
in a temperature range, for example, from -78.degree. to the
boiling point of the solvent. Most preferably, H.sub.3PO.sub.4 in
acetonitrile at 60.degree. C. is used.
[0109] The conversion of a lactone of formula (I a) or (I b),
respectively, into a salt of the acid of formula (I) is carried
out, for example, in a mixture of a protic solvent, e.g. ethanol,
and water, by using an alkalimetall hydroxide, such as LiOH, NaOH
or Ca(OH).sub.2. Alternatively, the lactone can be hydrolysed by
using an alkalimetall hydroxide, such as LiOH, NaOH and the
resulting salt can be converted into the calcium salt of the acid
of pitavastatin by addition of an aqueous solution of CaCl.sub.2 in
water.
[0110] A variant to the process according to the present invention
comprises the direct formation of a lactone of a compound of
formula (I). The formation of said lactone can be carried out by
treating a compound of formula (I) or (II h) with an acid, such as
a mineral acid, preferable with H.sub.3PO.sub.4.
[0111] The conversion of a resulting compound of formula (I)
wherein the element represents --CH.dbd.CH-- into a compound of
formula (I) wherein the element represents --CH.sub.2--CH.sub.2--
is carried out by selectively hydrogenating the double bond
--CH.dbd.CH--, especially with an appropriate reduction agent, for
example, by catalytic hydrogenation in the presence of a
hydrogenation catalyst, for example, a Ruthenium catalyst, such as
(Ru(cod)(nu-3-(2-methylally))2, by reduction with hydrogen in the
presence of a hydrogenation catalyst or with a hydride, for
example, a hydride which, if desired, may be complex, such as a
hydride formed from an element of the 1st and 3rd main groups of
the periodic table of the elements, for example borohydride or
aluminohydride, for example lithium borohydride, lithium aluminium
hydride, diisobutylaluminium hydride (an additional reduction step
using alkali metal cyanoborohydride, such as sodium
cyanoborohydride, may be necessary), and also diborane.
[0112] Instead of converting a resulting compound of formula (I)
wherein the element represents --CH.dbd.CH-- into a compound of
formula (I) wherein the element represents --CH.sub.2--CH.sub.2--,
the hydrogenation of the double bond --CH.dbd.CH-- can be effected,
with compounds of formulae (II e), (II g) or (II h), respectively,
e.g. in addition to reaction steps (c), (d) or (e),
respectively.
[0113] The process for the manufacture of compounds of formula (I)
and salts thereof can be, for example, illustrated by means of the
following reaction scheme for the manufacture of pitavastatin:
##STR00033## ##STR00034##
[0114] The process for the manufacture of compounds of formula (I)
and salts thereof can be, for example, illustrated by means of the
following reaction scheme for the manufacture of fluvastatin:
##STR00035##
WORKING EXAMPLES
Manufacture of Starting Material for Pitavastatin
Preparation of (3-ethoxycarbonyl-3-oxopropyl) triphenyl phosphonium
chloride
[0115] According to Literature: C. M. Moorhoff; J. C. S. Perkin
Trans I, 1987 (1997)
[0116] To a solution of ethyl-4-chlor-acetoacetat (16.46 g, 100
mmol) in 50 ml anhydrous toluene is added triphenylphosphine (26.25
g, 100 mmol) under argon atmosphere at room temperature and stirred
for 4 days. The suspension is filtered and washed with 3.times.30
ml of toluene. The colourless crystals are dried in vacuum to give
(3-ethoxycarbonyl-3-oxopropyl) triphenyl phosphonium chloride. MS:
426.88
Example 1
a) Preparation of ethyl
3-oxo-4-(triphenylphosphoranylidene)butanoate
[0117] To a solution of (3-ethoxycarbonyl-3-oxopropyl)triphenyl
phosphonium chloride (11 g, 25.77 mmol) in 100 ml dichlormethane is
added within 30 minutes (min) under vigorous stirring sodium
carbonate (3.38 g, 27.36 mmol) in 100 ml water at room temperature
and stirred for 4 hours (h). The yellow organic phase is separated,
washed with 30 ml water and dried over anhydrous sodium sulfate.
The solvent is evaporated and the oily residue is dried in vacuum
to maintain a waxy mass. After adding diethylether the wax
crystallizes to form slight yellow crystals of
3-oxo-4-(triphenylphosphoranylidene)butanoate. MS: 390.43
[0118] .sup.1H-NMR (CDCl.sub.3, 400 MHz): .delta.=7.56 (m, 6H,
ortho H-phenyl), 7.44 (m, 3H, para H-phenyl), 7.35 (m, 6H, meta
H-phenyl), 4.08 (q, 2H, OCH.sub.2CH.sub.3), 3.72 (d, 1H, H-4), 3.26
(d, 2H, H-2), 1.17 (t, 3H, OCH.sub.2CH.sub.3)
b)
5-(2-Cyclopropyl-4-fluoro-phenyl)-quinolin-3-yl)-3-oxo-pent-4-enoic
acid ethyl ester
[0119] The ylide 3-oxo-4-(triphenylphosphoranylidene)butanoate
(4.82 g, 12.36 mmol) is solved under argon atmosphere in 100 ml
acetonitrile. Under vigorous stirring
2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde (3 g,
10.3 mmol) is added in 5 portions and then heated to reflux. After
50 h the reaction is cooled to room temperature. The slight brown
solvent is evaporated and the residue is dried under vacuum to
obtain a brown waxy oil. Chromatography over silica gel with
hexane:ethylacetate (4:1/v:v) give a yellow oil of
5-(2-cyclopropyl-4-fluoro-phenyl)-quinolin-3-yl)-3-oxo-pent-4-enoic
acid ethyl ester. MS: 403.45
c) rac
5-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-hydroxy-pent--
4-enoic acid ethyl ester
[0120] 85.8 mg (0.21 mmol) of
5-(2-cyclopropyl-4-fluoro-phenyl)-quinolin-3-yl)-3-oxo-pent-4-enoic
acid ethyl ester are solved in 10 ml ethanol under argon atmosphere
and cooled to -15.degree. C.
[0121] Sodiumborhydride (8.58 mg, 0.22 mmol) is added under
vigorous stirring. During the reaction time the mixture became
slightly yellow. After 3 h the reaction is allowed to rise to room
temperature and stirred for another 1.5 h. Then the mixture is
quenched with 15 ml of a saturated ammonium chloride solution.
After extraction with diethylether (3.times.15 ml), the combined
organic layers are washed with water (15 ml), dried over sodium
sulfate, filtered and evaporated in vacuum to give a yellow oil of
rac
5-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-hydroxy-pent-4-enoi-
c acid ethyl ester. MS: 405.47
[0122] HPLC-Analytics: Chiracel-OD 10 .mu.m, length: 250 mm,
internal-dm: 4.6 mm; isokratic n-hexane: 2-propanol 96:4; flowrate:
0.6 ml/min; column temp: 35.degree. C.; UV detection wavelength:
230 nm; chrom. time: 45 min; inject. volume: 10 .mu.l (1.022 mg/ml
in n-hexane:2-propanol 96:4)
[0123] Ret. Time 1: 16.17 min; 51.52% (area)
[0124] Ret. Time 2: 18.00 min; 48.48% (area)
d) Procedure for the Enantioselective Transfer hydrogenation of
(E)-5-[2-Cyclopropyl-4-(4-fluoro-phenyl)-
quinolin-3-yl]-3-hydroxy-pent-4-enoic-acid-ethylester
[0125] I: A mixture of
(E)-5-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-oxo-pent-4-enoi-
c-acid-ethylester (105.8 mg, 0.262 mmol) and
Ru[(1R,2R)-p-TsNCH(C.sub.6H.sub.5)CH (C.sub.6H.sub.5)NH](72
.sup.6-p-cymene) (6.2 mg, 0.104 mmol) in 2-propanol (2.6 ml) is
stirred at 23.degree. C. for 72 h. The reaction mixture is
concentrated under reduced pressure. The residue is purified by
flash chromatography on silica gel using a 4:1 hexane-MTBE
(methyl-tert-butyl-ether) mixture as eluent to afford of
(E)-5-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-hydroxy-pent-4--
enoic-acid-ethylester.
[0126] II: A solution of
(E)-5-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3yl]-3oxo-pent-4-enoic--
acid-ethylester (1.6 g, 3.97 mmol),
Ru[(1R,2R)-p-TsNCH(C.sub.6H.sub.5)CH(C.sub.6H.sub.5)NH.sub.2]Cl(.eta..sup-
.6-p-cymene) (12.6 mg, 0.02 mmol) and a mixture of HCOOH (1.095 g,
23.8 mmol)/NEt.sub.3 (0.963 g, 9.52 mmol) is heated in DMF (6.0 ml)
at 50.degree. C. for 20 h. After that the solution is diluted with
MTBE (5 ml) and neutralised with NaHCO.sub.3 (4 ml). Standard
aquous work-up with NaCl solution and extraction with MTBE and
removal of the solvent give the crude product. Chromatography on
silica gel using a 4:1 hexane-MTBE mixture as eluent to afford of
(E)-5-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-hydroxy-pent-4e-
noic-acid-ethylester.
[0127] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.96 (d, .sup.2J: 8.4 Hz,
1H), 7.60 (t, .sup.2J: 6.6 Hz, 1H), 7.38-7.28 (m, 2H), 7.25-7.15
(m, 4H), 6.61 (d, .sup.2J: 16.3 Hz, 1H), 5.65 (dd, .sup.2J: 16.2,
5.7 Hz, 1H), 4.57-4.51 (m,1 H), 4.17 (q, .sup.2J: 7.1 Hz, 2H), 3.10
(br s, H), 2.44-2.37 (m,1H), 2.36 (t, .sup.2J: 9.4 Hz, 2H),
1.41-1.25 (m, 2H), 1.29 (t, .sup.2J: 7.2 Hz, 3H),1.04 (dd, .sup.2J:
8.1, 2.8 Hz,2H).
[0128] .sup.13C NMR (100 MHz, CDCl.sub.3): 172.2, 163.6, 161.1,
160.7, 146.9, 144.4, 138.2, 133.4, 132.0, 131.9, 131.9, 131.8,
129.0, 128.9, 126.5, 126.1, 125.5, 115.5, 115.3, 68.8, 41.1, 16.1,
14.2, 10.4, 10.3. MS: 405.47
[0129] Literature for the preparation of the catalyst: Haack,
K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew.
Chem., Int. Ed. Engl. 1997, 36 ,285-288.
e)
(E)-(S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-hydroxy-3-
-oxo-hept-6-enoic acid tert-butyl ester
[0130] To a solution of diisopropylamine (0.93 g, 9.20 mmol) in
tetrahydrofuran (THF) (10 ml) at 0.degree. C. is added n-BuLi (5.55
ml, 8.88 mmol of a 1.6 M solution in hexane) over 10 min. After 30
min the solution is cooled to -78.degree. C. and t-butyl acetate
(1.03 g, 8.88 mmol) is added over 10 min. After 30 min the
resulting solution at -78.degree. C. is transferred to a solution
of
(E)-5-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-hydroxy-pent-4--
enoic-acid-ethylester (0.90 g, 2.22 mmol) in THF (11 ml) at
0.degree. C. The solution is stirred 3 h at room temperature (RT).
A NH.sub.4Cl solution (3 ml) is added. The mixture is poured into
water (5 ml) and extracted with MTBE (50 ml). The combined organic
extracts are dried over Na.sub.2SO.sub.4, filtered, concentrated,
and the residue purified by flash chromatography (hexane/MTBE 5:1)
to afford ketoester
(E)-(S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-hydroxy-3-o-
xo-hept-6-enoic acid tert-butyl ester. MS: 475.57
f)
(E)-(3R,5S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dih-
ydroxy-hept-6-enoic acid tert-butyl ester
[0131] To a solution of ketoester
(E)-(S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-hydroxy-3ox-
o-hept-6-enoic acid tert-butyl ester (0.80 g, 1.68 mmol) in THF (20
ml) and MeOH (4 ml) at -78.degree. C. is added diethylmethoxyborane
(2.10 ml of a 1 M solution in THF, 2.096 mmol). After 1 h
NaBH.sub.4 (0.127 g, 3.36 mmol) is added. After an additional 3 h
at -78.degree. C. pH 7 buffer (5 ml) is added followed by MeOH (6
ml). After 10 min a solution of MeOH (6 ml) and 30% aqu.
H.sub.2O.sub.2 (6 ml) is added slowly. The cold bath is removed and
the solution stirred for 1.5 h. The mixture is poured into
NaHCO.sub.3 (60 ml) and extracted with CH.sub.2Cl.sub.2 (3.times.50
ml). The organic extracts are dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The residue is dissolved in hot EtOAc
(10 ml), filtered and stirred for 12 h at RT. After filtration diol
(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5
dihydroxy-hept-6-enoic acid tert-butyl ester is obtained. MS:
477.58
g)
(E)-(3S,5S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dih-
ydroxy-hept-6-enoic acid tert-butyl ester
[0132] To a cooled (-35.degree. C.) solution of
Me.sub.4NHB(OAc).sub.3 (1.38 g, 5.26 mmol) in MeCN/AcOH (15 ml,
1:1) is added a solution of ketoester
(E)-(S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-h-
ydroxy-3-oxo-hept-6-enoic acid tert-butyl ester (0.50 g, 1.05 mmol)
in CH.sub.3CN (2 ml). The mixture is stirred at -35.degree. C. for
3 h and at 0.degree. C. for 30 min before a solution of potassium
sodium tartrate (10 ml) is added. After 10 min the suspension is
poured into CH.sub.2Cl.sub.2 (30 ml) and a solution of
Na.sub.2CO.sub.3 (7 ml) is carefully added. The organic layer is
separated and the aquous layer is extracted with CH.sub.2Cl.sub.2
(2.times.50 ml). The combined organic extracts are dried over
Na.sub.2SO.sub.4, filtered, concentrated, and the residue is
purified by flash chromatography (hexane/MTBE 1:1) or
crystallization (ethylacetate=EtOAc) to afford diol
(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihyd-
roxy-hept-6-enoic acid tert-butyl ester. MS: 477.58
h)
(E)-(3R,5S)-7-[2-Cylopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihy-
droxy-hept-6-enoic acid calcium salt
[0133] To a solution of diol
(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihyd-
roxy-hept-6-enoic acid tert-butyl ester (1.0 g, 2.09 mmol) in EtOH
(5 ml) is added an aquous solution of NaOH (10 ml, 1 M) and the
resulting suspension is stirred until the ester disappeared. After
completion of the hydrolysis aqueous HCl (15 ml, 1 M) is added and
the solvent is removed in vacuum. Then CH.sub.2Cl.sub.2 (10 ml) is
added and the organic layer is separated. The aqueous layer is
extracted with CH.sub.2Cl.sub.2 (2.times.30 ml) and the combined
organic extracts are removed in vacuum. The residue is dissolved in
H.sub.2O (20 ml) and a solution of CaCl.sub.2 (8 ml, 0.1 M) is
added dropwise. The reaction solution is stirred overnight and the
resulting white precipitate is collected by filtration to obtain
(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-
-3,5-dihydroxy-hept-6-enoic acid calcium salt. MS: 880.98
Manufacture of Starting Material for Fluvastatin:
i.
(E)-5-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-oxo-pent-4-enoi-
c acid ethyl ester
[0134] The ylide 3-oxo-4-(triphenylphosphoranylidene)butanoate (5.0
g, 12.8 mmol) is solved under argon atmosphere in 100 ml
acetonitrile. Under vigorous stirring
3-(4-Fluoro-phenyl)-1-isopropyl-1H-indole-2-carbaldehyde (4.2 g,
10.7 mmol) is added in 5 portions and then heated to reflux. After
50 h the reaction is cooled to room temperature. The slight brown
solvent is evaporated and the residue is dried under vacuum to
obtain a brown waxy oil. Chromatography over silica gel with
hexane:ethylacetate (4:1/v:v) give a yellow oil of
(E)-5-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-oxo-pent-4-enoic
acid ethyl ester. MS: 393.46
j.
(E)-(S)-5-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-hydroxy-pen-
t-4-enoic acid ethyl ester
[0135] A solution of
(E)-5-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-oxo-pent-4-enoic
acid ethyl ester (2.0 g, 5.08 mmol), Ru[(1R,2R)-
-p-TsNCH(C.sub.6H.sub.5)CH(C.sub.6H.sub.5)NH.sub.2]Cl(.eta..sup.6-p-cymen-
e) (12.8 mg, 0.025 mmol) and a mixture of HCOOH (1.40 g, 30.5
mmol)/NEt.sub.3 (1.23 g, 12.2 mmol) is heated in DMF (8.0 ml) at
50.degree. C. for 21 h. After that the solution is diluted with
MTBE (5 ml) and neutralised with NaHCO.sub.3 (4 ml). Standard
aquous work-up with NaCl solution and extraction with MTBE and
removal of the solvent give the crude product. Chromatography on
silica gel using a 4:1 hexane-MTBE mixture as eluent to afford of
(E)-(S)-5-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-hydroxy-pent--
4-enoic acid ethyl ester. MS: 395.48
k.
(E)-(S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-o-
xo-hept-6-enoic acid tert-butyl ester
[0136] To a solution of diisopropylamine (0.96 g, 9.53 mmol) in
tetrahydrofuran (THF) (10 ml) at 0.degree. C. is added n-BuLi (6.32
ml, 10.12 mmol of a 1.6 M solution in hexane) over 10 min. After 30
min the solution is cooled to -78.degree. C. and t-butyl acetate
(1.17 g, 10.12 mmol) is added over 10 min. After 30 min the
resulting solution at -78.degree. C. is transferred to a solution
of
(E)-(S)-S[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-hydroxy-pent-4-
-enoic acid ethyl ester (1.0 g, 2.53 mmol) in THF (12 ml) at
0.degree. C. The solution is stirred 3 h at room temperature (RT).
A NH.sub.4Cl solution (3 ml) is added. The mixture is poured into
water (5 ml) and extracted with MTBE (50 ml). The combined organic
extracts are dried over Na.sub.2SO.sub.4, filtered, concentrated,
and the residue purified by flash chromatography (hexane/MTBE 5:1)
to afford ketoester
(E)-(S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)quinolin-3-yl]-5-hydroxy-3-ox-
o-hept-6enoic acid tert-butyl ester. MS: 465.57
l.
(E)-(3R,5S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihyd-
roxy-hept-6-enoic acid tert-butyl ester
[0137] To a solution of ketoester
(E)-(S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-
-hept-6-enoic acid tert-butyl ester (1.0 g, 2.15 mmol) in THF (22
ml) and MeOH (4 ml) at -78.degree. C. is added diethylmethoxyborane
(2.70 ml of a 1 M solution in THF, 2.682 mmol). After 1 h
NaBH.sub.4 (0.163 g, 4.30 mmol) is added. After an additional 3 h
at -78.degree. C. pH 7 buffer (6 ml) is added followed by MeOH (7
ml). After 10 min a solution of MeOH (6 ml) and 30% aqu.
H.sub.2O.sub.2 (6 ml) is added slowly. The cold bath is removed and
the solution stirred for 1.5 h. The mixture is poured into
NaHCO.sub.3 (70 ml) and extracted with CH.sub.2Cl.sub.2 (3.times.50
ml). The organic extracts are dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The residue is dissolved in hot EtOAc
(10 ml), filtered and stirred for 12 h at RT. After filtration diol
(E)-(3R,5S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydro-
xy-hept-6-enoic acid tert-butyl ester is obtained. MS: 467.58
m.
(E)-(3S,5S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihyd-
roxy-hept-6-enoic acid tert-butyl ester
[0138] To a cooled (-35.degree. C.) solution of
Me.sub.4NHB(OAc).sub.3 (1.38 g, 5.26 mmol) in MeCN/AcOH (15 ml,
1:1) is added a solution of ketoester
(E)-(S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-h-
ydroxy-3-oxo-hept-6-enoic acid tert-butyl ester (0.50 g, 1.07 mmol)
in CH.sub.3CN (2 ml). The mixture is stirred at -35.degree. C. for
3 h and at 0.degree. C. for 30 min before a solution of potassium
sodium tartrate (10 ml) is added. After 10 min the suspension is
poured into CH.sub.2Cl.sub.2 (30 ml) and a solution of
Na.sub.2CO.sub.3 (7 ml) is carefully added. The organic layer is
separated and the aquous layer is extracted with CH.sub.2Cl.sub.2
(2.times.50 ml). The combined organic extracts are dried over
Na.sub.2SO.sub.4, filtered, concentrated, and the residue is
purified by flash chromatography (hexane/MTBE 1:1) or
crystallization (ethylacetate=EtOAc) to afford diol
(E)-(3S,5S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydro-
xy-hept-6-enoic acid tert-butyl ester. MS: 467.58
n. Sodium
(E)-(3R,5S)-7-[3-(4-fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,-
5-dihydroxy-hept-6-enoate
[0139] To 30 g of ester
E)-(S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo--
hept-6-enoic acid tert-butyl ester in 150 ml of ethanol is added
under stirring 63 ml of sodium hydroxide solution while maintaining
the temperature below 12.degree. C. The solution is stirred for 1
hour, the mixture is concentrated at 25 mm Hg and 45.degree. C.,
then 220 ml of water are added, destination is continued to a
remaining volume of 100 ml, then 280 ml of water are added and the
solution is washed with a total of 450 ml of MTBE in 3 portions.
The aquous layer is concentrated at 25 mm Hg and 45.degree. C. to a
volume of about 200 ml, 150 ml water are added, and the clear
aquous solution is lyophylized over 3 days. MS: 433.21
* * * * *