U.S. patent application number 13/939983 was filed with the patent office on 2013-11-21 for convergent synthesis of renin inhibitors and intermediates useful therein.
This patent application is currently assigned to DSM IP ASSETS B.V.. The applicant listed for this patent is Jeroen Antonius Franciscus BOOGERS, Anna Maria Cornelia Francisca CASTELIJNS, Ben DE LANGE, Andreas Hendrikus Maria DE VRIES, Johannes Gerardus DE VRIES. Invention is credited to Jeroen Antonius Franciscus BOOGERS, Anna Maria Cornelia Francisca CASTELIJNS, Ben DE LANGE, Andreas Hendrikus Maria DE VRIES, Johannes Gerardus DE VRIES.
Application Number | 20130310577 13/939983 |
Document ID | / |
Family ID | 39357956 |
Filed Date | 2013-11-21 |
United States Patent
Application |
20130310577 |
Kind Code |
A1 |
DE LANGE; Ben ; et
al. |
November 21, 2013 |
CONVERGENT SYNTHESIS OF RENIN INHIBITORS AND INTERMEDIATES USEFUL
THEREIN
Abstract
Described is a method for the preparation of renin inhibitors
such as aliskiren, and intermediates useful therein. The method
introduces a nitrogen-containing intermediate such as a lactone of
formula (8). ##STR00001## with R.sub.4 being a branched C.sub.3-6
alkyl. In the preparation of the lactone, or related intermediates,
a desired stereochemical configuration can be controlled by
starting from a chiral aldehyde satisfying formula (10).
##STR00002##
Inventors: |
DE LANGE; Ben;
(Munstergeleen, NL) ; CASTELIJNS; Anna Maria Cornelia
Francisca; (Spaubeek, NL) ; DE VRIES; Johannes
Gerardus; (Maastricht, NL) ; DE VRIES; Andreas
Hendrikus Maria; (Maastricht, NL) ; BOOGERS; Jeroen
Antonius Franciscus; (Maastricht, NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DE LANGE; Ben
CASTELIJNS; Anna Maria Cornelia Francisca
DE VRIES; Johannes Gerardus
DE VRIES; Andreas Hendrikus Maria
BOOGERS; Jeroen Antonius Franciscus |
Munstergeleen
Spaubeek
Maastricht
Maastricht
Maastricht |
|
NL
NL
NL
NL
NL |
|
|
Assignee: |
DSM IP ASSETS B.V.
Heerlen
NL
|
Family ID: |
39357956 |
Appl. No.: |
13/939983 |
Filed: |
July 11, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12810220 |
Sep 22, 2010 |
|
|
|
PCT/EP08/68072 |
Dec 19, 2008 |
|
|
|
13939983 |
|
|
|
|
Current U.S.
Class: |
549/321 ;
435/126; 435/128; 556/176; 556/416; 556/418; 558/315; 558/441;
564/157 |
Current CPC
Class: |
C07F 1/02 20130101; C07C
231/18 20130101; C07D 307/33 20130101; C07C 231/02 20130101; C07C
231/18 20130101; C07F 7/1804 20130101; C07D 307/32 20130101; C07C
237/22 20130101 |
Class at
Publication: |
549/321 ;
558/441; 558/315; 435/128; 435/126; 556/416; 556/418; 556/176;
564/157 |
International
Class: |
C07D 307/33 20060101
C07D307/33; C07C 231/02 20060101 C07C231/02 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 24, 2007 |
EP |
07025093.1 |
Claims
1. A compound selected from the group consisting of the compounds
satisfying the following formulae (7a) through (7h): ##STR00043##
wherein R.sub.4 is a branched C.sub.3-6 alkyl; R.sub.6 represents
H, or optionally substituted C.sub.1-12alkyl, optionally
substituted C.sub.1-12 alkylaryl, or optionally substituted
C.sub.1-12aryl; R.sub.7 represents H, or is an O-protecting group;
or R.sub.6 forms with R.sub.7 an optionally substituted
C.sub.1-12(hetero)cyclic compound, as such protecting both the acid
and alcohol group; Z is a N-protecting group; R.sub.11 is a
O-protecting group; R.sub.12 and R.sub.13 are either the same or
different fragments, chosen from the group of H, optionally
substituted C.sub.1-12alkyl, optionally substituted
C.sub.1-12alkylaryl and optionally substituted C.sub.1-12aryl, or
R.sub.12 and R.sub.13 are joined together in a
C.sub.1-20(hetero)cyclic structure; Ra.sup.+ is a counter-cation;
and St is a group capable of stabilising the imine.
2. A compound according to formula (8), selected from the group
consisting of the compounds satisfying the following formulae:
##STR00044## wherein R.sub.4 is a branched C.sub.3-6 alkyl; Z is a
N-protecting group; R.sub.11 is a O-protecting group; R.sub.12 and
R.sub.13 are either the same or different fragments, chosen from
the group of H, optionally substituted C.sub.1-12 alkyl, optionally
substituted C.sub.1-12alkylaryl and optionally substituted
C.sub.1-12 aryl, or R.sub.12 and R.sub.13 are joined together in a
C.sub.1-20(hetero)cyclic structure; Ra.sup.+ is a counter-cation;
and St is a group capable of stabilising the imine.
3. A compound according to claim 1 or 2, wherein R.sub.4 is
2-propyl.
4. A method for the preparation of a compound according to claim 1
or 2 comprising at least the following step: reacting an aldehyde
satisfying formula (10) ##STR00045## with R.sub.4 and R.sub.6
having the meaning as indicated above, with a cyanide, under
appropriate conditions.
5. A method according to claim 4, wherein the reaction is conducted
in the presence of a chiral catalyst.
6. A method according to claim 5, wherein the chiral catalyst is an
enzyme.
7. A method according to claim 6, wherein the enzyme hydroxynitrile
lyase.
8. A method for the preparation of a compound satisfying formula
(9a) or (11a) or a mixture thereof, ##STR00046## comprising at
least the following steps: a) reacting a compound according to
formula (2a) ##STR00047## wherein R.sub.1 is selected from the
group consisting of F, Cl, Br, I, C.sub.1-6halogenalkyl,
C.sub.1-6alkoxy-C.sub.1-6alkyloxy, and
C.sub.1-6alkoxy-C.sub.1-6alkyl; R.sub.2 is selected from the group
consisting of F, Cl, Br, I, C.sub.1-4alkyl or C.sub.1-4alkoxy;
R.sub.3 is a branched C.sub.3-6 alkyl; and Re denotes a reactive
moiety selected from F; Cl; Br; I; M(X).sub.n, wherein X is F, Cl,
Br, I, CN, C.sub.1-12alkyl, or C.sub.1-6alkoxy and M is a metal,
preferably M is Mg, Ce, Li, Ba, Al, B, Cu, Zn, Mn, Ti, Zr, In and n
is 0, 1, 2, 3, or 4; MM'(X).sub.n(Y).sub.n', wherein M and M' are a
metal, preferably M and M' are each independently Mg, Ce, Li, Ba,
Al, B, Cu, Zn, Mn, Ti, Zr, In, where X and Y are each independently
chosen from F, Cl, Br, I, or CN, C.sub.1-12alkyl, C.sub.1-6alkoxy
and n, n' are each independently chosen from the values as
described above for n; with a second compound selected from the
group consisting of the compounds satisfying the following formulae
(7a) through (7h): ##STR00048## wherein R.sub.4 is a branched
C.sub.3-6 alkyl; Z is a N-protecting group; R.sub.11 is a
O-protecting group; R.sub.12 and R.sub.13 are either the same or
different fragments, chosen from the group of H, optionally
substituted C.sub.1-12alkyl, optionally substituted
C.sub.1-12alkylaryl and optionally substituted C.sub.1-12aryl, or
R.sub.12 and R.sub.13 are joined together in a
C.sub.1-20(hetero)cyclic structure; Ra.sup.+ is a counter-cation;
and St is a group capable of stabilising the imine, b) followed by
stereoselective hydrogenation of the C.dbd.C double bond,
originating from compound according to formula (2a).
9. A compound according to formula (6a) and (6b), ##STR00049##
wherein R.sub.4 is a branched C.sub.3-6 alkyl; R.sub.6 represents
H, or optionally substituted C.sub.1-12alkyl, optionally
substituted C.sub.1-12 alkylaryl, or optionally substituted
C.sub.1-12aryl; and R.sub.7 represents H, or is an O-protecting
group; or R.sub.6 forms with R.sub.7 an optionally substituted
C.sub.1-12(hetero)cyclic compound, as such protecting both the acid
and alcohol group.
10. A compound selected from the group consisting of the compounds
satisfying the following formulae (8a) through (8h): ##STR00050##
wherein R.sub.4 is 2-propyl, Z is a N-protecting group; R.sub.11 is
a O-protecting group; R.sub.12 and R.sub.13 are either the same or
different fragments, chosen from the group of H, optionally
substituted C.sub.1-12alkyl, optionally substituted
C.sub.1-12alkylaryl and optionally substituted C.sub.1-12aryl, or
R.sub.12 and R.sub.13 are joined together in a
C.sub.1-20(hetero)cyclic structure; and Ra.sup.+ is a
counter-cation.
Description
[0001] This application is a divisional of commonly owned U.S.
application Ser. No. 12/810,220, filed Sep. 22, 2010 (now U.S. Pat.
No. ______), which is the national phase application under 35 USC
.sctn.371 of PCT/EP2008/009050, Dec. 19, 2008, which designated the
US and claims benefit of EP Patent Application No. 07025093.1,
filed Dec. 24, 2007, the entire contents of each of which are
hereby incorporated by reference.
[0002] The invention pertains to a convergent synthesis route for
the preparation of certain
2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl
amide derivatives, or pharmaceutically acceptable salts thereof,
such as the compound aliskiren. The invention particularly relates
to a synthetic route that will introduce the nitrogen of the above
mentioned compounds ultimately required for the amino-group at C-5,
at a relative early stage of the synthesis. The invention further
relates to novel intermediates useful in the manufacture of the
above mentioned compounds. Particularly, the
2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl
amide derivatives to which the methods of the present invention
applies are any of those having renin inhibitory activity and,
therefore, pharmaceutical utility, e.g., those disclosed in U.S.
Pat. No. 5,559,111, WO 2006/061427, or WO 2006/095020.
[0003] The
2(S),4(S),5(S);7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octano- yl
amide derivatives, or pharmaceutically acceptable salts thereof to
which the invention pertains, satisfy the general formula (1).
##STR00003##
[0004] Herein R.sub.1 is halogen, C.sub.1-6halogenalkyl,
C.sub.1-6alkoxy-C.sub.1-6alkoxy or C.sub.1-6alkoxy-C.sub.1-6alkyl;
R.sub.2 is halogen, C.sub.1-6alkyl or C.sub.1-6alkoxy; R.sub.3 and
R.sub.4 are independently branched C.sub.3-6alkyl; and R.sub.5 is
C.sub.1-12cycloalkyl, C.sub.1-12alkyl, C.sub.1-12hydroxyalkyl,
C.sub.1-6alkoxy-C.sub.1-6alkyl,
C.sub.1-6alkanoyloxy-C.sub.1-6alkyl, C.sub.1-12-aminoalkyl,
C.sub.1-6alkylamino-C.sub.1-6alkyl,
C.sub.1-6dialkylamino-C.sub.1-6alkyl,
C.sub.1-6alkanoylamino-C.sub.1-6alkyl, HO--(O)C--C.sub.1-12alkyl,
C.sub.1-6alkyl-O--(O)C--C.sub.1-6alkyl,
H.sub.2N--C(O)--C.sub.1-12alkyl,
C.sub.1-6alkyl-HN--C(O)--C.sub.1-6alkyl,
(C.sub.1-6alkyl).sub.2--N--C(O)--C.sub.1-6alkyl; saturated,
unsaturated, or partially saturated C.sub.1-12heterocyclyl bonded
via a carbon atom, and which heterocyclyl is optionally substituted
one or more times by C.sub.1-6alkyl, trifluoromethyl, nitro, amino,
N-mono- or N,N-di-C.sub.1-6alkylated amino, C.sub.1-6alkanoyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonylamino, C.sub.0-6alkylcarbonylamino,
C.sub.1-6alkylcarbonyloxy, C.sub.1-12aryl, N-mono or
N,N-di-C.sub.1-6alkylated carbamoyl, optionally esterified
carboxyl, cyano, halogen, halo-C.sub.1-6alkoxy halo-C.sub.1-6alkyl,
C.sub.1-12heteroaryl, saturated, unsaturated or partially saturated
C.sub.1-6heterocyclyl, hydroxyl, nitro; or the salt of compound
according to formula (1), especially pharmaceutically acceptable
salt thereof.
[0005] In the convergent synthesis of compounds according to
formula (1), it is known to separately provide e.g. two synthons
commensurate with the following structural parts and, in the course
of the entire synthesis route, couple these and convert as
necessary. A reference in this respect is Sandham et al.
Tetrahedron Letters 2000, 41, 10091-10094.
[0006] The structural parts referred to are an aromatic part
typically satisfying the structural formula (5),
##STR00004##
wherein R.sub.1 is 3-methoxy-propoxy, R.sub.2 is methoxy, and
R.sub.3 are 2-propyl, and the Cl-group is transferred to the
corresponding Grignard compound and subsequently transmetallated
with CeCl.sub.3, prior to the coupling with an aldehyde part
typically satisfying the structural formula (3),
##STR00005##
wherein R.sub.4, is 2-propyl, and Ph stands for phenyl.
[0007] The above more particularly pertains to the synthesis of
compounds of formula (4), the fumaric acid salt of which is known
as aliskiren,
(2S,4S,5S,7S)-7-(3-(3-methoxypropoxy)-4-methoxybenzyl)-5-amino-N-(2-carba-
moyl-2-methylpropyl)-4-hydroxy-2-isopropyl-8-methylnonanamide.
[0008] In the present application, any reference to aliskiren is
deemed to include reference to all pharmaceutically acceptable
salts, and prodrugs thereof.
##STR00006##
[0009] For the synthesis of the aforementioned parts, and the
resulting linked compounds, generally multistep processes are used.
In typical cases, the yields of one or more of these steps are low,
and the overall yield is further affected by the desire to
ultimately obtain a diastereomerically pure compound.
[0010] A critical step in the process is the chemo- and
stereoselective introduction of nitrogen so as to create the
5-amino group. In the above routes of synthesis, the nitrogen is
introduced after coupling of the described structural parts by
substituting the obtained alcohol moiety using several, laborious
steps. Moreover, some of these steps are difficult to perform at
production scale.
[0011] Coupling of the compound of formula (5) wherein R.sub.1 is
3-methoxy-propoxy, R.sub.2 is methoxy, and R.sub.3 are 2-propyl,
with a nitrogen containing building block derived from the compound
of formula (3) is Dondoni et al. Tetrahedron Letters 2001, 41,
4819-4823, wherein, prior to the coupling, the Cl-group of compound
according to formula (5) is transferred to the corresponding
Grignard compound and subsequently transmetallated with
CeCl.sub.3.
[0012] This route results, at best, in a very small excess of the
desired diastereomer (55:45), only if additional measures are
employed, such as the addition of a chelate complex-destroying
agent. In general, the opposite of the desired diastereomer is
obtained in excess. As indicated in the paper, a substantial
dominance of the desired S-epimer could not be achieved.
[0013] The invention now provides a novel route for coupling new
nitrogen containing compounds of formula (7) and (8) to a compound
of formula (2) (see below). Surprisingly, such coupling can be
achieved with a much simpler nitrogen containing compound, in
particular a compound not comprising a chiral auxiliary. It is an
advantage of the new nitrogen containing compounds, that the
desired coupling products can be obtained with a higher yield of
the compound with the desired configuration at the C-5 stereogenic
center.
[0014] It would be advantageous to provide a convergent synthesis
route for compounds of formula (1) which satisfies one or more of
the following: [0015] a reduced number of steps; [0016] an improved
overall yield; [0017] a relatively easy introduction of the
"5-amino" group; [0018] providing a nitrogen-containing compound
(preferably in a short and scalable route) that is capable of being
coupled with the compound according to formula (2).
[0019] By preference, it would be advantageous to achieve one or
more of the following: [0020] an increased diastereomeric
selectivity in the aforementioned coupling step; [0021] providing
an enantiomerically enriched (most preferably pure)
nitrogen-containing compound that is capable of being coupled with
the compound according to formula (2), resulting in the coupling
product with the desired stereochemical configuration, or at least
so as to provide the 5(S) configuration in excess.
[0022] In order to better address the foregoing, in one aspect, the
invention provides a synthesis route to compounds of formula
(1a).
##STR00007##
[0023] Herein, the R groups have the above-indicated meaning. The
synthesis route is based on a novel nitrogen-containing compound
according to formula (7), or the corresponding lactone of formula
(8), as described below.
[0024] In another aspect, the invention provides a novel chiral
aldehyde (10), as a precursor for the nitrogen-containing
intermediates, and thus as an intermediate to facilitate the
synthesis of the compounds concerned. In another aspect, the
invention presents processes for the stereoselective conversion of
the chiral aldehyde into the nitrogen containing compound.
[0025] In yet a further aspect, the invention provides the coupling
of compounds of structure (2) with the nitrogen containing
compounds of formula (7) and/or (8), under the appropriate
conditions, resulting in compounds depicted by formula (9a) and/or
(11a), with the configuration of the C-5 stereogenic center being
undefined, optionally followed by a purifying step in order to
obtain the desired configurational purity at the C-5 stereogenic
center, or the coupling of compounds of structure (2) with the
nitrogen containing compound of formula (7) and/or (8) is resulting
in the compounds depicted by formula (9) and/or (11).
[0026] In a still further aspect, the invention provides a
synthesis route to compounds of formula (1), notably to aliskiren
and closely related compounds.
[0027] The overall synthetic route to compound (1), as an example
of synthetic routes according to the invention, can be as
follows:
##STR00008##
[0028] The abbreviations in this scheme, other than chemical
elements have the following meaning: [0029] DiBAL-H is diisobutyl
aluminum hydride; [0030] p-TsOH is para-toluene sulfonic acid;
[0031] HNL is hydroxynitrile lyase; [0032] R.sub.1, R.sub.2,
R.sub.3, R.sub.4, and R.sub.5 are as described for the compound
according to formula (1); [0033] Re is a reactive moiety selected
from F; Cl; Br; I; M(X).sub.n, wherein X is F, Cl, Br, I, CN,
C.sub.1-12alkyl, or C.sub.1-6alkoxy and M is a metal, preferably M
is Mg, Ce, Li, Ba, Al, B, Cu, Zn, Mn, Ti, Zr, In and n is 0, 1, 2,
3, or 4; MM'(X).sub.n(Y).sub.n', wherein M and M' are a metal,
preferably M and M' are each independently Mg, Ce, Li, Ba, Al, B,
Cu, Zn, Mn, Ti, Zr, In, where X and Y are each independently chosen
from F, Cl, Br, I, or CN, C.sub.1-6alkoxy and n, n' are each
independently chosen from the values as described above; or Re is
OR.sub.9, wherein R.sub.9 is a group capable of making OR.sub.9 a
leaving group, such group being known to the person skilled in the
art, for example R.sub.9 is acetyl, trifluoroacetyl;
CF.sub.3SO.sub.2, CH.sub.3SO.sub.2, CH.sub.3C.sub.6H.sub.4SO.sub.2,
C(O)OCH.sub.3, or C(O)OC.sub.4H.sub.9; [0034] R.sub.6 represents H,
or optionally substituted C.sub.1-12alkyl, optionally substituted
C.sub.1-12alkylaryl, or optionally substituted C.sub.1-12aryl;
[0035] R.sub.7 represents H, or is an O-protecting group as
described in J. F. W. McOmie, "Protective Groups in Organic
Chemistry", Plenum Press, London and New York 1973; or in T. W.
Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis",
Third edition, Wiley, New York 1999; [0036] or R.sub.6 forms with
R.sub.7 an, optionally substituted C.sub.1-12(hetero)cyclic
compound, as such protecting both the acid and alcohol group;
[0037] R.sub.8 denotes H, or a group remaining after the reaction
of the Nf group as it was present in compound of formula (8), or
R.sub.8 represents a group, put on independently in an additional
reaction step, making the moiety attached via the N-atom to the C-5
stereogenic center of the compound depicted by formula (11)
inactive for reaction steps thereafter,
[0038] With reference to the overall reaction Scheme I, the various
novel intermediates and the various related reaction steps are
separately discussed hereinafter.
The Nitrogen-Containing Compounds
[0039] This can be a compound depicted by formula (7), or the
corresponding lactone compound of formula (8):
##STR00009##
[0040] In these formulae, R.sub.4 has the meaning given above with
reference to formula (1). In the specific synthesis route to
aliskiren, this represents a 2-propyl group.
[0041] R.sub.4, R.sub.6, and R.sub.7, have the meaning given above,
and Nf is a group comprising a carbon atom directly bonded to a
nitrogen atom, preferably Nf is a group resulting in the compounds
depicted by formulae (7a) to (7h), and compounds depicted by
formulae (8a) to (8h),
##STR00010## ##STR00011##
wherein R.sub.4, R.sub.6, and R.sub.7, have the meaning given
above, and Z is a N-protecting group; R.sub.11 is an O-protecting
group, e.g acetyl, trifluoroacetyl, trialkylsilyl, or benzyl, or
groups as described in T. W. Greene and P. G. M. Wuts, "Protective
Groups in Organic Synthesis", Third edition, Wiley, New York 1999;
R.sub.12 and R.sub.13 are either the same or different fragments,
chosen from the group of H, optionally substituted C.sub.1-12alkyl,
optionally substituted C.sub.1-12alkylaryl, or optionally
substituted C.sub.1-12aryl, or they are joined together in a
C.sub.1-20(hetero)cyclic structure; Ra.sup.+ is a counter-cation;
St is a group capable of stabilising the imine.
[0042] The N-protecting group depicted as Z is preferably a group
which can be easily removed in a latter stage of the synthesis,
such as optionally substituted benzyl, para-methoxyphenyl,
(2-pyridyl)sulfonyl or any group described in T. W. Greene and P.
G. M. Wuts, "Protective Groups in Organic Synthesis", Third
edition, Wiley, New York 1999;
[0043] Ra.sup.+ is a counter-cation, for example the one remaining
after the partial reduction of the cyano group, e.g.
Al(iBu).sub.2.sup.+, as is depicted as example in Scheme 1 (when
DiBAL-His used as reducing agent);
[0044] St is a group capable of stabilising the imine, preferably
the remaining group after partial reduction of the cyano group,
e.g. B(R.sub.10).sub.3, if LiBH(R.sub.10).sub.3 was used, R.sub.10
being H or a C.sub.1-6 alkyl group.
[0045] The partial reduction of the nitrile group in the compounds
depicted by formulae (7a) and (8a), resulting in compounds of
formula (7e and f) and (8e and f), can be conducted in a variety of
ways known to the skilled person, as described in Andreoli et al.
J. Org. Chem. 1990, 55, 4199-4200; Masahiko et al. Synlett 1991, 7,
479-480; Zandbergen et al. Tetrahedron 1992, 48, 3977-3982;
Cainelli et al. Tetrahedron 1993, 49, 3809-3826; Itsuno et al. J.
Chem. Soc. Perkin Trans. 11991, 1767-1769; Ramachandran and Biaswas
Org. Lett. 2007, 9, 3025-3027.
[0046] The cyanohydrin compound of formula (7a) (Nf=CN) can be
prepared by reacting the chiral aldehyde of formula (10) with a
cyanide, preferably with HCN, NaCN, KCN, (R).sub.3SiCN (with R
selected from C.sub.1-6alkyl, C.sub.1-10alkylaryl, and
C.sub.1-10aryl), optionally in the presence of a chiral catalyst.
Said catalyst can be a chiral organic compound, a chiral metal
complex, or an enzyme, as described in by F. X. Chen and X. M. Feng
in "Asymmetric synthesis of cyanohydrins" Current Organic Synthesis
2006, 3, 77-97, and references therein; and by P. Poechlauer, W.
Skranc, and M. Wubbolts in "The large-scale biocatalytic synthesis
of enantiopure cyanohydrins" in Asymmetric Catalysis on Industrial
Scale; H. U. Blaser and E. Schmidt, Eds. Wiley-VCH, 2004, pp
151-164. Preferably HCN, or (R).sub.3SiCN in the presence of a
suitable chiral catalyst is used. More preferred HCN and the enzyme
HNL (hydroxynitrile lyase) are used. Suitable conditions for the
synthesis of compound of formula (7a) are known by the person
skilled in the art and are described in the references above, and
references therein.
[0047] The nitrile containing compound of formula (7a) and (8a) can
be converted to other nitrogen containing compounds according to
formula (7b-g) and (8b-g) by using methods known in the art, for
example by partial reduction as described above. Examples of
various imine-type compounds, and applied conditions can be found
in Bloch Chem. Rev. 1998, 98, 1407-1438; Friestad and Mathies
Tetrahedron 2007, 63, 2541-2569 and references therein. Optionally,
the partial reduction can be followed by immediate hydrolysis to
the corresponding aldehyde group resulting in the formation of
compounds of formula (6a) or (6b),
##STR00012##
wherein R.sub.4, R.sub.6, and R.sub.7, have the meaning given
above, and subsequent reaction to the imine, oxime or hydrazone
compounds. The compounds according to formula (6a) and (6b) can be
purified and isolated, or immediately converted to the
corresponding nitrogen containing compounds of formula (7) and (8).
Preferably, the compounds according to formula (6a) and (6b) are
converted without isolation to the corresponding nitrogen
containing compounds of formula (7) and (8).
[0048] One example of such a preferred sequence (without isolation
of compound of formula (6a) is depicted in Scheme II.
##STR00013##
[0049] The nitro analogue of compound of formula (7h,
Nf=(H)C(H)NO.sub.2) can be prepared by addition of nitromethane to
the chiral aldehyde of formula (10), the so-called Henry reaction,
preferably in the presence of a chiral compound, said chiral
compound can be an organic compound, a metal complex, or an enzyme.
Preferably, said chiral compound is used in catalytic amounts,
preferably less than 10 mol % compared to the amount of chiral
aldehyde. Suitable examples of said chiral compounds are for
example described by Boruwa et al. in Tetrahedron Asymmetry 2006,
17, 3315-3326 and references therein.
[0050] The nitrogen containing compounds of formula (7) can be
converted into the corresponding lactone compounds of formula (8)
by using methods known in the art, in analogy with regular
deprotection methods and ester synthesis, e.g. catalyzed by
para-toluene sulfonic acid. For the lacton formation, R.sub.6 is
preferentially C.sub.1-6alkyl, more preferentially methyl.
[0051] The lactone nitrile of formula (8a) in the
diastereochemically desired configuration can be obtained by
ring-closing the cyanohydrin of formula (7a) in the desired
configuration, or by ring-closing both diastereomers of the
cyanohydrin of formula (7a) with fixed configuration at C-2
stereogenic center, followed by epimerization of the C-4
steroegenic center to the thermodynamically preferred diastereomer,
also being the desired diastereomer. Said epimerisation can be
conducted by heating the lactone nitrile, optionally in a suitable
solvent, and optionally in the presence of a base or other suitable
additives. Alternatively, the diastereoisomer with the desired
configuration can be separated from the other diastereoisomer
making use of their different physical properties (e.g.
preferential crystallization), or by means of classic or separating
moving beds (SMB) chromatography. Suitable examples of SMB
chromatography can be found in Schulte and Strube J. Chromatogr. A
2001, 906, 399-416 and references therein.
[0052] Preferably the lactone nitrile of formula (8a) in the
diastereochemically desired configuration is obtained by
ring-closing an optically pure cyanohydrin of formula (7a).
[0053] It will be appreciated that the nitrogen-containing
intermediates can be used in the synthesis of compounds of formula
(1), as is depicted in the overall reaction scheme by reacting
compound of formula (9a) or (11a), or a mixture thereof, with an
appropriate amine, i.e. of a general formula H.sub.2N--R.sub.5,
under conditions sufficient to form an amide bond, optionally
followed by purification in order to obtain the desired
configuration of the C-5 sterogenic center. Suitable conditions for
the amide bond formation are known to the person skilled in the
art, and are for example described in Sandham (Tetrahedron Letters,
2000, 41, 10091-10094), referred to above.
[0054] More directly, the nitrogen-containing compounds of formula
(7) or (8), or a mixture thereof, are reacting with a compound
according to formula (2)
##STR00014##
wherein R.sub.1, R.sub.2, and R.sub.3 and Re have the
aforementioned meaning, which reaction results in the synthesis of
a compound according to formula (9a) or (11a), or a mixture
thereof.
##STR00015##
[0055] Herein, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.6,
R.sub.7, and R.sub.8 have the previously given meanings.
[0056] When compounds according to formula (7a-g) or compounds
according to formula (8a-g), or a mixture thereof, are reacting
with compound of formula (2) the Re group denotes preferably
M(X).sub.n, or MM'(X).sub.n(Y).sub.n'. Optionally, compounds
according to formula (7a-g) or compounds according to formula
(8a-g), or a mixture thereof, are reacting with compound according
to formula (2) in the presence of a metal complex, preferably a
metal complex used in catalytically amounts, and optionally in the
presence of an additive. Said catalysts can be any metal complex,
preferably transition metal complexes, more preferred metal
complexes derived from group VII and group VIII of the periodic
system, most preferred manganese or iron complexes are used, such
as MnCl.sub.2, and FeCl.sub.3, Fe(acac).sub.3, FeCl.sub.2.
[0057] Suitable additives are Lewis acids, such as ZnCl.sub.2,
CuCl; CuI, INCl.sub.3, TiCl.sub.4, alkali metal salts, such as
LiCl; tertiary amines and tertiary diamines, such as
Et.sub.3N,N-methylpyrrolidine, tetramethylendiamine (TMEDA); amides
and ureas, such as N-methylpyrrolidinone (NMP) and
1,3-dimethyl-2-oxohexahydropyrimidine (DMPU); hexamethylphosphoric
acid triamide (HMPA); tris(dialkylamino)phosphines, such as
tris(dimethylamino)phosphine (HMPT).
[0058] Said metal complexes or additives can be chiral to enhance
the amount of compound of formula (9a) or (11a) or mixture thereof,
with the desired configuration at the C-5 stereogenic center.
Chiral metal complexes can be prepared beforehand or prepared in
situ, by mixing the metal complex with an suitable chiral ligand.
Suitable chiral ligands are known to the person skilled in the art,
for example chiral amino alcohols, optionally alkylated at the
amine functionality, such as ephedrine; chiral phosphor containing
compounds, such as (3,5-dioxa-4-phosphacyclohepta[2,1-a;
3,4-a']dinapthalen-4-yl)dimethylamine (MonoPhos), chiral
bisphosphines, such as
2,2'-Bis(di-p-tolylphosphino)-1,1'-binaphthyl (BINAP).
[0059] Suitable chiral additives are any additive mentioned above
with a stereogenic center or other form of chirality. Preferred are
chiral amines and amine derivatives, such as N,N-dimethylamino acid
methyl esters, N,N-dimethylmethylbenzylamine and chiral phosphor
containing compounds, such as (3,5-dioxa-4-phosphacyclohepta[2,1-a;
3,4-a']dinapthalen-4-yl)dimethylamine (MonoPhos).
[0060] When the compound according to formula (7h) or the compound
according to formula (8h), or a mixture thereof, is reacting with
compound of formula (2) the Re group denotes preferably Cl, Br, I,
or OR.sub.9, wherein R.sub.9 is a group capable of making OR.sub.9
a leaving group, such group being known to the person skilled in
the art, for example R.sub.9 is acetyl, trifluoroacetyl;
CF.sub.3SO.sub.2, CH.sub.3SO.sub.2, CH.sub.3C.sub.6H.sub.4SO.sub.2,
C(O)OCH.sub.3, or C(O)OC.sub.4H.sub.9, and this reaction is
performed in the presence of a base, or metal complex. Suitable
bases are any base capable of, optionally partly, deprotonating the
carbon center with the nitro group directly attached to it, such as
bases are known to the person skilled in the art, for example
sodium hydride, sodium methoxide, n-butyllithium, sec-butyllithium,
tertiar-butyllithium, KOtertiar-butyl, KOAc, KOH, NaOH, and so on.
Suitable metal complexes are similar complexes as used for the
synthesis of compounds of formula (7h) or (8h) or mixture thereof,
as also described in Boruwa et al. in Tetrahedron Asymmetry 2006,
17, 3315-3326 and references therein.
[0061] Said bases or metal complexes can be chiral to enhance the
amount of compound of formula (9a) or (11a) or mixture thereof,
with the desired configuration at the C-5 stereogenic center.
Suitable chiral bases are for example alkali-metal amides, such as
chiral lithium amides similar to those described in Cailleau et al.
Org. Biomol. Chem. 2007, 5, 3922-3931 and references therein.
[0062] With reference to producing a compound satisfying formula
(1), it will be apparent that the corresponding compound of formula
(9a) or (11a), or a mixture thereof, is formed with an undefined
configuration at the C-5 stereogenic center (the carbon center with
the HR.sub.8N moiety attached to it). It will be appreciated that
the nitrogen-containing compounds of formula (7) or (8), or mixture
thereof, employed in the synthesis of compound of formula (9a) or
(11a), or mixture thereof, are able to react with a compound of
formula (2) in a diastereoselective manner, due to a preferential
direction of attack during the coupling reaction and the presence
of neighbouring fixed stereogenic centers. The diastereoselectivity
is influenced by the nature of the reagents of formula (7a-h),
(8a-h) and (2), optionally, by the addition of a catalyst, base,
and/or additive as described above. Optionally, the
diastereoselectivity can be increased by making use of the
different physical properties of the diastereoisomers (e.g.
preferential crystallization), or by means of classic or separating
moving beds (SMB) chromatography as described above. Optionally
this additional purification is performed in the presence of a
suitable agent capable of racemising the C-5 center. The
racemization could be done in the same vessel or by external
loops.
[0063] In the case of the compound according to formula (7h) or the
compound according to formula (8h), or a mixture thereof, reacting
with compound of formula (2) the intermediate compound obtained of
formula (12) or (13) or mixture thereof is in particular suitable
for preferential crystallization and racemisation (in the presence
of a suitable base).
##STR00016##
[0064] Said techniques to obtain a theoretical 100% yield of the
desired enantiomer, or diastereomer using racemising techniques and
techniques and/or reactions to take out the desired enantiomer or
diastereomer from the reaction mixture, are well known by the
person skilled in the art. Said techniques are called dynamic
kinetic resolution techniques, see for example described by
Pelliessier, Tetrahedron 2003, 59, 8291-8327, and references
therein.
[0065] The compounds of formula (2), with R.sub.1, R.sub.2,
R.sub.3, as described above, and with Re is Cl can be made in known
ways. References in this respect are Sandham et al. Tetrahedron
Lett. 2000, 41, 10091-10094 and Sturm et al. Adv. Synth. Catal.
2003, 345, 160-164.
[0066] The preparation of the corresponding Grignard reagent
(Re=MgCl) is described by Sandham. The preparation of many other
organometallic compounds can be performed by the transmetalation
reaction of the appropriate metal salts with a magnesium or lithium
organometallic compound of formula (2). These transmetallation
procedure are known to persons skilled in the art.
[0067] As a part of the invention, the coupling of the
organometallic reagent according to formula (2) with the nitrogen
containing compound of formula (7a) or formula (8a), or a mixture
thereof, can be performed as depicted in the Scheme III:
##STR00017##
or for example by first reducing the cyanohydrin and the lactone
nitrile to the corresponding iminium ions of formula (7e) and (8e),
as depicted in Scheme IV.
##STR00018##
[0068] In Schemes III and IV, R.sub.1, R.sub.2, R.sub.3, Re,
R.sub.4, R.sub.6, R.sub.7, R.sub.8, and Ra.sup.+ have the
previously given meanings.
[0069] The said iminium compounds retain the stereochemistry from
the cyanohydrin and lactone nitrile.
[0070] In the event of an organometallic coupling reaction of a
compound according to formula (2) with any nitrogen-containing
compound of formula (7), the hydroxyl group in compound according
to formula (7) can be protected in various ways using known alcohol
protecting groups, e.g. as depicted in Scheme V:
##STR00019##
[0071] Herein, the abbreviation TBDMSiCl stands for
tert-butyldimethylsilyl chloride. DMF is dimethyl formamide, and RT
is room temperature.
[0072] Alternatively, the nitrogen-containing compound is the
nitro-compound of formula (7h) or (8h), or mixture thereof. A
possible sequence of the coupling of compound of formula (7h) and
compound of formula (2), and the following steps producing compound
of formula (1) are depicted in Scheme VI.
##STR00020##
[0073] Here, R.sub.1, R.sub.2, R.sub.3, Re, R.sub.4, R.sub.6,
R.sub.7, and R.sub.8 have the previously given meanings.
[0074] As an alternative, a variant of a compound of formula (2) is
used that itself does not possess the desired chirality, yet. This
refers to a compound of formula (2a), which has the advantage of
being more reactive:
##STR00021##
[0075] The coupling of this compound of formula (2a) can be
performed with any of the compounds of formula (7), and formula
(8), or a mixture thereof. The required chirality at C-7 of
compound of formula (1) can then later be introduced through
hydrogenation of the C.dbd.C double bond (as for example shown for
compound of formula (14) in Scheme VII). Said hydrogenation can be
performed with any reducing agent, e.g. NaBH.sub.4, BH.sub.3,
LiAlH.sub.4; or hydrogen gas, optionally in the presence of a
catalyst. Said catalyst can be a well known heterogeneous catalyst,
such as Pd on Carbon or any support, or can be a homogeneous
catalyst, e.g. those based on late transition metals, such as Rh,
Ru, Ir, or Pd. Optionally, a chiral hydrogenation reagent, or a
chiral catalyst is used. Said chiral catalyst can be any transition
metal with a chiral ligand, or of any enzymatic origin, or the
so-called organo-catalysts. Suitable chiral catalysts, are for
example heterogeneous Pd on Carbon with cinchonidine alkoloids, or
homogeneous rhodium complexes with chiral ligands, or for example
enzymes called reductases. Suitable chiral ligands for the
homogeneous catalysts are known in the art, for example chiral
phosphor-containing ligands such as BINAP, JosiPhos, ChiraPhos,
MonoPhos.
[0076] An alternative synthesis route to compound of formula (1)
could for example satisfy the following reaction scheme VII (here
shown for the reaction of compounds (2a) and (8e)):
##STR00022##
[0077] Herein, R.sub.1, R.sub.2, R.sub.3, Re, R.sub.4, and R.sub.8
have the previously given meanings.
[0078] Preferably Re in compound of formula (2a) is M(X)n with the
meanings for M, X and n as given above, more preferably M is
Ba.
[0079] The coupling reaction of compound of (2a) with compound of
formula (7) or compound of formula (8), or mixture thereof, is
performed preferably according to as described above for the
coupling of compound of formula (2) with compound of formula (7) or
compound of formula (8), or mixture thereof.
[0080] The nitrogen-containing compound of formula (7a) can be
obtained in many different ways and is part of the invention. For
example the following route depicted in Scheme VIII can be
used:
##STR00023##
[0081] The chiral lactone nitrile (8a), also being part of the
invention can be made in various ways, e.g. according to Scheme
IX:
##STR00024##
[0082] In Schemes VIII and IX the R groups have the meanings given
above.
[0083] Preferably, the nitrogen-containing compound of formula (7),
or formula (8), or mixture thereof, is obtained via a novel chiral
aldehyde compound as depicted below in FIG. (10), allowing the
enantioselective addition of HCN, or related reagents, or allowing
the addition of nitromethane, as mentioned above.
The Chiral Aldehyde
[0084] This refers to a compound that is useful as a precursor for
the nitrogen-containing compounds, and that is a novel compound,
representing a conceptually different synthetic route, in the
preparation of compounds of formula (1). The chiral aldehyde
satisfies the following formula (10):
##STR00025##
[0085] With R.sub.4 and R.sub.6 as indicated above. More
particularly, the aldehyde intermediate provides a building-block
for aliskiren, as can be used in the synthesis thereof, and then
satisfies formula (10a):
##STR00026##
[0086] The use of the chiral aldehyde of formula (10) or formula
(10a) are representing a novel approach to the synthesis of
compounds of formula (1), and particularly of aliskiren. It has an
advantage in the sense that it introduces the desired
stereochemistry at the C-2 stereogenic center atom of compounds of
formula (1) without the use of stoichiometric amounts of relative
expensive chiral auxiliaries as shown in Sandham et al. Tetrahedron
Lett. 2000, 41, 10091-94.
[0087] The chiral aldehyde of formula (10) exhibits a further
advantage in that it introduces immediately the required nitrogen
in a stereochemically desired way by catalytic addition of HCN, or
related reagents, or the stereochemically desired addition of
nitromethane, both approaches as discussed above in connection with
the synthesis of the nitrogen-containing compounds of formula (7)
and (8), or a mixture thereof. Thus, the aldehyde can be converted
into compound of formula (8a), optionally via compound of formula
(7a).
[0088] By way of example, the following scheme (Scheme X)
illustrates the HNL catalyzed addition of HCN to the chiral
aldehyde (10) forming compound of formula (7a), followed by acid
catalyzed lactonisation to compound of formula (8a).
##STR00027##
[0089] The chiral aldehyde itself can be obtained in various
alternative ways, e.g. as depicted in the following Schemes XI (a)
through XI (g); wherein, the specific compounds chosen are
illustrative, and can be translated to the corresponding other
aldehydes commensurate with the respective structural part of the
compounds of formula (1).
##STR00028## ##STR00029## ##STR00030##
[0090] Wherein R in Scheme XI (g) denotes a H, C.sub.1-6 alkyl, or
Cl. The oxidation depicted in Scheme XI (g) could also be performed
by ozonolysis. Alternatively, the chiral aldehyde can be
synthesized using a chiral pool strategy, for which several options
are available, e.g. from the required enantiomer of Valine or
Carvone.
[0091] The various reaction steps are identified with reference to
terminology and names commonly known in the art, and to the person
skilled in the art are understandable as such.
Overall Synthesis
[0092] The aforementioned compounds can be used in a convergent
synthesis route to the compounds of formula (9) or (11), or a
mixture thereof, and ultimately to the compounds of formula (1),
preferably aliskiren.
[0093] The convergence, resulting in a compound of formula (9) or
(11) or mixture thereof, comes when the intermediates representing
the aromatic part are reacted with the nitrogen-containing
intermediate. Other than in previous routes which lead to an excess
of the desired diastereomer, at the convergence stage of this
invention the critical 5-amino nitrogen is already present in the
molecule. Moreover, provided that the preferred choices are made in
the synthetic route from the aforementiond chiral aldehyde, the
amino group is present in the desired stereomeric
configuration.
[0094] The compound of formula (9) can be converted into the
desired end-product, such as a compound according to formula (1),
by allowing it to react with the appropriate amine
NH.sub.2--R.sub.5, optionally followed by hydrolysis of the amine
protecting group. Such reactions have been described, e.g in WO
2007/039183 and WO 2006/131304. It will be apparent to the skilled
person that in the event of the synthesis of aliskiren, this amine
will satisfy formula (15), and be synthesized in a known
manner.
##STR00031##
[0095] Thus, a straightforward convergent synthesis results,
without undue complexity. The two aforementioned building blocks
are provided, coupled and, subsequently, with one or two steps the
desired end-product results.
[0096] In the case of optionally substituted groups are mentioned
or used in the invention, optionally substituted groups do mean all
the groups possible which will not interfere with the aimed
reaction and/or reactions afterwards.
Salts
[0097] As mentioned above in respect of aliskiren, the compounds of
formula (1) include salts, especially pharmaceutically acceptable
salts. In view of the close relationship between the compounds and
intermediates in free form and in the form of their salts,
including those salts that can be used as intermediates, for
example in the purification or identification of the compounds or
salts thereof, any reference to "compounds", "precursors" and
"intermediates" is to be understood as referring also to one or
more salts thereof or a mixture of a corresponding free compound,
intermediate or starting material and one or more salts thereof,
each of which is intended to include also any solvate, metabolic
precursor such as ester or amide of the compound of formula (1), or
salt of any one or more of these, as appropriate and expedient and
if not explicitly mentioned otherwise. Different crystal forms may
be obtainable and then are also included.
[0098] Salts, including pharmaceutically acceptable salts are known
and described in U.S. Pat. No. 5,559,111, column 11 line 50 to
column 12, line 35, and incorporated herein by reference.
General Process Conditions
[0099] The following, in accordance with the knowledge of a person
skilled in the art about possible limitations in the case of single
reactions, applies in general to all processes mentioned in the
foregoing description, or hereinafter in the Examples and Claims,
while reaction conditions specifically mentioned above or below are
preferred:
[0100] All the above-mentioned process steps can be carried out
under reaction conditions that are known per se, preferably those
mentioned specifically, in the absence or, customarily, in the
presence of solvents or diluents, preferably solvents or diluents
that are inert towards the reagents used and dissolve them, in the
absence or presence of catalysts, condensation or neutralizing
agents, for example ion exchangers, such as cation exchangers, e.g.
in the H.sup.+ form, depending on the nature of the reaction and/or
of the reactants at reduced, normal or elevated temperature, for
example in a temperature range of from about -100.degree. C. to
about 190.degree. C., preferably from approximately -80.degree. C.
to approximately 150.degree. C., for example at from -80 to
-60.degree. C., at room temperature, at from -20 to 40.degree. C.
or at reflux temperature, under atmospheric pressure or in a closed
vessel, where appropriate under pressure, and/or in an inert
atmosphere, for example under an argon or nitrogen atmosphere.
[0101] The solvents, from which those solvents that are suitable
for any particular reaction may be selected, include those
mentioned specifically or, for example, water; esters, such as
lower alkyl-lower alkanoates, for example ethyl acetate; ethers,
such as aliphatic ethers, for example diethyl ether, or cyclic
ethers, for example tetrahydrofurane or dioxane; liquid aromatic
hydrocarbons, such as benzene or toluene; alcohols, such as
methanol, ethanol or 1- or 2-propanol; nitriles, such as
acetonitrile; halogenated hydrocarbons, e.g. as methylene chloride
or chloroform; acid amides, such as dimethylformamide or dimethyl
acetamide; bases, such as heterocyclic nitrogen bases, for example
pyridine or N-methylpyrrolidin-2-one; carboxylic acid anhydrides,
such as lower alkanoic acid anhydrides, for example acetic
anhydride; cyclic, linear or branched hydrocarbons, such as
cyclohexane, heptane or (iso)pentane; or mixtures of these, for
example aqueous solutions, unless otherwise indicated in the
description of the processes. Such solvent mixtures may also be
used in working up, for example by chromatography or partitioning.
Where required or desired, water-free or absolute solvents can be
used.
[0102] Where required, the working-up of reaction mixtures,
especially in order to isolate desired compounds or intermediates,
follows customary procedures and steps, e.g. selected from the
group comprising but not limited to extraction, neutralization,
crystallization, chromatography, evaporation, drying, filtration,
centrifugation and the like. The invention relates also to those
forms of the process in which a compound obtainable as intermediate
at any stage of the process is used as starting material and the
remaining process steps are carried out, or in which a starting
material is formed under the reaction conditions or is used in the
form of a derivative, for example in protected form or in the form
of a salt, or a compound obtainable by the process according to the
invention is produced under the process conditions and processed
further in situ. In the process of the present invention those
starting materials are preferably used which result in compounds of
formula (1) which are described as being preferred. Special
preference is given to reaction conditions that are identical or
analogous to those mentioned in the Examples. The invention relates
also to novel starting compounds and intermediates described
herein, especially those leading to compounds mentioned as
preferred herein.
[0103] It is to be understood that the invention is not limited to
the embodiments and formulae as described hereinbefore. It is also
to be understood that in the claims the word "comprising" does not
exclude other elements or steps. Where an indefinite or definite
article is used when referring to a singular noun e.g. "a" or "an",
"the", this includes a plural of that noun unless something else is
specifically stated.
[0104] The invention will be illustrated with reference to the
following, non-limiting Examples.
EXAMPLE 1
Preparation of the Grignard Reagent with Formula (2) where
Re=MgCl
##STR00032##
[0106] A solution of the aromatic chloride (7.87 g, 25.0 mmol) and
1,2-dibromoethane (50 .mu.L) in THF (24 mL) was added dropwise,
under a nitrogen atmosphere, to an over-dried round bottomed flask
containing a suspension of magnesium powder (670 mg, 27.5 mmol, 1.1
eq.) and few crystals of I.sub.2 in THF (1 mL). The temperature was
maintained at 65-69.degree. C. during the addition and for the
following 2 hours, after which time the stirring was stopped and
the mixture was allowed to reach room temperature overnight.
[0107] After treatment with a saturated aqueous solution of
NH.sub.4Cl, a sample of reaction mixture was analyzed by
.sup.1H-NMR and showed full consumption of the starting material.
Before use, the titration of the grignard reagent was performed
using sec-BuOH in the presence of 1,10-phenantroline. The titer was
generally found to be 0.71-0.82 M.
EXAMPLE 2
Preparation of
2-(3-methoxypropoxy)-4-(R)-2-(iodomethyl)-3-methylbutyl)-1-methoxybenzene
##STR00033##
[0109] A solution of the aromatic chloride (9.5 g, 30.0 mmol) in
acetone (30 mL) containing NaI (9.0 g, 60.0 mmol, 2 eq.) was
stirred at room temperature for 5 days. A sample analyzed by
.sup.1H-NMR showed a ratio of 40:60 between starting material and
product. The solvent was then removed and water was added. The
aqueous layer was extracted with diethyl ether. The organic layer
was washed with brine, dried over Na.sub.2SO.sub.4 and the solvent
removed under reduced pressure. Acetone (30 mL) was added to the
crude mixture, followed by NaI (9.0 g, 60.0 mmol, 2 eq.). The
reaction mixture was stirred at 56.degree. C. for extra 5 days. It
was decided to stop the reaction when a ratio of 92:8 was reached.
The work up was performed as previously described. The crude
mixture was purified by flash column chromatography on silica gel
affording the desired compound in 80.5% yield, as a light brown
solid.
[0110] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 6.76-6.62 (m,
3H), 4.05 (t, J=6.5 Hz, 2H), 3.76 (s, 3H), 3.51 (t, J=6.1 Hz, 2H),
3.28 (s, 3H), 3.18-2.97 (m, 2H), 2.75-2.65 (m, 1H), 2.34-2.21 (m,
1H), 2.10-1.98 (m, 2H), 1.73-1.57 (m, 1H), 1.15-1.05 (m, 1H), 0.94
(d, J=6.5 Hz, 3H), 0.87 (d, J=6.9 Hz, 3H).
EXAMPLE 3
Preparation of a Compound with Formula (2) where Re=Li
##STR00034##
[0112] In an oven-dried flask kept under a nitrogen atmosphere, the
aromatic iodide (406.3 mg, 1.0 mmol) was dissolved in diethyl ether
(2.5 mL) and the solution was cooled to -78.degree. C. A pentane
solution of t-BuLi (1.7 M, 0.7 mL, 1.2 eq.) was then added dropwise
and the reaction mixture was stirred for 1 h at -78.degree. C.,
after which time it was allowed to reach room temperature and it
was stirred for an extra hour. A sample was quenched by the
addition of an aqueous HCl solution (3 M), which was extracted with
ethylacetate. The organic layer was dried over Na.sub.2SO.sub.4,
the solvent was removed and the residue was analyzed by
.sup.1H-NMR, revealing full conversion of the starting material and
presence of 73.0% of the hydrolysis compound related to the desired
product.
EXAMPLE 4
Preparation of Chiral Aldehyde (10): (S)-methyl
2-(formylmethyl)-3-methylbutanoate
##STR00035##
[0114] In a 1 ltr Schott-bottle with magnetic stirrer 18 g of
(S,E)-methyl 5-chloro-2-isopropylpent-4-enoate (0.094 mol) was
mixed with 680 ml of acetonitrile and 88 ml of water and it was
stirred at 25.degree. C. To this solution 39.6 g of NalO.sub.4
(0.184 mol) and 1.08 g of RuCl.sub.3xH.sub.2O were added at once.
The temperature was maintained at 35.degree. C. The progress of the
reaction was followed by TLC (eluent: heptane/ethylacetate
3/2).
[0115] When the reaction was finished the mixture was cooled to RT
and the precipitate was filtered off and washed with ethylacetate.
The organic liquid phase was successively washed once with 50 ml of
a saturated aqueous solution of sodium thiosulfate, once with 50 ml
of brine, once with 50 ml of a saturated aqueous solution of sodium
bicarbonate and once with 40 ml of brine. The organic solution was
dried over Na.sub.2SO.sub.4. After filtering off Na.sub.2SO.sub.4,
the organic solvent was removed under reduced pressure yielding
18.4 g of crude aldehyde.
EXAMPLE 5
Synthesis of Enantiomerically Enriched Hydroxy Nitrile: (S)-methyl
2-((S)-2-cyano-2-hydroxyethyl)-3-methylbutanoate
##STR00036##
[0117] The chiral aldehyde (10) (0.033 mol) was diluted with 345 ml
of toluene and 500 mL of a (S)--HNL solution (pH=5.6) was added.
The two phases were mixed by stirring and, at a temperature of
0.degree. C., 20 mL of pure HCN (0.53 mol) was dosed over 5
minutes. The mixture was stirred for 3 hours at 0.degree. C. The
conversion of the aldehyde was >94% and the enantiomeric excess
of the product was 94%.
[0118] The reaction mixture was diluted with 1 L of MTBE and the
aqueous layer was extracted several times with MTBE. The combined
organic extracts (approximately 2.5 L) were stabilized with 0.5 mL
of phosphoric acid (conc.) and concentrated under reduced pressure
yielding 12.4 g of the title compound as a crude mixture which was
used without further purification.
EXAMPLE 6
Synthesis of the Lactone Nitrile:
(2S,4S)-tetrahydro-4-isopropyl-5-oxofuran-2-carbonitrile
##STR00037##
[0120] The crude cyanohydrin (12.4 g) was diluted with 120 mL of
toluene and 25 g of mol sieves 5 .ANG. were added. To this mixture,
250 mg of p-toluenesulfonic acid was added and, whilst stirring,
the mixture was heated at 70.degree. C. for 1 hour. After cooling
to RT, the molecular sieves were filtered off and washed with
toluene. The collected organic phase was washed with a saturated
aqueous solution of sodium bicarbonate and dried over
Na.sub.2SO.sub.4. After filtering off the Na.sub.2SO.sub.4, the
organic phase was concentrated under reduced pressure yielding 10.7
g of crude lactone. Purification by flash column chromatography on
silica gel yielded the title compound with >98% purity.
[0121] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 5.11 (dd, J=8.4,
2.3 Hz, 1H), 2.84-2.74 (m, 1H), 2.62-2.41 (m, 2H), 2.31-2.16 (m,
1H), 1.10 (d, J=6.9 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H).
EXAMPLE 7
Synthesis of the TBS-Protected Cyanoydrin: (S)-methyl
2-[(S)-2-cyano-2-(t-butyldimethylsilyl)oxyethyl]-3-methylbutanoate
##STR00038##
[0123] Imidazole (7.35 g, 108 mmol) was added at 0.degree. C. to a
solution of the crude hydroxyl nitrile (10 g) in DMF (180 mL),
followed by TBDMSiCl (9.77 g, 64.8 mmol). The mixture was stirred
at room temperature overnight. Subsequently, the reaction mixture
was poured over an ice-cold aqueous HCl solution (1 M, 80 mL).
After the addition of diethyl ether (100 mL), the organic layer was
separated and the aqueous layer was further extracted with diethyl
ether (2.times.100 mL). The combined organic layers were washed
with a saturated aqueous solution of sodium bicarbonate and brine,
dried over Na.sub.2SO.sub.4 and the solvent was then removed under
reduced pressure. The crude mixture was purified by flash column
chromatography on silica gel.
[0124] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 4.26 (dd, J=9.2,
3.4 Hz, 1H), 3.50 (s, 3H), 2.37-2.29 (m, 1H), 2.08-1.96 (m, 1H),
1.86-1.68 (m, 2H), 0.81-0.68 (m, 15H), 0.00 (s, 3H), -0.08 (s,
3H).
EXAMPLE 8
Synthesis of N-diisobutylaluminium (2S)-methyl
4-(t-butyldimethylsilyl)oxy-5-imino-2-isopropylpentanoate
##STR00039##
[0126] A solution of TBS-protected cyanohydrin (75 mg, 0.25 mmol)
in pentane (2 mL) was cooled to -78.degree. C. and kept under a
nitrogen atmosphere. A pentane solution of DiBAL-H (1 M, 0.25 mL)
was then added dropwise. The reaction mixture was stirred at
-78.degree. C. for extra 4 hours. The consumption of the starting
material was followed by TLC and GC. The resulting metallo-imine
was maintained at the same temperature and used without any further
purification.
EXAMPLE 9
Synthesis of the Triethylborane-Complexed Imine: (2S)-methyl
4-(t-butyldimethylsilyl)oxy-5-imino-2-isopropylpentanoate
triethylborane complex
##STR00040##
[0128] A solution of TBS-protected cyanohydrin (75 mg, 0.25 mmol)
in Et.sub.2O (2 mL) was cooled to -78.degree. C. and kept under a
nitrogen atmosphere. A THF solution of LiBEt.sub.3H (1 M, 0.25 mL)
was then added dropwise. The consumption of the starting material
was followed by TLC and GC. After stirring at the same temperature
for 2 hours, MeOH (10 .mu.L, 1 eq.) was added to the reaction
mixture, which was then stirred for extra 30 minutes at room
temperature. The development of a light turbidity was observed,
probably due to the presence in solution of MeOLi. The resulting
metallo-imine was analyzed and used without any further
purification.
[0129] Metallo-imine relevant peaks .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 9.48 (m, 1H), 7.54 (m, 1H), 4.34 (m, 1H), 3.63
(s, 3H), 2.19 (m, 2H), 0.60 (t, 9H), 0.14 (q, 6H).
EXAMPLE 10
Synthesis of the TBS-Protected .alpha.-hydroxy aldehyde: (S)-methyl
2-((S)-2-formyl-2-(t-butyldimethylsilyl)oxy
ethyl)-3-methylbutanoate
##STR00041##
[0131] The crude solution of the previously obtained metallo-imine
was treated with an aqueous HCl solution (1 M), which was extracted
with diethyl ether. The organic layer was dried over
Na.sub.2SO.sub.4, the solvent was removed under reduced pressure.
Purification by flash column chromatography on silica gel yielded
the title compound.
[0132] .sup.1H-NMR (400 MHz, CDCl.sub.3): 9.53 (d, J=1.5 Hz, 1H),
9.47 (d, J=1.9 Hz, 1H), 3.95-3.85 (m, 1H), 3.61 (s, 3H), 3.60 (s,
3H), 2.42-2.29 (m, 1H), 2.07-1.94 (m, 1H), 1.92-1.80 (m, 1H),
1.61-1.50 (m, 1H), 0.91-0.77 (m, 15H), 0.03-(-)0.04 (m, 6H).
EXAMPLE 11
##STR00042##
[0134] 363 mg (1.0 mmol, 1.03 eq) zinctriflate, 1 ml (18.5 mmol, 19
eq) nitromethane and 174 .mu.l (1.0 mmol, 1.03 eq)
diisopropylethylamine were placed in a dry schlenk vessel under
Nitrogen. The yellow slurry was cooled in ice and 153.3 mg (0.97
mmol) (S)-methyl 2-isopropyl-4-oxobutanoate was added. The reaction
mixture was stirred for 3 h, after which it was quenched with 2 ml
1 N ammonium chloride solution. After separation the water phase
was extracted 3 times with 4 ml dichloromethane and the combined
organic phases were washed with 4 ml brine and dried with
Na.sub.2SO.sub.4, yielding 365 mg crude material after film
evaporation, which contained still diisopropylethylamine according
to NMR. The material was dissolved in 5 ml dichloromethane, washed
3 times with 1 ml 1 N HCl, dried with sodiumsulphate yielding 161
mg after removal of the solvent. Column separation (30/70 v/v
ethylacetate/heptane) gave the pure target compound
(3S)-3-isopropyl-5-(nitromethyl)dihydrofuran-2(3H)-one.
* * * * *