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Patent 2516623 Summary

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(12) Patent Application: (11) CA 2516623
(54) English Title: METHOD FOR PRODUCING THE ENANTIOMERIC FORMS OF CIS 1,3-CYCLOHEXANEDIOL DERIVATIVES
(54) French Title: PROCEDE POUR REALISER LES FORMES ENANTIOMERES DE DERIVES DE CIS 1,3-CYCLOHEXANDIOL
Status: Dead
Bibliographic Data
(51) International Patent Classification (IPC):
  • C07C 29/00 (2006.01)
  • C07D 263/32 (2006.01)
  • C12P 41/00 (2006.01)
(72) Inventors :
  • HOLLA, WOLFGANG (Germany)
  • KEIL, STEFANIE (Germany)
(73) Owners :
  • SANOFI-AVENTIS DEUTSCHLAND GMBH (Germany)
(71) Applicants :
  • AVENTIS PHARMA DEUTSCHLAND GMBH (Germany)
(74) Agent: BERESKIN & PARR LLP/S.E.N.C.R.L.,S.R.L.
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 2004-02-19
(87) Open to Public Inspection: 2004-09-10
Examination requested: 2009-02-19
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/EP2004/001580
(87) International Publication Number: WO2004/076390
(85) National Entry: 2005-08-19

(30) Application Priority Data:
Application No. Country/Territory Date
103 08 350.2 Germany 2003-02-27

Abstracts

English Abstract




The invention relates to a method for producing chiral, non-racemic, cis 1,3-
disubstituted cyclohexanols of formula (I), in which the groups are defined as
cited in the description, using an enzymatic resolution of racemates.


French Abstract

L'invention concerne un procédé pour réaliser des cyclohexanols cis 1,3-disubstitués non racémiques et chiraux de formule (I), dans laquelle les groupes ont les significations indiquées, par dédoublement racémique enzymatique.

Claims

Note: Claims are shown in the official language in which they were submitted.



68

Claims:

1. A process for preparing a chiral, nonracemic compound of the
formula I
Image
where:
R1 is
Image

where:
ring A is phenyl, 5-12 membered heteroaromatic ring which may contain
from one to four heteroatoms from the group of N, O and S, 8 to 14
membered aromatic ring, (C3-C8)-cycloalkyl;
R3 is H, F, Cl, Br, OH, NO2, CF3, OCF3, (C1-C6)-alkyl, (C3-C8)-
cycloalkyl, phenyl;
R4, R5 are H, F, Cl, Br, OH, NO2, CF3, OCF3, OCF2H, OCF2-CF3,
OCF2-CHF2, SCF3, O-phenyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl, O-
(C1-C6)-alkyl-O-(C1-C3)-alkyl;
n is from 1 to 3;
and
R2 is (C1-C8)-alkyl where one or more CH2 groups in the alkyl groups
may be replaced by O, CO, S, SO or SO2, and alkyl may be one to


69

trisubstituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH-CO-
C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxy,
CO-O(C1-C6)-alkyl, tetrazole, thiazolidine-2,4-dione, indole and
(C6-C10)-aryl, where thiazolidine-2,4-dione and aryl may in turn be
substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc,
NHCbz, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH,
CO-benzoxy, CO-O(C1-C6)-alkyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl or
tetrazole, or;
R2 is an OH protecting group (PG), for example benzyloxymethyl,
benzyl, para-methoxybenzyl or tert-butyldimethylsilyl;
which comprises
A)
a) alkylation (alk-R2/alk-PG)
reacting cis-1,3-cyclohexanediol of the formula (II)
Image
with a compound of the formula (III)
X1-R2 (III)
where R2 is as defined above and
X1 is Cl, Br, I, OMs, OTs, OTf;
in the presence of bases in a suitable solvent to give a racemic compound
of the formula (IV)
Image


70

where R2 is as defined above;
b1) enzymatic ester formation (EF) + separation (S)
subjecting the resulting compounds of the formula (IV) to stereoselective
enzymatic ester formation (EF), in which the alcohols are admixed with an
acyl donor and the enzyme in an organic solvent and the resulting mixture
is stirred at -20 to 80°C and, after the reaction has ended, one
stereoisomer is present as an ester of the formula (V)
Image
where
R6 is C(=O)-(C1-C16)-alkyl, C(=O)-(C2-C16)-alkenyl, C(=O)-(C3-C16)-
alkynyl, C(=O)-(C3-C16)-cycloalkyl, where one or more carbon
atoms may be replaced by oxygen atoms and be substituted by 1-3
substituents from the group of F, Cl, Br, CF3, CN, NO2, hydroxyl,
methoxy, ethoxy, phenyl and CO-O(C1-C4)-alkyl, CO-O(C2-C4)-
alkenyl, which may in turn be substituted by 1-3 substituents from
the group of F, Cl, Br, CF3, and
R2 is as defined above,
and the other stereoisomer is present unchanged as the alcohol of the
formula (IV), and are therefore separated from each other by utilizing their
different chemical or physicochemical properties (separation S)
or
b2) enzymatic ester hydrolysis [=chemical esterification (CE) +
enzymatic hydrolysis (EH)] + separation (S)
subjecting the resulting compound of the formula (IV) to a stereoselective
enzymatic ester hydrolysis, in which the racemic alcohol is initially
converted by chemical esterification (CE), for example by means of acid


71

chloride R6-Cl or acid anhydride R6-O- R6, in the presence of bases, to the
racemic ester of the formula (V)
Image
where R6 and R2 are each as defined above,
which, to carry out the stereoselective enzymatic ester hydrolysis (EH), is
then taken up in homogeneous or heterogeneous, aqueous, aqueous-
organic or organic medium, and reacted, in the presence of an enzyme in
the case of hydrolysis with water and in the case of alcoholysis with an
alcohol, at a temperature of 10-80°C, and after the reaction has ended,
one
stereoisomer is present as the alcohol of the formula (IV) and the other is
present unchanged as the ester of the formula (V) and can thus be
separated from each other as described under b1), and
the enantiomer of the formula (IV) occurring as an alcohol is further
processed as described under d), or
c) chemical hydrolysis (CH)
hydrolyzing the enantiomer of the formula (V) occurring as an ester to the
chemically enantiomeric alcohol by known methods and
d) alkylation (alk- R1)
reacting further with a compound of the formula (VI)
Image
where
ring A, R3, R4, R5 and n are each as defined above and


72


X2 is Cl, Br, I, OTs, OMs, OTf;
in the presence of bases in a suitable solvent to give the compound of the
formula (I), and
e) detachment of the protecting group PG (detPG)
if R2 is an OH protecting group (PG) as defined above under R2, converting
the compound of the formula (Ia)

Image

where R1 and PG are each as defined above,
by detaching the protecting group by known methods to a compound of the
formula (VII)

Image

where R1 is as defined above,
f) alkylation (alk- R2)
then reacting it with a compound of the formula (III)

X1-R2 (III)

where X1 and R2 are each as defined above,
in the presence of bases in a suitable solvent to give a compound of the
formula (I), the product or the enantiomeric form,



73


it being also possible to change the sequence of individual reaction steps
as described above under A):
A) alk-R2 .fwdarw. EF + S/CE + EH + S [.fwdarw. CH] .fwdarw. alk- R1 [-+ DetPG
.fwdarw. alk-
R2] .fwdarw. product/enantiomeric form
to:
B) alk- R1 .fwdarw. EF + S/CE + EH + S [.fwdarw. CH] .fwdarw. alk- R2
[.fwdarw. DetPG .fwdarw. alk-
R2] .fwdarw. product/enantiomeric form
or
C) alk-PG.fwdarw.EF+S/CE+EH+S.fwdarw.NCH.fwdarw.alk-R2-
.fwdarw.DetPG.fwdarw.Balk-R1
.fwdarw. product/enantiomeric form
or
D) alk-PG .fwdarw. EF + S/CE + EH + S .fwdarw. alk- R1 .fwdarw. DetPG .fwdarw.
alk- R2 .fwdarw.
product/enantiomeric form.

2. The process as claimed in claim 1, wherein the processes C) and D)
are employed.

3. The process as claimed in claim 1 or 2, wherein compounds of the
formula (III)

X1 - R2 (III)

are used where
X1 is Cl, Br, I, OMs or OTs.

4. The process as claimed in any of claims 1 to 3, wherein compounds
of the formula (III)

X1 - R2 (III)

are used where


74


X1 is Cl, Br or I.

5. The process as claimed in claims 1 to 4, wherein a compound of the
formula (I)

Image

is prepared where:
R1 is

Image

where
ring A is phenyl, 5-12 membered heteroaromatic ring which may contain
from one or more heteroatoms from the group of N, O and S,
fused/bicyclic 8 to 14 membered aromatic ring, (C3-C8)-cycloalkyl;
R3 is H, CF3, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, phenyl;
R4, R5 are H, F, Br, CF3, OCF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl;
n is from 1 to 2 and
R2 is (C1-C8)-alkyl where one or more CH2 groups in the alkyl groups
may be replaced by O, CO, S, SO or SO2, and alkyl may be one to
trisubstituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH-CO-
C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxy,
CO-O(C1-C6)-alkyl, tetrazole, thiazolidine-2,4-dione, indole and
(C6-C10)-aryl, where thiazolidine-2,4-dione and aryl may in turn be
substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc,
NHCbz, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH,


75


CO-benzoxy, CO-O(C1-C6)-alkyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl or
tetrazole.

6. The process as claimed in any of claims 1 to 5, wherein a compound
of the formula (I)

Image

is prepared where:
R1 is

Image

where
ring A is phenyl;
R3 is (C1-C4)-alkyl;
R4, R5 are H, (C1-C4)-alkyl, O-(C1-C4)-alkyl;
n is 1 and
R2 is (C1-C8)-alkyl where one or more CH2 groups in the alkyl groups
may be replaced by O, CO, S, SO or SO2 and alkyl may be one to
trisubstituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHBoc, NH-CO-
C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH, CO-benzoxy,
CO-O(C1-C6)-alkyl, tetrazole, thiazolidine-2,4-dione, indole and
(C6-C10)-aryl, where thiazolidine-2-4-dione and aryl may in turn be
substituted by F, Cl, Br, CF3, CN, NO2, NHAc, NHTs, NHBoc,
NHCbz, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C1-C6)-alkyl, COOH,
CO-benzoxy, CO-O(C1-C6)-alkyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl or
tetrazole.

Description

Note: Descriptions are shown in the official language in which they were submitted.




CA 02516623 2005-08-19
WO 20041076390 PCTIEP20041001580
1
Description
Method for producing the enantiomeric forms of cis 1,3-cyclohexanediol
derivatives
The invention relates to a process for preparing chiral, nonracemic, cis-
configured 1,3-disubstituted cyclohexanols of the formula (I)
R1', 0,,,.
Variously substituted, cis-configured 1,3-disubstituted cyclohexane
derivatives (compounds of the formula (I) where R~ ~ Rz) are central
building blocks or precursors of the active pharmaceutical ingredients
which are described in WO 03/020269 and are generally suitable for
treating lipid metabolism disorders, type II diabetes and syndrome X, inter
alia.
The syntheses which are described in the patent application 03/020269 of
the nonracemic, cis-configured 1,3-cyclohexane derivatives cannot be
considered as industrial processes: for example, alkylations with NaH/DMF
on the multi-kg scale cannot be carried out safely (C&EN, September 13,
1982, 5). Moreover, the alkylation by the Bu2Sn0 method on the industrial
scale entails unacceptably high cost and inconvenience; the removal of the
tin compounds from the desired products is very difficult and usually
incomplete even when chromatographic separating methods are used. The
disposal of the tin compounds is a further problem and a cost factor. The
separation of the enantiomers (optical resolution) by chromatography on a
chiral phase is likewise inconvenient and too expensive. In addition, it is
necessary for chromatographic enantiomer resolution that the racemic
compound is present in good chemical purity, which can be achieved in
many cases by additional, preceding chromatography.



CA 02516623 2005-08-19
2
Other methods which have been described in literature for synthesizing cis-
1,3-cyclohexanediol building blocks or derivatives, for example the opening
of epoxycyclohexanes (P. Crotti, V. Di Bussolo, L. Favero, M. Pineschi,
F. Marianucci, G. Renzi, G. Amici, G. Roselli, Tetrahedron 2000, 56, 7513-
7524 and cit. lit.) or the metallized-catalyzed hydroboration of cyclohexene
derivatives (J.A. Brinkmann, T.T. Nguyen, J.R. Sowa, Jr., Org. Lett. 2000,
2, 981-983; C.E. Garrett, G.C. Fu, J. Org. Chem. 1998, 63, 1370-1371) are
predominantly unsatisfactory with regard to the regioselectivity and the
stereoselectivity. The total number of stages is additionally distinctly
higher.
They cannot be considered as industrial processes.
The synthesis of cis-1,3-cyclohexanediol derivatives starting from cis,cis-
1,3,5-cyclohexanetriol or cis,cis-1,3,5-cyclohexanetriol derivatives
(L. Dumortier, M. Carda, J. Van der Eycken, G. Snatzke, M. Vandewalle,
Tetrahedron: Asymmetry 1991, 2, 789-792; H. Suemune, K. Matsuno,
M. Uchida, K. Sakai, Tetrahedron: Asymmetry 1992, 3, 297-306) are
likewise very complicated and uneconomic as a consequence of the high
number of stages and therefore unsuitable for industrial use. The
enzymatic reaction of the cis/trans mixture of 1,3-cyclohexanediol with S-
ethyl thiooctanoate cannot be considered as an industrial process. Apart
from the odor nuisance which can barely be avoided when working with the
sulfur compounds and the fact that to achieve the required conversion, the
ethanethiol which is released has to be removed continuously, the reaction
described leads to a mixture of 9 isomeric forms or derivatives of
cyclohexanediol, i.e. the unconverted isomers (S,S)-diol, (R,R)-diol and
(R,S)-diol, also the monoacylated products (S,S)-monooctanoate, (R,R)-
monooctanoate and (R,S)-monooctanoate, and thirdly the group of the
diacylated products (S,S)-dioctanoate, (R,R)-dioctanoate and (R,S)-
dioctanoate. The optically active, monoacylated, cis-configured (R,S)-
monooctanoate takes up only a proportion of about 12% in the fraction of
the monoacylated cyclohexanediols. A preparation and isolation of this
product on the preparative scale has not been described, but in view of the
ratios of amounts and the separating problem outlined, cannot be
economic. In addition, it is known that partially acylated di- or polyhydroxy
compounds tend to acyl group migrations. When this occurs, for example,
in the course of the purification of the (R,S)-monooctanoate (for example in
the chromatography on silica gel or in aqueous extraction) or in the course
of a subsequent reaction (for example during the alkylation of the free
hydroxyl group), this leads to a distinct reduction in the optical purity or
to
racemization.



CA 02516623 2005-08-19
3
The cis-configured (R,S)-diols and the diacylated (R,S)-compounds are not
optically active and therefore not of interest.
It is therefore an object of the present invention to develop a process which
does not have the disadvantages mentioned.
The present invention provides a process for preparing a chiral,
nonracemic compound of the formula I
R1 ~ 0 ~~'
where:
R~ is
R4 R3
O
Ring A
N ~(CH2)n_
R5
where:
ring A is phenyl, 5-12 membered heteroaromatic ring which may contain
from one to four heteroatoms from the group of N, O and S, 8 to 14
membered aromatic ring, (C3-Cg)-cycloalkyl;
R3 is H, F, CI, Br, OH, N02, CF3, OCF3, (C~-Cg)-alkyl, (C3-Cg)-
cycloalkyl, phenyl;
R4, R5 are H, F, CI, Br, OH, N02, CFg, OCF3, OCF2H, OCF2-CF3,
OCF2-CHF2, SCF3, O-phenyl, (C~-Cg)-alkyl, O-(C~-Cg)-alkyl, O-
(C~-Cg)-alkyl-O-(C~-C3)-alkyl;
n is from 1 to 3;



CA 02516623 2005-08-19
4
and
R2 is (C~-Cg)-alkyl where one or more CH2 groups in the alkyl groups
may be replaced by O, CO, S, SO or S02, and alkyl may be one to
trisubstituted by F, CI, Br, CF3, CN, N02, NHAc, NHBoc, NH-CO-
C(CH3)3, hydroxyl, OCF3, O-(C~-Cg)-alkyl, COOH, CO-benzoxy,
CO-O(C~-Cg)-alkyl, tetrazole, thiazolidine-2,4-dione, indole and
(Cg-Cep)-aryl, where thiazolidine-2,4-dione and aryl may in turn be
substituted by F, CI, Br, CF3, CN, N02, NHAc, NHTs, NHBoc,
NHCbz, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C~-Cg)-alkyl, COOH,
CO-benzoxy, CO-O(C~-Cg)-alkyl, (C~-Cg)-alkyl, O-(C~-Cg)-alkyl or
tetrazole, or;
R2 is an OH protecting group (PG), for example benzyloxymethyl,
benzyl, para-methoxybenzyl or tert-butyldimethylsilyl;
which comprises
A)
a) alkylation (alk-R2/alk-PG)
reacting cis-1,3-cyclohexanediol of the formula (II)
HO,, ,~, OH
(It)
with a compound of the formula (III)
X~-R2 (III)
where R2 is as defined above and
X~ is CI, Br, I, OMs (O-mesyl), OTs (O-tosyl), OTf (O-triflate);
in the presence of bases in a suitable solvent to give a racemic compound
of the formula (I~



CA 02516623 2005-08-19
HO,,,, ,~
(IV)
where R2 is as defined above;
5 b1 ) enzymatic ester formation (EF) + separation (S)
subjecting the resulting compounds of the formula (I~ to stereoselective
enzymatic ester formation (EF), in which the alcohols are admixed with an
acyl donor, for example a vinyl ester R6-O-CH=CH2 or an acid anhydride
R6-O- R6, where R6 is as defined above, and the enzyme in an organic
solvents, for example dichloromethane, and the resulting mixture is stirred
at -20 to 80°C and, after the reaction has ended, one stereoisomer is
present as an ester of the formula (~
R6~~'~. ,~~ ~y
fV1
where
R6 is C(=O)-(C~-C~6)-alkyl, C(=O)-(C2-Cog)-alkenyl, C(=O)-(C3-C~6)-
alkynyl, C(=O)-(C3-Cog)-cycloalkyl, where one or more carbon
atoms may be replaced by oxygen atoms and be substituted by 1-3
substituents from the group of F, CI, Br, CF3, CN, N02, hydroxyl,
methoxy, ethoxy, phenyl and CO-O(C~-C4)-alkyl, CO-O(C2-C4)
alkenyl, which may in turn be substituted by 1-3 substituents from
the group of F, CI, Br, CF3, and
R2 is as defined above,
and the other stereoisomer is present unchanged as the alcohol of the
formula (I~, and are therefore separated from each other by utilizing their
different chemical or physicochemical properties (for exariiple Rf values or
solubility differences in water or other solvents) (separation S), for example
by simple chromatography on silica gel, by extraction (for example
heptane/methanol or org. solvent/water) or else by a further subsequent



CA 02516623 2005-08-19
6
chemical reaction, for example of the alcohol, in which the ester does not
take part,
or
b2) enzymatic ester hydrolysis [=chemical esterification (CE) +
enzymatic hydrolysis (EH)] + separation (S)
subjecting the resulting compounds of the formula (I~ to a stereoselective
enzymatic ester hydrolysis, in which the racemic alcohol is initially
converted by chemical esterification (CE), for example by means of acid
chlorides R6-CI or acid anhydrides R6-O- R6, in the presence of bases, for
example triethylamine, to the racemic ester of the formula (~
R6'' o'~. ,.
i~
where R6 and R2 are each as defined above,
which, to carry out the stereoselective enzymatic ester hydrolysis (EH), is
then taken up in homogeneous or heterogeneous, aqueous, aqueous-
organic or organic media, and reacted, in the presence of an enzyme in the
case of hydrolysis with water and in the case of alcoholysis with an alcohol,
for example n-butanol, at a temperature of 10-80°C, and after the
reaction
has ended, one stereoisomer is present as the alcohol of the formula (I~
and the other is present unchanged as the ester of the formula (~ and can
thus be separated from each other as described under b1 ), and
the enantiomer of the formula (I~ occurring as an alcohol is further
processed as described under d), or
c) chemical hydrolysis (CH)
hydrolyzing the enantiomer of the formula (~ occurring as an ester to the
chemically enantiomeric alcohol by known methods and



CA 02516623 2005-08-19
7
d) alkylation (alk- R~)
reacting further with a compound of the formula (VI)
R3 r
Ring A ~ ~ (VI)
(CHz)n _ Xz
where
ring A, R3, R4, R5 and n are each as defined above and
X2 is CI, Br, I, OTs, OMs, OTf;
20
in the presence of bases in a suitable solvent to give the compound of the
formula (I), and
e) detachment of the protecting group PG (detPG)
if R2 is an OH protecting group (PG) as defined above and R2, converting
the compound of the formula (la)
R1 ~~~~~, ~'~ ~~pG
(la)
where R1 and PG are each as defined above,
by detaching the protecting group by known methods, for example
detachment of PG = benzyloxymethyl or PG = benzyl by hydrogenating
over Pd/C, or detachment of PG = para-methoxybenzyl with, for example
DDQ (2,3-dichloro-5,6-dicyanobenzoquinone), or detachment of PG = tert-
butyldimethylsilyl, for example with Bu4NF,
to a compound of the formula (VII)



CA 02516623 2005-08-19
,0,,, , OH
R1
{Vtl)
where R~ is as defined above,
f) alkylation (alk- R2~
15
then reacting it with a compound of the formula (III)
X1-R2 lIII)
where X1 and R2 are each as defined above,
in the presence of bases in a suitable solvent to give a compound of the
formula (I), the product or the enantiomeric form,
it being also possible to change the sequence of individual reaction steps
as described above under A):
A) alk- R2 -~ EF + S/CE + EH + S [-> CH] ~ alk- R~ [-~ DetPG ~ alk-
R2] ~ product/enantiomeric form
to:
B) alk- R1 -~ EF + S/CE + EH + S [~ CH] --~ alk- R2 [-~ DetPG ~ alk-
R2] --~ product/enantiomeric form
or
C) alk-PG-~EF+S/CE+EH+S-NCH->alk-R2-~DetPG-~alk-
R1 ~ product/enantiomeric form
or
D) alk-PG -~ EF + S/CE + EH + S -+ alk- R1 -~ DetPG -~ alk- R2 ->
productlenantiomeric form.



CA 02516623 2005-08-19
Possible process variants are illustrated hereinbelow in Schemes I to IV:



CA 02516623 2005-08-19
U
O
w ,.O
O


V


O O


O
U
N


N
~ U
O


~ O
N


~N



O O,
O


d


Y_
O a ~


O
a' N
d'


O ~


Q O


z


/ Z Y
O O V~ Q


N


0



Q~ U ~ 0 0
~o



0 o w


o~


O o
.U



+


tD


Uj


0
N


0
0


O .U vi


~U


I


Y_
Q Y


z
0


0


W
Z r-. o~ .-. 0






CA 02516623 2005-08-19
O
i
U ~ V
O N
O .....
U .O
i
O O O C
7,~ O a \ ~ d
U ~ i
'' .p
N1
,C~ U O Y
o ~ C Q
O O 2
0
0
O'
1 0_
~fi \
Q N
V
0 0
~o
0 0
i
p O ~ ,+ r
O O
Q z
O
0
O: O .v
\ \
0
+ \
u~
o U
Y o
N
~U
0
Q
Q
o O
o ~-. Oz



CA 02516623 2005-08-19
U O
U
O .T
p'_ N
w
C
O
O a O
O
O
\_
O'
\ ~ O
T d
Y
Q
a O
O i \
O T
O O
\
O
C7
' a
O ,
O
O
T
U
Q
a a
O O
p' O
~O
u~
a
i
O
ti
u-i
O
S
y_
Q
z
O
W
U



CA 02516623 2005-08-19
U
O E
a ~ _
0
D Q ~ v
w
z a~
c~ N o
..' o
/ U,
O O -p C
O
d. N
ON
Cf: ~ ~ 1
LY
Y_
Q Q
Q
/
O O
0
Ct
~C
U
a
p o
F
M
p O
Z
~O CA
co +
I
uJ
C7
/
W
U
O
U
/
0
0
z
Q
~l
0
0



CA 02516623 2005-08-19
i
,~, O
U
7
'O -~----
O
L
a
0
.
N
Q
o x
a~ o
x O
0
0
0
0
a
a D QS
O c~
a
o
O
.
O
x
U
O O
a a
o O
f
O_ O
O
LL
u~
O
o.
o
O
x
a
x
o
w
w
z ~. o~
U ets x



CA 02516623 2005-08-19
0
Y U .'
s-
a ~ of
o /' o a o 0
c
C ~ Y_
O Q
O
O
O
/
O
a~
0
ON
._~C
Q
0 Y_
Q
ON. Q !Y C
U
'n o. o
~o
Z
w
a
0
.v
0
~o
u~
U
c~
a
/
O U
f'
~U
0
Y_
Q
Z
U
U



CA 02516623 2005-08-19
16
The process according to the invention is economic, simple and rapid. The
process completely eliminates the risk of acyl group migration, does not
require equimolar amounts of optically pure starting materials or auxiliaries,
any expensive reagents, any optical resolution by chromatography on chiral
phases, any disproportionately large amounts of solvent or any cost-
intensive working steps.
The loss of 50% which is typical for optical resolutions can be avoided by
using both enantiomers and changing the sequence of the alkylations.
Preference is given to what is known as the enantioconvergent method
(see Scheme IV or Method C and D)) in which the procedure is, for
example, as follows: alkylation of cis-1,3-cyclohexanediol of the formula (II)
with a compound of the formula (III) with a PG selected as R2 such that PG
can be detached again simply and selectively in the course of the further
synthesis, and PG is thus, for example, benzyl, or para-methoxybenzyl or
tert-butyldimethylsilyl, subjecting the resulting compound of the formula (IV)
to stereoselective enzymatic ester formation or ester hydrolysis (see
above) and, after completion of separation of unconverted alcohol and
ester, converting them separately and by different routes to the same
optically pure product by reacting the alcohol (as described in the first
part),
for example, with a compound of the formula (VI) to give a compound of the
formula (la), then converting it by detaching the PG group to give a
compound of the formula (VII), and then reacting it with a compound of the
formula (III) where R2 is as desired in the product to give a compound of
the formula (I), and converting the isomeric ester by simple ester hydrolysis
to a compound of the formula (IV), and then reacting with a compound of
the formula (III) where R2 is as desired in the product to give a compound
of the formula (VIII)
R2 PG (VIII)
then converting it by detaching the PG group to give a compound of the
formula (IV)



CA 02516623 2005-08-19
17
~ ~O OH
and then reacting it with a compound of the formula (VI) to give a
compound of the formula (I). j
0 0 0~ , o
~R1 R1 ~ ~ R2
Preference is given to using compounds of the formula (III)
X' - RZ (III)
where
X' is CI, Br, I, OMs or OTs,
particular preference to using those where
X' is CI, Br or I.
Preference is given to a process for preparing the compounds of the
formula (I)
R1~O~~', ~'~O~R2
where
R~ is



CA 02516623 2005-08-19
18
R4 R3
O
Ring A
(CHZ)n-
R5
where
ring A is phenyl, 5-12 membered heteroaromatic ring which may contain
one or more heteroatoms from the group of N, O and S,
fused/bicyclic 8 to 14 membered aromatic ring, (C3-Cg)-cycloalkyl;
R3 is H, CF3, (C~-Cg)-alkyl, (C3-Cg)-cycloalkyl, phenyl;
R4, R5 are H, F, Br, CF3, OCF3, (C~-Cg)-alkyl, O-(C~-Cg)-alkyl;
n is from 1 to 2;
R2 is (C~-Cg)-alkyl where one or more CH2 groups in the alkyl groups
may be replaced by O, CO, S, SO or S02, and alkyl may be one to
trisubstituted by F, CI, Br, CF3, CN, N02, NHAc, NHBoc, NH-CO-
C(CH3)3, hydroxyl, OCF3, O-(C~-Cg)-alkyl, COOH, CO-benzoxy,
CO-O(C~-Cg)-alkyl, tetrazole, thiazolidine-2,4-dione, indole and
(Cg-Cep)-aryl, in which thiazolidine-2,4-dione and aryl may in turn be
substituted by F, CI, Br, CF3, CN, N02, NHAc, NHTs, NHBoc,
NHCbz, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C~-Cg)-alkyl, COOH,
CO-benzoxy, CO-O(C~-Cg)-alkyl, (C~-Cg)-alkyl, O-(C~-Cg)-alkyl or
tetrazole.
Particular preference is given to a process for preparing the compounds of
the formula (I)
R1~~~~''~ '~~~~R2
(I)
where:
R~ is



CA 02516623 2005-08-19
19
R4 R3
O
Ring A
H (CHZ)n_
RS
where
ring A is phenyl;
R3 is (C~-C4)-alkyl;
R4, R5 are H, (C~-C4)-alkyl, O-(C~-C4)-alkyl;
n is 1;
R2 is (C~-Cg)-alkyl where one or more CH2 groups in the alkyl groups
may be replaced by O, CO, S, SO or S02 and alkyl may be one to
trisubstituted by F, CI, Br, CF3, CN, N02, NHAc, NHBoc, NH-CO-
C(CH3)3, hydroxyl, OCF3, O-(C1-Cg)-alkyl, COOH, CO-benzoxy,
CO-O(C1-Cg)-alkyl, tetrazole, thiazolidine-2,4-dione, indole and
(Cg-Cep)-aryl, in where thiazolidine-2,4-dione and aryl may in turn be
substituted by F, CI, Br, CF3, CN, N02, NHAc, NHTs, NHBoc,
NHCbz, NH-CO-C(CH3)3, hydroxyl, OCF3, O-(C~-Cg)-alkyl, COOH,
CO-benzoxy, CO-O(C~-Cg)-alkyl, (C~-Cg)-alkyl, O-(C~-Cg)-alkyl or
tetrazole.
The alkyl radicals in the substituents R2, R3, R4 and R5 may be either
straight-chain or branched.
In this context, a heteroaromatic ring refers to both mono- and bicyclic rings
having a maximum of 4 heteroatoms, in particular those which contain up
to 4 nitrogen atoms and/or 1 oxygen or 1 sulfur atom, for example furan,
thiophene, thiazole, oxazole, thiadiazole, triazole, pyridine, triazine,
quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzotriazole.
Aromatic rings may be mono- or bicyclic and also be fused, for example
naphthyl, benzo[1,3]dioxole, dihydrobenzo[1,4]dioxin.



CA 02516623 2005-08-19
The racemic, cis-configured 1,3-cyclohexane derivatives of the formula (IV)
and of the formula (VII) are prepared by monoalkylating cis-
cyclohexanediol (compound of the formula II), but can also be prepared by
reductively opening appropriate acetals (R. Hunter et al., J. Org. Chem.
5 1993, 85, 6756), and also by reductive ether formation starting from silyl
ethers and aldehydes or ketones (J.S. Bajwa, X. Jiang, J. Slade, K. Prasad,
O. Repic, T.J. Blacklock, Tetrahedron Lett. 2002, 43, 6709-6713).
The alkylating reagents of the formula III are commercially obtainable or
10 can be prepared by literature methods, for example by free-radical side
chain halogenation (see literature review by R.C. Larock, Comprehensive
Organic Transformations, p. 313, 1989 VCH Publishers, Inc.) or from the
alcohols or derivatives preparable therefrom (see literature review by
R.C. Larock, Comprehensive Organic Transformations, p. 353-363, 1989
15 VCH Publishers, Inc.).
Also known (see J. Chem. Soc. 1925, 127, 2275-2297; J. Chem. Soc.
1922, 727, 2202-2215) is the preparation of various 2-bromomethylbenzoyl
bromides by free-radical bromination, which may then be converted by
20 further reaction with alcohols to the bromomethylbenzoic esters belonging
to the group of the alkylating reagents of the formula III.
The alkylating reagents of the formula (VI) or the alcohols X2 = OH which
can serve as precursors are commercially obtainable or can be prepared
by literature methods [a). The Chemistry of Heterocyclic Compounds (Ed.:
A. Weissberger, E.C. Taylor): Oxazoles (Ed.: I.J. Turchi); b) Methoden der
Organischen Chemie, Houben-Weyl, 4t" edition, Hetarene III, subvolume 1;
c) I. Simit, E. Chindris, Arch. Pharm. 1971, 304, 425; d) Y. Goto,
M. Yamazaki, M. Hamana, Chem. Pharm. Bull. 1971, 19 (10), 2050-2057].
The alkylating reagents of the formula III and VI are reacted with 1,3-
cyclohexanediol or 1,3-cyclohexanediol derivatives in the presence of
bases. Suitable bases are, for example, hydroxides such as KOH,
carbonates such as Cs2C03, alkoxides such as KOtBu and also
compounds such as LDA, BuLi, LiHMDS, KH, NaH and NaHMDS. Suitable
solvents are, for example, THF, MTBE, DME, NMP, DMF and
chlorobenzene.



CA 02516623 2005-08-19
21
For optical resolution of the alcohols, they are taken up in organic solvents,
for example dimethoxyethane (DME), methyl tert-butyl ether (MTBE),
diisopropyl ether (DIPE), THF, n-hexane, cyclohexane, toluene,
chlorobenzene, acetone, dimethylformamide (DMF), dichloromethane, 1,2-
dichloroethane and tent-butanol, acyl donors such as vinyl acetate, vinyl
propionate, vinyl butyrate, 2,2,2-trifluoroethyl 2H,2H-perfluorodecanoate,
ethoxyvinyl acetate, p-vitro- or p-chlorophenyl acetate, oxime esters, acetic
i
anhydride, propionic anhydride, succinic anhydride, glutaric anhydride,
isovaleric anhydride, 2,2,2-trichloroethyl butyrate, 2,2,2-trifluoroethyl
2H,2H-perfluorodecanoate are added and the reaction mixture is
subsequently admixed with a suitable enzyme and stirred at from -20 to
80°C. The proportion of cosolvent in the solution is preferably 10-90%,
but
it is in some cases also advantageous to carry out the enzymatic reaction
in pure acyl donor, for example vinyl acetate, without cosolvent.
For optical resolution of the ester derivatives, for example acetyl-,
propionyl-, butyryl- or glutaryl-, they are subjected in homogeneous or
heterogeneous, aqueous, aqueous-organic or organic media, in the
presence of a suitable enzyme, to stereoselective hydrolysis or alcoholysis
(for example with n-butanol) at a temperature of 10-80°C, optionally in
the
presence of cosolvents (see above) and of a buffer, the reaction mixture
preferably containing 2-50% by weight of ester.
The abovementioned ester derivatives can be prepared by literature
methods, for example by reacting the alcohol with acid chlorides such as
acetyl chloride or anhydrides such as acetic anhydride, in the presence of
an amine, for example triethylamine or pyridine (see literature review by
R.C. Larock, Comprehensive Organic Transformations, p. 978, 1989 VCH
Publishers, Inc.).
When the reaction has ended, the products or the enantiomers can be
separated in a simple manner, for example by extraction by literature
methods [a). T. Yamano, F. Kikumoto, S. Yamamoto, K. Miwa, M. Kawada,
T. Ito, T. Ikemoto, K. Tomimatsu, Y. Mizuno, Chem. Lett. 2000, 448;
b). B. H.ungerhoff, H. Sonnenschein, F. Theil, J. Org. Chem. 2002, 67,
1781] or by employing chromatographic methods.
A further method is, on completion of the enzymatic reaction, to distinctly
increase the water solubility of the remaining alcohol by derivatization, for
example by acylation with cyclic anhydrides, e.g. with glutaric anhydride, or



CA 02516623 2005-08-19
22
by conversion to a cholin ester [a). H. Kunz, M. Buchholz, Chem. Ber.
1979, 112, 2145; b). M. Schelhaas, S. Glomsda, M. Hansler,
H.-D. Jakubke, H. Waldmann, Angew. Chem. 1996, 108, 82] and thus to
achieve separation from the water-insoluble or sparingly water-soluble
esters by extraction. After the separation, the derivatization of the alcohols
can be reversed by chemical or enzymatic hydrolysis.
A particularly interesting means for separating the enantiomers in the case
of the enzymatic acylation is to select the acyl donor in such a way that the
acylated enantiomer is distinctly more water-soluble than the unconverted
alcohol. Suitable acyl donors are, for example, cyclic anhydrides such as
succinic anhydride. On completion of the enzymatic acylation, the acylation
product bears a free carboxyl group which enables rapid removal of the
product by aqueous extraction under basic conditions, for example with sat.
aqueous NaHC03 solution.
In enzymatic optical resolution by ester hydrolysis, the procedure is
preferably to admix an ester of the formula (I), for example where
R~ = COCH3, COCH2CHg or CO,CH2CH2CH2COOH in an aqueous or
alcoholic solution, with an esterase or lipase and stirred.
It may be advantageous to buffer the solution mentioned, for example with
phosphate or TRIS [= tris(hydroxymethyl)methylamine] buffer. The additive
may, for example, be 0.01-1.0 molar. A favorable buffer range is pH 5-10.
The enzymes used are preferably hydrolases from mammalian livers, for
example lipase from porcine pancreas (fluka), or from microorganisms, for
example Lipase B from Candida antarctica (Roche Diagnostics), Lipase OF
from Candida rugosa (Meito Sangyo), Lipase SL from Pseudomonas
cepacia (Meito Sangyo), Lipase L-10 from Alcaligenes spec. (Roche
Diagnostics), and Lipase QL from Alcaligenes spec. (Meito Sangyo). When
the esters used are glutaric acid derivatives, for example mono-(3-
benzyloxycyclohexyl) glutarate, it may be advantageous, instead of the
abovementioned lipases, to use glutaryl-7-ACA Acylase (Roche
Diagnostics).
Particular preference is given to using Lipase B from Candida antarctica
(Roche Diagnostics), and it may be advantageous to use the free enzyme
or an immobilized form of the enzyme, for example one of the three
products which are currently obtainable commercially.



CA 02516623 2005-08-19
23
Each of the enzymes mentioned can be used in free or in immobilized form
(Immobilized Biocatalysts, W. Hartmeier, Springer Verlag Berlin, 1988).
The amount of enzyme is selected freely depending on the reaction rate or
on the desired reaction time and on the type of the enzyme (for example
free or immobilized) and can be determined easily by simple preliminary
experiments. The enzyme can be recovered by freeze-drying. The removal
(and optional later reuse) of the enzyme can be eased by immobilization.
Suitable reaction control always succeeds in obtaining at least one
enantiomer in optically pure form. When optically pure ester is desired, the
conversion in the case of an enzymatic ester formation should be less than
(or equal to) 50%, or in the case of an enzymatic hydrolysis or alcoholysis,
greater than (or equal to) 50%. When optically pure alcohol is desired, the
conversion in the case of enzyme-catalyzed ester formation should be
greater than (or equal to) 50%, or in the case of hydrolysis or alcoholysis,
less than (or equal to) 50%.
The conversion of the enzymatic reaction was determined either by HPLC
directly from the reaction mixture or by calculation from the optical purities
of the reaction products (ester and acid) which were likewise determined
directly from the reaction mixture by HPLC on a chiral phase.
The examples which follow are intended to illustrate the present invention
i
in detail.
Examples:
All isolated products and crude product mixtures were identified by
~ H NMR and mass spectra or by HPLC.
The optical purity of the esters and alcohols was determined by HPLC, for
example on Chiralpak AD 250 x 4.6 (Daicel) or Chiracel OD 250 x 4.6.
Scheme la:
Example 1
Synthesis of racemic methyl cis-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate



CA 02516623 2005-08-19
24
~l
Ho,, ,,o
CO Me
rac.
500 g (4.3 mol) of cis-1,3-cyclohexanediol were dissolved in 5 I of NMP and
admixed with 336 g (3.0 mol) of potassium tert-butoxide (KOtBu). The
internal temperature rose to 28°C. The mixture was stirred for 30 min,
then
cooled to -5°C and admixed dropwise with 370 g (approx. 94%, approx.
1.4 mol) of methyl 2-bromomethyl-6-methylbenzoate which may be
prepared, for example, by methanolyzing 2-bromomethyl-6-methylbenzoyl
bromide or by brominating methyl 2,6-dimethylbenzoate. The mixture was
stirred for 30 min and then diluted with 5 I of water. After washing three
times with 31 of n-heptane each time and discarding the n-heptane
solutions, the remaining aqueous phase was extracted four times with 2.5 I
of MTBE each time. The combined MTBE phases were washed once with
51 of water, dried over Na2S04 and subsequently concentrated by
evaporation under reduced pressure. 234 g of the desired compound were
obtained as a yellowish oil and were used in the next reaction (for example
an optical resolution) without further purification; ~ H NMR (CDC13), b = 1.27
(m, 1 H), 1.45 (m, 1 H), 1.55 (m, 1 H), 1.74 (m, 1 H), 1.83 (m, 1 H), 2.05 (m,
1 H), 2.34 (s, 3H), 3.47 (m, 1 H), 3.72 (m, 1 H), 3.91 (s, 3H), 4.58 (dd, 2H),
7.15 (d, 1 H), 7.20 (d, 2H), 7.27 (m, 1 H).
Example 2
Optical resolution of methyl cis-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate
HO,,, ,,,0
rac. C02Me
490 g of the crude, racemic methyl cis-2-(3-hydroxycyclohexyloxymethyl)-
6-methylbenzoate (see Example 1) were dissolved in 3.1 I of methylene
chloride and 850 ml of vinyl acetate, admixed with 18 g of Novozym 435
and stirred at 21-24°C. After 28 h, a further 2 g of Novozym 435 were
added. After a total of 44 h, the reaction was ended by filtering off the



CA 02516623 2005-08-19
enzyme and the filtrate was concentrated by evaporation under reduced p
pressure to obtain 540 g. Chromatography of the residue on approx. 6 kg of
silica gel (1:1 ethyl acetate/n-heptane) gave 184 g of methyl (1 R,3S)-2-(3-
hydroxycyclohexyloxymethyl)-6-methylbenzoate; > 98% ee (HPLC on
5 Chiralpak AD-H 250 x 4.6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0.5 + ;
0.1 % TFA); ~ H NMR (CDC13), 8 = 1.27 (m, 1 H), 1.45 (m, 1 H), 1.55 (m, 1 H),
1.74 (m, 1 H), 1.83 (m, 1 H), 2.05 (m, 1 H), 2.34 (s, 3H), 3.47 (m, 1 H), 3.72
(m, 1 H), 3.91 (s, 3H), 4.58 (dd, 2H), 7.15 (d, 1 H), 7.20 (d, 2H), 7.27 (m, 1
H)
and 239 g of the (1S,3R)-acetate (93% ee, HPLC on Chiralcel OD/20
10 250 x 4.6, 1 ml/min, 100:1:0.5 heptane/EtOH/CH3CN).
Example 3
Synthesis of 4-iodomethyl-2-(3-methoxyphenyi)-5-methyloxazole
/ \ O
'N I
Me0
150.0 g (0.63 mol) of 4-chloromethyl-2-(3-methoxyphenyl)-5-methyloxazole
were dissolved in 2.7 I of THF and admixed with 106 g (0.71 mol) of Nal.
The mixture was stirred for 4 h and left to stand overnight, the salts were
filtered off with suction and the filtrate was concentrated under reduced
pressure. After approx. 1-2 hours, the desired iodide solidified, yield: 216
g,
mp 58-59°C. ~ H NMR (CDC13): 8 = 2.30 (s, 3H), 3.88 (s, 3H), 4.34 (s,
2H),
6.97 (dd, 1 H), 7.34 (t, 1 H), 7.52 (d, 1 H), 7.58 (d, 1 H).
Example 4
Synthesis of methyl (1 R,3S)-2-{3-[2-(3-methoxyphenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexyl-1-oxymethyl}-6-methylbenzoate
0
Me0 ~ ~ \ O,, ,O
~N
/ COzMe
184 g (0.66 mol) of methyl (1 R,3S)-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate (see Example 2) were dissolved in 2.2 I of t-BuOMe.



CA 02516623 2005-08-19
26
88.0 g (approx. 55%, 1.8 mmol) of NaH were added and the mixture was
stirred at 20-22°C for 45 minutes. 282 g (83.8 mmol) of 4-iodomethyl-2-
(3-
methoxyphenyl)-5-methyloxazole (see Example 3) were added, and the
mixture was stirred at 22°C for 8 hours and left to stand overnight.
The
mixture was stirred for a further 4 h and then, with cooling, 200 ml of water
were added cautiously, and later a further 1.5 I. The organic phase was
removed, dried (Na2S04) and concentrated under reduced pressure. 383 g
of crude product were obtained and were chromatographed on approx.
6 kg of silica gel (19:1 dichloromethane/acetone), yield: 199 g of a
yellowish oil; ~ H NMR (CDC13), b = 1.15-1.32 (m, 4H), 1.81 (m, 1 H), 2.00
(m, 1 H), 2.07 (m, 1 H), 2.34 (s, 3H), 2.40 (s, 3H), 2.51 (m, 1 H), 3.27 (m,
1 H), 3.37 (m, 1 H), 3.87 (s, 3H), 3.90 (m, 3H), 4.48 (s, 2H), 4.60 (s, 2H),
6.96 (m, 1 H), 7.12-7.35 (m, 4H), 7.53 (s, 1 H), 7.58 (d, 1 H).
Example 5
Synthesis of (1 R,3S)-2-{3-[2-(3-methoxyphenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexyl-1-oxymethyl}-6-methylbenzoic acid
0
Me0 \ ~ \ O ,, , O \
~N
/ C02H
199 g (0.41 mol) of methyl (1 R,3S)-2-{3-[2-(3-methoxyphenyl)-5-
methyloxazol-4-ylmethoxy]cyclohexyl-1-oxymethyl}-6-methylbenzoate (see
Example 4) were dissolved in 2 I of ethanol. 250 ml of 33% NaOH were
added and the mixture was heated to reflux for 15 hours. Ethanol was
distilled ofF under reduced pressure, and the residue was dissolved in
approx. 2 I of water and washed four times with 500 ml of MTB ether each
time. The aqueous phase was acidified to pH 1 using conc. hydrochloric
acid with cooling, and the oily product was extracted using 1.5 I of ethyl
acetate. The ethyl acetate solution was dried and concentrated under
reduced pressure. The residue was dissolved in 1.2 I of DIPE at approx.
40°C. Crystallization and drying under reduced pressure at 60°C
resulted in
132.5 g of the desired carboxylic acid; mp 103-105°C; > 98% ee (HPLC on
Chiralpak AD-H 250 x 4.6; 1 ml/min, 90:7:1 heptane/EtOH/CH3CN + 0.1%
TFA); ~ H NMR (CDC13), 8 = 1.14-1.38 (m, 4H), 1.80 (m, 1 H), 1.93 (m, 2H),
2.41 (s, 3H), 2.44 (s, 3H), 2.61 (m, 1 H), 3.40 (m, 2H), 3.86 (s, 3H), 4.53
(s,



CA 02516623 2005-08-19
27
2H), 4.68 (dd, 2H), 6.98 (dd, 1 H), 7.17-7.36 (m, 4H), 7.55 (s, 1 H), 7.61 (d,
1 H).
Example 6
Synthesis of 4-iodomethyl-2-(4-methylphenyl)-5-methyloxazole
O
1
N
6.0 g of 4-chloromethyl-2-(4-methylphenyl)-5-methyloxazole were dissolved
in 120 ml of THF and admixed with 4.18 g (27.9 mmol) of Nal. The mixture
was stirred for 3.5 h, a further 1.5 g of Nal were added and the mixture was
heated to 35°C. After 30 minutes, the salts were filtered off with
suction and
the filtrate was concentrated under reduced pressure; yield: 10.1 g,
mp 104-105°C; ~ H NMR (CDC13): 8 = 2.29 (s, 3H), 2.39 (s, 3H), 4.34 (s,
2H), 7.24 (d, 2H), 7.88 (d, 2H). i
Example 7
Synthesis of methyl (1 R,3S)-2-{3-[2-(4-methylphenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexyl-1-oxymethyl~-6-methylbenzoate
0
o., ,o w
~N
COZMe
36.0 g (0.129 mol) of methyl (1R,3S)-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate (see Example 2) were dissolved in 430 ml of tBuOMe.
17.2 g (approx. 55%, 0.35 mol) of NaH were added and the mixture was
stirred at 23°C for 30 minutes. 55.1 g (0.166 mol) of 4-iodomethyl-2-(4-

methylphenyl)-5-methyloxazole (Example 6) were added. After stirring for 6
hours and leaving to stand over 2 days, 400 ml of water were added and
the organic phase was removed. After drying (Na2S04) and concentrating,
the crude product (75 g) was chromatographed on silica gel (approx. 1 kg)
(19:1 dichloromethane/acetone), yield: 42 g of the dialkylated 1,3-
cyclohexanediol derivative as a yellowish oil; ~H NMR (CDC13), 8 = 1.16-
1.31 (m, 4H), 1.80 (m, 1 H), 1.97-2.1 (m, 2H), 2.34 (s, 3H), 2.39 (s, 3H),



CA 02516623 2005-08-19
28
2.40 (s, 3H), 2.52 (m, 1 H), 3.27 (m, 1 H), 3.37 (m, 1 H), 3.89 (s, 3H), 4.47
(s,
2H), 4.59 (s, 2H), 7.13 (d, 1 H), 7.20-7.28 (m, 4H), 7.88 (d, 1 H).
Example 8
Synthesis of (1 R,3S)-2-{3-[2-(4-methylphenyl)-5-methyloxazol-4-yl-
methoxy]cyclohexyl-1-oxymethyl}-6-methylbenzoic acid
\ o- ,o ~ I
~N
I / COZH
42.0 g (0.09 mol) of methyl (1 R,3S)-2-{3-[2-(4-methylphenyl)-5-
methyloxazol-4-ylmethoxy]cyclohexyl-1-oxymethyl}-6-methylbenzoate (see
Example 7) were dissolved in 420 ml of ethanol. 45 ml of 33% NaOH were
added and the mixture was heated to reflux for approx. 20 hours. Ethanol
was distilled off under reduced pressure, the, residue was dissolved in
500 ml of water and the solution was washed four times with in each case
100 ml of MTB ether. The aqueous phase was acidified (pH 1) using conc.
hydrochloric acid with cooling and the oily product was extracted using
ethyl acetate. The ethyl acetate solution was dried and concentrated under
reduced pressure. The residue was dissolved in 250 ml of DIPE with
heating. On cooling, the crystallization set in. When the crystallization had
ended, and after drying under reduced pressure at 60°C, 28.4 g of the
desired carboxylic acid were obtained; mp 117-119°C; > 98% ee (HPLC on
Chiralpak AD-H 250 x 4.6; 1 ml/min, 90:7:1 heptane/EtOH/CH3CN + 0.1
TFA); ~ H NMR (CDC13), b = 1.14-1.36 (m, 4H), 1.80 (m, 1 H), 1.91 (m, 2H),
2.39 (s, 3H), 2.40 (s, 3H), 2.46 (s, 3H), 2.64 (m, 1 H), 3.40 (m, 2H), 4.54
(s,
2H), 4.68 (dd, 2H), 7.17-7.30 (m, 5H), 7.91 (d, 2H).
Example 9
Synthesis of 4-iodomethyl-2-(3-methylphenyl)-5-methyloxazole
N I



CA 02516623 2005-08-19
29
6.0 g of 4-chloromethyl-2-(4-methylphenyl)-5-methyloxazole were dissolved
in 120 ml THF and admixed with 4.5 g (30 mmol) of Nal. The mixture was '
stirred for 5 h and then left to stand overnight. The removal of the solid and
concentration of the filtrate under reduced pressure gave 10.2 g of the
desired iodide; mp ~ 32°C; ~ H NMR (CDC13): b = 2.30 (s, 3H), 2.40 (s,
3H),
4.34 (s, 2H), 7.24 (d, 1 H), 7.32 (t, 1 H), 7.77 (d, 1 H), 7.83 (d, 1 H).
f
Example 10
Synthesis of methyl (1 R,3S)-2-{3-[2-(3-methylphenyl)-5-methyloxazol-4- ~
ylmethoxy]cyclohexyl-1-oxymethyl}-6-methylbenzoate
O
\ w \ O,, ,O \
~N
/ C02Me
36.0 g (0.129 mol) of methyl (1 R,3S)-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate (see Example 2) were dissolved in 430 ml of tBuOMe.
17.19 g (approx. 55%, 0.35 mol) of NaH were added and the mixture was
stirred at 20-22°C for 30 minutes. 55.1 g (0.166 mol) of 4-iodomethyl-2-
(3-
methylphenyl)-5-methyloxazole (see Example 9) were added. After stirring
for 6 hours and leaving to stand over 2 days, 400 ml of water were added
with cooling and the organic phase was removed. After drying (Na2S04)
and concentrating, the crude product (75 g) was chromatographed on silica
gel (1.2 kg) (19:1 dichloromethane/acetone), yield: 49 g of methyl (1 R,3S)-
2-{3-[2-(3-methylphenyl)-5-meth~loxazol-4-ylmethoxy]cyclohexyl-1-
oxymethyl}-6-methylbenzoate; H NMR (CDC13), 8 = 1.13-1.31 (m, 4H),
1.80 (m, 1 H), 1.97-2.1 (m, 2H), 2.34 (s, 3H), 2.40 (s, 3H), 2.41 (s, 3H),
2.52
(m, 1 H), 3.27 (m, 1 H), 3.37 (m, 1 H), 3.90 (s, 3H), 4.48 (s, 2H), 4.59 (s,
2H),
7.12-7.33 (m, 4H), 7.78 (d, 1 H), 7.84 (s, 1 H).
Example 11
Synthesis of (1 R,3S)-2-{3-[2-(3-methylphenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexyl-1-oxymethyl}-6-methylbenzoic acid



CA 02516623 2005-08-19
O
O ,, , O
~N
C02H
49.0 g (0.09 mol) of methyl (1R,3S)-2-f3-[2-(3-methylphenyl)-5-
methyloxazol-4-ylmethoxy]cyclohexyl-1-oxymethyl}-6-methylbenzoate (see
5 Example 10) were dissolved in 500 ml of ethanol. 50 ml of 33% NaOH were
added and the mixture was heated to reflux for approx. 14 hours. Ethanol
was dissolved off under reduced pressure, the residue was dissolved in
500 ml of water and the solution was washed three times with in each case
150 ml of MTB ether. The aqueous phase was acidified (pH 1) using conc.
10 hydrochloric acid with cooling, and the oily product was extracted with
ethyl
acetate. The ethyl acetate solution was dried and concentrated under
reduced pressure. The residue was dissolved in 250 ml of DIPE with
heating. On cooling, crystallization set in. When the crystallization has
ended, and after drying under reduced pressure at 60°C, 29.9 g of the
15 desired carboxylic acid are obtained; mp 109-111 °C; > 98% ee (HPLC
on
Chiralpak AD-H 250 x 4.6; 1 ml/min, 90:7:1 heptane/EtOH/CH3CN +0.1
TFA); ~ H NMR (CDC13), 8 = 1.14-1.36 (m, 4H), 1.80 (m, 1 H), 1.93 (m, 2H),
2.40 (s, 2 x 3H), 2.45 (s, 3H), 2.64 (m, 1 H), 3.40 (m, 2H), 4.53 (s, 2H),
4.68
(dd, 2H), 7.17-7.34 (m, 5H), 7.81 (d, 1 H), 7.85 (s, 1 H).
Scheme Ila
Example 12
Optical resolution of cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexan-1-of
0
Me0 ~ ~ ' O ,, , OH
~N
rac.
24.9 g of the racemic cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexan-1-of (prepared by alkylating cis-1,3-cyclohexanediol
with 4-iodomethyl-2-(3-methoxyphenyl)-5-methyloxazole) were dissolved in
100 ml of vinyl acetate, admixed with 1.0 g of Chirazyme L-2, lyo., and



CA 02516623 2005-08-19
31
stirred at 20-23°C. After about 30 minutes, the enzyme was filtered off
and
the solution concentrated under reduced pressure, crude product: 25.8 g.
After chromatography on silica gel (10:1-0:1 n-heptane/ethyl acetate),
13.7 g of (1 S,3R)-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexan-1-of and 11.3 g of the (1 R,3S)-acetyl compound
were obtained.
Example 13
Preparation of (1 R,3S)-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-yl-
methoxy]cyclohexan-1-of
O
Me0 ~ w \ O ,, , OH
~N
11.2 g of the (1 R,3S)-acetate from Example 12 were dissolved in approx.
100 ml of MeOH, admixed with 0.5 ml of NaOMe (30%) and stirred at
20-23°C. After 3.5 h, the mixture was neutralized with concentrated
acetic
acid, taken up with ethyl acetate, washed with NaHC03, dried over
Na2S04 and concentrated under reduced pressure. After filtration through
silica gel (10:1-0:1 n-heptane/ethyl acetate), 8.8 g of (1 R,3S)-3-[2-(3-
methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexan-1-of having 92%
ee (HPLC on Chiralpak AD-H 250 x 4.6; 1 ml/min, 90:7:1
heptane/EtOH/CH3CN + 0.1 % TFA) were obtained.
Example 14
Synthesis of methyl (1 R,3S)-2-{3-[2-(3-methoxyphenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexyl-1-oxymethyl}-6-methylbenzoate
0
Me0 \ ~ ' O,, ,O \
~N
/ COZMe
1.4 g (4.4 mmol) of (1 R,3S)-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexanol (see Example 13) were taken up in 15 ml of
tBuOMe, admixed at 24-27°C with 1.20 g (10.7 mmol) of KOtBu and.
stirred



CA 02516623 2005-08-19
32
for approx. 30 minutes. The mixture was cooled to 0-5°C, 1.89 g
(approx.
94%, approx. 7.4 mmol) of methyl 2-bromomethyl-6-methylbenzoate were
added dropwise and the mixture was stirred at 0-5°C for an initial 30
minutes. Without further cooling, the reaction mixture had a temperature of
approx. 20°C after 1.5 hours. After stirring overnight and adding
approx.
200 mg of KOtBu, the reaction was complete after stirring at 22°C for a
further hour. Distilling off the solvent under reduced pressure, partitioning
the residue between water and tBuOMe and drying the product-containing
organic phase resulted, after concentrating under reduced pressure, in
1.6 g of methyl (1 R,3S)-2-{3-[2-(3-methoxyphenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexyl-1-oxymethyl}-6-methylbenzoate as a yellowish oil;
~ H NMR (CDC13), 8 = 1.15-1.32 (m, 4H), 1.81 (m, 1 H), 2.00 (m, 1 H), 2.07
(m, 1 H), 2.34 (s, 3H), 2.40 (s, 3H), 2.51 (m, 1 H), 3.27 (m, 1 H), 3.37 (m,
1 H), 3.87 (s, 3H), 3.90 (s, 3H), 4.48 (s, 2H), 4.60 (s, 2H), 6.96 (m, 1 H),
7.12-7.35 (m, 4H), 7.53-7.60 (m, 2H).
Example 15
Synthesis of methyl (1 S,3R)-2-{3-[2-(3-methoxyphenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexyl-1-oxymethyl}-6-methylbenzoate
0
Me0 \ ~ \ O O \
N
COZMe
Starting from (1S,3R)-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-yl-
methoxy]cyclohexan-1-of from Example 12, alkylation in a similar manner
to Example 14 gives (1S,3R)-2-{3-[2-(3-methoxyphenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexyl-1-oxymethyl}-6-methylbenzoate; the ~ H NMR data
agree with those in Example 14.
Example 16
Optical resolution of cis-3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]-
cyclohexan-1-ol, preparation of (1 S,3R)-3-[2-(4-fluorophenyl)oxazol-4-
ylmethoxy]cyclohexan-1-of



CA 02516623 2005-08-19
33
a
o
y0 OH
\ wN k
F
30 mg of racemic cis-3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]cyclohexan-
1-0l were taken up in about 3 ml dichloromethane, admixed with 60 mg of E
a
p-nitrophenyl acetate and stirred at 20-23°C with 10 mg of Novozyme
435.
After 70 h, the immobilized enzyme was filtered off. The determination of
the optical purity directly from the reaction mixture which had been
concentrated by evaporation gave > 95% ee (HPLC on Chiralpak AD
250 x 4.6; 1 ml/min, acetonitrile) for (1 S,3R)-3-[2-(4-fluorophenyl)oxazol-4-
ylmethoxy]cyclohexan-1-of and 95% ee for the (1 R,3S)-acetate (HPLC on
Chiralpak AD 250 x 4.6; 1 ml/min, acetonitrile). To isolate (1 S,3R)-3-[2-(4-
fluorophenyl)oxazol-4-ylmethoxy]cyclohexan-1-ol, the crude mixture was
chromatographed on silica gel (ethyl acetate/n-heptane); yield 12 mg,
96% ee.
Example 17
Synthesis of methyl (1 S,3R)-2-{3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]-
cyclohexyl-1-oxymethyl}-6-methylbenzoate
o ~I
~~o o \
N _
/ COZMe
Starting from (1 S,3R)-3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]cyclohexan-
1-0l from Example 16, alkylation with methyl 2-bromomethyl-6-
methylbenzoate gives methyl (1S,3R)-2-{3-[2-(4-fluorophenyl)oxazol-4-yl-
methoxy]cyclohexyl-1-oxymethyl}-6-methylbenzoate (see Example 35).
Example 18
Optical resolution of 3-[2-(4-methylphenyl)-5-methyloxazol-4-yl-
methoxy]cyclohexan-1-of



CA 02516623 2005-08-19
34
O
w \ O ., , OH
~N
rac.
where R4 = p-Me-, R5 = H and R3 = Me)
16.3 g of the racemic 3-[2-(4-methylphenyl)-5-methyloxazol-4-yl-
methoxy]cyclohexan-1-of were dissolved in 100 ml of vinyl acetate,
admixed with 1.9 g of Chirazyme L-2, lyo., and stirred at 20-23°C.
After
about 30 minutes, the enzyme was filtered off and the solution
concentrated under reduced pressure, crude product: 16.6 g. After
chromatography on silica gel (10:1-0:1 n-heptane/ethyl acetate), 8.6 g of
(1 S,3R)-3-[2-(4-methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexan-1-of
and 6.8 g of the (1 R,3S)-acetate are obtained.
Example 19
Preparation of (1 R,3S)-3-[2-(4-methylphenyl)-5-methyloxazol-4-ylmethoxy]-
cyclohexan-1-of
O
o,, ,oH
~N
6.8 g of the (1 R,3S)-acetyl compound from the Example 18 were dissolved
in approx. 65 ml of MeOH, admixed with 0.32 ml of NaOMe (30%) and
stirred at 20-23°C. After 4 h, the mixture was neutralized with acetic
acid,
concentrated under reduced pressure, taken up with ethyl acetate, washed
with NaHC03, dried (Na2S04) and concentrated under reduced pressure.
After filtration through silica gel (10:1-0:1 n-heptane/ethyl acetate), 8.8 g
of
the desired (1 R,3S)-3-[2-(4-methylphenyl)-5-methyloxazol-4-ylmethoxy]-
cyclohexan-1-of with 95% ee (HPLC on Chiralpak AD 250 x 4.6; 1 ml/min,
90:7:1 heptane/EtOH/CH3CN + 0.1 % TFA) are obtained.
Example 20
Optical resolution of cis-3-[2-phenyl-5-methyloxazol-4-ylmethoxy]-
cyclohexan-1-of



CA 02516623 2005-08-19
0
o,, ,oH
~N
rac.
f
t
2.0 g of racemic cis-3-[2-phenyl-5-methyloxazol-4-ylmethoxy]cyclohexan-1
5 0l were dissolved its 50 ml of vinyl acetate, admixed with 0.1 g of
Chirazyme L-2, lyo., and stirred at 20-23°C. After about 5 h, the
enzyme
was filtered off and the solution concentrated under reduced pressure. After
chromatography on silica gel (2:1-1:2 n-heptane/ethyl acetate), 1.0 g of
(1S,3R)-3-[2-phenyl-5-methyloxazol-4-ylmethoxy]cyclohexan-1-of was
10 obtained as a bright yellow solid and 0.96 g of the acetylated (1 R,3S)
compound as a colorless oil.
Example 21
Preparation of (1 R,3S)-3-[2-phenyl-5-methyloxazol-4-ylmethoxy]-
15 cyclohexan-1-of I
4
0
0 , , , ~ ~"~ 1
I ~N
0.96 g of the (1 R,3S)-acetyl compound from Example 20 was dissolved in
20 approx. 5-10 ml of MeOH, admixed with 0.1 ml of NaOMe (30%) and stirred
at 20-23°C. After 3 h, the mixture was neutralized with acetic acid and
concentrated under reduced pressure, taken up with ethyl acetate, washed
with saturated NaHC03, dried (MgS04) and concentrated under reduced
pressure. After filtration through silica gel (10:1-0:1 n-heptanelethyl
25 acetate), 0.84 g of the desired (1 R,3S)-3-[2-phenyl-5-methyloxazol-4-
ylmethoxy]cyclohexan-1-of having 95% ee (HPLC on Chiralpak AD
250 x 4.6; 1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN + 0.1 % TFA) was
obtained.
30 Example 22
Optical resolution of cis-3-[2-(4-methoxyphenyl)-5-methyloxazol-4-yl-
methoxy]cyclohexan-1-of



CA 02516623 2005-08-19
36
O
w ' O ,, ,, OH
~N
Me0 ~ rac
2.0 g of the racemic cis-3-[2-(4-methoxyphenyl)-5-methyloxazol-4-yl-
methoxy]cyclohexan-1-of were dissolved in 50 ml of vinyl acetate, admixed
with 0.1 g of Chirazyme L-2, lyo., and stirred at 20-23°C. After about
5 h,
the enzyme was filtered off and the solution concentrated under reduced
pressure. After chromatography on silica gel (2:1-1:2 n-heptane/ethyl
acetate), 1.16 g of (1 S,3R)-3-[2-(4-methoxyphenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexan-1-of and 0.79 g of the (1 R,3S)-acetate were
obtained.
Example 23
Preparation of (1 R,3S)-3-[2-(4-methoxyphenyl)-5-methyloxazol-4-yl-
methoxy]cyclohexan-1-o)
O
w ' O ,,. , OH
N
Me0
0.79 g of acetate from Example 22 were dissolved in approx. 5-10 ml of
MeOH, admixed with 0.1 ml of NaOMe (30%) and stirred at 20-23°C.
After
3 h, the mixture was neutralized with dilute acetic acid and concentrated
under reduced pressure, taken up with ethyl acetate, washed with
saturated NaHC03, dried (MgS04) and concentrated under reduced
pressure. After filtration through silica gel (10:1-0:1 n-heptane/ethyl
acetate), 0.84 g of (1 R,3S)-3-[2-(4-methoxyphenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexan-1-of were obtained as a yellow oil having 92% ee
(HPLC on Chiralpak AD 250 x 4.6; 1 ml/min, 90:7:1 heptane/EtOHICH3CN
+ 0.1 % TFA).



CA 02516623 2005-08-19
37
Example 24 '
Optical resolution of cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-yl-
methoxy]cyclohexan-1-of
O
w ' O,, ,OH
\ ~N ,
F rac.
1.70 g of the racemic cis-3-[2-(4-fluoropheny!)-5-methyloxazol-4-yl-
methoxy]cyclohexan-1-of were dissolved in 50 ml of vinyl acetate, admixed
with 0.1 g of Chirazyme L-2, lyo., and stirred at 20-23°C. After about
1.5 h,
the enzyme was filtered off and the solution concentrated under reduced
pressure. After chromatography on silica gel (5:1-1:1 n-heptane/ethyl
acetate), 1.0 g of (1S,3R)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-yl-
methoxy]cyclohexan-1-of and 0.75 g of the (1 R,3S)-acetate were obtained.
t
Example 25
Preparation of (1 R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]-
cyclohexan-1-of a
O
\ w \ O,, ,OH
i
F
0.75 g of acetate from Example 24 was dissolved in approx. 30 ml of
MeOH, admixed with 0.2 ml of NaOMe (30%) and stirred at 20-23°C.
After
1 h, the mixture was neutralized with dilute acetic acid and concentrated
under reduced pressure, taken up with ethyl acetate, washed with
saturated NaHC03, dried (MgS04) and concentrated under reduced
pressure, yield: 0.59 g of (1 R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexan-1-of as a white solid having 94% ee (HPLC on
Chiralpak OD/19 250 x 4.6; 1 ml/min, 110:2:1 heptanelEtOH/CH3CN +
0.05% TFA).



CA 02516623 2005-08-19
38
Scheme Ilb
Example 26
Stereoselective hydrolysis of 3-[2-(4-fluorophenyl)oxazol-4-ylmethoxyl]-
cyclohexyl acetate, preparation of (1 R,3S)-3-[2-(4-fluorophenyl)oxazol-4-yl-
methoxy]cyclohexan-1-of
O
y0,, ,OH
_N
F
Approx. 10 mg of 3-[2-(4-fluorophenyl)oxazol-4-ylmethoxyl]cyclohexyl
acetate (prepared by reacting 3-benzyloxycyclohexan-1-of with acetic
anhydride, in a similar manner to the synthesis of mono(3-
benzyloxycyclohexyl) glutarate see Example 39) were taken up in 2 ml of
phosphate buffer (0.1 M, pH = 7.0) and 2 ml of DME and stirred with
approx. 5 mg of Chirazyme L-2, lyo., at 20-23°C for approx. 20-24 h.
The
reaction mixture was extracted with dichloromethane. The organic phase
was admixed with toluene and concentrated by evaporation under reduced
pressure. The determination of the optical purity for (1 R,3S)-3-[2-(4-
fluorophenyl)oxazol-4-ylmethoxy]cyclohexan-1-of gave 99.4% ee (HPLC on
Chiralpak AD 250 x 4.6; 1 ml/min, acetonitrile) and 98.9% ee for the
(1 S,3R)-acetate (HPLC on Chiralcel OD 250 x 4.6; 1 ml/min, 110:5:1
heptane/EtOH/CH3CN + 0.1 % TFA).
Scheme Illa
Example 27
Synthesis of racemic cis-3-benzyloxycyclohexan-1-of
HO,, ,,O
rac.
150.0 g (1.29 mol) of cis-1,3-cyclohexanediol were dissolved in 1.5 I of
NMP, admixed with 111.6 g (0.99 mol) of potassium tert-butoxide (KOtBu)



CA 02516623 2005-08-19
39
and stirred at 25-27°C. After about 30 minutes, the mixture was cooled
to
0°C and admixed dropwise with 78.1 g (0.46 mol) of benzyl bromide. The
mixture was stirred at approx. 0°C for 15 min and then 1.5 I of water
were
added. After washing three times with 700 ml of n-heptane and discarding
the n-heptane solutions, the aqueous solution was extracted four times with
500 ml of MTBE. The combined MTBE phases were washed twice with in
each case 1 I of water, dried (Na2S04) and subsequently concentrated by
evaporation under reduced pressure. 48.0 g of the desired compound were
obtained as a clear, yellow oil; ~ H NMR (CDC13), 8 = 1.29 (m, 1 H),
1.43-1.93 (m, 6H), 2.06 (m, 1 H), 2.55 (s (br.), 1 H), 3.56 (m, 1 H), 3.74
(br,
1 H), 4.55 (dd, 2H), 7.25-7.36 (m, 5H).
Example 28
Optical resolution of 3-benzyloxycyclohexan-1-of
HO,, ,,O
G
rac. a
20.3 g of cis-3-benzyloxycyclohexan-1-of were dissolved in 35 ml of vinyl
acetate and 125 ml of methylene chloride, admixed with 2.0 g of Novozym
435 and stirred at 20-23°C for 6 h. After leaving to stand overnight,
the
enzyme was filtered off. A sample was withdrawn and concentrated by
evaporation under reduced pressure. The enantiomeric excess of (1 S,3R)-
3-benzyloxycyclohexan-1-of was > 99% (HPLC on Chiralpak AD-H
250 x 4.6; 1 ml/min, 25:1:0.5 heptane/EtOH/CHgCN + 0.1 % TFA), and the
enantiomeric excess of the (1 R,3S)-acetate was 78% (HPLC on
Chiralcel OD 250 x 4.6; 1 ml/min, 100:1:0.5 heptane/EtOH/CH3CN).
Example 29
Optical resolution of 3-benzyloxycyclohexan-1-of
HO,, ,,O
rac.



CA 02516623 2005-08-19
100.0 g of cis-3-benzyloxycyclohexan-1-of were dissolved in 170 ml of vinyl
acetate and 630 ml of methylene chloride, admixed with 5.0 g of Novozym
435 and stirred at 20-23°C for 26 h. The enzyme was filtered off, and a
5 sample was withdrawn and concentrated by evaporation under reduced
pressure. The enantiomeric excess of (1S,3R)-3-benzyloxycyclohexan-1-of
was > 99% (HPLC on Chiralpak AD-H 250 x 4.6; 1 ml/min, 25:1:0.5
heptane/EtOH/CH3CN + 0.1 % TFA), and the enantiomeric excess of the
(1 R,3S)-acetate was 90% (HPLC on Chiralcel OD 250 x 4.6; 1 ml/min,
10 100:1:0.5 heptane/EtOH/CH3CN).
Example 30
Isolation of (1 S,3R)-3-benzyloxycyclohexan-1-ol, separation of the mixture
of acetate and alcohol with pyridine-S03
1.9 g of the crude acetate/alcohol mixture from the stereoselective
enzymatic acetylation of 3-benzyloxycyclohexan-1-of (from Example 29)
were stirred with 2 g of pyridine-S03 at 20-22°C in 10 ml of pyridine
and
2 ml of DMF. After 4 h, the conversion of the benzylcyclohexanol to the
pyridine salt of the sulfuric ester was virtually quantitative. The reaction
mixture was diluted with 40 ml of water and extracted twice with approx.
20 ml of MTBE. The MTBE phases contain the unchanged (1 R,3S)-acetate
quantitatively. The remaining, acetate-free aqueous phase was
concentrated by evaporation under reduced pressure. The residue was
admixed with MTBE, and the sulfation product solidified; yield: 2.7 g.
2.7 g of pyridine salt of the sulfuric ester of (1 S,3R)-benzylcyclohexan-1-of
were stirred at 55°C in 45 ml of THF, 4 ml of water and 1 ml of conc.
sulfuric acid for 2 h. The mixture was admixed with 40 ml of water, approx.
10 ml of MTBE were added, the phases were separated and the aqueous
phase was extracted once with MTBE. The combined organic phases were
dried (Na2S04) and concentrated by evaporation; yield: 640 mg of a bright
yellow oil. The NMR data agree with the data quoted in Example 16; the
testing of the optical purity gave > 99% ee.
Example 31
Isolation of (1S,3R)-3-benzyloxycyclohexan-1-ol,
separation of the mixture of acetate and alcohol by extraction



CA 02516623 2005-08-19
41
g of the crude acetate/alcohol mixture from Example 29 were taken up
Y.
in approx. 90 ml of methanol and approx. 70 ml of water and washed three
times with in each case approx. 50 ml of n-heptane. The combined heptane
phases (contain predominantly the acetate) are extracted with 50 ml of 1:1
5 methanol/water. The combined aqueous phases are washed again with
n-heptane. After concentrating the aqueous phase, 3.6 g of the desired v
s
(1 S,3R)-3-benzyloxycyclohexan-1-of were obtained, and the concentration
of the combined heptane phases gave 5.5 g of the (1 R,3S)-acetate.
10 Example 32 '
Synthesis of 4-iodomethyl-2-(4-fluorophenyl)oxazole
O
F
N I
4.0 g (18.9 mmol) of 4-chloromethyl-2-(4-fluorophenyl)oxazole were i
dissolved in 80 ml of THF and admixed with 3.18 g (21.2 mmol) of Nal. The
mixture was stirred at 20-23°C for 3 h and at 50°C for about 12
h, the salts
were filtered off with suction and the filtrate was concentrated under
reduced pressure, yield: 6.1 g. The product crystallized; mp 100-102°C;
~ H NMR (CDC13): 8 = 4.34 (s, 2H), 6.97 (dd, 1 H), 7.14 (m, 2H), 7.68 (s,
1 H), 8.03 (m, 2H).
Example 33
Synthesis of (1S,3R)-4-(3-benzyloxycyclohexyl-1-oxymethyl)-2-(4-
fluorophenyl)oxazole
O
y0, .,O W
N
F /
2.0 g (9.7 mmol) of (1S,3R)-3-benzyloxycyclohexan-1-of were dissolved in
35 ml of tBuOMe. 1.3 g (approx. 55%, 43.7 mmol) of NaH were added and
the mixture was stirred at 22°C for 60 minutes. 3.9 g (12.9 mmol) of 4-
iodomethyl-2-(4-fluorophenyl)oxazole (Example 32) were added and the
mixture was stirred at 22-23°C for about 3 hours. After leaving to
stand



CA 02516623 2005-08-19
42
overnight, the mixture was stirred at 22-23°C for a further 11 h. Water
(approx. 30 ml) was added with cooling and the organic phase was
removed. Drying (Na2S04), concentrating (crude yield: 4.5 g) and
chromatography on silica gel (19:1 dichloromethane/acetone) gave 2.4 g of
the desired, cis-configured, optically pure, dialkylated 1,3-cyclohexanediol
derivative as a white solid; mp 61-62°C; ~ H NMR (CDC13), 8 = 1.11-1.39
(m, 4H), 1.82 (m, 1 H), 2.07 (m, 2H), 2.55 (m, 1 H), 3.38 (m, 2H), 4.55 (s,
2H), 4.57 (s, 2H), 7.13 (m, 2H), 7.25-7.35 (m, 5H), 7.63 (s, 1 H), 8.02 (m,
2H).
Example 34
Synthesis of (1 R,3S)-3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]cyclohexanol
by hydrogenation
0
y0,. ,OH
~N
2.4 g of (1S,3R)-4-(3-benzyloxycyclohexyl-1-oxymethyl)-2-(4-fluorophenyl)-
oxazole were dissolved in approx. 40 ml of methanol, admixed with a
spatula tip of Pd/C (10%, comprising 50% water) hydrogenated at 20-23°C
under atmospheric pressure for approx. 8 hours. Filtering off the catalyst
and concentrating the remaining solution gave 1.8 g of the desired cis-
configured, monoalkylated 1,3-cyclohexanediol derivative as an oil which
crystallized when DlPE was added; yield 1.6 g; mp 81-82°C; ~H NMR
(CDC13), b = 1.25-2.14 (m, 9H), 3.63 (m, 1 H); 3.75 (m, 1 H), 4.55 (dd, 2H),
7.13 (m, 2H), 7.64 (s, 1 H), 8.02 (m, 2H); MS (DCI): 292.3 (100%).
Example 35
Synthesis of methyl (1 R,3~S)-2-{3-[2-(4-fluorophenyl)oxazol-4-y(methoxy]-
cyclohexyl-1-oxymethyl}-6-methylbenzoate
o ., , o ~ I
w
N
C02Me



CA 02516623 2005-08-19
43
0.8 g (2.75 mmol) of (1 R,3S)-3-(2-(4-fluorophenyl)oxazol-4-ylmethoxy]-
cyclohexanol (from Example 34) was taken up in 10 ml of tBuOMe, .
admixed with 0.78 g (6.95 mmol) of KOtBu and stirred at 22-27°C for
approx. 30 minutes. The mixture was cooled to 0-5°C, 1.24 g (approx.
94%,
approx. 4.8 mmol) of methyl 2-bromomethyl-6-methylbenzoate were added
dropwise, the mixture was stirred initially at 3°C for 2 hours and at
20°C for
a further hour. The mixture is left to stir overnight at 18-21 °C, then
the
solvent is distilled off. The residue is partitioned between water and
tBuOMe. The organic phase is dried (Na2S04) and concentrated under
reduced pressure; yield: 1.04 g of methyl (1 R,3S)-2-{3-[2-(4-
fluorophenyl)oxazol-4-ylmethoxy]cyclohexyl-1-oxymethyl}-6-methyl-
benzoate as a yellowish oil; ~ H NMR (CDC13), 8 = 1.15-1.32 (m, 4H), 1.82.
(m, 1 H), 1.98-2.1 (m, 2H), 2.34 (s, 3H), 2.50 (m, 1 H), 3.27 (m, 1 H), 3.39
(m,
1 H), 3.90 (s, 3H), 4.54 (s, 2H), 4.60 (s, 2H), 7.11-7.30 (m, 5H), 7.63 (s, 1
H),
8.02 (m, 2H).
Example 36
Synthesis of (1S,3R)-4-(3-benzyloxy-cyclohexyl-1-oxymethyl)-2-(3-
methoxyphenyl)-5-methyloxazole
Me0 O ,, , O \
4.6 g (22.3 mmol) of (1S,3R)-3-benzyloxycyclohexan-1-of were dissolved in
70 ml of chlorobenzene. 6.6 g (58.8 mmol) of KOtBu were added, the
mixture was stirred at 22°C for 30 minutes and then 10.3 g (31.3 mmol)
of
4-iodomethyl-2-(3-methoxyphenyl)-5-methyloxazole were added. The
temperature rose to 35°C. The reaction was cooled slightly and stirred
at
22-23°C for a further 2 hours. After the chlorobenzene had been
distilled off
under reduced pressure, the residue was partitioned between tBuOMe and
water. The organic phase was dried (Na2S04) and concentrated under
reduced pressure; crude yield: 10.6 g. The substance was used in the next
reaction (hydrogenation, see Example 37) without further purification.



CA 02516623 2005-08-19
44
Example 37
Synthesis of (1 R,3S)-3-[2-(3-methoxyphenyl)oxazol-4-ylmethoxy]-
cyclohexanol by hydrogenation
O
Me0 ~~0,,, ,,OH
\ ~N
10.5 g of (1S,3R)-4-(3-benzyloxycyclohexyl-1-oxymethyl)-2-(3-methoxy-
phenyl)oxazole were dissolved in approx. 120 ml of methanol, admixed
with 2 g of Pd/C (10%, having 50% of water) and hydrogenated at 20-23°C
under atmospheric pressure overnight. Filtering off the catalyst and
concentrating the remaining solution, partitioning between MTB ether and
water and drying the organic phase gave 6.4 g of the desired cis-
configured, monoalkylated 1,3-cyclohexanediol derivative as a yellow oil.
1 g of the substance was chromatographed on silica gel (ethyl acetate):
0.8 g of a colorless oil were obtained; ~ H NMR (CDC13), 8 = 1.25-1.90 (m, 7
H), 2.12 (m, 1 H), 2.41 (s, 3 H), 3.61 (m, 1 H), 3.75 (m, 1 H), 3.87 (s, 3 H),
4.48 (dd, 2 H), 6.96 (d, 1 H), 7.33 (t, 1 H), 7.53 (s, 1 H), 7.58 (d, 1 H); MS
(ES+): 318.27 (83%), 243.18 (100 %).
Example 38
Synthesis of methyl (1 R,3S)-2-~3-[2-(3-methoxyphenyl)-5-methyloxazol-4-
ylmethoxy]cyclohexyl-1-oxymethyl}-6-methylbenzoate
O \
Me0 ~~0,,, ,,,0 I /
\ ~N
I / CO Me
2
136 mg (0.4 mmol) of (1 R,3S)-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-yl-
methoxy]cyclohexanol (from Example 37, hydrogenation) were dissolved in
1 ml of chlorobenzene, admixed at 24-27°C with 120 mg (1.07 mmol) of
KOtBu and stirred for approx. 30 minutes. The mixture was cooled to 0-
5°C, 189 mg (approx. 94%, approx. 0.78 mmol) of methyl 2-bromomethyl-
6-methylbenzoate were added dropwise and the mixture was stirred at 0-
5°C for an initial 30 minutes. Without further cooling, the reaction
mixture
had a temperature of approx. 20°C after 1.5 hours. After leaving to
stand



CA 02516623 2005-08-19
overnight and adding approx. 20 mg of KOtBu, the reaction was complete
after a further hour of stirring at 22°C. Distilling off the
chlorobenzene under
reduced pressure, partitioning the residue between water and tBuOMe and
drying the product-containing organic phase gave, after concentrating
5 under reduced pressure, 160 mg of methyl (1 R,3S)-2-{3-[2-(3-
methoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-1-oxymethyl}-6-
methylbenzoate as a yellowish oil; ~H NMR (CDC13), b = 1.15-1.32 (m, 4
H), 1.81 (m, 1 H), 2.00 (m, 1 H), 2.06 (m, 1 H), 2.34 (s, 3 H), 2.40 (s, 3 H),
E
2.51 (m, .1 H), 3.27 (m, 1 H), 3.36 (m, 1 H), 3.87 (s, 3 H), 3.90 (m, 3 H),
4.48 i
10 (s, 2 H), 4.60 (s, 2 H), 6.96 (m, 1 H), 7.12-7.35 (m, 4 H), 7.53-7.60 (m, 2
H).
Scheme Illb
15 Example 39
Synthesis of mono(3-benzyloxycyclohexyl) glutarate
~ '
HO 0,,, ,,O w I
O O
rac.
20 3.0 g of 3-benzyloxycyclohexan-1-ol, 2.15 g of glutaric anhydride and
3.03 g of triethylamine were stirred at 21-23°C in 25 ml of methylene
chloride. After complete conversion, the mixture was added to water,
extracted, and dried over MgS04. After concentrating under reduced
pressure, 4.3 g of the desired compound were obtained; ~ H NMR (CDCIg),
25 8 = 1.20-1.28 (m, 4H), 1.82 (m, 1 H), 1.90-1.97 (m, 3H), 2.05 (m, 1 H),
2.32-2.42 (m, 5H), 3.39 (m, 1 H), 4.55 (dd, 2H), 4.69 (m, 1 H), 7.25-7.33 (m,
5H), 8.7 (br., 1 H).
Example 40
30 Stereoselective hydrolysis of mono(3-benzyloxycyclohexyl) glutarate,
preparation of (1 R,3S)-3-benzyloxycyclohexan-1-of



CA 02516623 2005-08-19
46
~l
HO O \
20 mg of racemic mono(3-benzyloxycyclohexyl) glutarate (from
Example 39) were partitioned into 2 ml of phosphate buffer, pH 8, and 3-5
drops of DME, admixed with 3-5 mg of Novozyme 435 and stirred at
21-23°C. After approx. 50% conversion, the reaction solution was
partitioned between saturated aqueous NaHC03 solution and ethyl
acetate. The ethyl acetate phase was dried and concentrated, yield: 5 mg
of (1 R,3S)-3-benzyloxycyclohexan-1-ol, and the enantiomeric excess was
> 95% (HPLC on Chiralpak AD-H 250 x 4.6; 1 ml/min, 25:1:0.5
heptane/EtOH/CH3CN + 0.1 % TFA).
Example 41
Synthesis of (1 R,3S)-4-(3-benzyloxycyclohexyl-1-oxymethyl)-2-(4-fluoro-
phenyl)oxazole
O /
y0 O \
~N
F
Starting from (1 R,3S)-3-benzyloxycyclohexan-1-of (see Example 40),
alkylation with 4-iodomethyl-2-(4-fluorophenyl)oxazole (see Example 32)
results in (1 R,3S)-4-(3-benzyloxycyclohexyl-1-oxymethyl)-2-(4-fluoro-
phenyl)oxazole, cf. Example 33.
Further examples of the alkylation of cis-1,3-cyciohexanedioi
Example 42
Synthesis of racemic methyl cis-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate



CA 02516623 2005-08-19
47
HO,,, ,,O \
rac. C02Me
g (42.8 mmol) of cis-1,3-cyclohexanediol were dissolved in 50 ml of
dimethoxyethane (DME), admixed at 20-23°C with 3.36 g (30 mmol) of
5 potassium tert-butoxide (KOtBu) and stirred. After about 30 minutes, the
mixture is cooled to 5°C and 3.7 g (approx. 50%) of methyl 2-
bromomethyl-
6-methylbenzoate, which may be prepared, for example, by methanolyzing
the acid bromide (2-bromomethyl-6-methylbenzoyl bromide) or by
brominating methyl 2,6-dimethylbenzoate, are added dropwise. The
mixture is stirred at 5-10°C for 1 h and then at 20-23°C
overnight. Water
and methyl tert-butyl ether (MTBE) are added, the mixture is stirred
vigorously, the phases are separated, the aqueous phase is washed once
more with MTBE and the combined organic phases are concentrated under
reduced pressure. The residue is chromatographed on silica gel (1:1 ethyl f
acetate/n-heptane). 600 mg of the desired compound are obtained as a
light yellow oil, ~ H NMR (CDC13), 8 = 1.27 (m, 1 H), 1.45 (m, 1 H), 1.55 (m,
1 H), 1.74 (m, 1 H), 1.83 (m, 1 H), 2.05 (m, 1 H), 2.34 (s, 3H), 3.47 (m, 1
H),
3.72 (m, 1 H), 3.91 (s, 3H), 4.58 (dd, 2H), 7.15 (d, 1 H), 7.20 (d, 2H), 7.27
(m, 1 H). ,
Example 43
Synthesis of racemic methyl cis-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate
Ho,, ,,o \
rac. COzMe
10.0 g (86 mmol) of cis-1,3-cyclohexanediol were taken up in 150 ml of
methyl tert-butyl ether (MTBE), admixed at approx. 20°C with 6.72 g
(59.9 mmol) of potassium tert-butoxide (KOtBu) and stirred. After about 30
minutes, the suspension was cooled to 5°C and admixed dropwise with
7.4 g (approx. 50%) of methyl 2-bromomethyl-6-methylbenzoate, which



CA 02516623 2005-08-19
48
may be prepared, for example, by methanolyzing the acid bromide
(2-bromomethyl-6-methylbenzoyl bromide) or by brominating methyl
2,6-dimethylbenzoate. The mixture was stirred at 0-5°C for 1 h, heated
to
20-23°C and left to stir overnight. Water was added, the mixture was
stirred
vigorously, the phases were separated, the organic phase was washed
once more with water and then the organic phase was concentrated under
reduced pressure. The residue (4.6 g) was chromatographed on silica gel
(1:1 ethyl acetateln-heptane). 1.2 g of the desired compound were obtained
as a light yellow oil, ~ H NMR (CDCI3), 8 = 1.27 (m, 1 H), 1.45 (m, 1 H), 1.55
(m, 1 H), 1.74 (m, 1 H), 1.82 (m, 1 H), 2.05 (m, 1 H), 2.34 (s, 3H), 3.46 (m,
1 H), 3.72 (m, 1 H), 3.91 (s, 3H), 4.58 (dd, 2H), 7.15 (d, 1 H), 7.20 (d, 2H),
7.27 (m, 1 H).
Example 44
Synthesis of racemic methyl cis-2-(3-hydroxycyclohexyloxymethyl)-
6-methylbenzoate
HO,, ,,,0
C02Me
rac.
5 g (42.8 mmol) of cis-1,3-cyclohexanediol were dissolved in 40 ml of
chlorobenzene and 10 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone (DMPU, dimethylpropyleneurea), admixed at 20-23°C with
3.36 g (30 mmol) of potassium tert-butoxide (KOtBu) and stirred. After 10-
15 minutes, the mixture was cooled to 15-20°C and 3.7 g (approx. 50%)
of
methyl 2-bromomethyl-6-methylbenzoate were added dropwise. The
mixture was stirred at 20°C for 1.5 h and then added to water. The
organic
phase was removed and concentrated under reduced pressure. The
residue was taken up in NMP/water and, to remove impurities, washed
twice with n-heptane. Subsequently, the product was isolated by extracting
twice with MTBE. The combined MTBE phases were washed with water,
dried (Na2S04) and concentrated under reduced pressure. The residue
(1.2 g) was chromatographed on silica gel (1:1 ethyl acetate/n-heptane).
580 mg of the desired compound were obtained as a slightly yellow oil;
'H NMR (CDC13), 8 = 1.27 (m, 1 H), 1.45 (m, 1 H), 1.55 (m, 1 H), 1.74 (m, 1



CA 02516623 2005-08-19
49
H), 1.83 (m, 1 H), 2.05 (m, 1 H), 2.34 (s, 3 H), 3.47 (m, 1 H), 3.72 (m, 1 H),
3.91 (s, 3 H), 4.58 (dd, 2 H), 7.15 (d, 1 H), 7.20 (d, 2 H), 7.27 (m, 1 H).
Further examples of the optical resolution by stereoselective ester
formation (EF)
E
Example 45
Optical resolution of methyl cis-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate
Ho., ,,o ~ l
rac. C02Me
730 mg of the racemic methyl cis-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-
methylbenzoate are dissolved in 5 ml of methylene chloride and 2 ml of E
vinyl acetate, heated to 38°C and admixed with 100 mg of Novozym 435.
After approx. 5 h, the reaction was ended by filtering off the enzyme and
the optical purity of the acetate formed and of the unconverted alcohol were
r
determined by HPLC (HPLCacetate:Chiralcel OD 250 x 4.6, 1 mllmin,
100:1:0.5 heptane/EtOH/CH3CN; HPLCa~cohol:Chiralpak AD 250 x 4.6;
1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN +0.1 % TFA). The determination
of the optical purity for methyl (3S,1R)-2-(3-hydroxycyclohexyl-1
oxymethyl)-6-methylbenzoate gave 98% ee and 86% ee for the (3R,1 S)- ,
acetate.
Example 46
Optical resolution of methyl cis-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-
methylbenzoate
Ho,,, ,,o
rac. C~ZMe
20 mg of the racemic methyl cis-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-
methylbenzoate were dissolved in 2 ml of chlorobenzene and 1 ml of vinyl



CA 02516623 2005-08-19
acetate, admixed at 22-25°C with 8 mg of Chirazyme L-2, lyo. (Roche),
and
stirred. After approx. 6 h, the reaction was ended by filtering off the enzyme
and the optical purity of the acetate formed and of the unconverted alcohol
were determined by HPLC (HPLCacetate:Chiralcel OD 250 x 4.6, 1 ml/min,
5 100:1:0.5 heptane/EtOH/CH3CN; HPLCaIcohoI~Chira(pak AD 250 x 4.6;
1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN + 0.1 % TFA) were determined:
84% ee of methyl (3S,1 R)-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-
methylbenzoate and 95% ee of the (3R,1 S)-acetate.
10 Example 47
Optical resolution of methyl cis-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-
methylbenzoate
HO,, ,,O
rac. COZMe
1.0 g of methyl cis-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoate
were dissolved in 10 rnl of 1,2-dichloroethane and 2 ml of vinyl propionate,
admixed with 25 mg of Chirazyme L-2, lyo. (Roche) and stirred at 21-
24°C
for 40 h. Filtering off the enzyme, concentrating the filtrate under reduced
pressure and chromatography of the residue on silica gel (1:1 ethyl
acetate/n-heptane) gave 0.49 g of the (3R,1 S)-propionate having 92% ee
(HPLC on Chiralcel OD 250 x 4,6, 1 ml/min, 100:1:0.5 heptane/-
EtOH/GH3CN), ~H NMR (CDC13), 8 = 1.13 (t, 3H), 1.15-1.36 (m, 4H), 1.79
(m, 1 H), 1.91 (m, 1 H), 2.01 (m, 1 H), 2.30 (q, 2H), 2.34 (s, 3H), 2.35 (m,
1 H), 3.34 (m, 1 H), 3.90 (s, 3H), 4.58 (dd, 2H), 4.67 (m, 1 H), 7.14 (d, 1
H),
7.19 (d, 1 H), 7.26 (m, 1 H), and also 0.3 g of the unconverted methyl
(3S,1R)-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoate having
98% ee (HPLC on Chiralpak AD-H 250 x 4.6; 1 ml/min, 25:1:0.5
heptane/EtOH/CH3CN + 0.1 % TFA), ~ H NMR (CDC13), 8 = 1.27 (m, 1 H),
1.45 (m, 1 H), 1.55 (m, 1 H), 1.74 (m, 1 H), 1.83 (m, 1 H), 2.05 (m, 1 H),
2.34
(s, 3H), 3.47 (m, 1 H), 3.72 (m, 1 H), 3.91 (s, 3H), 4.58 (dd, 2H), 7.15 (d,
1 H), 7.20 (d, 2H), 7.27 (m, 1 H).



CA 02516623 2005-08-19
51
Example 48
Optical resolution of methyl cis-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-
methylbenzoate
HO,, ,O \
rac. COZMe
10 mg of the racemic methyl cis-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-
methylbenzoate were dissolved in 1 ml of vinyl acetate, admixed with
approx. 4-6 mg of Lipase TL (Pseud. stutzeri, Meito Sangyo) and stirred at
22-25°C. After > 50% conversion, the reaction was ended by filtering
off the
enzyme and the optical purity of the unconverted methyl (3S,1R)-2-(3-
hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoate was determined:
> 98% ee (HPLC on Chiralpak AD 250 x 4.6; 1 ml/min, 25:1:0.5
heptane/EtOH/CH3CN + 0.1 % TFA).
Example 49
Optical resolution of methyl cis-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate
HO,, ,,O \
CO Me
raC.
3.9 g of the racemic methyl cis-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-
methylbenzoate were dissolved in 25 ml of methylene chloride and 10 ml of
vinyl acetate, heated to 45°C and admixed with 250 mg of Novozym 435.
After approx. 45% conversion, the reaction was ended by filtering off the
enzyme and the reaction mixture was concentrated. Chromatography of the
residue on silica gel (1:1 ethyl acetate/n-heptane) gave 1.9 g of the
(3R,1S)-acetate (> 95% ee, HPLC on Chiralcel OD 250 x 4.6, 1 ml/min,
100:1:0.5 heptane/EtOH/CH3CN) and 1.9 g of the unconverted methyl
(3S,1 R)-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoate (82% ee,
HPLC on Chiralpak AD 250 x 4.6; 1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN
+ 0.1 % TFA).



CA 02516623 2005-08-19
52
Example 50
Optical resolution of methyl cis-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate
Ho,, ,,o
rac. C02Me
20 mg of the racemic methyl cis-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-
methylbenzoate were dissolved in 2 ml of toluene and 1 ml of vinyl acetate,
admixed at 20-23°C with 6-8 mg of Chirazyme L-2, lyo. (Roche), and
stirred. After approx. 45% conversion, the reaction was ended by filtering
off the enzyme and the optical purity of the (3R,1S)-acetate formed was
determined: 94% ee (HPLC on Chiralcel OD 250 x 4.6, 1 ml/min, 100:1:0.5
heptane/EtOH/CH3CN).
Example 51
Optical resolution of methyl cis-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate
Jf
HO,,, ,,O
rac. COZMe
10 mg of the racemic methyl cis-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-
methylbenzoate were dissolved in 1 ml of vinyl acetate, admixed with
approx. 4-6 mg of Lipase QL (Alcaligenes spec., Meito Sangyo) and stirred
at 20-23°C. After approx. 52% conversion, the reaction was ended by
filtering off the enzyme and the optical purity of the acetate formed and of
the unconverted alcohol were determined, ee of the acetate: 91 % (HPLC
on Chiralcel OD 250 x 4.6, 1 mllmin, 100:1:0.5 heptane/EtOH/CH3CN), ee
of the methyl (3S,1 R)-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methyl-
benzoate: > 98% ee (HPLC on Chiralpak AD 250 x 4.6; 1 ml/min, 25:1:0.5
heptane/EtOH/CHgCN + 0.1 % TFA).



CA 02516623 2005-08-19
53
Example 52
Optical resolution of methyl cis-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate
/~
HO,, ,,O \
rac. COzMe
10 mg of the racemic methyl cis-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-
methylbenzoate were dissolved in 1 ml of vinyl acetate, admixed with
approx. 4-6 mg of Lipase SL (Pseud. cepacia, Meito Sangyo) and stirred at
20-23°C. After approx. 52% conversion, the reaction was ended by
filtering
off the enzyme and the optical purity of the acetate formed and of the
unconverted alcohol were determined, ee of the acetate: 90% (HPLC on
Chiralcel OD 250 x 4.6, 1 ml/min, 100:1:0.5 heptane/EtOH/CH3CN), ee of
k
the methyl (3S,1R)-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methyl- t
t
benzoate: > 95% ee (HPLC on Chiralpak AD 250 x 4.6; 1 ml/min, 25:1:0.5
heptane/EtOH/CH3CN + 0.1 % TFA).
Example 53
Optical resolution of methyl cis-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate
HO,, ,,O \
rac. C02Me
39 g of methyl cis-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoate
were dissolved in 250 ml of methylene chloride and 50 ml of vinyl acetate,
heated to 45°C and admixed with 1.0 g of Novozym 435. After 25 h, a
further 0.5 g of Novozym 435 was added. After a further 6.5 hours, the
enzyme was filtered off and the reaction mixture concentrated.
Chromatography of the residue on 630 g of silica gel (1:1 ethyl
acetate/n-heptane) gave 18.2 g of methyl (3S,1R)-2-(3-hydroxycyclohexyl-
1-oxymethyl)-6-methylbenzoate (> 98% ee, HPLC on Chiralpak AD-H



CA 02516623 2005-08-19
54
250 x 4.6; 1 mllmin, 25:1:0.5 heptanelEtOH/CH3CN + 0.1 % TFA), ~ H NMR
(CDC13), 8 = 1.27 (m, 1 H), 1.45 (m, 1 H), 1.55 (m, 1 H), 1.74 (m, 1 H), 1.83
(m, 1 H), 2.05 (m, 1 H), 2.34 (s, 3H), 3.47 (m, 1 H), 3.72 (m, 1 H), 3.91 (s,
3H), 4.58 (dd, 2H), 7.15 {d, 1 H), 7.20 (d, 2H), 7.27 (m, 1 H).
Example 54
Optical resolution of methyl cis-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate
HO,,, ,,O
rac. COZMe
20 mg of the racemic methyl cis-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-
methylbenzoate were dissolved in 2 ml of THF and 1 ml of vinyl acetate,
admixed at 20-23°C with 6-8 mg of Chirazyme L-2, lyo. (Roche), and
stirred. After approx. 6 h, the reaction was ended by filtering off the enzyme
and the optical purity of the acetate formed and of the unconverted alcohol
were determined by HPLC (HPLCa~tate:Chiralcel OD 250 x 4.6, 1 ml/min,
100:1:0.5 heptane/EtOH/CH3CN; HPLCalcohol:Chiralpak AD 250 x 4.6;
1 ml/min, 25:1:0.5 heptanelEtOHICH3CN + 0.1 % TFA): ee of the methyl
(3S,1 R)-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoate 89% and
ee of the (3R,1S)-acetate 95% and
Example 55
Optical resolution of methyl cis-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate
H 0 ,, ,, O
rac. C02Me
Approx. 15 mg of the racemic methyl cis-2-(3-hydroxycyclohexyl-1-
oxymethyl)-6-methylbenzoate were dissolved in 2 ml of tent-butanol and
1 ml of vinyl acetate, admixed at 20-23°C with approx. 6 mg of



CA 02516623 2005-08-19
Novozym 435 and stirred. After approx. 24 h, the reaction was ended by
filtering off the enzyme and the optical purity of the acetate formed and of
the unconverted alcohol were determined by HPLC: (3R,1S)-acetate
91 % ee (HPLC: Chiralcel OD 250 x 4.6, 1 ml/min, 100:1:0.5
5 heptane/EtOH/CH3CN), methyl (3S,1R)-2-(3-hydroxycyclohexyl-1-
oxymethyl)-6-methylbenzoate 96% ee (HPLC: Chiralpak AD 250 x 4.6;
1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN + 0.1 % TFA).
Example 56
10 Optical resolution of methyl cis-2-(3-hydroxycyclohexyloxymethyl)-6-
methylbenzoate
HO,, ,,O \
F
rac. C02Me
15 10 mg of the racemic methyl cis-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-
methylbenzoate were dissolved in 1 ml of vinyl acetate, admixed with i
approx. 4-6 mg of Lipase TL (Pseud. stutzeri, Meito Sangyo) and stirred at
20-23°C. After > 50% conversion, the reaction was ended by filtering
off the
enzyme and the optical purity of the unconverted alcohol was determined:
20 methyl (3S,1R)-2-(3-hydroxycyclohexyl-1-oxymethyl)-6-methylbenzoate
> 98% ee (HPLC on Chiralpak AD 250 x 4.6; 1 ml/min, 25:1:0.5 i
heptane/EtOH/CH3CN + 0.1 % TFA).
Example 57
25 Optical resolution of cis-3-benzyloxycyclohexan-1-of
HO,, ,O \
rac.
35-40 mg of racemic cis-3-benzyloxycyclohexan-1-of were dissolved in
30 0.5-1 ml of vinyl acetate and 2-3 ml of methylene chloride, admixed with
approx. 8-10 mg of Novozym 435 and stirred at 22-25°C. After 4 days,
the
reaction was ended by filtering off the enzyme. The optical purity of the



CA 02516623 2005-08-19
56
alcohol, (1S,3R)-3-benzyloxycyclohexan-1-ol, was > 98% ee (HPLC on
Chiralpak AD-H 250 x 4.6; 1 mllmin, 25:1:0.5 heptane/EtOH.CH3CN +
0.1 % TFA), and the ee of the (1 R,3S)-acetate was 82% (HPLC on
Chiralcel OD 250 x 4.6; 1 ml/min, 100:1:0.5 heptane/EtOHICH3CN).
Example 58
Optical resolution of cis-3-benzyloxycyclohexan-1-of
HO,, ,O
rac.
15
10 mg of the racemic cis-~-benzyloxycyclohexan-1-of were dissolved in
1 ml of vinyl acetate and 3 ml of THF, admixed with approx. 5 mg of Lipase
L-10 and stirred at 22-25°C. After >_ 50% conversion, the reaction
was
ended by filtering off the enzyme. The optical purity of (1 S,3R)-3-
benzyloxycyclohexan-1-of was >_ 90% ee (HPLC on Chiralpak AD-H
250 x 4.6; 1 ml/min, 25:1:0.5 heptane/EtOHICH3CN + 0.1 % TFA).
Example 59
Optical resolution of cis-3-benzyloxycyclohexan-1-of
HO,,, ,,O
rac.
10 mg of the racemic cis-3-benzyloxycyclohexan-1-of were dissolved in
1 ml of vinyl acetate and 3 m1 of chlorobenzene, admixed with 10 mg of
Novozym 435 and stirred at 22-25°C. After 4 hours, the reaction
was ended
by filtering off the enzyme. The optical purity of (1S,3R)-3
benzyloxycyclohexanol was 68% ee (HPLC on Chiralpak AD-H 250 x 4.6,
1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN + 0.1 % TFA), and the ee of the
enantiomeric acetate was 95% (HPLC on Chiralcel OD 250 x 4.6; 1 mllmin,
100:1:0.5 heptane/EtOHICH3CN).



CA 02516623 2005-08-19
57
Example 60
Optical resolution of cis-3-benzyloxycyclohexan-1-of -
t
HO,, ,,O \
i
rac.
10 mg of the racemic cis-3-benzyloxycyclohexan-1-of were dissolved in !
1 ml of vinyl acetate and 3 ml of cyclohexane, admixed with approx. 5 mg
of Lipase QL and stirred at 22-25°C. After 24 hours, the reaction was
ended by filtering off the enzyme. The optical purity of (1S,3R)-3
benzyloxycyclohexan-1-of was 94% ee (HPLC on Chiralpak AD-H
250 x 4.6; 1 ml/min, 25:1:0.5 heptanelEtOHICH3CN + 0.1 % TFA).
Example 61
Optical resolution of cis-3-benzyloxycyclohexan-1-of
a
HO,,, ,,O \ C
rac.
10 mg of the racemic cis-3-benzyloxycyclohexan-1-of were dissolved in
1 ml of vinyl acetate and 3 ml of toluene, admixed with 10 mg of
Novozym 435 and stirred at 22-25°C. After 4 hours, the reaction
was ended
by filtering off the enzyme. The optical purity of (1 S,3R)-3-
benzyloxycyclohexan-1-of was 70% ee (HPLC on Chiralpak AD-H
250 x 4.6, 1 mllmin, 25:1:0.5 heptane/EtOH/CH3CN + 0.1 % TFA), and the
ee of the (1 R,3S)-acetate was 95% (HPLC on Chiralcel OD 250 x 4.6;
1 mllmin, 100:1:0.5 heptane/EtOH/CH3CN).
Example 62
Optical resolution of cis-3-benzyloxycyclohexan-1-of



CA 02516623 2005-08-19
58
HO,,, ,,O
rac.
mg of the racemic cis-3-benzyloxycyclohexan-1-of were dissolved in
1 ml of vinyl acetate and 3 ml of cyclohexane, admixed with approx. 10 mg
5 of Novozym 435 and stirred at 22-25°C. After approx. 4 hours, the
reaction
was ended by filtering off the enzyme. The optical purity of (1S,3R)-3-
benzyloxycyclohexan-1-of was 95% ee (HPLC on Chiralpak AD-H
250 x 4.6, 1 ml/min, 25:1:0.5 heptane/EtOHICH3CN + 0.1 % TFA), and the
ee of the (1 R,3S)-acetate was 90% (HPLC on Chiralcel OD 250 x 4.6;
10 1 ml/min, 100:1:0.5 heptanelEtOH/CH3CN).
Example 63
Optical resolution of cis-3-benzyloxycyclohexan-1-of
HO,, ,,O
rac.
10 mg of the racemic cis-3-benzyloxycyclohexan-1-of were dissolved in
1 ml of vinyl acetate and 3 ml of cyclohexane, admixed with approx. 5 mg
of Lipase L-10 and stirred at 22-25°C. After 24 hours, the reaction was
ended by filtering off the enzyme. The optical purity of (1S,3R)-3-
benzyloxycyclohexan-1-of was > 95% ee (HPLC on Chiralpak AD-H
250 x 4.6; 1 ml/min, 25:1:0.5 heptanelEtOHICH3CN + 0.1 % TFA).
Example 64
Optical resolution of cis-3-benzyloxycyclohexan-1-of
HO,, ,,O
rac.



CA 02516623 2005-08-19
59
Approx. 10 mg of the racemic cis-3-benzyloxycyclohexan-1-of were
dissolved in 1 ml of vinyl acetate and 3 ml of THF, admixed with 10 mg of
Novozym 435 and stirred at 22-25°C. After 4 hours, the reaction
was ended
by filtering off the enzyme. The optical purity of (1S,3R)-3-benzyloxy-
cyclohexanol was 73% ee (HPLC on Chiralpak AD-H 250 x 4.6; 1 ml/min,
25:1:0.5 heptane/EtOH/CH3CN + 0.1 % TFA), and the ee of the (1 R,3S)-
acetate was 94% (HPLC on Chiralcel OD 250 x 4.6; 1 ml/min, 100:1:0.5
heptane/EtOH/CH3CN).
Example 65
Optical resolution of cis-3-benzyloxycyclohexan-1-of
HO,, ,,O \
i
rac.
10 mg of the racemic cis-3-benzyloxycyclohexan-1-of were dissolved in
1 ml of vinyl acetate and 3 ml of chlorobenzene, admixed with approx. 5 mg
of Lipase L-10 and stirred at 22-25°C. After >_ 50% conversion, the
reaction
was ended by filtering off the enzyme. The optical purity of (1S,3R)-3-
benzyloxycyclohexan-1-of was >_ 92% ee (HPLC on Chiralpak AD-H
250 x 4.6; 1 mi/min, 25:1:0.5 heptane/EtOHICH3CN + 0.1 % TFA).
Example 66
Optical resolution of cis-3-benzyloxycyclohexan-1-of
~f
HO,, ,,O \
rac.
Approx. 10 mg of the racemic cis-3-benzyloxycyclohexan-1-of were
dissolved in 1 ml of vinyl acetate and 3 ml of ethyl acetate, admixed with
approx. 10 mg of Novozym 435 and stirred at 22-25°C. After 4 hours, the
reaction was ended by filtering off the enzyme. The optical purity of
(1 S,3R)-3-benzyloxycyclohexan-1-of was 77% ee (HPLC on
Chiralpak AD-H 250 x 4.6; 1 mllmin, 25:1:0.5 heptane/EtOHICHgCN +



CA 02516623 2005-08-19
0.1% TFA), and the ee of the (1R,3S)-acetate was 93% (HPLC on
Chiralcel OD 250 x 4.6; 1 ml/min, 100:1:0.5 heptane/EtOH/CH3CN).
Example 67
5 Optical resolution of cis-3-benzyloxycyclohexan-1-of
Ho,,, ,.o ~ i
rac.
10 mg of the racemic cis-3-benzyloxycyclohexan-1-of were dissolved in
10 1 ml of vinyl acetate and 3 ml of chlorobenzene, admixed with approx. 5 mg
of Lipase SL and stirred at 22-25°C. After >_ 50% conversion, the
reaction
was ended by filtering off the enzyme. The optical purity of (1S,3R)-3-
benzyloxycyclohexan-1-of was >_ 87% ee (HPLC on Chiralpak AD-H
250 x 4.6; 1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN + 0.1 % TFA).
Example 68
Optical resolution of cis-3-benzyloxycyclohexan-1-of
HO,, ,,p
rac.
10 mg of the racemic cis-3-benzyloxycyclohexan-1-of were dissolved in
1 ml of vinyl acetate and 3 ml of diisopropyl ether, admixed with 10 mg of
Novozym 435 and stirred at 22-25°C. After 4 hours, the reaction
was ended
by filtering off the enzyme. The optical purity of (1S,3R)-3-benzyloxy-
cyclohexan-1-of was 90% ee (HPLC on Chiralpak AD-H 250 x 4.6;
1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN + 0.1 % TFA), and the ee of the
(1 R,3S)-acetate was 90% (HPLC on Chiralcel OD 250 x 4.6; 1 ml/min,
100:1:0.5 heptane/EtOH/CH3CN).
Example 69
Optical resolution of cis-3-benzyloxycyclohexan-1-of



CA 02516623 2005-08-19
61
HO,, ,,O ~
rac.
mg of the racemic cis-3-benzyloxycyclohexan-1-of were dissolved in
1 ml of vinyl acetate and 3 ml of MTBE, admixed with 10 mg of
5 Novozym 435 and stirred at 22-25°C. After 4 hours, the reaction was
ended
4
by filtering off the enzyme. The optical purity of (1S,3R)-3-benzyloxy-
cyclohexan-1-of was 93% ee (HPLC on Chiralpak AD-H 250 x 4.6;
1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN + 0.1 % TFA), and the ee of the
(1 R,3S)-acetate was 89% (HPLG on Chiralcel OD 250 x 4.6; 1 ml/min,
10 100:1:0.5 heptane/EtOH/CH3CN).
Example 70
Optical resolution of cis-3-benzyloxycyclohexan-1-of
HO,, ,,O
rac.
t
10 mg of the racemic cis-3-benzyloxycyclohexan-1-o! were dissolved in
1 ml of vinyl acetate and 3 ml of cyclohexane, admixed with approx. 5 mg
of Lipase SL and stirred at 22-25°C. After 24 hours, the reaction was
ended
by filtering off the enzyme. The optical purity of (1S,3R)-3-benzyloxy-
cyclohexan-1-of was > 90% ee (HPLC on Chiralpak AD-H 250 x 4.6;
1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN + 0.1 % TFA).
Example 71
Optical resolution of cis-3-benzyloxycyclohexan-1-of
HO,, ,.O \
rac.



CA 02516623 2005-08-19
62
27 mg of racemic cis-3-benzyloxycyclohexan-1-of were dissolved in 3 ml of
methylene chloride, admixed with 65 mg of isovaleric anhydride and with
11 mg of Novozyme 435 and stirred at 22-25°C. After 45-50% conversion,
the reaction was ended by filtering off the enzyme. The optical purity of
(1S,3R)-3-benzyloxycyclohexan-1-of was 87% ee (HPLC on Chiralpak
AD-H 250 x 4.6; 1 ml/min, 25:1:0.5 heptane/EtOH/CHgCN + 0.1 % TFA),
and the enantiomeric excess of the (1 R,3S)-isovaleric acid derivative was
> 95% (HPLC on Chiralcel OD 250 x 4.6; 1 mllmin, 100:1:0.5
heptane/EtOH/CHgCN).
Example 72
Optical resolution of cis-3-benzyloxycyclohexan-1-of
HO,, ,, p
rac.
200 mg of the racemic cis-3-benzyloxycyclohexan-1-of were dissolved in
3 ml of chlorobenzene, admixed with 100 mg of succinic anhydride and
10 mg of Chirazyme L-2, lyo., and stirred at 25-27°C. After 29 hours,
the
reaction was ended by filtering off the enzyme. A sample which had been
concentrated by evaporation was used to determine the optics! purity both
of the unconverted substrate and of the acylation product formed. The
optical purity of (1 S,3R)-3-benzyloxycyclohexan-1-of was > 98% ee (HPLC
on Chiralpak AD-H 250 x 4.6; 1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN +
0.1 % TFA), and the optical purity of the succinic acid derivative was
94% ee (HPLC on Chiralcel OD 250 x 4.6; 1 mllmin, 25:1:0.5
heptane/EtOH/CH3CN + 0.1 % TFA).



CA 02516623 2005-08-19
63
Example 73
Optical resolution of cis-3-benzyloxycyclohexan-1-of
HO,, ,,O \
i
rac.
200 mg of the racemic cis-3-benzyloxycyclohexan-1-of were dissolved in
3 ml of DME, admixed with 100 mg of succinic anhydride and 10 mg of
Chirazyme L-2, lyo., and stirred at 25-27°C. After 29 hours, the
reaction
was ended by filtering off the enzyme. A sample which had been
concentrated by evaporation was used to determine the optical purity both
i
of the unconverted substrate and of the acylation product formed. The
optical purity of (1S,3R)-3-benzyloxycyclohexan-1-of was > 95% ee (HPLC
on Chiralpak AD-H 250 x 4.6; 1 ml/min, 25:1:0.5 heptanelEtOH/CHgCN + '
0.1 % TFA), and the optical purity of the succinic acid derivative was
> 97% ee (HPLC on Chiralcel OD 250 x 4.6; 1 ml/min, 25:1:0.5
heptane/EtOH/CH3CN + 0.1 % TFA).
Example 74
Optical resolution of cis-3-benzyloxycyclohexan-1-of
HO,, ,,O \
rac.
200 mg of the racemic cis-3-benzyloxycyclohexan-1-of were dissolved in
3 ml of THF, admixed with 100 mg of succinic anhydride and 10 mg of
Chirazyme L-2, lyo., and stirred at 25-27°C. After 29 hours, the
reaction
was ended by filtering off the enzyme. A sample which had been
concentrated by evaporation was used to determine the optical purity both
of the unconverted substrate and of the acylation product formed. The
optical purity of (1S,3R)-3-benzyloxycyclohexan-1-of was 84% ee (HPLC
on Chiralpak AD-H 250 x 4.6; 1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN +
0.1 % TFA), and the optical purity of the succinic acid derivative was



CA 02516623 2005-08-19
64
> 95% ee (HPLC on Chiralcel OD 250 x 4.6; 1 ml/min, 25:1:0.5
heptanelEtOHICH3CN + 0.1 % TFA).
Example 75
Optical resolution of cis-3-benzyloxycyclohexan-1-of
HO,, ,,O
rac.
200 mg of the racemic cis-3-benzyloxycyclohexan-1-of were dissolved in
3 ml of methylene chloride, admixed with 100 mg of succinic anhydride and
10 mg of Chirazyme L-2, lyo., and stirred at 25-27°C. After 29 hours,
the
reaction was ended by filtering off the enzyme. A sample which had been
concentrated by evaporation was used to determine the optical purity both
of the unconverted substrate and of the acylation product formed. The
optical purity of (1S,3R)-3-benzyloxycyclohexan-1-of was > 98% ee (HPLC
on Chiralpak AD-H 250 x 4.6; 1 ml/min, 25:1:0.5 heptane/EtOHICH3CN +
0.1 % TFA), and the optical purity of the succinic acid derivative was
88% ee (HPLG on Chiralcel OD 250 x 4.6; 1 ml/min, 25:1:0.5
heptanelEtOH/CH3CN + 0.1 % TFA).
Example 76
Optical resolution of cis-3-benzyloxycyclohexan-1-of
HO,,, ,,O
rac.
200 mg of the racemic cis-3-benzyloxycyclohexan-1-of were dissolved in
3 ml of acetone, admixed with 100 mg of succinic anhydride and 10 mg of
Chirazyme L-2, lyo., and stirred at 25-27°C. After 29 hours, the
reaction
was ended by filtering off the enzyme. A sample which had been
concentrated by evaporation was used to determine the optical purity both
of the unconverted substrate and of the acylation product formed. The
optical purity of (1S,3R)-3-benzyloxycyclohexan-1-of was > 99% ee (HPLC



CA 02516623 2005-08-19
on Chiralpak AD-H 250 x 4.6; 1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN +
0.1 % TFA), and the optical purity of the succinic acid derivative was
78% ee (HPLC on Chiralcel OD 250 x 4.6; 1 ml/min, 25:1:0.5
heptane/EtOH/CHgCN + 0.1 % TFA).
5
Example 77
Optical resolution of cis-3-benzyloxycyclohexan-1-ol,
separation of alcohol and succinic acid derivative
E
1
HO,, ,,O \
rac.
8.15 g (39.5 mmol) of the racemic cis-3-benzyloxycyclohexan-1-of were
dissolved in 120 ml of THF, admixed with 3.9 g (39.0 mmol) of succinic
anhydride and 390 mg of Chirazyme L-2, lyo., and stirred at 22-25°C.
After
approx. 40% conversion, the reaction was ended by filtering off the
enzyme. The filtrate was concentrated under reduced pressure. The
residue was taken up with tBuOMe and extracted intensively three times
with in each case 100 ml of sat. aqueous NaHC03 solution. The organic
phase was dried (MgS04) and concentrated under reduced pressure; '
G
yield: 4.4 g; the optical purity of (1S,3R)-3-benzyloxycyclohexan-1-of was
70% ee (HPLC on Chiralpak AD-H 250 x 4.6; 1 ml/min, 25:1:0.5
heptane/EtOH/CH3CN + 0.1 % TFA). The optical purity of the succinic acid
derivative dissolved in the combined aqueous phases was > 99% ee
(HPLC on Chiralcel OD 250 x 4.6; 1 mllmin, 25:1:0.5
heptane/EtOH/CH3CN + 0.1 % TFA).
By treating with cons. sodium hydroxide solution, the aqueous solution of
the succinic acid derivative was hydrolyzed chemically. The (1R,3S)-3-
benzyloxycyclohexan-1-of formed was extracted with tBuOMe; yield: 2.9 g.
Example 78
Optical resolution of cis-3-benzyloxycyclohexan-1-ol,
separation of alcohol and succinic acid derivative



CA 02516623 2005-08-19
66
HO,,, ,,O \
rac.
5.06 g (24.5 mmol) of the racemic cis-3-benzyloxycyclohexan-1-of were
dissolved in 75 ml of THF, admixed with 2.52 g (25.2 mmol) of succinic
anhydride and 3.1 g of Novozym 435, and stirred at 22-25°C. After 28.5
h,
the reaction was ended by filtering off the enzyme. The filtrate was
concentrated down fio approx. 15 ml under reduced pressure. The residue
was admixed with 30 ml of water and the remaining THF was distilled off
under reduced pressure. 15 ml of saturated aqueous NaHC03 solution, 15
ml of water and 30 ml of methylene chloride were added and the mixture
was stirred intensively for 15-30 min. After phase separation, the organic
phase was extracted first with 90 ml of saturated aqueous NaHC03 solution
and 150 ml of water, and then with 15 ml of saturated aqueous NaHC03
solution and 30 ml of water, and washed twice with 30 ml of water. The
organic phase was dried (MgS04) and concentrated under reduced
pressure; yield: 2.52 g (50%), [a] D +12.1 ° (c = 1.0, MeOH); the
optical
purity of (1S,3R)-3-benzyloxycyclohexan-1-of was > 99% ee (HPLC on
Chiralpak AD-H 250 x 4.6; 1 ml/min, 25:1:0.5 heptane/EtOHICH3CN +
0.1 % TFA).
The combined aqueous phases were admixed with 20 ml of (glacial) acetic
acid and extracted twice with 20 ml of methylene chloride. The organic
phase was dried (MgS04) and concentrated; yield: 3.55 g (47%) of the
succinic acid derivative; the optical purity was > 99% ee (HPLC on
Chiralcel OD 250 x 4.6; 1 ml/min, 25:1:0.5 heptanelEtOHICH3CN + 0.1
TFA); 'H NMR (CDC13) 8: 1.2-1.43 (m, 4H), 1.82 (m, 1 H), 1.93 (m, 1 H),
2.04 (m, 1 H), 2.40 (m, 1 H), 2.58-2.70 (m, 4H), 3.39 (m, 1 H), 4.54 (m, 2H),
4.71 (m, 1 H); 7.23-7.36 (m, 5H).
Example 79
Preparation of racemic cis-3-(tert-butyldimethylsilanyloxy)cyclohexanol
HO. .OSiMe2tBu
rac



CA 02516623 2005-08-19
67
TBDMSCI (28.62 g, 1.1 eq) was added slowly to a solution, cooled to
10°C,
of 1,3-cyclohexanediol (20.05 g, 0.173 mol), Et3N (28.79 ml, 1.2 eq) and
DMAP (0.844 g, 0.04 eq) in CH2Clz (600 ml). After stirring at 20-23°C
for 18
hours, the reaction mixture was washed with H20 (2 x 100 ml). The organic ,
phase was washed with sat. NH4C1 (2 x 100 ml), dried over MgS04 and
concentrated under reduced pressure. Chromatography on silica gel, (20:1 '
n-heptane/ethyl acetate) gave 18.77 g (47%) of the desired monsilyl ether;
'H NMR (CDC13) 8: 0.0-0.1 (m, 6H), 0.8-0.9 (m, 9H), 1.2-2.0 (m, 8H), 3.2 (s,
br., 1 H), 3.8 (m, 1 H), 3.95 (m, 1 H).
Example 80
Preparation of cis-(1 S, 3R)-3-(tert-butyldimethylsilanyloxy)cyclohexanol
HO. .OSiMe2tBu
770 mg of racemic cis-3-(tert-butyldimethylsilanyloxy)cyclohexanol were
dissolved in 10 ml of acetone, admixed with 0.36 ml of vinyl acetate and
400 mg of Novozym 435 and stirred at 21-24°C. After 47 h (approx. 50%
conversion), the reaction was ended by filtering off the enzyme and the
solution was concentrated by evaporation under reduced pressure.
Chromatography of a portion of silica gel (3:1 n-heptane/ethyl acetate)
gave (1 S,3R)-3-(tert-butyldimethylsilanyloxy)cyclohexanol having [a] o
+12.8° (c = 1.0, MeOH).

Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Administrative Status , Maintenance Fee  and Payment History  should be consulted.

Administrative Status

Title Date
Forecasted Issue Date Unavailable
(86) PCT Filing Date 2004-02-19
(87) PCT Publication Date 2004-09-10
(85) National Entry 2005-08-19
Examination Requested 2009-02-19
Dead Application 2012-02-20

Abandonment History

Abandonment Date Reason Reinstatement Date
2011-02-21 FAILURE TO PAY APPLICATION MAINTENANCE FEE
2011-05-09 R30(2) - Failure to Respond

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $400.00 2005-08-19
Maintenance Fee - Application - New Act 2 2006-02-20 $100.00 2005-08-19
Registration of a document - section 124 $100.00 2005-10-28
Registration of a document - section 124 $100.00 2006-03-20
Maintenance Fee - Application - New Act 3 2007-02-19 $100.00 2007-01-19
Maintenance Fee - Application - New Act 4 2008-02-19 $100.00 2008-01-14
Maintenance Fee - Application - New Act 5 2009-02-19 $200.00 2009-01-30
Request for Examination $800.00 2009-02-19
Maintenance Fee - Application - New Act 6 2010-02-19 $200.00 2010-02-04
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
SANOFI-AVENTIS DEUTSCHLAND GMBH
Past Owners on Record
AVENTIS PHARMA DEUTSCHLAND GMBH
HOLLA, WOLFGANG
KEIL, STEFANIE
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
Documents

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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Abstract 2005-08-19 1 61
Cover Page 2005-10-21 1 28
Claims 2005-08-19 8 208
Description 2005-08-19 67 2,357
Representative Drawing 2005-08-19 1 1
Correspondence 2005-10-19 1 27
PCT 2005-08-19 4 115
Assignment 2005-08-19 4 86
Assignment 2005-10-28 2 53
Assignment 2006-03-20 28 1,777
PCT 2007-03-23 5 205
Prosecution-Amendment 2009-02-19 1 42
Prosecution-Amendment 2009-04-17 1 31
Prosecution-Amendment 2010-11-08 2 66