PROCEDE POUR DES 2-DESOXYGLUCOSIDES

PROCESS FOR 2-DEOXYGLUCOSIDES

Abrégé anglais

2085748 9119724 PCTABS00008
The invention provides a process for the preparation of methyl
tri-O-acetyl-2-deoxyglucoside by the reaction of
tri-O-acetyl-D-glucal with methanol in the presence of hydrogen bromide or a
source thereof. .alpha.-Methyl tri-O-acetyl-2-deoxyglucoside is
especially useful as an intermediate in the preparation of
pharmaceutically useful mevalonic acid derivatives.

Revendications

WO 91/19724 PCT/GB91/00995
- 8 -
CLAIMS
1. A process for the preparation of methyl tri-
O-acetyl-2-deoxyglucoside of the formula:
<IMG> I
which comprises the reaction with methanol of a compound of
the formula:
<IMG> II
in the presence of a catalyst comprising hydrogen bromide
or a source thereof.
2. A process according to claim 1 in which the
methyl tri-O-acetyl-2-deoxyglucoside product comprises at
least 90% of .alpha.-methyl tri-O-acetyl-2-deoxyglucoside of the
formula:

WO 91/19724 PCT/GB91/00995
- 9 -
<IMG> Ia
3. A process according to claim 1 or 2 in which
the reaction is carried out in, as solvent, chloroform,
dichloromethane, toluene, ethyl acetate, dimethylformamide,
dimethyl sulphoxide, N-methylpyrrolidinone, acetone,
tetrahydrofuran or t-butyl methyl ether.
4. A process according to claim 1 or 2 in which
the process is carried out in, as solvent, acetonitrile or
1,2-dimethoxyethane.
5. A process according to any one of the
preceding claims in which the reaction is carried out in
the presence of, as catalyst, hydrobromic acid or
triphenylphosphine hydrobromide.
6. A process according to any one of the
preceding claims in which the molar proportion of catalyst
to starting material of formula II is at least 10%.
7. A process according to claim 6 in which the
molar proportion is from 20% to 50%.
8. A process according to any one of the

WO 91/19724 PCT/CB91/00995
- 10 -
preceding claims in which the reaction is carried out under
an inert atmosphere and at or near room temperature.
9. A process for the preparation of .alpha.-methyl 2-
deoxyglucoside of the formula
<IMG> III
which comprises the hydrolysis of a compound of the
formula:
<IMG> Ia
10. Use of a compound of the formula Ia depicted
in claim 9 in the preparation of mevalonic acid analogues.
11. Use of a compound of the formula III
depicted in claim 9 in the preparation of mevalonic acid
analogues.

Description

VO 91/19724 2C8579~8 PCr/GB91/00995
DESCRIPIION
PROCESS FOR 2 DEOXYGLUCOSIDES
THIS INVENTION relates to a new process for the
preparation of intermediates useful in the preparation
of pharmaceuticals, to their use in the preparation of
said pharmaceu~.icals, and to pharmaceuticals prepared
from said intermediates.
The new process of the present invention, which
has not ~ee~ described specifically hitherto, is for
-the preparation o~ methyl tri-O-acetyl-2-deoxyglucoside
hereinafter depicted in formula I from tri-O-acetyl-D-
glucal hereinafter depicted in formula II.
The pxocess is carried out by reaction with
methanol in a suitable solvent selected from, for
example, chloroform, dichloromethane, toluene, ethyl
acetate, dimethylformamide, dimethyl sulphoxide,
N-methylpyrrolidinonë 7 acetone, and ethers, e.g.
tetrahydrofuran and t-butyl methyl ether, and, more
especially, acetonitrile and 1,2-dimethoxyethane, and in
the presence of a catalyst comprising hydrogen bromide
or a source thereof, for ex~mple h~drobromic acid or
triphenylphosphine hydrobromide. Preferably the
molar proportion of catalyst to starting material of
formula II is at least 10~, preferably from 20% to 50%
or more. The reaction is conveniently carried out

~Osl/l9724 2C85748 pcT/GBsl/oo995
under an inert atmosphere, e~g. nitrogen, and at or
near room temperature.
The compound of formula Ia is a key intermediate
in a reaction sequence which permits the stereospecific
preparation of analoguès of mevalonic acid without the
necessity to use potentially hazardous mercury
compounds employed in previously known processes
described, for example, by Rosen et al, J. org. Chem.,
~. _
1984, 49, 3g94-4003 and Corey et al, J. Am. Chem. Soc.,
--1980, 102, 1439.
The use of compounds prepared by the pxocess of
the present invention in a reaction seguence which
permits the preparation of analogues of mevalo~ic acid,
and analogues of mevalonic acid prepared thereby, are
further features of the present ~nvention.
The said analogues of mevalonic acid are
valuable pharmaceutically active compounds, more
especially competitive inhibitors of 3-hydroxy-3-
methylglutaryl coenzyme A reductase, and are
consequently inhibitors of cholesterol biosynthesis
and as a result are of use in the prevention or
treatment of hypercholesterolaemic and
hyperlipoproteinaemic states, atherosclerosis and
as~sociated conditions.
Examples of such mevalonic acid analogues are
described, for example, in the specifications of
... ; ' , . '
.

2~57~
"'091/197~ PC~/GB91/00995
granted South African Patents Nos. 88/5~52 and 89/0645 and
of their equivalents in other countries, for example United
states Patent Applications Nos. 07~230038 and 07~302389.
The process of the present invention has good
stereospecificity, i.e. the product contains a high ratio.
of ~-methyl tri-O-acetyl-2-deoxyglucoside, hereinafter
depicted in formula Ia, to ~-methyl tri-O-acetyl-2-
deoxyglucoside, he~einafter depicted in formula Ib~
typically a ratio of up to lO:l or more. The compound of
.._
formul~ Ia may be sPparated by the application or
adaptation of known methods, for example by chromatography,
or, especially when the product contains at least 90% of
Ia, it may be used as such.
The ~-methyl tri-0-acetyl-2-deoxyglucoside anomer
is the preferred product because currently it is of greater
utility in the preparation of pharmaceuticals than is the
~-methyl tri-O-acetyl-2-deoxyglucoside anomer.
The compound of formula Ia may be hydrolysed by
the application or adaptation of known methods to give ~-
methyl 2-deoxyglucoside, hereinafter depicted in formula
III, which may thereafter be elaborated to prepare the said
mevalonic acid analogues, by the application or adaptation
of known methods.
Compounds of formula II may be prepared by the
application or adaptation of known methods.
- By the ~erm "known methods" as used in this
specifica~ion is meant methods used heretofore or known in
the literature.

2~8574~3
~0 91/19724
P~/CB91 /00995
~ 4 -
-- C~3COOC~2
C~3COO '~\ ~ OC 3
C~3COO
C~ CGOC~
. CII3COO ~),.. ,OC~I3 Ia
.
CE3COO
C~3COOC~2
CH3CCC ""~~ CC~3 Ib
C~3C
C~3~~2
C~13COO "' ' S~ II
CEI3COO
IIOCE[2~_o
HO ~
~0

2~ 74~
`VO9l/l9724 PCT/GB91/00995
-- 5 --
The following Examples illustrate the present
invention.
In the Examples, "% cat" denol:es the molar
proportion of catalyst to compound ol formula II in
the initial reactio~ mixture, "TPHB" denotes triphenyl-
phosphine hydrobromide, "aq.~3r" denotes 48%w/w
hydrobromic acid, "DCM" denotes dichloromethane, "MeCN"
denotes acetonitrile, "DME" denotes 1,2-dimethoxy-
. .~. _
-ethane,'"% yield" denotes the percentage yield of
compound of formula I based upon the starting material
of formula II, and ":~" denotes the ratio of the
anomers in the product ~determined by examination of
the nuclear magnetic resonance spectrum of the crude
product in deuterochloroform).
` EX~MPLES 1 to 10
No.~ catcatal~st solvent % yield :~
1 5 TPHB DCM 75 2:1
2 5 TPHB MeCN 86 4:1
3 10 TP B MeCN 81 8:1
4 20 TP B MeCN 81 9:1
TP B MeCN 82 lO:1
6 20 TPHB DME 81 10:1
7 20 aq. B r DME 53 5:1
8 5 aq.~Br DME 38 2:1
9 5 ' aqOHBr MeCN 64 4:1
lQ 20 ~3r DME ~ 3:1

~C85~48
--~091/19724 PCT/GB91/00995
In Examples 1 to lO the catalyst was added to a
10%w/w solution of tri-O-acetyl-D-glucal (4~moles) and
methanol ~6mmoles) in the solvent at room temperature
under nitrogen and stirred overnight at room
temperature. The solution was then concentrated and
the product was subjected to chromatography on silica
gel, eluting with a mixture of ethyl acetate ancl
cyclohexane (l:3v/v) to give a mixture of a-methyl
tri-O-ace~yl-2-deoxyglucoside and ~-methyl tri-O-
- -- acetyl-2-deoxyglucoside in the ratio stated in the
table.
*In Example lO the product was a complex
mixture.
EXAMPLE 11
% cat cataly~t solvent % ~ield a:~
20 HBr MeCN 93 5:l
A 25%w/w solution of hydrogen bromide in 6
mmoles of methanol was added to a lO~w/w solution of
tri-O-acetyl-D-glucal (4mmoles) in acetonitrile a~ room
temperature under nitrogen and stirred overnight at
room temperature. The solution was then concentrated
and the residue was partitioned between water and
dichloromethane. The organic layer was washed with
saturated aqueous sodium bicarbonate solution and then
with water, dried over magnesium sulphate, and
concentrated in vacuo to give a mixture of a-methyl
- ' : ' ' ' :,

2~857~8
~91/19724 PCT/GB91/00995
-- 7 --
tri-O-acetyl-2-deoxyglucoside and ~-methyl tri-O-
acetyl-2-deoxyglucoside in the ratio 5:1.