Title: Process for the preparation of 2-(6-substituted-1,-3-dioxane-4-yl)acetic acid derivatives
Abstract: The invention relates to the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives of formula (1), where X stands for a leaving group, and R.sup.1, R.sub.2, and R.sub.3 each independently stand for an alkyl group with 1-3 carbon atoms from 4-hydroxy-6-X-substituted-methyl-tetrahydropyran-2-one compounds, where X is as defined above, with the aid of an acetalization agent, in the presence of an acid catalyst. The invention also relates to the novel compounds of formula (1) as well as salts and acids to be prepared from these, with the OR.sub.3 group in formula (1) being replaced by an OY group, where X, R.sub.1 and R.sub.2 have the meanings defined above and where Y stands for an alkaline (earth) metal or a substituted or unsubstituted ammonium group or stands for hydrogen, and to the novel compounds of formula (2). The products concerned are, after conversion into the t-butyl ester of 2-(6-hydroxymethyl-1,3-dioxane-4-yl)acetic acid, important as intermediary products in the preparation of statins.
Patent Number: 6,870,059 Issued on 03/22/2005 to Kooistra, et al.
| Inventors:
|
Kooistra; Jacob Hermanus Mattheus Hero (Venlo, NL);
Zeegers; Hubertus Josephus Marie (Baarlo, NL);
Mink; Daniel (Eupen, NL);
Mulders; Joannes Maria Cornelis Antonius (Geleen, NL)
|
| Assignee:
|
Astrazeneca UK Ltd. (London, GB)
|
| Appl. No.:
|
333351 |
| Filed:
|
January 17, 2003 |
| PCT Filed:
|
July 12, 2001
|
| PCT NO:
|
PCT/NL01/00535
|
| 371 Date:
|
January 17, 2003
|
| 102(e) Date:
|
January 17, 2003
|
| PCT PUB.NO.:
|
WO02/06266 |
| PCT PUB. Date:
|
January 24, 2002 |
Foreign Application Priority Data
| Current U.S. Class: |
549/375; 549/374 |
| Intern'l Class: |
C07D 319//06 |
| Field of Search: |
549/374,375,230
548/252,253
|
References Cited [Referenced By]
U.S. Patent Documents
| 3325466 | Jun., 1967 | Anderson et al. | 530/335.
|
| 5278313 | Jan., 1994 | Thottathil et al. | 548/252.
|
| 5457227 | Oct., 1995 | Thottathil et al. | 560/174.
|
| 5594153 | Jan., 1997 | Thottathil et al. | 549/374.
|
| 6331641 | Dec., 2001 | Taoka et al. | 549/292.
|
| 6340767 | Jan., 2002 | Nishiyama et al. | 554/115.
|
| 6344569 | Feb., 2002 | Mitsuda et al. | 549/375.
|
| Foreign Patent Documents |
| 1024139 | Aug., 2000 | EP.
| |
| 0 862 646 | Apr., 2002 | EP.
| |
| 885516 | Dec., 1961 | GB.
| |
| 04266879 | Sep., 1992 | JP.
| |
| WO 91/13876 | Sep., 1991 | WO.
| |
| WO 93/06235 | Apr., 1993 | WO.
| |
| WO 96/31615 | Oct., 1996 | WO.
| |
| WO 97/19185 | May., 1997 | WO.
| |
| WO 99/57109 | Nov., 1999 | WO.
| |
| WO 00/08011 | Feb., 2000 | WO.
| |
| WO 00/34264 | Jun., 2000 | WO.
| |
| WO 00/68221 | Nov., 2000 | WO.
| |
Other References
Bennett, F., et al., "Methyl (3R)-3-Hydroxyhex--5-Enoate" Journal of the
Chemical Society, Perkin Transactions 1. 1:133-140 (1991).
Chevallet et al., Tetr. Let. 34(46):7409 (1993).
Crowther et al., Org. Synth. 51:96 (1971).
Inanaga et al., Bull. Chem. Soc. Japan 52(7):1989 (1979).
International Search Report mailed on Oct. 9, 2001, for PCT patent
application No. PCT/NL01/00535, filed on Jul. 12, 2001, 4 pages.
Murakami et al., Heterocycles 31(11):2055 (1990).
Murphy and Koehler, J. Org. Chem. 35:2429 (1970).
Rayle and Fellmeth, Org Process R&D 3:172 (1999).
Sakaki, J., "Lipase Catalysed Asymetric Synthesis of
6-(3-Chloro-2-Hydroxypropyl)-1,3-Dioxin-4-Ones" Tetrahedron: Asymmetry
2(5):343-6 (1991).
Takeda et al., Synthesis p. 1063 (1994).
Thierry et al., Tetr. Let. 39:1557 (1998).
Watanabe, M., et al., Drugs of the Future 24(5):511-513 (1999).
Watanabe et al., Bioorg. & Med. Chem. 5(2):437-444 (1997).
Weissenefels et al., Z. Chem 12(7):264 (1972).
Ziegler and Berger, Synth. Comm. 9:539-543 (1979).
Mar., Advanced Organic Chemistry, reactions, Mechanisms and Structure 1992,
p. 392.
Murphy and Koehler, J. Org. Chem. (1970) 35(7):2429-2430.
|
Primary Examiner: Tsang; Cecilia J.
Assistant Examiner: Oh; Taylor V.
Attorney, Agent or Firm: Morrison & Foerster LLP
Claims
What is claimed is:
1. A method for the preparation of a compound of formula 1
##STR7##
where X is a leaving group, and each R.sub.1, R.sub.2, and R.sub.3 is
independently an alkyl group with 1-3 carbon atoms, which method comprises
treating a compound of formula 2
##STR8##
where X is as defined above, with an acetalization agent in the presence of
an acid catalyst.
2. The method of claim 1, wherein X is Cl.
3. The method of claim 1, wherein R.sub.1 =R.sub.2 =R.sub.3 =CH.sub.3.
4. The method of claim 1, which further includes hydrolyzing the compound
of formula (1) in the presence of a base and water to form the
corresponding salt of formula 3
##STR9##
wherein X, R.sub.1 and R.sub.2 are as defined in claim 1 and Y is an
alkaline metal, an alkaline earth metal or a substituted or unsubstituted
ammonium group.
5. The method of claim 4, wherein Y is Na, Ca or tetraalkyl ammonium.
6. The method of claim 4, which further comprises converting the salt
obtained to a free acid wherein Y in formula 3 is H.
7. The method of claim 4, wherein the
2-(6-substituted-1,3-dioxane-4-yl)acetic acid of formula 3 has both an
enantiomeric and a diastereomeric excess of 4R,6S higher than 99%.
8. The method of claim 4, which further comprises the converting the salt
of formula (3) into the corresponding ester of formula 1a, where R.sub.3
=t-butyl
##STR10##
9. The method of claim 8, which further comprises converting of the
resulting ester of formula 1a, where R.sub.3 stands for t-butyl, into the
t-butyl ester of 2-(6-hydroxymethyl-1,3-dioxane-4-yl)acetic acid.
10. The method of claim 9, which further comprises converting the t-butyl
ester of 2-(6-hydroxymethyl-1,3-dioxane-4-yl)acetic acid into a statin.
11. The method of claim 1, wherein said compound of formula (2) is in the
(4R,6S) form.
12. The method of claim 11, wherein said compound of formula 2 has a
length/diameter ratio between 1:1.5 and 1:6, and a particle length between
0.05 and 2 mm.
13. The method of claim 11, wherein X in said compound of formula 2 is a
halogen, a tosylate group, a mesylate group, an acyloxy group, an
aryloxy-substituted benzene sulfonyl group, or a nitro-substituted benzene
sulfonyl group.
14. The method of claim 6, which further comprises converting the acid
obtained into the corresponding ester of formula 1a, where R.sub.3
=t-butyl
##STR11##
15. The method of claim 12, wherein said compound of formula 2 has a
length/diameter ratio between 1:1.5 and 1:6.
16. The method of claim 12, wherein said compound of formula 2 has a
particle length between 0.1 and 1 mm.
Description
The invention relates to a process for the preparation of a
2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivative of formula 1
##STR1##
where X stands for a leaving group, and R.sub.1, R.sub.2 and R.sub.3 each
independently stand for an alkyl group with 1-3 carbon atoms, starting
from a compound of formula 2
##STR2##
where X is as defined above, use being made of a suitable acetalization
agent, in the presence of an acid catalyst.
The invention also relates to the new compounds of formula 1, as well as
salts and acids of formula 3 that can be obtained therefrom
##STR3##
where R.sub.1 and R.sub.2 have the above-mentioned meanings and where Y
stands for an alkaline (earth)metal or a substituted or non-substituted
ammonium group or stands for hydrogen.
Applicant has surprisingly found that the 2-(6-substituted
1,3-dioxane-4-yl)-acetic acid derivative can be obtained selectively and
in a high yield from the corresponding compound of formula (2), it being
possible to prepare these products, which are relatively little stable,
under mild conditions. This is all the more interesting since this
provides a simple route via the corresponding salt, the corresponding
t-butyl ester, and the 2-hydroxymethyl-substituted compound as
intermediates in the preparation of HMG-CoA reductase inhibitors.
Optionally the conversion proceeds (depending on the reaction conditions
chosen) via an intermediary salt or ester, with the ring in the compound
according to formula (2) being opened.
An added advantage of the process according to the invention is that both
the starting compounds of formula (2) and the products of formula 3 are
found to be crystalline compounds. This is advantageous in obtaining
products with a (chemically and stereochemically) high purity. This is
important in particular in view of the intended pharmaceutical
application. For the intended application in particular the
(4R,6S)-2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivative is
important. It can be prepared from the corresponding
6-substituted-2,4,6-trideoxy-D-erythrohexose. The invention, therefore,
also relates to the starting compounds of formula 1, in particular where
X.dbd.Cl, and to particles of such compounds. In particular more than 90
wt. % of the particles has a length/diameter ratio between 1:1.5 and 1:6,
preferably between 1:2 and 1:4.4 and a length of the particles between
0.05 and 2 mm, in particular between 0.1 and 1 mm. The invention also
relates to such particles. The compound of formula II gives clear
crystalline particles with a sharp melting point of 73-74 .degree. C. The
products of formula 3 derived from the
(4R,6S)-2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivative of
formula 1 can according to the invention be prepared with an enantiomeric
excess (e.e.) of more than 95%, in particular more than 99.5%, and with a
diastereomeric excess (d.e.) of more than 90%, in particular more than
99.5%.
Examples of suitable leaving groups X that can be applied in the process
according to the invention are halogens, in particular Cl, Br or l;
tosylate groups; mesylate groups; acyloxy groups, in particular acetoxy
and benzoyloxy groups; an aryloxy-, in particular benzyloxy-, or a
nitro-substituted benzene sulphonyl group. For practical reasons Cl is
preferably chosen as leaving group.
The groups R.sub.1, R.sub.2 and R.sub.3 each separately stand for an alkyl
group with 1-3 carbon atoms, preferably methyl or ethyl. In practice
R.sub.1.dbd.R.sub.2.dbd.R.sub.3 =methyl is most preferred.
Examples of suitable acetalization agents that can be applied in the
process according to the invention are dialkoxypropane compounds, with the
alkoxy groups each preferably having 1-3 carbon atoms, for instance
2,2-dimethoxypropane or 2,2-diethoxypropane; alkoxypropene, with the
alkoxy group preferably having 1-3 carbon atoms, for instance
2-methoxypropene or 2-ethoxypropene. Most preferred is
2,2-dimethoxypropane. This can optionally be formed in situ from acetone
and methanol, preferably with water being removed.
As acid catalyst use can be made of the acid catalysts known for
acetalization reactions, preferably non-nucleophilic strong acids, for
example sulphonic acids, in particular p-toluene sulphonic acid, methane
sulphonic acid of camphor sulphonic acid; inorganic acids with a
non-nucleophilic anion, for example sulphuric acid, phosphoric acid: acid
ion exchangers, for example DOWEX; or solid acids, for example the
so-called heteropolyacids.
The acetalization can be carried out without using a separate solvent; if
desired the reaction can also be carried out in an organic solvent.
Examples of suitable organic solvents are ketones, in particular acetone,
hydrocarbons, in particular aromatic hydrocarbons, for example toluene,
chlorinated hydrocarbons, for example methylene chloride.
The temperature at which the acetalization reaction is carried out
preferably lies between -20.degree. C. and 60.degree. C., in particular
between 0.degree. C. and 30.degree. C. The acetalization reaction is
preferably carried out under an inert atmosphere.
The molar ratio of acetalization agent to starting compound of formula (2)
preferably lies between 1:1 and 20:1, in particular between 3:1 and 5:1.
Using an organic solvent the molar ratio is in particular between 1:1 and
2:1.
The molar ratio of acid catalyst to starting compound of formula (2)
preferably lies between 1:1 and 0.001:1, in particular between 0.01:1 and
0.05:1.
The resulting 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivative can
subsequently be hydrolyzed in the presence of a base and water to form the
corresponding salt of formula 3
##STR4##
where Y stands for an alkaline metal, an alkaline earth metal, or a
substituted or unsubstituted ammonium group, preferably Na, Ca or a
tetraalkyl-ammonium compound. Optionally, the hydrolysis is followed by
conversion to the acetic acid according to formula 3 with Y.dbd.H.
The hydrolysis of the compound of formula (3) is preferably carried out
with at least 1 base equivalent, in particular 1-1.5 base equivalents,
relative to the compound of formula (3). In principle a larger excess can
be used, but in practice this usually does not offer any advantages.
The reaction is preferably carried out at a temperature between -20.degree.
C. and 60.degree. C., in particular between 0.degree. C. and 30.degree. C.
The hydrolysis can for example be carried out in water, an organic solvent,
for example an alcohol, in particular methanol or ethanol, an aromatic
hydrocarbon, for example toluene, or a ketone, in particular acetone or
methyl isobutyl ketone (MIBK), or a mixture of an organic solvent and
water, optionally catalysed by a phase transfer catalyst (PTC) or addition
of a cosolvent.
The hydrolysis can also be carried out enzymatically, the desired
diastereomer optionally being hydrolyzed selectively.
Examples of enzymes that can suitably be used in the process according to
the invention are enzymes with lipase or esterase activity, for example
enzymes from Pseudomonas, in particular Pseudomonas fluorescens,
Pseudomonas fragi; Burkholderia, for example Burkholderia cepacia;
Chromobacterium, in particular Chromobacterium viscosum; Bacillus, in
particular Bacillus thermocatenulatus, Bacillus licheniformis;
Alcaligenes, in particular Alcaligenes faecalis; Aspergillus, in
particular Aspergillus niger, Candida, in particular Candida antarctica,
Candida rugosa, Candida lipolytica, Candida cylindracea; Geotrichum, in
particular Geotrichum candidum; Humicola, in particular Humicola
lanuginosa; Penicillium, in particular Penicillium cyclopium, Penicillium
roquefortii, Penicillium camembertii; Rhizomucor, in particular Rhizomucor
javanicus, Rhizomucor miehei; Mucor, in particular Mucor javanicus;
Rhizopus, in particular Rhizopus oryzae, Rhizopus arhizus, Rhizopus
delemar, Rhizopus niveus, Rhizopus japonicus, Rhizopus javanicus; porcine
pancreas lipase, wheat germ lipase, bovine pancreas lipase, pig liver
esterase. Preferably, use is made of an enzyme from Pseudomonas cepacia,
Pseudomonas sp., Burkholderia cepacia, porcine pancreas, Rhizomucor
miehei, Humicola lanuginosa, Candida rugosa or Candida antarctica or
subtilisin. If an enantioselective enzyme is used, even further enantiomer
enrichment is realized during the hydrolysis. Such enzymes can be obtained
using commonly known technologies. Many enzymes are produced on a
technical scale and are commercially available.
The salts (acids) obtained are novel. The invention therefore also relates
to these products of formula 3
##STR5##
where X stands for a halogen, in particular Cl, Br or l, a tosylate or
mesylate group, an acyloxy group with 3-10 carbon atoms, or a
nitro-substituted benzene sulphonyl group and Y stands for H, an alkaline
(earth) metal, or a substituted or unsubstituted ammonium group.
The resulting salt of formula 3 can subsequently be converted into the
corresponding t-butyl ester (formula 1a with R.sub.3 =t-butyl), in a way
known per se.
##STR6##
In the process according to the invention the compound of formula (3) can
for example be esterified to form the corresponding tert.butyl ester using
the following methods, which in general are described in literature:
reaction with isobutene and strong acid, for example paratoluene sulphonic
acid (pTS), sulphuric acid or a strongly acidic ion exchanger (U.S. Pat.
No. 3,325,466);
reaction via the acid chloride and t-butanol, under the influence of a
base, for example triethylamine (Et.sub.3 N), dimethylamino pyridine
(DMAP). The acid chloride can be prepared with the aid of for example
SOCl.sub.2, POCl.sub.3, (COCl).sub.2 and catalyzed by for example dimethyl
formamide (DMF) (J. Org. Chem. 35 2429 (1970));
reaction via the acid chloride with Li-t-butanolate (Org. Synth. 51 96
(1971));
transesterification with t-butyl acetate under the influence of a strong
acid (Z. Chem. 12(7) 264 (1972));
reaction of the salt with t-butyl bromide, preferably in DMF, dimethyl
acetamide (DMAA), 1-methyl-2-pyrrolidinone(NMP) and using a phase transfer
catalyst (PTC) (Tetr. Let. 34 (46) 7409 (1993));
reaction of the acid with t-butanol, 1,3-dicyclohexyl carbodiimide (DCC)
and DMAP (Synth. Comm. 9,542 (1979));
reaction of the acid with t-butyl-trichloro acetamidate (Tetr. Let. 39,
1557 (1998));
reaction of the salt with carboxyl diimidazole (CDl) and t-butanol;
reaction of the acid with pivaloyl chloride and t-butanol under the
influence of DMAP or N-methyl-morpholin (NMM) (Bull. Chem. Soc. Japan 52
(7) 1989 (1979));
reaction of the salt with di-tert.butyl dicarbonate, DMAP and t-butanol
(Synthesis 1063 (1994));
reaction of the acid with cyanuric chloride and pyridine or triethylamine
(Org Process R&D 3, 172 (1999); Heterocycles 31 11, 2055 (1990)).
The resulting t-butyl ester of 2-(6-substituted-1,3-dioxane-4-yl)acetic
acid can subsequently be converted into the
2-(6-hydroxymethyl-1,3-dioxane-4-yl)acetic acid, for example as described
in U.S. Pat. No. 5,594,153 or in EP-A-1024139, in the presence of a
tetraalkyl ammonium halogenide and/or a carboxylic acid in the salt, via
conversion into a compound of formula la with R.sub.3 =t-butyl and X=an
acyloxy, for example an acetoxy group. The acyloxy group can subsequently
be converted via solvolysis, in a way otherwise generally known, to a
hydroxyl group. The solvolysis can be performed using a base (Na.sub.2
CO.sub.3, K.sub.2 CO.sub.3, or sodium methanolate in methanol), optionally
by simultaneous distillation of the methyl acetate formed.
The t-butyl ester of 2-(6-hydroxymethyl-1,3-dioxane-4-yl)acetic acid is a
desirable intermediate product in the preparation of various statins, for
example ZD-4522, as described in Drugs of the future, (1999), 24(5),
511-513 by M. Watanabe et al., Bioorg. & Med. Chem. (1997), 5(2), 437-444.
The invention therefore provides a novel, interesting route to these
intermediate products and to the end products, in particular statins.
The starting compounds of formula 2 can for example be obtained as
described in WO-A-96/31615.
The invention will be elucidated with reference to the following examples,
without however being restricted by these.
EXAMPLE I
Preparation of (4R,6S)-4-Hydroxy-6-chloromethyl-tetrahydropyran-2-one
(Compound II; Covered by Formula 2)
At room temperature 2.1 ml bromine was added in 45 minutes to a mixture of
6.7 g (40 mmol) 6-chloro-2,4,6-trideoxy-D-erythro-hexose (compound I;
prepared according to the method described in WO-A-96/31615) and 6.7 g
sodium bicarbonate in 40 ml methylene chloride and 10 ml water. CO.sub.2
gas escaped, while the pH remained at 5. After stirring for one hour,
according to gas-liquid chromatography (GLC) the starting material had
been fully converted. The bromine excess was neutralized with solid
Na.sub.2 S.sub.2 O.sub.3. After phase separation the water phase was
extracted with 2 times 100 ml ethyl acetate. The combined organic phases
were dried over-Na.sub.2 SO.sub.4 and filtered. After rotavap evaporation
5.5 g yellow oil was obtained (82% yield of the compound of formula (2)
with X.dbd.Cl relative to compound 1).
.sup.1 H NMR (200 MHz, CDCl.sub.3): .delta. 1.8-2.1 (m, 2H); 2.6-2.7 (m,
2H); 3.5-3.8 (m, 2H (CH.sub.2 Cl)); 4.4 (m, 1H); 4.9 (m, 1H).
EXAMPLE II
Preparation of (4R,6S)-4-Hydroxy-6-chloromethyl-tetrahydropyran-2-one
(Compound II; Covered by Formula 2)
To a solution of 75 g (450 mmole) compound I in 390 ml water was added 114
g (715 mmole) of bromine at 15-25.degree. C. in 3 hours. The pH of the
reaction mixture was maintained at 5-6 via the simultaneous addition of
sodium carbonate (88 g total amount). The excess of bromine was
neutralized with sodium bisulfite. The product was extracted from the
water phase with ethyl acetate (counter-current extraction).
The product was crystallized from ethyl acetate/ heptane (125 g/62 g).
After cooling to 0.degree. C., the crystals were filtered, washed with 50
ml of heptane/ethyl acetate (w:w=9:1) and dried, yielding 49.2 g (67%
relative to compound 1) of compound II as colourless needles (m.p.
73-74.degree. C.).
EXAMPLE III
Preparation of (4R-cis)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-yl
acetic acid methyl ester (Compound III)
5.5 g of compound II as obtained in example I was added to 20 ml commercial
dimethoxy propane and 100 mg p-toluene sulphonic acid monohydrate at room
temperature. After stirring for one hour at room temperature GLC analysis
showed that full conversion had taken place and a clear solution had been
formed. After addition of 500 mg NaHCO.sub.3 stirring took place for 30
minutes at room temperature. After filtration and rotavap evaporation 7.1
g compound III was obtained as a light-yellow oil (91% relative to
compound II).
.sup.1 H NMR (200 MHz, CDCl.sub.3): .delta. 1.25 (dt, 1H); 1.40 (s, 3H);
1.47 (s, 3H); 1.79 (dt, 1H); 2.42 (dd, 1H); 2.58 (dd, 1H); 3.40 (dd, 1H);
3.52 (dd, 1H); 3.70 (s, 3H); 4.1 (m, 1H); 4.35 (m, 1H).
EXAMPLE IV
Preparation of (4R-cis)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-yl
acetic acid methyl ester (Compound III)
To a solution of 49.2 g (300 mmole) of compound II in 100 ml of toluene was
added 47 g (450 mmole) dimethoxy propane and 850 mg p-toluene sulphonic
acid monohydrate (4.5 mmole).
After stirring for one hour at room temperature, GLC analysis showed
complete conversion of compound II.
The toluene phase was washed with 50 ml of a 0.2N NaOH solution in water.
After evaporation 67 g of compound III was obtained as a light-yellow oil
(94% relative to compound II).
EXAMPLE V
(4R-cis)-(6-chloromethyl)-2,2-dimethyl-1,3-dioxane-4-yl-acetic acid, sodium
salt (Compound IV)
55 g (233 mmol) of compound III was added to 200 ml water. At room
temperature 20 g of a 50% NaOH solution in water was added dropwise in 2
hours at pH=12. The hydrolysis was monitored using GLC. After 20 g the pH
remained constant. Concentrated hydrochloric acid was used to lower the pH
to 10. The water phase was washed with 100 ml ethyl acetate and evaporated
using a rotavap. The oil formed was dried by stripping with absolute
ethanol and toluene. The solid was stirred into 200 ml acetone, filtered
and washed with cold acetone. Yield after vacuum drying: 45.6 g=80% Na
salt relative to compound III.
.sup.1 H NMR (200 MHz, CDCl.sub.3 /CD.sub.3 OD): .delta. 1.21 (dt, 1H);
1.36 (s, 3H); 1.49 (s, 3H); 1.79 (dt, 1H); 2.25 (dd, 1H); 2.45 (dd, 1H);
3.46 (m, 2H); 4.11 (m, 1H); 4.36 (m, 1H).
EXAMPLE VI
(4R-cis)-(6-chloromethyl)-2,2-dimethyl-1,3-dioxane-4-yl-acetic acid, sodium
salt (Compound IV)
Starting from 49.2 g compound 1, a solution of compound III in toluene was
prepared as described in example IV. 5 g methanol and 25 ml of water were
added. At room temperature 25 g of a 50% solution of NaOH in water was
added dropwise in 1 hour.
After stirring for 4 hours at room temperature, GLC analysis indicated
complete hydrolysis.
The excess of base was neutralized to pH 8.5-9.5 with 33% HCl solution in
water. The waterphase was separated and dried via azeotropic distillation
using 470 ml of toluene, yielding 65 g compound IV as a 16 w/w %
suspension in toluene with KF<0.1%.
The suspension can be used for the synthesis of compound V.
EXAMPLE VII
(4R-cis)-(6-chloromethyl)-2,2 dimethyl-1,3-dioxane-4-yl-acetic acid,
t-butyl ester (Compound V)
45.5 g IV, sodium salt (186 mmol) was added to a solution of 159 g
ditert.butyl dicarbonate in 1400 ml dry tert.butanol. After addition of
6.8 g dimethylamino pyridine stirring took place for 16 hours at
40.degree. C. The reaction mixture was poured out into 1500 ml ethyl
acetate and 1000 ml saturated ammonium chloride. The water phase was
re-extracted with 1500 ml ethyl acetate. The combined organic phases were
washed with 600 ml saturated NaCl solution. The organic layer was dried
over Na.sub.2 SO.sub.4, filtered and then evaporated under vacuum,
yielding 51.9 g yellow oil (100% relative to compound IV).
.sup.1 H NMR (200 MHz, CDCl.sub.3): .delta. 1.15-1.33 (m, 1H); 1.40 (s,
3H); 1.45 (s, 3H); 1.47 (s, 9H) 1.77 (dt, 1H); 2.33 (dd, 1H); 2.46 (dd,
1H); 3.40 (dd, 1H); 3.49 (dd, 1H) 4.08 (m, 1H); 4.28 (m, 1H).
EXAMPLE VIII
(4R-cis)-6-[(acetoxy)methyl]-2,2-dimethyl-1,3-dioxane-4-yl-acetic acid,
t-butyl ester (Compound VI)
Starting from 33 g of compound V obtained according to example VII, in 16
hours 29 g of compound VI was obtained at 100.degree. C. according to U.S.
Pat. No. 5,457,227 (using 40 g tetra-n-butyl ammonium acetate and in 200
ml DMF), as a solid after crystallization from 75 ml heptane.
.sup.1 H NMR (200 MHz, CDCl.sub.3): .delta. 1.1-1.3 (dt, 1H); 1.39 (s, 3H);
1.45 (s, 9H); 1.47 (s, 3H); 1.57 (dt, 1H); 2.08 (s, 3H); 2.32 (dd, 1H);
2.46 (dd, 1H); 4.0-4.2 (m, 3H); 4.3 (m, 1H).
EXAMPLE IX
(4R-cis)-6-[hydroxymethyl]-2,2-dimethyl-1,3-dioxane-4-yl-acetic acid,
t-butyl ester (Compound VII)
Starting from 29 g of compound VI according to example V, 25.0 g compound
VII was obtained as a light-yellow oil with e.e.=100%, d.e.=99.9%
(according to GLC) according to U.S. Pat. No. 5,457,227 (use being made of
6.9 g potassium carbonate in 300 ml methanol).
.sup.1 H NMR (200 MHz, CDCl.sub.3): Spectrum was in line with literature
(Synthesis 1014, 1995).
*
