Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
2000-11-22
2001-10-09
Lilling, Herbert J. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C435S221000, C435S130000, C549S423000
Reexamination Certificate
active
06300106
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the production of 3-[2-{(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol methane sulfonate, more particularly to the preparation of a single optical isomer of the product involving the resolution of a racemic mixture of intermediate products.
2. Prior Art
The production of certain pharmaceuticals involves the use 3-[2-{(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol methane sulfonate (MTBS). Related compounds to MTBS are disclosed in PCT Publication No. WO 97/19080. Preparation of MTBS and related compounds has traditionally involved using relatively expensive starting materials. Some of these methods are described in Journal of Organic Chemistry, Vol. 63, No. 6, pp. 1961-1973 (1998) and one synthesis route is shown in the following reaction scheme. In this synthesis technique, (R)-glycidol (graphic formula A) is protected with triphenylmethyl (Tr) to yield trityl glycidol (graphic formula B), and the glycidol ring is opened by treatment with vinylmagnesium bromide to produce the ether of graphic formula C. Allylation of compound C produces the ether of graphic formula D. Ozonolysis of compound D followed by subsequent sodium borohydride reduction yields the diol of graphic formula E which is treated with methane sulfonyl chloride (MsCl) to produce (S)-3-[2-{(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol methane sulfonate (graphic formula F).
This method of producing MTBS is not commercially economical. Accordingly, a need remains for preparing 3-[2-(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol methane sulfonate which uses readily available and relatively inexpensive starting materials.
SUMMARY OF THE INVENTION
This need is met by the method of the present invention according to which the S-isomer or R-isomer of (3,6-dihydro-2H-pyran-2-yl)-methanol is formed via a process which produces a racemic mixture of intermediate reaction products. The racemic mixture is resolved to selectively isolate the desired isomer of the alcohol. The desired isomer of the alcohol is then further reacted to yield 3-[2-(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol methane sulfonate.
The method of the present invention includes the steps of:
(a) reacting 1,3-butadiene with a ketoethanal to form a racemic mixture of a 2-carbonyl-3,6-dihydropyran compound; and
(b) converting the 2-carbonyl-3,6-dihydropyran compound to one isomer of (3,6-dihydro-2H-pyran-2-yl)-methanol.
The method further includes a step of enzymatically resolving the racemic mixture of the dihydropyran derivative produced in step (a) to isolate one isomer of the dihydropyran of step (a) in between steps (a) and (b). Alternatively, the racemic mixture may be converted to a racemic mixture of the alcohol of step (b) and the resulting racemic mixture of the 2-carbonyl-3,6-dihydropyran compound is chemically or enzymatically resolved to isolate the desired isomer of (3,6-dihydro-2H-pyran-2-yl)-methanol
A preferred method of isolating the desired isomer of the 2-carbonyl-3,6-dihydropyran compound of step (a) includes reacting the racemic mixture with a hydrolase, preferably a protease, more preferably a
Bacillus lentus
protease. The isomers of the dihydropyran derivative are selectively hydrolyzed to a carboxylic acid by reaction with the hydrolase creating an aqueous phase containing one isomer and an organic phase containing the other isomer. The organic and aqueous phases are separated from each other to yield an enantiomeric pure mixture comprising the desired isomer. The reduction step (b) preferably includes reacting the dihydropyran derivative with lithium aluminum hydride to form an alcohol.
The R- or S- isomer of (3,6-dihydro-2H-pyran-2-yl)-methanol may be further treated to produce 3-[2-(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol methane sulfonate by the additional steps of:
(c) reacting the alcohol with triphenylmethyl chloride to form a triphenylmethoxy-substituted 3,6-dihydropyran;
(d) ozonolyzing the triphenylmethoxy-substituted 3,6-dihydropyran to form a reaction product;
(e) reducing the reaction product to form a diol; and
(f) reacting the diol with a methanesulfonyl compound to form an isomer of 3-[2-{(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol, methane sulfonate.
Step (c) may include adding a catalyst to the alcohol. In step (d), ozone preferably is bubbled through a solution of the triphenylmethoxy-substituted 3,6-dihydropyran to produce an ozonated solution which is immediately reduced in step (e) without separation by adding a reducing agent such as sodium borohydride to the ozonated solution.
DETAILED DESCRIPTION OF THE INVENTION
The method of the present invention includes following the steps depicted in Reaction A followed by Reactions B or C to produce an isomer of (3,6-dihydro-2H-pyran-2-yl)-methanol and optionally following the steps of Reaction D to produce an isomer of 3-[2-{(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol, methane sulfonate.
In Reaction A, 1,3-butadiene represented by graphic formula I is reacted with a ketoethanal represented by graphic formula II wherein R
1
represents a hydroxyl group, a linear or branched C
1
-C
12
alkoxy group, an unsubstituted or C
1
-C
12
alkyl substituted phenoxy group, or the group —NR
2
R
3
where R
2
and R
3
are the same or different and are hydrogen or C
1
-C
12
alkyl or R
2
and R
3
are joined together to form a 2 to 12 membered ring with one or more of the cyclic atoms being a heteroatom. A preferred heteroatom is the sulfur of a sulfonyl group. Preferably, R
1
is a hydroxyl or C
1
-C
12
alkoxy group. Compounds I and II are dissolved in a suitable solvent such as toluene with a stabilizer such as hydroquinone and heated in an autoclave to produce a racemic mixture of the compound of graphic formula III. The racemic mixture of compound III may be purified by distillation or a similar technique.
In Reaction B, where R
1
is not a hydroxyl group, the enantiomers of graphic formula III are separated by enzyme resolution. The compounds of graphic formula III are treated with a hydrolase such as an aqueous solution of
Bacillus lentus
protease yielding an aqueous phase containing the R-isomer of 3,6-dihydropyran-2-carboxylic acid (not shown) and an organic phase of the desired S-isomer represented by graphic formula IV. Compound IV is separated from the aqueous phase and is reduced with a reducing agent such as lithium aluminum hydride or PMHS (polymethylhydrosiloxane) in a solvent such as tetrahydrofuran (THF) to produce (S)-(3,6-dihydro-2H-pyran-2-yl)-methanol represented by graphic formula V. Other suitable reducing agents include bis(2-methoxyethoxy)aluminum hydride, sodium borohydride and the like. Catalytic hydrogenation may also be used.
Alternate routes of producing an isomer of (3,6-dihydro-2H-pyran-2-yl)-methanol are shown in Reaction C. In Reaction C, compound III from Reaction A is reduced with a reducing agent such as lithium aluminum hydride in a solvent such as THF to produce a racemic mixture of the alcohol of compound Va. Compound Va is reacted with vinyl acetate or a similar compound represented by graphic formula VI (where R
4
is hydrogen or C
1
-C
6
alkyl) in the presence of a lipase to produce the acetate ester represented by graphic formula VII and the alcohol of graphic formula V. This lipase-catalyzed reaction is described further in Journal of the American Chemical Society, Vol. 110, No. 21, pp. 7200-7205 (1988). Compound V is separated from compound VII by a conventional technique such as distillation or chromatography. Compound Va may also be chemically resolved to isolate one isomer thereof by treatment with a chemical resolving agent such as a chiral acid to produce the isomer of (3,6-dihydro-2H-pyran-2-yl)-methanol represented by compound V.
An alternative route may be used when compound III is a
Lilling Herbert J.
Millman Dennis G.
PPG Industries Ohio Inc.
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