Process for the production of alkanediol derivative

Details Process for the production of alkanediol derivative Process for the production of alkanediol derivative

2001-07-13

2004-04-13

Nazario-Gonzalez, Porfirio (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C568S626000, C568S664000, C568S665000, C568S671000, C568S672000

Reexamination Certificate

active

06720463

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a process for producing an alkanediol derivative.
BACKGROUND ART
Alkanediol derivatives represented by the following general formula (II):
and, in particular, optically active (R)— or (S)-alkanediol derivatives are useful as a building block for agrochemical or pharmaceutical. For obtaining such a derivative, there has been known a process which comprises reducing a hydroxy carboxylic acid ester (e.g. an optically active 2-hydroxypropanoate or an optically active 3-hydroxybutanoate) or a compound obtained by protecting the hydroxyl group of the above ester with dihydropyran or the like, using lithium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride.
The above lithium aluminum hydride and sodium bis(2-methoxyethoxy)aluminum hydride, however, are difficult to handle in a large amount industrially from the safety standpoint. Therefore, active investigations have been made on a process for conducting the above-mentioned reduction using sodium borohydride which is easy to handle industrially.
However, it is generally impossible to reduce ester group to alcohol group using sodium borohydride [Tetrahedron, Vol.35, p.567 (1979)]. Hence, various reaction conditions have long been studied. For example, there were proposed a process which comprises conducting the reaction in the presence of a Lewis acid (e.g. aluminum chloride) [J. Am. Chem. Soc., Vol.78, p.2582 (1956)] and a process which comprises conducting the reaction in the presence of a metal salt (e.g. lithium chloride, lithium bromide or potassium bromide) [J. Am. Chem. Soc., Vol.77, p.6209 (1955)].
There were also proposed a process which comprises suspending sodium borohydride in tetrahydrofuran or tertiary butyl alcohol and slowly adding thereto a primary alcohol (e.g. methanol) under refluxing [Bull. Chem. Soc. Jpn., Vol.57, p.1948 (1984)], a process using a mixed solvent of an ether type solvent and a primary alcohol [Synlett., p.1636 (1999): WO 98/8793], a process using a polyethylene glycol as a solvent (JP-A-10-507996), a process using a mixed solvent of 1,2-dichloroethane and methanol (JP-A-1-250369), etc.
However, in obtaining an alkanediol derivative represented by the above general formula (II) by conducting reduction according to any of the above known processes, there are various problems. That is, for example, in the processes using a Lewis acid or a metal salt, the Lewis acid or the metal salt added results in an increase in the amount of waste material, which is not preferred; and in the process of dropwise adding a primary alcohol under refluxing, a large amount of hydrogen is generated rapidly when the process is carried out on a large scale, which is dangerous. In view of that solvent recovery is necessary in an industrial application of the above processes using a solvent, the process using an ether type solvent has a problem of requiring special facilities for ether separation from alcohol as well as for security against peroxide, and the use of 1,2-dichloroethane is restricted for its ozone depletion and global warming.
Thus, in the technical field to which the present invention belongs, no proposal has been made on a process for producing an alkanediol derivative represented by the general formula (II) safely without giving rise to racemization, and development of such a process has been desired.
The present invention aims at solving the above-mentioned problems and providing a novel and efficient process for producing an (R)—, (S)— or (RS)-alkanediol derivative which is useful as a building block.
DISCLOSURE OF THE INVENTION
In order to achieve the above aim, the present inventors made a study on a process for producing an alkanediol derivative represented by the general formula (II) by reducing a corresponding ester compound with sodium borohydride. As a result, it was found out surprisingly that the above ester compound is reduced with sodium borohydride at room temperature in a mixed solvent of a non-polar aprotic solvent, i.e. an aromatic hydrocarbon (e.g. chlorobenzene or toluene), an aliphatic hydrocarbon (e.g. hexane or heptane), an alicyclic hydrocarbon (e.g. cyclohexane or methylcyclohexane) or the like and a primary alcohol (e.g. methanol or ethanol) and is converted to an alkanediol derivative of the general formula (II) at a high yield without giving rise to racemization when the ester compound is optically active. The present invention has been completed based on the above finding. Incidentally, that the ester group of the ester compound is reduced to an alcohol with sodium borohydride at room temperature in a non-polar solvent with an addition of a primary alcohol, is an entirely novel finding which is far beyond the anticipation of those skilled in the art.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is described in detail below.
The present invention provides the following inventions [1] and [2].
[1] A process for producing an alcohol derivative represented by the following general formula (II):
(wherein R
2
and R
3
are each independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; X is a hydrogen atom or a protecting group for hydroxyl group; and n is 0 or 1), which process comprises reducing an ester compound represented by the following general formula (I):
(wherein R
1
is an alkyl group having 1 to 4 carbon atoms; and R
2
, R
3
, X and n have the same definitions as given above) with sodium borohydride in a mixed solvent of at least one kind of solvent selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons and alicyclic hydrocarbons and a primary alcohol.
[2] A process according to the above [1], wherein the primary alcohol is methanol.
First, description is made on the ester compound represented by the general formula (I) which is used as a raw material in the present invention.
In the ester compound represented by the general formula (I) which is used as a raw material in the present process, the substituent represented by R
1
in the general formula (I) is an alkyl group having 1 to 4 carbon atoms, exemplified by methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group and isobutyl group; and the substituents represented by R
2
and R
3
are each independently a hydrogen atom or, similarly to R
1
, an alkyl group having 1 to 4 carbon atoms.
The substituent represented by X in the general formula (I) is a hydrogen atom or a protecting group for hydroxyl group; and n is 0 or 1, indicating that the ester compound represented by the general formula (I) includes a compound wherein hydroxyl group is adjacent to carboxyl group and a compound wherein a carbon atom is present between hydroxyl group and carboxyl group.
Accordingly, as the ester compound represented by the general formula (I) wherein the substituent represented by X is a hydrogen atom, there can be mentioned, for example, methyl (R)-lactate, ethyl (R)-lactate, isobutyl (R)-lactate, methyl (S)-lactate, ethyl (S)-lactate, methyl (R)-3-hydroxybutanoate, methyl (S)-3-hydroxybutanoate and methyl (S)-3-hydroxy-2-methylpropionate or the like.
As the ester compound represented by the general formula (I) wherein the substituent represented by X is a protecting group for hydroxyl group, there can be mentioned, for example, compounds obtained by protecting the hydroxyl group of a compound represented by the general formula (I) wherein the substituent represented by X is a hydrogen atom, such as methyl (R)-lactate, ethyl (R)-lactate, isobutyl (R)-lactate, methyl (S)-lactate, ethyl (S)-lactate, methyl (R)-3-hydroxybutanoate, methyl (S)-3-hydroxybutanoate, methyl (S)-3-hydroxy-2-methylpropionate or the like, according to a conventional method.
The protecting group for hydroxyl group, used in the present invention is preferably a group which can be removed under an acidic condition, such as substituted methyl group, substituted ethyl group or the like. The substituted methyl group can be exe

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