MXPA99001833A - Process for the preparation of butane triols - Google Patents

Abstract

A process for the preparation of butane triols is provided. In the process, a malic acid diester is reduced with sodium borohydride in the presence of an ether and an alcohol. Preferably, the malic acid diester is an ethyl or methyl ester, the ether is tetrahydrofuran or bis(2-methoxyethyl) ether (diglyme), and the alcohol comprises ethanol. Advantageously, the reaction is carried out at ambient temperature.

Description

PROCESS FOR THE PREPARATION OF BUTANOTRIOLS DESCRIPTION OF THE INVENTION This invention relates to a process for manufacturing butanotriols and butanotrichols made by the process. Butanotriols are valuable chemical intermediates for the pharmaceutical and agrochemical industries. For example butanotriols are used in the preparation of antiviral compounds (US 5,036,071) and platelet activation factors (Tet Lett, vol 26, No. 42, pp 5195-5198, 1985).

There is a need for commercially viable processes for the manufacture of butanotrichols that give a high yield of good quality product, be practical in scale plants and not produce unpleasant odors. An article in Chemistry Letters, 1984, pp. 1389-1392, published by The Chemical Society of Japan, describes an attempted reduction of (S) - (-) - metalic acid di-ethyl ester in tetrahydrofuran using sodium borohydride, but the The resulting product consists of multiple components that could not be separated for the REF. 29496 structural diagnosis. Attempts using the pyrophoric complex and unpleasant odor borane-dimethyl sulfide gave the corresponding mono-ester in 88% yield and the triol was not detected. The reduction of the malic acid di ethyl ester (also known as dimethyl malate) in ethanol using KBH4 is described in J. Chem. Soc, 1963, pp 2743-7. However, this process gave only 25% yield of butane-1,2,4-triol. The Journal of Organic Chemistry, 1987, 52, pp. 2896-2901 describes the reduction of the malic acid dimethyl ester on a small scale (600 mg) in THF / H20 (1: 1, 15 ml) using an excess of sodium borohydride. Although this article claims a 96% yield of (S) - (-) - butane-1,2,4-triol the present inventors were unable to achieve even close performance when they repeated the experiment several times. Additionally, the complex product was difficult to purify. There is also a risk of a sudden and vigorous release of hydrogen if THF and water are immiscible and sodium borohydride will suddenly come into contact with water.

An article in Heterocycles, vol 24, No. 5, 1986, pp 1331-1346, describes the reduction of L-malic acid using diborane prepared in situ from the previous reaction of BF3 etherate with sodium borohydride. However, the BF3 etherate is expensive and quite annoying to handle because of its tear-producing properties and diborane presents a potential fire risk. According to the present invention there is provided a process for preparing a butanetriol comprising the reduction of a malic acid diester in a mixture comprising an ether, an alcohol and sodium borohydride. The malic acid diester may be a diester of (R) -malic acid, (S) -malic acid diester or (R, S) -malic acid diester. The ester groups may be optionally substituted alkyl or aryl, for example optionally substituted phenyl esters, but are preferably alkyl esters. Especially preferred malic acid diesters are the diesters of (R) -, (S) - and (R, S) -malic acid of the formula: C02RJ CH2 I CHOH wherein R1 and R2 are each independently optionally substituted alkyl. Preferably R.sup.1 and R.sup.2 are each independently C? _4 alkyl / more preferably methyl or ethyl, especially methyl. Examples of the malic acid diesters are the dimethyl ester of (R, S) -malic acid, (R, S) -malic acid diethyl ester, (R, S) -malic acid ethyl ester, ester (R, S) -malic acid diisopropyl and the corresponding diesters of (R) -malic acid and diesters of (S) -malic acid. When the ester group is substituted, the substituent is preferably selected from the group consisting of alkoxy, such as C? _ Alkoxy; aryloxy, such as phenoxy; cyano and halo, such as bromine, but particularly the fluorine or chlorine groups. Preferably, the ester group is unsubstituted. The ratio of ether to alcohol is preferably in the range of 1: 1 to 10: 1, more preferably 1.5: 1 to 9: 1, especially 2: 1 to 8: 1 by weight. Preferably the ratio of malic acid diester to the mixture is preferably in the range of 1% to 25%, more preferably 10% to 23%, especially 12% to 20%, by weight to volume (i.e. grams of malic acid diester per 100 ml in total of alcohol and ether used in the reduction process). The number of moles of sodium borohydride used in the preference process exceeds the number of moles of malic acid diester. Preferably from 1.2 to 5.0 moles of sodium borohydride is used per mole of malic acid diester, more preferably from 1.3 to 4.0. The ether preferably has a boiling point above 50 ° C, more preferably above 60 ° C. For convenience, the ether preferably has a boiling point below 200 ° C, more preferably below 175 ° C, because the ether is then removable in a rotary evaporator. In many embodiments, it is preferred that the ether be an alkyl mono-, di- or tri-ether in which each alkyl portion comprises up to 3 carbon atoms, or is a cycloaliphatic ether. Examples of preferred alkyl mono-, di- or tri-ethers include diethyl ether, 1,2-diethoxyethane, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether (diglyme), 2,2-dimethoxypropane and ether. diisopropyl Examples of the preferred cycloaliphatic ether include 1,4-dioxane and particularly tetrahydrofuran. Especially preferred ethers are tetrahydrofuran and bis (2-methoxyethyl) ether (diglyme). The alcohol is preferably an alkanol, more preferably an alkanol having at least two carbon atoms, especially a C 2-6 alkanol. Examples of suitable albandes include ethanol, propan-1-ol, propan-2 ol, n-butanol, sec-butanol, tert-butanol and mixtures thereof. During the course of the process it is possible that trans-esterification occurs whereby alcohol replaces some of the alcohol residues in the ester groups. It has also been found that by using an alkanol having at least two carbon atoms (for example a C2-6 alkanol) the amount of sodium borohydride required is lower than when the alcohol is methanol and the process proceeds at a more controlled rate. As a result the process advantageously produces less hydrogen gas, the reduction of the ester groups to hydroxy groups proceeds more efficiently and the process is carried out more cheaply. Accordingly, a further aspect of the invention provides a process for preparing a butanetriol, comprising the reduction of a malic acid diester in a mixture comprising an ether and an alkanol having at least two carbon atoms and sodium borohydride. In view of the discovery that less sodium borohydride is required when the process uses an alkanol having at least two carbon atoms, it is preferred that the additional aspect of the invention be carried out in the presence of 1.3 to 2.5 moles, more preferably from 1.4 to 2.0 moles of sodium borohydride per mole of malic acid diester. It has also been found that it is not always necessary to heat the reaction under reflux when ethanol is used as the alcohol, although heating under reflux can be carried out if desired. Accordingly, the alkanol having at least two carbon atoms is preferably ethanol. In view of the foregoing, a preferred process according to the invention is where: (i) butanetriol is (R) -butane-1,2,4-triol, (S) -butane-1,2,4-triol or (R, S) -butane-1,2,4-triol; (ii) the ether is tetrahydrofuran or bis (2-methoxyethyl) ether (diglyme); (iii) the alcohol is ethanol, propan-1-ol, propan-2-ol, n-butanol, sec-butanol, tert-butanol or a mixture thereof; (iv) the ratio of ether to alcohol is in the range of 1: 1 to 10: 1, by weight; (v) the ratio of the malic acid diester to the mixture is in the range of 1% to 25% by weight to volume; and (vi) the number of moles of sodium borohydride is from 1.2 to 5.0 moles of sodium borohydride per mole of malic acid diester. Preferably the process comprises adding a solution of the malic acid diester in an alcohol to a solution or suspension of sodium borohydride in THF or bis (2-methoxyethyl) ether (diglyme). The addition of diester to borohydride is preferably carried out in increments or continuously during an addition period from a few minutes to several hours, for example from 30 minutes to 10 hours. The process of preference is carried out at a temperature in the range of -10 ° C to 70 ° C, more preferably -10 ° C to 65 ° C. When the alcohol is ethanol the process can be advantageously carried out at -10 ° C to 30 ° C and when the alcohol is iso-propanol, t-butanol or sec-butanol the process can be advantageously carried out at 10 ° C to 60 ° C, more preference of 15 ° C to 55 ° C. However, it is more preferred that the reaction be carried out at room temperature, such as from 15 to 25 ° C. In a preferred embodiment the present process comprises the steps of: (i) dissolving a malic acid diester in an alcohol, preferably an alkanol having at least two carbon atoms; (ii) adding the product of step (i) to a mixture of sodium borohydride and ether; (iii) optionally heating the product of step (ii); and (iv) optionally separating the resulting butanetriol from the ether, alcohol and sodium borohydride. If desired, one or more dopants, for example potassium, lithium and / or calcium halides, may be included in the mixture. Preferably, such dopants if employed are included in small amounts, for example, catalytic. The preferred dopants are LiCl and KC1. The precursor preferably is present in an amount of 0 to 20%, more preferably 0 to 15%, especially of up to 0 to 10% by weight relative to the weight of sodium borohydride. Such dopants can be used to accelerate the process, although in some cases one may not want the process to proceed faster and the dopant is therefore omitted. The reaction time of the process of the present invention will depend on a number of factors, for example the concentrations of the reagent, the relative amounts of reagents and particularly the reaction temperature. Typically the reaction times, in addition to the reagent addition times, are in the range from 1 hour to 48 hours, with reaction times of 3 to 20 hours being common. When the reaction is carried out at room temperature, reaction times are often used from 5 to 18 hours. The invention is further illustrated by the following examples, in which all parts and percentages are by weight unless otherwise specified. THF means tetrahydrofuran.

Example 1 A solution of (S) -dimethyl malate (27 g, 160 mmol) in methanol (150 ml) was added dropwise over a period of 120 minutes, with stirring, to a suspension of sodium borohydride (21). g, 555 mmole) in THF (600 ml) from 20 ° C to 30 ° C. The mixture was stirred at 20 ° C to 30 ° C for 30 minutes, then heated under reflux (65 ° C) for 1 hour. A considerable amount of hydrogen was released during the methanol addition and heating to reflux. The mixture was cooled to 25 ° C then methanol (750 ml) was added. The pH was lowered to pH7 using concentrated H2SO4. The resulting inorganic precipitate was removed by filtration, washed with methanol (2 x 100 mL) and the combined filtrate and washes were dried in vacuo to give (S) -l, 2,4-butanetriol (17.9 g).

Example 2 A solution of (S) -dimethyl malate (7.7 g, 46 mmol) in industrial methyl alcohol, (essentially ethanol, 12 ml) was added dropwise over a period of 60 minutes, with stirring, to a suspension of sodium borohydride (3.2 g, 83 mmol) in THF (42 ml) at 25 ° C. The mixture was stirred under reflux for 2.5 hours. The mixture was cooled to room temperature, then the pH was adjusted to 7 using concentrated HC1 (7 ml). The inorganic compounds were separated by filtration and the filter cake was washed with THF (2 x 25 mL). The filtrates were combined, then concentrated to dryness in va cuo. The residue was dissolved in methanol (120 ml) and again concentrated to dryness in vacuo to give (S) -1,2,4-butanetriol (4.9 g, 95% yield).

Example 3 A solution of dimethyl malate (8.4 g, 50 mmol) in industrial methyl alcohol (8 ml) at 25 ° C was added dropwise with stirring over a period of 9 hours to a suspension of sodium borohydride (3.46). g, 89 mmol) in THF (40 ml) at 0 ° C. After the addition was complete, stirring was continued at 0 ° C for an additional 14 hours and the mixture was then heated at 20 ° C for 4 hours and kept at this temperature for 1 hour. The mixture was then cooled to 6 ° C and acetone (11.4 ml) was added for 1/2 hour. The mixture was cooled to 5 ° C and concentrated HC1 (8 mL) was added to lower the pH to 7. The mixture was filtered, the cake was washed with THF (2 x 25 mL) and the combined filtrates were concentrated by in-drying. go cuo. Methanol (120 ml) was added to the material and the process was repeated to give a quantitative yield of high purity butane-1, 2, 4-triol. The procedure produced very little hydrogen gas.

Example 4 A solution of dimethyl malate (30.8 g, 186 mmol) in propan-2-ol (70 ml) at 25 ° C was added dropwise with stirring over a period of 6 hours to a suspension of sodium borohydride ( 13 g, 336 mmol) in THF (210 ml) at 50 ° C. The heating was removed as the addition started in such a way that most of the addition was carried out at 20-25 ° C. The batch was kept at 20-25 ° C for 24-48 hours, then acetone (50 ml) was added for 1/2 hour below 30 ° C. The mixture was aged or stabilized by standing for 1/2 hour below 30 ° C, then methanol (50 ml) was added for 1/2 hour keeping the temperature below 30 ° C. Again the mixture was stabilized by resting for 1/2 hour. HC1 (21 ml) was added to bring the pH to 7, at this point the batch was filtered, the cake was washed with THF (56 ml) and the combined filtrates were concentrated to dryness in vacuo. The residue was treated with methanol (200 ml) and the material was concentrated to dryness to give butane-1,2,4-triol, 16.7 g, 85%. This procedure produced very little hydrogen gas.

Example 5 A solution of (S) -dimethyl malate (30.8 g, 186 mmol) in propan-2-ol (62 ml) at 25 ° C was added dropwise with stirring over a period of 6 hours to a suspension of Sodium borohydride (13 g, 336 mmol) in THF (160 ml) at 50 ° C. The reaction mass was stabilized by standing for 1 hour at 50 ° C, then cooled to 25 ° C and stabilized by standing for 48 hours. The mixture was worked up as described in Example 4 to give (S) -butane-1,2,4-triol (16.7 g, 85% yield).

Example 6 The method of Example 5 was repeated, except that instead of propan-2-ol, tert-butanol was used.

Very little hydrogen gas was produced during the process and the (S) -butane-1,2,4-triol was obtained in 80% yield.

Example 7 A solution of (S) -dimethyl malate (1 g, 6.2 mmol) in industrial methyl alcohol (1 ml) was added dropwise over a period of 60 minutes, with stirring, to a suspension of sodium borohydride ( 0.42 g, 11.1 mmol) in THF (5 mL) at 25 ° C. The mixture was stirred at 20 to 30 ° C for 16 hours and then the pH was adjusted to 7 using concentrated HC1 (1 ml). The inorganic compounds were separated by filtration and the filter cake was washed with THF (2 x 3.5 ml). The filtrates were combined, then concentrated to dryness in va cuo. The residue was dissolved in methanol (15 mL) and again concentrated to dryness in vacuo. The methanol solution and concentration to dryness was repeated two more times to give (S) -1,2,4-butanetriol (0.59 g, 90% yield).

Example 8 A solution of (R) -dimethyl malate (2.11 g, 13 mmol) in industrial methyl alcohol (2 mL) was added dropwise over a period of 60 minutes, with stirring, to a suspension of sodium borohydride (0.91 g, 23.4 mmol) in THF (10 mL) at 25 ° C. The mixture was stirred at 20 to 30 ° C for 16 hours, and then the pH was stirred at 7 using concentrated HCl (1 mL). The inorganic compounds were separated by filtration and the filter cake was washed with THF (2 x 6.5 ml). The filtrates were combined, then concentrated to dryness. The residue was dissolved in methanol (31 ml) and again concentrated to dryness in vacuo. The methanol solution and the concentration to dryness was repeated two more times to give (R) -1,2,4 -butanot r ol (0.59 g, 90% yield).

Example 9 The method of Example 7 was repeated, except that bis (2-me toxie ti 1) er er (diglyme) was used in place of THF to give (S) -1,2, -butanot r iol (0.57 g, 87 of performance).

Comparative Example A - THF solvent To a solution of dimethyl malate (0.6 g, 3.7 mmol) in THF (15 mL) was added sodium borohydride (0.2 g, 5 mmol) at 25 ° C. The mixture was stirred for 20 minutes during which time the viscosity was increased to a level that made the additional processing steps difficult. 30 ml of methanol were added and the pH was brought to 7 using Lowex 50WX8 resin. The mixture was filtered, then the solvent was removed in vacuo. Methanol (10 mL) was added and the mixture was again concentrated to dryness by evaporation to give tubano-1,2,4-triol in a yield of about 50% together with other components.

Comparative Example B - Industrial Methyl Alcohol Solvent A solution of dimethyl malate (4.1 g, mmol) in industrial methyl alcohol (10 ml) was added to a suspension of sodium borohydride (1.9 g, 50 mmol) in industrial methyl alcohol (35 ml) at 20 ° C for 2 hours. The mixture was stirred for 16 hours at 20-30 ° C, then adjusted to pH 7 with concentrated H2SO4. The mixture was filtered and the organic filtrate was concentrated in va c o. The filter cake was washed with methanol (75 ml) and the washing was combined with the concentrated filtrate. This solution was then concentrated in vacuo to give butane-1,2,4-triol (2.8 g, 50-60% purity). It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (14)

CLAIMS Having described the invention as above, property is claimed as contained in the following:

1. A process for preparing a butanetriol, characterized in that it comprises the reduction of a malic acid diester in a mixture comprising an ether, an alcohol and sodium borohydride.

2. A process according to claim 1, characterized in that the malic acid diester is a (R) -, (S) - or (R, S) -malic acid diester of the formula: COzR1 wherein R1 and R2 are each independently optionally substituted alkyl.

3. A process according to claim 2, characterized in that R1 and R2 are independently methyl or ethyl groups.

4. A process according to any of the preceding claims, characterized in that the ether has a boiling point above 50 ° C and below 200 ° C.

5. A process according to claim 4, characterized in that the ether is an alkyl mono-, di- or tri-ether in which each alkyl portion comprises up to 3 carbon atoms, or is a cycloaliphatic ether.

6. A process according to claim 5, characterized in that the ether is tetrahydrofuran or bis (2-methoxyethyl) ether.

7. A process according to any of the preceding claims, characterized in that the alcohol is an alcohol having at least two carbon atoms.

8. A process according to claim 7, characterized in that sodium borohydride is present in an amount of 1.3 to 2.5 moles per mole of malic acid diester.

9. A process according to any of the preceding claims, characterized in that it is carried out at a temperature in the range of -10 ° C to 70 ° C.

10. A process according to any of the preceding claims, characterized in that it is carried out at a temperature in the range of -10 ° C to 30 °, and the alcohol is ethanol.

11. A process according to any of claims 1 to 9, characterized in that it is carried out at 10 ° C to 60 ° C and the alcohol is isopropanol, t-butanol or sec-butanol.

12. A process according to any of the preceding claims, characterized in that the mixture contains from 0 to 20% of a catalytic dopant by weight relative to the weight of sodium borohydride.

13. A process for preparing a butanetriol, comprising the reduction of a malic acid diester in a mixture comprising an ether, an alcohol and sodium borohydride, characterized in that it comprises the steps of: (i) dissolving the malic acid diester in the alcohol; (ii) adding the product of step (i) to a mixture of sodium borohydride and ether; (iii) optionally heating the product of step (ii), and (iv) optionally separating the resulting butanetriol from the ether, the alcohol and the sodium borohydride.

14. A process according to claim 1 or 13, characterized in that: (i) butanetriol is (R) -butane-1,2,4-triol, (S) -butane-1,2,4-triol or (R) , S) - butane-1,2,4-triol; (ii) the ether is tetrahydrofuran or bis (2-methoxyethyl) ether; (iii) the alcohol is ethanol, propan-1-ol, propan-2-ol, n-butanol, sec-butanol, tert-butanol or a mixture thereof; (iv) the ratio of ether to alcohol is in the range of 1: 1 to 10: 1, by weight; (v) the ratio of the malic acid diester to the mixture is in the range of 1% to 25% by weight to volume; and (vi) the number of moles of sodium borohydride is from 1.2 to 5.0 moles of sodium borohydride per mole of malic acid diester.