JPS6016433B2 - How to split pantolactone - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for optical resolution of pantolactone.

Pantolactone has two optical antipodes, the D-form and the L-form, and only the D-form is the raw material for ○-calcium pantothenate, D-pantothenyl alcohol, etc., which are useful as pharmaceuticals.

Pantolactone, which is usually chemically synthesized, is a racemate, and the racemate is optically resolved to obtain a useful D-form. Conventional optical resolution methods for pantolactone include diastereomer methods using resolving agents such as quinine and brucine [US Pat. Nos. 2,319,545 and 23,902].
No. 81], (2) A method of converting pantolactone into a divisible derivative such as ammonium pantoate, lithium pantoate, or 0-acetylpantolactone, and converting it back to pantolactone after the division (Samurai Kosho No. 50-121448) ,
West German Patent Publication No. 2,350,610, Hakama Kosho 49
-16426), pantolactone is produced in the coexistence of a lactone or ester which is an alkane having at least one quaternary carbon and a hydroxyl group or an acetylated hydroxyl group and having 5 to 10 carbon atoms or a derivative thereof. Method of selectively dividing crystallization [Hakama Kosho 47-2222
No. 0] are known.

However, these known methods have various drawbacks,
It is hard to say that this method is industrially satisfactory.

For example, in the method {1}, the resolving agent is expensive and complicated operations are required to obtain highly pure D-pantolactone. In addition, the method {2--- involves an extra step of converting pantolactone once into a cleavable derivative and then returning it to pantolactone after the cleavage, which is undesirable. Furthermore, although the method of {31 is preferable in that pantolactone can be directly separated by selective crystallization, i) the compound coexisting is solid and difficult to handle, h) the boiling point and solubility of the compound coexisting and pantolactone are Because of their similarities, it is difficult to separate the two, for example, recovery of pantolactone from the split mother liquor requires complicated operations.Also, the stability of supersaturated solutions during crystallization is still insufficient. This method has several disadvantages and is not an industrially satisfactory method. The present inventors have conducted extensive research aimed at developing a new method for splitting pantolactone that eliminates the drawbacks of the conventional techniques as described above, and as a result, they have used an organic mixed solvent containing lactate as one component as a splitting solvent. In this case, we have discovered that pantolactone can be suitably separated by selective crystallization, leading to the present invention.

Although the operating method of separation by selective crystallization itself is well known, this method cannot be practiced universally, and there are very few examples in which it can be carried out suitably. In general, there is no regularity in the compounds and systems to which this method can be applied, and the manner of separation often changes completely due to minute differences in compounds, separation solvents and separation temperatures, addition of coexisting substances, etc. Therefore, it is impossible to predict a system to which this method will be suitably applied, and finding such a system is the key to success in optical resolution by selective crystallization.
Particularly in the case of pantolactone, it is extremely difficult to find and develop a system to which separation by this method can be suitably applied. In other words, this method is generally applied to compounds that tend to precipitate racemic mixture crystals [Industrial Chemistry Magazine Vol. 71, No. 5, pp. 676-679 (19 porridge), Vol. 72, No. 5, 1o80. Pages 10-10 (1969)], there is no report that racemic mixture type crystals of pantolactone have been crystallized. Even if crystals are formed, they easily change to other crystal forms, indicating that racemic mixture crystals are extremely unstable. In addition, in separation by selective crystallization, it is necessary that the separation solution maintains a supersaturated state during the separation operation, and a solution system in which the supersaturated state is stable is required.

However, supersaturated solutions of pantolactone in conventional organic solvents were relatively unstable and unsuitable for carrying out selective crystallization methods. In fact, there is no report that pantolactone, which has the above-mentioned properties, could be stably resolved by this method using an ordinary solvent. method was the only one.

However, the present invention uses a lactic acid ester of an aliphatic alcohol having 1 to 4 carbon atoms, carbon tetrachloride, 1,1-dichloroethane, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, Tetrachloroethylene, tetrachloroethane, bentachloroethane, 1,2
- A mixed solvent consisting of at least one selected from dichloropropane, 1,2.3-trichloropropane, chlorobutane, benzene, toluene, and xylene and containing 2 to 6 volume percent of lactic acid ester is used as a dividing solvent. Seed crystals of either optically active pantolactone are inoculated into a saturated or supersaturated solution of racemic pantolactone or one optically active form of pantolactone in which one optically active form is present in excess of the other, and selectively crystallized and split. It was discovered that pantolactone can be split more preferably by using the method.

According to the method of the present invention, pantolactone can be stably separated by crystallization using an easy-to-handle and inexpensive organic solvent and a simple operation. It is also easy to recover pantolactone from the split mother liquor; for example, by simply distilling off the split solvent, pantolactone can be recovered from the split mother liquor. The lactic acid ester used in the method of the present invention is a lactic acid ester of an aliphatic alcohol having 1 to 4 carbon atoms, and methyl lactate and ethyl lactate are particularly preferred.

Lactate esters of higher alcohols have high boiling points, which is disadvantageous when recovering pantolactone from the split mother liquor. Lactate ester has a high solubility of pantolactone,
Since it is difficult to perform a selective crystallization method using ester lactic acid alone, it is necessary to use a mixed solvent with another organic solvent that has a relatively low ability to dissolve pantolactone.

The amount of lactic acid ester varies depending on the type of organic solvent used in combination, etc., but usually 2 to 6 percent by volume is used, and 5 to 4 percent by volume is particularly preferred. (1) The organic solvent used in combination with lactic acid ester is miscible with lactic acid ester, does not have a high solubility of pantolactone, forms a stable supersaturated solution of pantolactone when used in combination with lactic acid ester, and crystallizes pantolactone without altering its properties. Carbon tetrachloride, 1,1-dichloroethane, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, tetrachlorethylene, tetrachlor Chlorinated hydrocarbons such as ethane, bentachloroethane, 1,2-dichloropro/gun, 1,2,3-trichloropro/gun, chlorbutane,
Aromatic hydrocarbons such as benzene, toluene and xylene are used.

Further, other solvents can also be used as the third component within the range that does not prevent the effects of the method of the present invention. The production strategy for the raw material pantolactone is not limited, and for example, those produced from isobutyraldehyde, formaldehyde and cyanide by ordinary chemical methods, those obtained by racemization of optically active forms, etc. can be used. Ru. The concentration of pantolactone in the splitting solution must be greater than or equal to the saturation solubility at the splitting operation temperature, and should be less than 7 weight percent, preferably less than 6 weight percent.

At high concentrations, the viscosity increases significantly, making it unfavorable for operation. When a mixed solvent of limited lactic acid esters as described above is used, a supersaturated solution of pantolactone prepared within the above range has sufficient stability to carry out the selective crystallization method.

The dividing operation temperature is preferably -5 to 250C, particularly 0 to 10qC.

If the separation operation temperature is high, the saturation solubility will increase, and the concentration of pantolactone in the separation solution must be increased, which is unfavorable in terms of operation. On the other hand, if it is too low, the supersaturation stability of the divided solution will decrease. Crystals of the active substance used as seed crystals can be those crystallized from ordinary organic solvents such as trichloroethylene, toluene, isopropyl ether, etc.; however, from the viewpoint of separation speed, it is preferable to crystallize from the separation solvent. It is best to use it by crushing it.

The larger the amount of seed crystals, the larger the amount of division per unit time can be, but there is no particular restriction on the amount, and in practice, 0.2% or more of the amount of solution is used. Also, appropriate damage during the splitting operation is effective for smooth crystallization.

The unit operation of crystallization separation in the method of the present invention can be performed by a known selective crystallization technique.

That is, racemic pantolactone or pantolactone in which one active form is present in excess over the other is dissolved in an organic mixed solvent containing lactic acid ester as one component, a saturated or supersaturated solution is prepared by cooling or other methods, and D is added to the solution. A seed crystal of an optically active form of the L- or L-form is inoculated, and the active form of the same type as the seed crystal is selectively crystallized and split. For example, after separating the crystals in a furnace, the crystals are washed with a small amount of separation solvent.
After drying, highly pure optically active pantolactone can be obtained. It was unexpected that pantolactone could be effectively and easily resolved by using a mixed solvent of lactic acid esters and chlorinated hydrocarbons or aromatic hydrocarbons as a resolving solvent in the present invention. This is of great industrial significance.

When carrying out the method of the present invention industrially, it is necessary not only to perform so-called one-sided splitting in which only one optically active substance is crystallized from a supersaturated solution, but also to separate the L-isomer and the L-isomer and By placing a seed crystal of the D-form and bringing it into contact with a supersaturated solution of the racemate, the L-form and the D-form are separated.
There are various conventionally known methods, such as a method of obtaining the active form at the same time as the active form of the seed crystal, or a method of precipitating the seed crystal on a seed plate and selectively crystallizing the active form of the same type as the seed crystal on the seed plate and dividing it. method can be applied.

Next, the present invention will be specifically explained using examples.

Example 1 Twenty minutes of a mixed solvent of ethyl lactate and 1,1,1-trichloroethane having an ethyl lactate content of 3 percent by volume and 30 minutes of racemic pantolactone were dissolved.

The solution was recrystallized from the splitting solvent while keeping it at 5°C.
One night of D-pantolactone seed crystals ground to 0-200 mesh was added. After the lamp was kept at 5° C. for 7 hours, the precipitated crystals were taken out in a furnace and washed with a small amount of the separated solvent to obtain D-pantolactone with a yield of 2.5 hours.

Specific rotation [a] color of the product. -49.50 (Sun 20, C
=1). Example 2 20 parts of racemic pantolactone was dissolved in 20 parts of a mixed solvent of methyl lactate and trichlorethylene having a methyl lactate content of 1% by volume.

The solution was kept at 1°C and recrystallized from the divided solvent to 100-2
One night of D-pantolactone seed crystals ground to 0.00 mesh was added. After continuing the lampshading at 1℃ for 4 hours, the precipitated crystals were collected in a furnace and washed with a small amount of splitting solvent.
．． D-pantolactone was obtained for 5 min.

Specific rotation of product [a] -49.30 (day 20, C=
1). Example 3 To the divided mother liquor of Example 2, 2.5 hours of racemic pantolactone was added and dissolved.

The solution was kept at 1°C and recrystallized from the divided solvent to 100-2
One night of L-pantolactone seed crystals ground to 0.00 mesh was added. After continuing to heat the lamp at 1°C for 5 hours, the precipitated crystals were collected in a furnace and washed with a small amount of splitting solvent.
．． 5 days of L-pantolactone was obtained.

Specific rotation [a] of product +49.00 (day 20, C=
1). Example 4 20 minutes of a mixed solvent of methyl lactate and toluene containing 1 volume percent of methyl lactate and 25 minutes of racemic pantolactone were dissolved.

The solution was kept at 1°C and recrystallized from the divided solvent to 100-2
One night of D-pantolactone seed crystals ground to 0.00 mesh was added. After continuing to heat the lamp at 1℃ for 3 hours, the precipitated crystals were collected in a furnace and washed with a small amount of splitting solvent.
．． ○- Pantolactone was obtained for 6 evenings.

Specific rotation of product [a] Keiichi 48. 〆(Sun 20, C; 1
). Example 5 Twenty-five minutes of racemic pantolactone was dissolved in a mixed solvent of ethyl lactate and xylene having an ethyl lactate content of 2 percent by volume.

The solution was kept at 3°C and recrystallized from the divided solvent to give 100-2
One night of D-pantolactone seed crystals ground to 0.00 mesh was added. After continuing heating at 3°C for 4 hours, the precipitated crystals were collected in a furnace and washed with a small amount of separated solvent to obtain 2.
One night of D-pantolactone was obtained.

Claims (1)

[Claims] 1 Consisting of a lactic acid ester of an aliphatic alcohol having 1 to 4 carbon atoms and at least one selected from trichloroethylene, 1,1,1-trichloroethane, toluene, and xylene, and the content of the lactic acid ester is 2 to 60 volumes %
Seed crystals of one of the optically active pantolactones are inoculated into a saturated or supersaturated solution of racemic pantolactone or one optically active form of pantolactone in which one optically active form is present in excess of the other, using a mixed solvent as the dividing solvent. A method for splitting pantolactone characterized by crystallization and splitting.