JPH0796537B2 - Method for purifying 3- (3,4-dihydroxyphenyl) serine - Google Patents

Description

TECHNICAL FIELD The present invention relates to an industrially advantageous method for purifying 3- (3,4-dihydroxyphenyl) serine (hereinafter abbreviated as DOPS).

[Conventional technology]

As a method for purifying DOPS, as shown in JP-A-51-32540, it is said that crude DOPS is dissolved in water under heating under reflux, and purified DOPS is obtained by filtering crystals that precipitate after cooling, so-called. Recrystallization purification methods were known.

[Problems to be solved by the invention]

The above-mentioned technique has not solved the following problems. For example, in the case of L-3- (3,4-dihydroxyphenyl) serine (hereinafter abbreviated as L-DOPS), it was as follows.

Since L-DOPS has poor thermal stability in an aqueous solution, it deteriorates when dissolved under heating under reflux. Therefore, if the heating time is extended, L-
Decomposition of DOPS progresses and the content decreases.

The thermal stability of L-DOPS in an aqueous solution is shown below.

Since it requires about 60 times as much water as crude L-DOPS, it has poor volumetric efficiency.

The purification yield of L-DOPS is as low as about 80%, and the recovery rate is poor.

The above problems are all major drawbacks from the viewpoint of industrial production, and in particular, the fact that the thermal stability in a solution in is poor is due to the extension of the time required for heating and dissolution during mass production. It is expected to cause a large decrease in yield.

Therefore, the above production method has many problems as an industrial production method, and it has been required to develop a more effective method as a purification method of DOPS.

[Means for solving problems]

Under such circumstances, as an industrial purification method for DOPS, the present inventors have earnestly studied a more advantageous method, and as a result, do not recrystallize by heating, and once dissolve DOPS as a mineral acid salt in an appropriate solvent to form a base. The present invention has been completed by finding a purification method for easily obtaining purified DOPS by precipitating DOPS as crystals by neutralization.

The method of the present invention will be described in detail below.

After suspending the crude DOPS in water or methanol containing 50% (W / W) or more of water, a mineral acid is added to dissolve the crude DOPS as a mineral acid salt. The amount of water or methanol containing 50% (W / W) or more of water can be 6 to 30 times as much as the weight of crude DOPS, and mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid can be used as crude DOPS. On the other hand, 1.0 to 2.0 equivalents can be used. Coarse DO
Room temperature is sufficient for dissolving PS, but it may be cooled to around 0 ° C or heated up to around 50 ° C. From the point of dissolving quickly and preventing the decomposition of DOPS
It is preferable to dissolve at 15 to 30 ° C. If necessary,
For the purpose of preventing air oxidation of DOPS, ascorbic acid, sodium sulfite, sodium bisulfite, 2,6-bis (1,1-
An antioxidant such as dimethyl-ethyl) -4-methylphenol (BHT) may be added in an amount of 0.1 to 5% by weight based on the crude DOPS.

An aqueous solution of a mineral acid salt of DOPS or a water-containing methanol solution can also be prepared by adding crude DOPS to water containing a mineral acid or water-containing methanol.

The DOPS mineral acid salt solution thus obtained is subjected to a filtration operation to remove insoluble matter or decolorization or adsorption of impurities before the precipitation of purified DOPS by neutralizing by adding a base. It is also possible to add a filtration operation after adding 0.5 to 10% by weight of activated carbon. Examples of the base used for neutralization include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate and the like, commonly used inorganic bases or organic amines such as triethylamine, diethylamine and monomethylamine, and ammonia and the like. it can. The neutralization point may be adjusted near the isoelectric point of DOPS, but in practice it can be carried out at pH 3 to 8, and in terms of yield and quality of purified DOPS obtained, pH 4.0 to 6.0 is recommended. Particularly preferred. The neutralization temperature may be around room temperature, but it is not an essential condition and it can be carried out at 0 to 50 ° C. For the purpose of increasing the yield, it is preferred to cool the purified DOPS after neutralization to around 0 ° C., and then collect the precipitated purified DOPS by filtration. The DOPS obtained by filtration is washed with cooled water and then dried to obtain high-quality purified DOPS with a good yield. The crude DOPS used in the present invention includes L-DOPS threo, erythro, and DL-DO.
Any of a threo body of PS, an erythro body, a threo body of D-DOPS or an erythro body may be used, and a preferable example thereof is a threo body of L-DOPS.

〔The invention's effect〕

Compared with the conventionally known water recrystallization method, the method of the present invention can avoid deterioration of DOPS due to heat because the refining operation can be carried out at a low temperature or near room temperature.

The volumetric efficiency in the refining process was improved and was improved by 2 to 10 times as compared with the conventional method.

The purification yield is greatly improved.

It is an industrial and useful DOPS refining method having advantages such as the following.

Next, the present invention will be described with reference to examples and reference examples, but the present invention is not limited thereto.

The net yields in Examples and Reference Examples are calculated by the following formula.

Purity (%) = quantitative value by absolute calibration curve method using high performance liquid chromatograph.

Example 1 To a mixed solution of 100 g of crude L-threo-3- (3,4-dihydroxyphenyl) serine (purity 94.2%), 1230 g of water and 1.0 g of L-ascorbic acid was added 36% hydrochloric acid 71.7 g with stirring at room temperature. Dissolved. After confirming dissolution, add 5.0 g of carborafine,
After stirring for 15 minutes, the mixture was filtered and washed with 135 g of water. In this filtrate
Add 43.6 g of 27% sodium hydroxide aqueous solution, and add 27
% Aqueous sodium hydroxide solution (61.3 g) was added dropwise over 1 hour. Further, pH is 5.20 with 3.6 g of 27% sodium hydroxide aqueous solution.
Adjusted to. Then, after stirring at room temperature for 1 hour, pH 4.8
After confirming that it was ˜5.3, it was cooled to 0˜5 ° C. and stirred at that temperature for 2 hours. The precipitated crystals were collected by filtration and cooled
After washing 3 times with 145 g of 0.05% L-ascorbic acid aqueous solution, further washing twice with 115 g of acetone, and then drying, 89.0 g of pure L-threo-3- (3,4-dihydroxyphenyl) serine (purity 99.9) %), [Α] _D −39.6 ° (C = 0.5, 0.1N hydrochloric acid). (Net yield 94.4%).

Example 2 Crude L-threo-3- (3,4-dihydroxyphenyl) serine 10.0 g (purity 94.2%), 50% hydrous methanol 268 g,
While stirring at room temperature, 4.52 g of 36% hydrochloric acid was added and dissolved in a mixed solution of 0.1 g of L-ascorbic acid. After confirming the dissolution, 0.5 g of carborafine was added, stirred for 15 minutes, filtered, and washed with 13.5 g of water. 4.51 g of triethylamine was added to this filtrate over 3 hours, and the pH was adjusted to 5.23. After stirring at room temperature for 1 hour, it was confirmed that pH was 4.8 to 5.3, cooled to 0 to 5 ° C, and stirred at that temperature for 2 hours. The precipitated crystals were collected by filtration, washed 3 times with 14.5 g of cooling water, further washed twice with 11.5 g of acetone, and then dried to obtain purified L-threo-3- (3,4-dihydroxyphenyl) serine. 8.96 g (purity 99.5%) and [α] _D- 39.1 ° (C = 0.5, 0.1N hydrochloric acid) were obtained. (Net yield 94.6%).

Example 3 Crude L-threo-3- (3,4-dihydroxyphenyl) serine 10 g (purity 94.2%), water 70 g, L-ascorbic acid 0.
7.17 g of 36% hydrochloric acid was added to and dissolved in 1 g of the mixed solution at room temperature with stirring. After confirming dissolution, the insoluble material was filtered off and washed with 13.5 g of water. 27% sodium hydroxide aqueous solution 10.86g in this filtrate
Was added dropwise over 1 hour to adjust the pH to 5.05. Then, the mixture was stirred at room temperature for 1 hour, cooled to 0 to 5 ° C, and stirred at that temperature for 2 hours. The precipitated crystals were collected by filtration, washed with 14.5 g of cooling water three times, and further washed with 11.5 g of acetone twice, and then,
By drying, the purified L-threo-3- (3,4-dihydroxyphenyl) serine 9.01 g (purity 99.6%), [α]
_D- 39.5 ° (C = 0.5, 0.1N hydrochloric acid) was obtained. (Net yield 95.7
%).

Example 4 To a mixture of 10 g of crude L-threo-3- (3,4-dihydroxyphenyl) serine (purity 94.2%) and 100 g of water, 5.43 g of concentrated sulfuric acid was added and dissolved under stirring at room temperature. After confirming dissolution, add 0.5 g of carborafine, stir for 15 minutes, and then filter with water 13.5
washed with g. 10% aqueous potassium hydroxide solution 31.
The dropping pH was adjusted to 5.01 in 10 g of 1 hour. After stirring at room temperature for 1 hour, it was confirmed that pH was 4.8 to 5.3, cooled to 0 to 5 ° C, and stirred at that temperature for 2 hours. The precipitated crystals were collected by filtration, washed 3 times with 14.5 g of cooling water, further washed twice with 11.5 g of acetone, and then dried to obtain purified L-threo-3- (3,4-dihydroxyphenyl) serine 8.80. g (purity 99.9%), [α] _D −39.7 ° (C = 0.
5,0.1 N hydrochloric acid) was obtained. (Net yield 93.3%).

Examples 5 to 15 By the same operation method as in Example 1, 10 g of crude L-DOPS (purity: 94.2%) was used, and the combination of the mineral acid, the base and the solvent shown in Table 1 and the used amount were used. Further obtained spirit
The results of L-DOPS are also shown in the table.

Reference Example Crude L-threo-3- (3,4-dihydroxyphenyl) serine 10.0 g (purity 94.2%) water 600 g, L-ascorbic acid
0.1 g of the mixture was heated to 100 ° C. When dissolved under heating under reflux, the solution was filtered while hot, and then washed twice with 6 g of hot water. The filtrate is gradually cooled, stirred and stirred at 0 to 5 ° C for 2 hours, and the precipitated crystals are collected by filtration, washed with 14.5 g of cooling water three times, and then dried to obtain purified L-threo-3- (3,4). -Dihydroxyphenyl)
Serine 7.54 g (purity 99.8%) [α] _D- 39.5 ° (C = 0.
5,0.1 N hydrochloric acid) was obtained. (Net yield 79.9%).

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-58-216146 (JP, A)

Claims (6)

[Claims] 1. Water or 50% containing 1 or more equivalents of mineral acid.
Crude 3- (3,4) consisting of methanol containing more than (W / W) water
A solution of -dihydroxyphenyl) serine is neutralized with a base to precipitate purified 3- (3,4-dihydroxyphenyl) serine, and 3- (3,4-dihydroxyphenyl) is characterized. ) A method for purifying serine. 2. The purification method according to claim 1, wherein the amount of the mineral acid is 1 to 2 equivalents relative to the crude 3- (3,4-dihydroxyphenyl) serine. 3. The amount of water or methanol containing 50% (W / W) or more of water is 6 to 30 times by weight the amount of crude 3- (3,4-dihydroxyphenyl) serine. The purification method according to item 1 or 2. 4. Crude L-3- (3,4-dihydroxyphenyl) as crude 3- (3,4-dihydroxyphenyl) serine
The purification method according to claim 1, 2, or 3, wherein serine or crude DL-3- (3,4-dihydroxyphenyl) serine is used. 5. The purification method according to claim 1, wherein sulfuric acid or hydrochloric acid is used as the mineral acid. 6. The purification method according to claim 1, wherein sodium hydroxide, potassium hydroxide, diethylamine or triethylamine is used as the base.