JPS6041676B2 - New method for producing S-2-(3-aminopropylamino)ethyldihydrodiene phosphorothioate monohydrate crystals - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION James R., Hyper et al. describe a series of 5-ω-1(ω-aminoalkylamino)alkyl dihydrodiene phosphorothioate derivatives useful as excellent radioprotectants, among which the most preferred S-2 -(3-aminopropylamino)ethyldihydrodiene phosphorothioate monohydrate was synthesized for the first time (U.S. Pat. No. 3,892,824)
issue).

According to the description in the US patent, 5-2-(3-aminopropylamino)ethyl dihydrocadiene phosphorothioate monohydrate is recrystallized by adding methanol to an aqueous solution of crystallized crystals in the final step of its synthesis. It has been isolated and purified. However, as a result of research conducted by the present inventors, it was found that methanol remains in the purified crystals with this method, and that methanol cannot be easily removed by ordinary solvent removal means. As is well known, methanol is extremely harmful to the human body as it causes serious eye damage, and is therefore subject to strict pharmaceutical regulations. For example, it is stipulated that pharmaceuticals extracted from natural products must not contain enough methanol to be detected by general test methods. It goes without saying that this provision usually applies mutatis mutandis to synthetic drugs as well. The inventors first attempted a method of drying methanol-containing crystals (Table 1, rod 1) obtained by the American patented method under reduced pressure over phosphorus pentoxide at room temperature, but methanol could not be completely removed. (Table 1, Rod 2) Moreover, methanol cannot be removed even by washing the crystals obtained by stirring them for a long time with various organic solvents such as ethanol, methylene chloride, acetone, ether, benzene, etc. It was possible (Table 1, rod 3). Therefore, the present inventors further conducted intensive research into methods for removing residual methanol, and found a method for reducing residual methanol by aerating the methanol-containing crystal with humid nitrogen gas or humid air. It was found that some of the monohydrated crystals turned into poly(mainly 25) hydrated crystals.

The poly (mainly 25) hydrated crystals obtained here are significantly inferior in stability and solubility compared to monohydrate crystals, and cannot be put to practical use at all (Table 1, Rod 4, Humidity On the other hand, when ethanol was used instead of methanol during the recrystallization process of the American patent method,
Although no residual methanol was observed, only poly(mainly 25) hydrate crystals were crystallized, and the desired monohydrate crystals could not be obtained ((Table 1, Rod 5)).

In addition, even when methanol is not used at all in the crystallization treatment and recrystallization treatment of the American patented method, and other organic solvents are used, only the poly(mainly 25) hydrated crystals obtained by the above method are crystallized.
Monohydrate crystals are not obtained as with methanol. As described above, the method described in the U.S. patent, especially the crystal force method, has a serious drawback in that methanol remains.
Moreover, despite the difficulty of removing residual methanol with the means for removing solvent from solvent-containing crystals commonly used in the industry, the present inventors have conducted extensive research and found that methanol We succeeded in obtaining monohydrate crystals of the present compound that do not contain any of them, and completed the present invention.

That is, the present invention provides (1) suspending polyhydrate crystals of S-2-(3-aminopropylamino)ethyl dihydrodiene phosphorothioate in ethanol and treating at ice-cooling to 60°C or lower to obtain 1
To convert into hydrated crystals. S-2-(3
A new method for producing -aminopropylamino)ethyldihydrodiene phosphorothioate monohydrate crystals (hereinafter referred to as the first production method) and (2) adding ethanol to an aqueous solution of crude S-2-(3-aminopropylamino)ethyldihydrodiene phosphorothioate. S-2-(3-aminopropylamino)ethyldihydrodiene phosphorothioate 1 water, characterized in that it is crystallized by adding a polyol containing or not containing it, or by adding the aqueous solution to ethanol and polyol alone or in a mixture thereof. Japanese crystal manufacturing method (
(hereinafter referred to as the second manufacturing method).

The first manufacturing method described above focuses on polyhydrate crystals that do not contain methanol, which are obtained by using ethanol instead of methanol during the recrystallization process of the American patent method, and converts unstable polyhydrate crystals into monohydrate crystals. Regarding methods of converting crystals, these methods have made true industrial production possible. That is, in the first production method, as a result of the research conducted by the present inventors, ethanol was only considered as a solvent that provides polyhydrate crystals, but monohydrate crystals were obtained by suspending polyhydrate crystals in ethanol. The main feature is that

On the other hand, the second production method described above is an improvement of the crystallization and recrystallization process of the American patented method, and uses a single or mixed solvent of polyol and ethanol, which are not normally used as a crystallization solvent, to produce pure compound 1. The fact that hydrated crystals were obtained was completely unexpected.

Note that specific examples of the polyol include polyhydric alcohols such as propylene glycol, ethylene glycol, and glycerin, and polyols such as polyethylene glycol. Below are crystals obtained under the various conditions mentioned above (rods 1 to 1).
5) and crystals obtained by the method of the present invention (rod 6)
Data comparing the properties of

The above method of the present invention will be explained in detail below. (1) First production method In this method, 25-hydrate crystals of S-2-(3-aminopropylamino)ethyl dihydrodiene phosphorothioate are suspended in 1 to 2 times the amount of ethanol, particularly preferably 4 to 8 times the amount. Then, stir at ice-cooling to below 60°C, preferably at room temperature, optimally at 15 to 35°C, for 10 to 7 [phases], preferably for 20 to 5 [phases], optimally for 0 hours. This is done by

The purpose of the present invention cannot be fully achieved at high temperatures, so heating is preferably limited to about 60°C. (2) Second manufacturing method The second manufacturing method is the crude S-2- obtained by the American patented method.
(3-Aminopropylamino)ethyl dihydrodiene phosphorothioate is dissolved in water, preferably water heated to 30-50'C, polyol with or without ethanol is added and kept at room temperature or under cooling. This is done by

The added solvent is preferably a mixed solvent of ethanol and polyol in order to suppress the viscosity of the polyol, and it is preferable to use the solvent in an amount 3 to 5 times that of water.

The particularly preferable usage amount is water:ethanol nipolyol is 1
．． 5-3: 4-5.5: 3.5-5. The obtained crystals are further stirred in the above-mentioned crystallization solvent, and then the crystals are collected, washed and dried under reduced pressure, or dried with ventilation. Ethanol is preferred as the cleaning liquid. In addition, S-2-(3
-aminopropylamino)ethyl dihydrodiene phosphorothioate 25-hydrate is a new product, and therefore its production method will be shown as a reference example. Reference Example 250 mL of methanol was added to a reaction mixture (aqueous solution) of 8.25 g of S-2-(3-aminopropylamino)ethyl dihydrodiene phosphorothioate prepared by the same method as in U.S. Patent No. 3,892,824, and the mixture was heated at 4°C overnight.
Cool to

The precipitate is collected and dried. Obtained crude solid 8
．． 90 g was dissolved in 40 ml of water, and insoluble matter was filtered off. Then 250 ml of ethanol is added to reprecipitate the product. After cooling the mixture for about 1 hour, the product was filtered, washed with ethanol, then washed with ether, and dried under reduced pressure at room temperature to yield white S-2-(3-aminopropylamino)ethyldihydrodiene phosphorothioate 25-hydrate. Thing 9
g is obtained. Example 1 100 g of S-2-(3-aminopropylamino)ethyl dihydrodiene phosphorothioate 25 hydrate obtained in Reference Example was suspended in 600 ml of ethanol to give a concentration of 30 to 35
Stir at ℃ for about an hour.

The precipitate is filtered out and washed with ethanol, then washed with ether and then dried under reduced pressure to obtain 86 g of S-2-(3-aminopropylamino)ethyldihydrodiene phosphorothioate monohydrate as white powder crystals. . The properties of the crystal obtained by this method are shown in Table 1, Rod 6. Example 2 4 kg of crude S-2-(3-aminopropylamino)ethyl dihydrodiene phosphorothioate monohydrate crystals
Dissolve in 8 ml of water heated to 0°C and add 225 ml of ethanol.
ml and 32 ml of a mixed solvent consisting of 20 ml of propylene glycol were added to crystallize the mixture, allowed to stand at room temperature, and then cooled on ice.

The obtained crystals were placed in 30 ml of a crystallization solvent (ethanol nipropylene glycol 4.5:4) and stirred at room temperature for 2 hours, then the crystals were collected and washed with ethanol, and then the ethanol was washed with ether. and dry under reduced pressure. This product corresponds to the standard product obtained in Example 1. Example 3 The following operations were carried out in the same manner as in Example 2, but the crystallization solvent composition was as follows.

Example 7 10 ml of a 17W/■% aqueous solution prepared in the same manner as in Example 2 was added to 60 ml of ethanol at 25°C to cause crystallization. The crystals thus crystallized were collected overnight, washed with ethanol, and then dried under reduced pressure to obtain a pure product. S-2-(3-aminopropylamino)ethyldihydrodiene phosphorothioate monohydrate crystals are obtained.

Claims (1)

[Claims] 1 Polyhydrate crystals of S-2-(3-aminopropylamino)ethyl dihydrodiene phosphorothioate are suspended in ethanol and treated at ice-cooling or below 60°C to form monohydrate crystals. A novel method for producing S-2-(3-aminopropylamino)ethyldihydrodiene phosphorothioate monohydrate crystals, characterized by converting the crystals. 2 Adding a polyol containing or not containing ethanol to an aqueous solution of crude S-2-(3-aminopropylamino)ethyl dihydrodiene phosphorothioate, or adding the aqueous solution to ethanol and polyol alone or in a mixture thereof to crystallize. S-2 characterized by
A method for producing -(3-aminopropylamino)ethyl dihydrodiene phosphorothioate monohydrate crystals.