JPS5934698B2 - Novel γ-trimethylammonium butyric acid methyl ester chloride monocrystal - Google Patents

Description

Detailed Description of the Invention The present invention provides a novel γ-trimethylammonium butyric acid methyl ester chloride crystal (hereinafter abbreviated as ACT・H2O).
Regarding.

ACT is a drug useful as a gastrointestinal function improving agent and a hair root function activator, and its physical properties include that it is easily soluble in water, methanol, ethanol, and dimethylformamide, and its solubility in water is particularly high (ACT19 is approximately It is known to be slightly soluble in acetone, ethyl acetate, ether, etc.).

Therefore, when isolating pure ACT from the final reaction mixture obtained by various production methods, conventionally a mixture of acetone (see Japanese Patent Publication No. 37-17961), methanol-acetone or dimethylformamide-acetone is used. solvent(
A method of crystallization using JP-A No. 48-5714) has been adopted as a preferred method. However, when ACT is crystallized using such a solvent, the crystallization rate of ACT is low, impurities are not sufficiently removed, and the obtained crystals are highly hygroscopic and difficult to handle. Industrial soil had undesirable defects.

The present inventors have made intensive studies to overcome these industrial deficiencies and have found that when ACT containing impurities is treated with a water-containing organic solvent, crystals with physical properties completely different from those of conventional ACT can be obtained. , this crystal is ACT itself obtained by crystallizing from a conventional organic solvent, that is, unlike anhydride, it is a new ACT with one molecule of crystal water bound to it.
It was confirmed by thermal analysis, IR spectrum, etc. that it was a quartz-containing crystal.

Attached FIG. 1 shows a differential thermal analysis curve diagram of ACT-H2O, and the analysis conditions are as shown in the table below.

The differences in physical properties between monoquartz and aquartz ACT are summarized as follows.

LJ) P]goυvν (8) Solubility in acetone-methanol (95:5) mixed solvent (solute/solution weight % in terms of anhydride) As is clear from the above data, ACT-H2O is uniquely different from anhydrous crystals. In contrast, the solubility of ACT-H2O in organic solvents is different from that of acetone-methanol mixed solvent, which is the most industrially advantageous. It has been found that the ratio is 1 to -1, and therefore, the desired product can be obtained with a good crystallization rate.

That is, as mentioned above, ACT has extremely high solubility in water and high hygroscopicity, so common sense would suggest that crystallization from a water-containing solvent would reduce the crystallization rate, but this is completely contradictory. He discovered a surprising fact. Furthermore, the ACT/H2O obtained in this way has a significantly lower hygroscopicity than quartz-free crystals, and is therefore easy to handle as a product, making it highly valuable as a commercial product. This is what I discovered.

Based on the above knowledge, the present inventors used a water-containing organic solvent in the process of crystallizing ACT to create a novel ACT-H2.
It was found that crystallizing as O crystals is extremely advantageous industrially, and more detailed crystallization conditions were studied and the following results were obtained.

The crystallization rate of ACT-H2O is 1.0 to 1.5 relative to ACT
A water-containing organic solvent to which twice the molar amount of water is added has the highest impurity removal rate, and the removal rate of impurities increases as the water content increases. Industrially advantageous crystallization conditions vary depending on the content of impurities, but AC
It can be said that a water-containing organic solvent in which water is added in an amount of 1 to 2 moles relative to T is preferable. In this case, the removal of impurities also gives much better results than in the case of conventional crystallization as an aquartz crystal.

For example, ACTlOOg with an impurity content of 1.0% is mixed with water, methanol, acetone (10ml:15ml:300Tt1).
), the impurity content in the obtained crystals decreased to 0.2-0.3%, whereas when treated with a mixed solvent of methanol-acetone (15ml:300ml), The impurity content in the obtained crystals is 0.7~
At 0.8%, the impurity removal effect is extremely small.
As described above, the present invention provides a method for producing a novel ACT-H2O with low hygroscopicity with high purity and high yield by treatment with a water-containing organic solvent.

The present invention will be explained below with reference to Examples. Example] ACT (anhydride) 1009 in water 10ml 11 methanol 2
Dissolve in 5 ml by heating, add 500 ml of acetone, and
The mixture was stirred at 10°C for 2 hours and the precipitated crystals were collected by filtration.

Dry for 3 hours at 40-50°C and 10-20 mmHg.

Yield: 92.89 (moisture content: 8.4%). This crystal is 10m
By drying for 8 hours at 75 to 85°C below mHg, the water content becomes 0.1% or less.

Example 2 ACT (anhydride) 1009 was heated and dissolved in 10 ml of water and 150 ml of amyl alcohol, treated with activated carbon, stirred at 5 to 10°C for 2 hours, and precipitated crystals were collected by filtration.

Dry for 4 hours at 40-50°C and 10-20 mmHg.

Yield: 89.59 (moisture content: 8.4%).

[Brief explanation of the drawing]

FIG. 1 is a differential thermal analysis curve diagram of ACT-H2O.

Claims (1)

[Claims] 1 γ-trimethylammonium butyric acid methyl ester chloride monocrystal.