JPH0428262B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel N-(2-hydroxyethyl)-
2-Aminoethanethiosulfate derivative [] (In the formula, R ¹ , R ² , R ³ are the same or different, hydrogen,
Indicates a lower alkyl or aryl group. ) and its manufacturing method.

The thiosulfate derivative represented by the formula [], which is the object compound of the present invention, is a novel compound unknown in the literature, and is itself a very useful compound as a drug or an intermediate for the production of a drug.

For example, compounds represented by the general formula [] are known, This compound has a remarkable anthelmintic effect, especially tetramisole ((±)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole), which is a representative compound among them.
['] (in the general formula [], Ar=phenyl) and the corresponding levorotatory compounds are particularly useful as anthelmintics. As described later, tetramisole ['] is a thiazolidine compound ['] as shown in (formula c).
(In the general formula [], R ¹ = phenyl, R ² = R ³ = hydrogen) from the thiosulfate derivative [′] (in the general formula [], R ¹ = phenyl, R ² = R ³ = hydrogen) Therefore, the thiosulfate derivative [], which is a new compound according to the present invention, is an extremely important precursor as an industrial raw material or an industrial intermediate for industrially producing useful compounds such as tetramisole [']. Therefore, its industrial usefulness is extremely large.

(Formula c) In general, a water-soluble aziridine derivative undergoes a quantitative reaction with sodium thiosulfate in the presence of sulfuric acid as shown in formula (d), and is used for quantitative determination of the aziridine derivative.

(General formula d) However, in this method, sodium sulfate, which is an inorganic substance, is produced from the sodium hydroxide produced by the reaction and the acid (sulfuric acid) used, so if this method was applied directly to the synthesis of [], it would be called removal of the by-product inorganic matter. This cannot be said to be an industrial method since it requires manipulation (Formula e).

(Formula e) In particular, when the produced thiosulfate derivative [ ] is water-soluble, it is difficult to separate it from the inorganic salt, making it impossible to isolate the target product in a pure manner. Alternatively, even if the thiosulfate derivative [ ] is insoluble in water, complicated operations such as extraction with an organic solvent are required. Therefore, such a method cannot be called a large-scale industrial method.

The present invention is the result of extensive research into the industrial synthesis of a new compound, a thiosulfate derivative, in order to solve the above-mentioned drawbacks, and the following new knowledge was discovered, and further research was carried out, and the invention was finally achieved. It is.
That is, by using a cation exchanger instead of sulfuric acid as an acid source, sodium ions generated by the reaction are captured by the exchanger as shown in (formula f).

(Formula f) R-[H ⁺ ]Na → R-[Na ⁺ ]+H (R-[H ⁺ ] represents a free-type cation exchanger, and R-[Na ⁺ ] represents a sodium-type exchanger. ) Unlike sodium sulfate, the exchanger that has become the sodium form is naturally insoluble in water, so the exchanger that has become the sodium form can be obtained by simply filtering the reaction solution (R-[Na ⁺ ]). can be separated by filtration, and if the filtrate is concentrated to dryness, there will be no inorganic substances mixed in.
We have newly discovered that the desired thiosulfate derivative [] can be obtained in almost pure form in high yield.

As the exchanger (free type) used in the present invention, a cation exchange resin is generally used, and free types of strongly acidic cation exchange resins and weakly acidic cation exchange resins can be used. The reaction solvent is usually preferably a mixed solvent such as water-methanol.

The cation exchange resin is usually used by a static ion exchange method (batch method), in which the ion exchange resin is dispersed in the reaction solution. The reaction is carried out by adjusting the pH to 4 or higher, preferably 4 to 7, by adding an exchange resin, and the reaction is further heated under reflux for 1 to 2 hours to complete the reaction. The ion exchange resin (R-[Na ⁺ ]) used in the reaction in the sodium form can be easily regenerated into the free form (R-[H ⁺ ]) with dilute hydrochloric acid and can be used repeatedly.

When producing the thiosulfuric acid derivative [], the advantages of the cation exchange resin as a source of acid are as described above, but mineral acids can also be used. The mineral acid used can be hydrochloric acid, sulfuric acid, nitric acid, etc., but in consideration of ease, it is preferable to use sulfuric acid that does not generate fumes, and it is preferable to use dilute sulfuric acid with a concentration of 5 to 6 normal. preferable.

The reason for this is that when a mineral acid is used, an inorganic salt is produced by the reaction with the thiosulfate used at the same time, resulting in a mixture of [ ] and the inorganic salt, as is clear from the reaction formula below. This is because there is no need for separation at all, and the process can proceed to the next step as it is. That is, since the reaction solvent for producing [] from [] is water, the by-produced inorganic salt is completely dissolved. On the other hand, the target compound [ ] is insoluble in water and is therefore precipitated and removed from the system. Therefore, after the completion of the reaction, the target compound can be easily obtained without the presence of inorganic substances by simply filtering the reaction solution.

(In the formula, R ¹ , R ² , and R ³ are the same as above, M〓 represents a monovalent salt, and M〓 represents a divalent salt.) The thiosulfate to be reacted with the aziridine derivative includes sodium thiosulfate, Potassium thiosulfate, calcium thiosulfate, magnesium thiosulfate, etc. are widely used.

In this way, N-(2-hydroxyphenethyl)-2-aminoethanethiosulfate, N-(2-hydroxyethyl)-2-aminoethanethiosulfate,
N-(2-hydroxypropyl)-2-aminoethanethiosulfate was produced.

By using the novel compound of the present invention, the formula [
A thiazolidine derivative represented by can be produced.

Among the compounds of the present invention (the above general formula []),
R ¹ = phenyl, R ² = R ³ = N- represented by hydrogen
(2-Hydroxyphenethyl)-2-amino-ethanethiosulfate ['] can be obtained in high yield by, for example, treatment with cyanide ions (CN) under basic conditions, as shown in formula (g). (2-hydroxyphenethyl)-2-iminothiazolidine [']
(In the above general formula [], R ¹ = phenyl, R ² = R ³
= hydrogen).

(Formula g) The base used is an alkali metal or alkaline earth metal hydroxide, any of which can be used freely, but sodium hydroxide is most preferably used. As a source of cyanide ions, any source having cyanide ions can be used as appropriate, but sodium cyanide or potassium cyanide is preferred, and sodium cyanide is more preferred.

Compound ['] is known and is very useful as an anthelmintic, tetramisole, i.e.
It is an important intermediate for producing (±)-2,3,5,6-tetrahydro-6-phenylimidazo[2.1-b]thiazole['], and its production method is as shown in (formula h) by Janssen Pharmacentica, J.
Med.Chem., 9 , 545 (1966) and A. Baklien et al., Aust.J.Chem., 21 , as shown in (formula i).
1557 (1968).

(Formula h) Compound [′] is thus an important intermediate for producing tetramisole [′],
Regarding the production method of [′], for example, A. Baklin et al.
al., Aust.J.Chem. 21 , 1557 (1968) and
Imperial Chemical Industries Limited, USP,
Several synthetic methods are known, including the method of 3855234 (1974), but all of these require extraction with an organic solvent such as ether or chloroform, and if this is to be carried out industrially, It is clear that this involves considerable difficulty, and it cannot be said to be an industrial method.

On the other hand, as mentioned above, the method for producing ['] using the novel compound ['] of the present invention (formula j) not only does not require these complicated operations, but also does not require an extraction solvent. This method is particularly excellent as an industrial method, as it does not cause any oxidation, leading to a reduction in raw material costs.

(Formula j) (In the formula, M〓 and M〓 are the same as above.) In this way, in addition to 3-(2-hydroxyphenethyl)-2-iminothiazolidine, 3-(2
-hydroxyethyl)-2-iminothiazolidine,
3-(2-hydroxypropyl)-2-iminothiazolidine can be produced.

Next, the present invention will be explained with reference to Examples, but the present invention is not limited thereto.

Example 1 N-(2-hydroxyphenethyl)-2-aminoethanethiosulfate ['] Sodium thiosulfate pentahydrate 49.6g (0.2mol)
After dissolving in 150ml of water, add 100ml of methanol. Add 1-(2-hydroxyphenethyl) to this solution.
32.6g (0.2mol) of aziridine in 50ml of methanol
The solution was added dropwise over 1 hour while cooling on ice. After dropping, remove the ice bath and return to room temperature.
This is strongly acidic cation exchange resin (product name SKIB).
Adjust the pH to 7.0 by carefully adding This requires approximately 200 ml of resin, and the liquid temperature rises to approximately 35°. This was further heated under reflux on a hot water bath for 1 hour to complete the reaction. After cooling to room temperature, the resin is filtered off under reduced pressure and washed with a small amount of methanol and then with water. The filtrate was concentrated under reduced pressure and solidified to give 40.0 g of pale yellow N-(2-hydroxyphenethyl)-2-aminoethanethiosulfate ['] (yield 76.8%).
is obtained. This product can be recrystallized from water to obtain a white crystalline powder.

mp 170-172℃ Elemental analysis value (as C ₁₀ H ₁₅ NO ₄ S ₂ ) C H N Calculated value (%) 43.32 5.42 5.05 Actual value (%) 42.95 5.48 5.05 IR data (KBr tablet) ν ^KBr _nax cm ^-1 ;3410, 1580, 1230, 1180, 1030 NMR data (DMSO-d ₆ , internal standard; sodium trimethylsilylpropionate) δppm2.80-3.50 (6H, m, -CH CH ₂ NHCH CH
₂ CH ₂ SSO ₃ H), 4.90 (1H, dd, PhCHOH, J ₁ =
8Hz, J ₂ = 4Hz) 6.00 (2H, broad, -OH, -
SSO ₃ H ), 7.35 (5H, m, Ph) Reference example 1 3-(2-hydroxyphenethyl)-2-iminothiazolidine ['] 8.0g (0.2mol) of sodium hydroxide in 250ml of water
dissolve in This was added to the N-(2
Add 55.4 g (0.2 mol) of -hydroxyphenethyl)-2-aminoethanethiosulfate ['] and stir.
dissolve. This includes 10.8g of sodium cyanide.
(0.22 mol) becomes a homogeneous solution,
A white precipitate forms after 2-3 minutes. At this time, the liquid temperature rises to approximately 40℃. After stirring this at room temperature for 1 hour, the white crystals formed were collected by filtration and washed with cold water to obtain the desired 3-(2-hydroxyphenethyl)-2.
-36.3 g (yield 81.7%) of iminothiazolidine are obtained. If necessary, this product can be recrystallized from 2-propanol to obtain glossy white plate-like crystals.

mp 126-127℃ Elemental analysis value (as C ₁₁ H ₁₄ N ₂ OS) C H N Theoretical value (%) 59.46 6.31 12.61 Actual value (%) 59.36 6.37 12.55 IR data (KBr tablet) ν ^KBr _nax cm ^-1 ; 3220, 3200, 1600 (C=N), 1440,
1420, 1350, 1250, 1660, 1080, 1060, 760, 700 NMR data ( _CDCl3 , internal standard; tetramethylsilane, δppm) 2.90-3.90 (6H, m, -CH2 - _x3 ), 5.00 (1H ,
dd, J ₁ = 8 Hz, J ₂ = 4 Hz, PhC H OH), 6.20
(2H, broad, -OH and =NH, disappeared by heavy water), 7.35 (5H, m, Ph) Reference example 2 3-(2-hydroxyphenethyl)-2-iminothiazolidine ['] Sodium thiosulfate pentahydrate 49.6g (0.2mol)
After dissolving in 150ml of water, add 100ml of methanol. Add 1-(2-hydroxyphenethyl) to this solution.
32.6g (0.2mol) of aziridine in 50ml of methanol
The solution was added dropwise over 1 hour at room temperature. After the dropwise addition is complete, add 5N sulfuric acid to adjust the pH to 7.0. Approximately 68 ml of 5N sulfuric acid was required. The mixture was further heated under reflux on a water bath for 1 hour to complete the reaction. The reaction solution was concentrated to dryness under reduced pressure to obtain 78.0 g of white crystalline powder. This is used in the next reaction without purification.

8.0g (0.2mol) of sodium hydroxide in 500ml of water
dissolve in 78.0 g of the above white crystalline powder was added to this and dissolved with stirring. When the mixture becomes homogeneous, add 10.8 g (0.22 mol) of sodium cyanide. Once the solution becomes homogeneous, a white precipitate is formed after 2 to 3 minutes.
At this time, the internal temperature rises to 40℃. After stirring for 1 hour at room temperature, the white precipitate formed is filtered and washed with cold water. 40.0 g of 3-(2-hydroxyphenethyl)-2-iminothiazolidine are obtained as white crystals. This product contains impurities, and when recrystallized from 2-propanol, 28.0 g of glossy white plate crystals (yield 63.0% from 1-(2-hydroxyphenethyl)aziridine) are obtained. m.
p.126-127℃. The IR data of this product completely matches the compound obtained in Example 2, including the fingerprint area.

In addition, examples of reactions leading to tetramisole from 3-(2-hydroxyphenethyl)-2-iminothiazolidine obtained in Reference Examples 1 and 2 are shown below as Reference Examples 3 and 4.

Reference example 3 Tellamisole hydrochloride [′]・HCl Stir 14.5 ml (0.26 mol) of 97% sulfuric acid while cooling with ice externally. 5.56 g (0.025 mol) of the above 3-(2-hydroxyphenethyl)-2-iminothiazolidine is added little by little while maintaining the liquid temperature at 10 to 18°C. Stop cooling and continue stirring for 1 hour.
The reaction solution was diluted by gradually adding it to 300 g of ice water, made alkaline by adding 20% (w/w) aqueous sodium hydroxide solution, and then extracted with toluene. Tetramisole hydrochloride is back-extracted by adding 7 ml of concentrated hydrochloric acid and then 100 ml of water to the extracted layer and shaking the mixture. 4.4g of white to slightly yellow crystals after drying the aqueous layer
(yield 73%). The IR spectrum of this compound completely matched that of the standard.

Reference example 4 Tetramisole hydrochloride [′]・HCl The above 3-(2-hydroxyphenethyl)-2-
22.2 g (0.1 mol) of iminothiazolidine is dissolved in 200 ml of chloroform. Dry ethanol saturated with hydrogen chloride gas is added dropwise to this solution under ice cooling until the pH reaches 2 using a wet test paper. After further stirring for 2 hours under ice cooling, the white crystals formed were collected by filtration, and 3-(2
-Hydroxyphenethyl)-2-iminothiazolidine hydrochloride [']・HCl25.8g (yield is quantitative)
get. Suspend this in 100ml of dichloroethane,
The mixture was heated to 40°C and 13.3 g of thionyl chloride was added dropwise thereto. Stir for a further 1 hour at this temperature. Next, while cooling from the outside with ice, 63 ml of water is added to decompose excess thionyl chloride, and then 50 g of sodium hydrogen carbonate is added. This mixture is heated at 60°C for 2 hours. After cooling, separate the organic layer and dry with anhydrous sodium carbonate. After filtering off the sodium carbonate, dry hydrogen chloride gas is passed through the filtrate. Excess hydrogen chloride gas is removed by heating and then cooled on ice. The white crystals formed are collected by filtration. Yield: 21.7 g (yield: 90.4%), mp: 260°C. This compound was confirmed to be tetramisole hydrochloride through a mixing test with known compounds and a comparison of IR spectra.

Claims (1)

[Claims] 1. General formula [] (In the formula, R ¹ , R ² , R ³ are the same or different, hydrogen,
Indicates a lower alkyl or aryl group. ) A novel compound thiosulfate derivative represented by 2 General formula [] (In the formula, R ¹ , R ² _{, R} ³ have the same meanings _as above.) The aziridine derivative [ _] represented by O ₃ ) (In the formula, M〓 represents a monovalent metal, and M〓 represents a divalent metal.) [] (In the formula, R ¹ , R ² and R ³ have the same meanings as above.) A method for producing a thiosulfate derivative represented by the following. 3. The manufacturing method according to claim 2, wherein the reaction is carried out at a pH of 4 or higher in the presence of an acid. 4. The manufacturing method according to claim 2, characterized in that a cation exchange resin or a mineral acid is used as the acid source.