JPH0759571B2 - Process for producing 1,3-oxazolidin-2-one derivative - Google Patents

Description

The present invention provides the following general formula (I) (In the formula, n represents an integer of 4 to 6, and * represents optical activity.) The present invention relates to the production of an optically active 1,3-oxazolidin-2-one derivative and an acid addition salt thereof.

The following general formula (I ') (In the formula, n is the same as above), the 1,3-oxazolidin-2-one derivative represented by the present inventors has an excellent glutamate-blocking action and a solid-contraction-releasing action for anemia decerebrate rigidified specimens. However, they have been found to be useful compounds as pharmaceuticals and agricultural chemicals. (Japanese Patent Laid-Open No. 61-83170) Generally, in order to obtain an optically active substance of such a compound, it is necessary to perform optical resolution somewhere along the route from the raw material to the target substance. Therefore, an expensive optical resolving agent is required, and in some cases, an extra step of introducing a protective group or the like is required.

Therefore, an object of the present invention is to use D or L-leucine as a raw material, introduce no special protection, and perform acid chloride synthesis Frie.
By using del-Crafts reaction, stereoselective reduction reaction with sodium borohydride, cyclization to 1,3-oxazolidin-2-one, and N-alkylation reaction, the above problems can be solved and the yield can be improved. In addition, the optical activity can be achieved with a short number of steps of 5
It is to provide a method for obtaining a 1,3-oxazolidin-2-one derivative.

That is, the present invention is a reaction of optically active leucine with phosphorus pentachloride, And reacting it with benzene in the presence of a Lewis acid, A compound represented by, and reducing this with sodium borohydride, As a compound represented by (X and Y are halogen atom, lower alkoxy group, amino group, or trichloromethyloxy group respectively) In the presence of an alkali carbonate or a bicarbonate, the compound represented by the general formula (Wherein Z represents a halogen atom, a tosyloxy group or a mesyloxy group, and n represents an integer of 4 to 6), and the product is converted to an acid addition salt if desired. formula (Wherein n is the same as above) and a method for producing an acid addition salt thereof.

In the method of the present invention, the compound represented by the general formula (II), which can be obtained by reacting optically active leucine with phosphorus pentachloride, is a known method [K. Dee. Koppuru et al., Journal of the American Chemical Society, 78, 6
199 (1956), KDKopple et al, J. Am. Chem. Soc., 78 , 6
199 (1956)] or according to this known method.

The obtained compound represented by the general formula (II) is isolated,
The reaction mixture can be directly used for the next Friedel-Crafts reaction without purification.

The compound represented by the general formula (III) has the same general formula (I
It can be obtained by the Friedel-Crafts reaction of the compound represented by I) with benzene.

As the solvent in the Friedel-Crafts reaction, those commonly used in this type of reaction can be used, benzene as a reaction substrate can be used as a solvent, and nitromethane carbon disulfide and the like can also be used. You can also do it.

As the Lewis acid as the catalyst, for example, one kind of anhydrous aluminum chloride, tin tetrachloride, boron trifluoride, zinc chloride, titanium chloride or the like or a mixture of two or more kinds thereof can be used. Among these Lewis acids, anhydrous aluminum chloride and the like are preferable.

The amount of Lewis acid used is usually 2 to 10 times mol, preferably 2 to 3 times mol, of the compound represented by the general formula (II).

The reaction temperature in the Friedel-Crafts reaction is 50-100.
At C, the reaction time is 2 to 6 hours.

Next, the compound represented by the general formula (III) is converted into the compound represented by the general formula (IV) by a reduction reaction.

The reaction is alcohols such as methanol and ethanol,
It can be carried out in a solvent such as ethers such as tetrahydrofuran.

The reaction temperature in the reduction reaction is in the range of -5 ° C to + 15 ° C.

The amount of sodium borohydride used is 0.5 to 1 times the mol of the compound represented by the general formula (III).

The compound represented by the general formula (VI) is the compound represented by the general formula (IV)
The compound represented by the formula (V) is reacted with a compound represented by the formula (V) to cyclize the compound. Examples of the compound represented by the general formula (V) include diethyl carbonate, phosgene, trichloromethyl chloroformate, ethyl chlorocarbonate, urea and the like.

The reaction between the compound represented by the general formula (IV) and the compound represented by the general formula (V) is carried out in the presence of an alkali such as sodium hydroxide in a heterogeneous solvent of an organic solvent such as ether or chloroform and water. It is carried out at temperatures between 10 ° C and room temperature. When the general formula (V) is, for example, ethyl chlorocarbon, it is further followed by the presence of a base such as sodium methoxide, sodium ethoxide or aluminum isopropoxide in an organic solvent such as toluene or xylene at 50 ° C to the reflux temperature. It is preferable to carry out the cyclization reaction by distilling off the alcohol by-produced together with the reaction solvent.

When the general formula (V) is diethyl carbonate or the like, the reaction is carried out in the presence of a base such as sodium ethoxide or sodium methoxide without reacting the compound represented by the formula (IV) with the compound of the general formula (V) without a solvent. It is carried out by heating at 50 ° C to the reflux temperature. When the general formula (V) is urea, the reaction is
It is carried out by heating the compound represented by V) and the compound of general formula (V) to 150 to 250 ° C. without a solvent.

The reaction between the compound represented by the general formula (VI) and the compound represented by the general formula (VII) is carried out in the presence of an alkali carbonate or an alkali bicarbonate, preferably potassium carbonate or potassium hydrogencarbonate, acetone, methyl ethyl ketone, isobutyl ketone, etc. It is carried out by heating at 50 ° C. to the reflux temperature for 2 to 50 hours in the organic solvent. In the reaction, it is preferable to use 1 to 2 mol of the compound (VII) and 2 to 8 mol of potassium carbonate or potassium hydrogen carbonate with respect to 1 mol of the compound (VI). Further, the compound represented by the general formula (VII) can also be used in the form of a stable acid addition salt such as a hydrochloride.

The compound represented by the general formula (VII) has the following general formula (VII
Compound represented by I) (J. Am. Chem. Soc., 76, 2317-2
2 ('54)) It can be obtained by reacting tosylic acid, mesylic acid or their reactive derivatives, or by reacting the compound represented by the general formula (VIII) with thionyl chloride.

When Z is chlorine in the general formula (VII), the following method (F.Leo
nard & L. Simet, J. Am. Chem. Soc., 77, 2855-60 ('5
It can also be obtained by 5)).

That is, it can be obtained by reacting 1-bromo-3-chloropropane (IX) with a compound represented by the general formula (X) in a solvent that does not participate in the reaction, for example, isopropyl ether (IPE).

The reaction temperature is preferably 30 to 40 ° C.

The compound represented by the general formula (I) obtained by the above-mentioned method of the present invention can be obtained by a conventional method using an acid addition salt thereof, for example, hydrochloride, fumarate, mesylate, oxalate, maleate, tartrate. And so on.

Next, the present invention will be described in more detail with reference to Examples and Reference Examples.

Example 1 (S) -2-Amino-4-methyl-1-phenylpentan-1-one hydrochloride 319 g of phosphorus pentachloride was suspended in 3.0 l of dry benzene, and the suspension was heated to about 10 ° C.
197 g of L-leucine was added to the mixture with cooling and stirring,
Stir at ~ 20 ° C for 4 hours. Then, while cooling to about 5 ° C., 600 g of anhydrous aluminum chloride was added. The reaction mixture is heated slowly and allowed to reach reflux temperature over 2 hours, and further 2
Heated to reflux for hours. After cooling, the reaction mixture was poured into a mixture of 3.0 kg of ice and 450 ml of concentrated hydrochloric acid with stirring. Then, the aqueous layer was separated, the organic layer was further extracted with 1 and 0.2 l of water, the aqueous layers were combined, and the crystals were precipitated by allowing this to stand overnight and washing with ether, The crystals were dried under reduced pressure to give 254 g (yield 75.0 g) of the title compound as white crystals. The physical properties of the title compound recrystallized from isopropanol are as follows.

mp; 206 - 208 ° C. (decomposition) ▲ [α] _{^{23 D ▼; -5.4 ° (C1.007}} , water) Example 2 (1R, 2S) -2-Amino-4-methyl-1-phenylpentan-1-ol (S) -2-amino-4-methyl-1 in 3.0 l of methanol.
Dissolve 254 g of phenylpentan-1-one hydrochloride,
56.7 g of sodium borohydride was added while cooling to below ℃. After stirring at the same temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure. Chloroform 1.5 l, water 0.75 in the concentrated residue
1 and subsequently 0.75 l of a 2N aqueous solution of caustic soda were added and stirred. The organic layer was separated, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated to give crude white crystals which were recrystallized from n-hexane to give white needle crystals. Compound 17
8 g (yield 81.9%) was obtained.

mp; 70-71 ℃ ▲ [α] ²³ _D ▼; -39.0 ° (C1.01, ethanol) Example 3 (4S, 5R) -4- (2-Methylpropyl) -5-phenyl-1,3-oxazolidin-2-one (A) (1R, 2S) -2-amino-4-methyl-1- Phenylpentan-1-ol 96.64 g (0.5 mol) was added to chloroform 80
Dissolve in 0 ml, add 400 ml of water, and cool with ice. Under stirring 10
47.5 ml of ethyl chlorocarbonate is added dropwise at a temperature below ℃. 10 more
At below ℃, 47.5 ml of ethyl chlorocarbonate is added dropwise at the same time with 150 ml of 7.5N sodium hydroxide aqueous solution, and both additions are completed at the same time. Furthermore, after continuing stirring at the same temperature for 30 minutes, the organic layer is separated and the aqueous layer is extracted with 80 ml of chloroform. The combined organic layers are dried over sodium sulfate and chloroform is distilled off under reduced pressure. Dissolve the residue in 1.5 l of toluene and add 200 m of toluene.
distill off l. After adding 2.0 g of aluminum isopropoxide and heating under reflux for 1 hour, 800 ml of toluene is distilled off in order to remove the alcohol by-produced. N- in the residue
Add 600 ml of hexane with stirring and leave at room temperature overnight. The precipitated white crystals were collected by filtration, and toluene-n-hexane (1:
1) It was washed twice with 300 ml and once with 300 ml of n-hexane and then dried to obtain 104.0 g of the title compound. (Yield 95%) mp; 163-164 ° C ▲ [α] ²⁵ _D ▼; -137.4 ° (C1.016, CHCl ₃ ) (B) (1R, 2S) -2-Amino-4-methyl-1-phenylpentan-1-ol 0.97 g (5 mmol) and urea 0.60 g (10 m
mol) mixture under stirring at 170-180 ° C for 30 minutes and then 200
Heat at ˜210 ° C. for 20 minutes. After cooling, chloroform and water were added and the mixture was extracted with chloroform and dried (Na ₂ SO ₄ ). The chloroform solution was filtered through Celite and then concentrated under reduced pressure.
The residual yellow crystals (1.04 g) were recrystallized from 80% methanol (6 ml) to obtain 0.68 g of the title compound as white crystals (yield 62%).

Example 4 (4S, 5R) -4- (2-methylpropyl) -3- [3-
(Perhydroazepin-1-yl) propyl] -5-phenyl-1,3-oxazolidin-2-one hydrochloride 1- (3-chloropropyl) perhydroazepine hydrochloride 1
7.25 g (81.25 mmol) was dissolved in 26 ml of water, and 2N-NaOH aqueous solution was added.
45.5 ml was added and extracted with 100 ml of methyl ethyl ketone.
The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After the desiccant was filtered off, 22.4 g (162.5 mmol) anhydrous potassium carbonate and (4S, 5R) -4- (2-
Methylpropyl) -5-phenyl-1,3-oxazolidin-2-one (14.25 g, 65 mmol) was added, and the mixture was stirred with 12
Heated to reflux for hours. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the solvent was concentrated under reduced pressure. The residue was dissolved in chloroform, 130 ml of 2N-HCl aqueous solution was added, and the mixture was stirred for 30 minutes. The chloroform layer was separated, washed with a 2N-HCl aqueous solution, and dried over anhydrous sodium sulfate. The desiccant is filtered off,
The solvent was distilled off under reduced pressure to obtain 25.17 g of white crystals (yield 98.7%). The crystals were dissolved in isopropanol by heating and n-
Hexane was added and recrystallized to give 20.6 of the title compound as white crystals.
got g.

mp; 182-184 ° C. (decomposition) ▲ [α] _{^{23 D ▼; + 14.5 ° (}} C5, MeOH) Example 5 (4S, 5R) -4- (2-methylpropyl) -5-phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin-2-one methanesulfonate hydrochloride 1- ( 3-chloropropyl) piperidine 12.38 g (6
2.5 mmol) is dissolved in water (12.4 ml) and 2N NaOH aqueous solution (35 m
l) is added and extracted with methyl ethyl ketone. The extracts are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and washed with methyl ethyl ketone. Anhydrous potassium carbonate (powder) in the combined filtrate and wash
17.25 g (125 mmol) and (4S, 5R) -4- (2-methylpropyl) -5-phenyl-1,3-oxazolidine-2-
Add 10.96 g (50 mmol) of on and heat to reflux for 12 hours with stirring. The reaction mixture is allowed to cool or cool to room temperature, suction filtered and washed with methyl ethyl ketone. After the filtrate and washings were combined and concentrated under reduced pressure, the remaining slightly yellow oily substance was dissolved in chloroform (100 ml) and a 2N HCl aqueous solution (100 m
Add l) and stir for 30 minutes. Separate the chloroform layer and
After washing with NH Cl aqueous solution, 2N NaOH aqueous solution (100 ml) is added and stirred for 30 minutes. The chloroform layer is separated, washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered and washed with chloroform. The filtrate and washings are combined and chloroform is distilled off under reduced pressure to obtain a pale yellow oily substance. This oil was added to ethanol-ethyl acetate (1: 1).
0) Dissolved in mixed solvent (65ml), methanesulfonic acid 4.80g
(50 mmol) is added together with ethanol-ethyl acetate (1:10) mixed solvent (4 ml), and the mixture is stirred at room temperature. The precipitated crystals were collected by filtration, washed with a mixed solvent of ethanol-ethyl acetate (1:20) and ethyl acetate, and dried to give white crystals of the title compound.
6.52 g is obtained (75% yield) mp; 129-131 ° C ▲ [α] ²³ _D ▼; + 11.7 ° (C5, O, MeOH) Reference Example 1 1- (3-chloropropyl) perhydroazepine hydrochloride 157.4 g (1 mol) of 1-bromo-3-chloropropane is dissolved in isopropyl ether (IPE) (240 ml). Hexamethyleneimine (198.4 g, 2 mol) is added dropwise with stirring over about 1.5 hours. At this time, the dropping rate is adjusted so that the reaction temperature is 30 to 40 ° C. Then heat and stir at 35-40 ° C for 10 hours,
Leave at room temperature overnight. The reaction mixture is washed with water and saturated brine, and dried over Glauber's salt. Glauber's salt was filtered off and IPE (50 ml x
Wash with 3). The filtrate and washings are combined and ice-cooled saturated HC
Add to a mixture of l-isopropanol (IPA) solution (130 ml) and isopropanol (270 ml) with stirring. The precipitated crystals were collected by filtration, washed with IPA-IPE (1: 1) (200 ml x 2),
Dry to obtain 159.3 g of the title compound. (Yield 75%) (mp; 2
06 ~ 207 ℃ (decomposition))

Claims (1)

[Claims] 1. An optically active leucine is reacted with phosphorus pentachloride, A compound represented by, and reacting this with benzene in the presence of a Lewis acid, A compound represented by, and reducing this with sodium borohydride, A compound represented by the general formula (X and Y are a halogen atom, a lower alkoxy group,
Amino group or trichloromethyloxy group) A compound represented by the general formula: in the presence of alkali carbonate or bicarbonate. (Wherein Z represents a halogen atom, a tosyloxy group or a mesyloxy group, and n represents an integer of 4 to 6), and the product is converted to an acid addition salt if desired. General formula (In the formula, n is the same as above) and a method for producing an acid addition salt thereof.