JPH0667916B2 - Enantiomers of phenoxy derivatives of benzylmorpholine and their salts - Google Patents

Description

The present invention relates to SS enantiomers of phenoxy derivatives of benzylmorpholine and salts thereof, processes for their preparation and pharmaceutical compositions containing them. U.S. Pat.No. 4,229,
In the specification of No. 449, the following formula (I) (Wherein, R is a C ₁ -C ₆ alkoxy group or a trihalomethyl group) 2- (α-phenoxy-benzyl)
-Morpholine derivatives and their pharmaceutically acceptable salts are described. 2 carbon atoms in the above formula (I)
There are two sets of enantiomers for the compound of formula (I) respectively due to the presence of two chiral centers in and 3.
These two pairs, which are in diastereoisomeric relationship with each other, are referred to as IUPAC nomenclature (IUPAC, NOMENCLATUR) for organic chemistry.
E OF ORGANIC CHEMISTRY) 1979 edition, Section E, 489, respectively, represented by the symbols (±) RS, RS and (±) RS, SR.

In formula (I) and other formulas herein, two chiral centers are conventionally labeled as 2 and 3 so that when known, the absolute configuration of each center can be clearly indicated. Numbered. However, such conventional numbering is independent of the numbering required for example by the IUPAC nomenclature for the exact names of the compounds described herein.

Specific diastereoisomers having the above formula (I), i.e., a set of enantiomers, are described in U.S. Pat. No. 4,229,449, except for a single enantiomer derived therefrom. Not specifically mentioned.

The present invention provides the 2S, 3S enantiomers of compounds of formula (I) and their pharmaceutically acceptable salts. Therefore, the enantiomer of the present invention exists as a dextro (+) enantiomer. Preferred compounds of the invention are those where R is methoxy, ethoxy or trifluoromethyl.

The present invention also provides a metabolite of the 2S and 3S enantiomers of the formula (I), a bioprecursor and a pharmaceutically acceptable salt described above, and a pharmaceutical composition containing the enantiomer or a salt thereof. Compositions are also included. Examples of pharmaceutically acceptable salts of the enantiomers of the present invention include organic acids such as salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and optically active acids such as citric acid, tartaric acid, methanesulfonic acid. , Both fumaric acid, maleic acid and salts with mandelic acid. Preferred salts are salts with hydrochloric acid and methanesulfonic acid, and more preferred are salts with methanesulfonic acid. Examples of particularly preferred compounds of the invention are the (+) enantiomers:

(+) 2- [α- (2-Methoxy-phenoxy) -benzyl] -morpholine, (-) 2- [α- (2-Methoxy-phenoxy) -benzyl] -morpholine, (+) 2- [α- (2-Ethoxy-phenoxy) -benzyl] -morpholine, (-) 2- [α- (2-ethoxy-phenoxy) -benzyl] -morpholine, (+) 2- [α- (4-trifluoromethyl-phenoxy) ) -Benzyl] -morpholine, (-) 2- [α- (4-trifluoromethyl-phenoxy) -benzyl] -morpholine, and their pharmaceutically acceptable salts, especially with hydrochloric acid or methanesulfonic acid.

The compounds of the present invention are (a) reacting the (±) RS, RS racemic form of the compound of formula (I) as a free base with an optically active acid to give a mixture of salts of two diastereoisomers, (b) The obtained salt is separated by crystallization, and (c) the dextro is separated from each separated salt.
Preparing a process comprising releasing the (+) enantiomer base and (d) forming a salt of the optionally obtained dextro (+) enantiomer base with a pharmaceutically acceptable acid. You can

The reaction of the compound of formula (I) as the free base with the (±) RS, RS racemic form and the optically active acid can be carried out using any suitable optically active acid, for example L (±) Mandelic acid, D (-) mandelic acid, 10 (+) camphorsulfonic acid, L (+) dibenzoyl tartaric acid, L (-) pyrrolidone-carboxylic acid, L (+) tartaric acid or D (-) tartaric acid Good. The salt forming reaction is preferably carried out in an organic, preferably anhydrous solvent, which may be, for example, methanol, ethanol, dioxane or dimethylformamide.

If necessary, precipitation of the salt obtained from the reaction solvent is preferably carried out by adding an anhydrous non-polar solvent such as diethyl ether, n-hexane or cyclohexane. Separation of the desired salt from the diastereoisomeric mixture is preferably carried out by fractional crystallization from a suitable solvent such as methanol or ethanol. Preferably anhydrous solvents are used.

Release of the corresponding dextro (+) enantiomeric base from the separated salt can be accomplished by treating with a small excess of the appropriate base. Preference is given to using inorganic bases such as alkali metal or alkaline earth metal hydroxides or carbonates or hydrogencarbonates. Sodium or potassium carbonate or hydrogen carbonate is a particularly preferred base.

Salt formation of the resulting dextro (+) enantiomer base is carried out by reaction with a stoichiometric amount or a small excess of the desired acid in a suitable solvent. Thus, for example, salts with hydrochloric acid are treated with anhydrous gaseous hydrochloric acid in anhydrous solvents such as diethyl ether, toluene, ethanol or with anhydrous alcoholic solutions of hydrochloric acid, and by evaporation or evaporation of the solvent. Obtained by isolating the hydrochloride salt. Similarly, a salt with methanesulfonic acid can be obtained, for example, by adding an ethanol solution of methanesulfonic acid to an ethanol mixture of enantiomeric bases. Precipitation of the methanesulphonate is conveniently carried out by adding anhydrous non-polar solvents such as diethyl ether, n-hexane or cyclohexane when necessary.

All reaction steps described in a) to d) above can be carried out at temperatures from about 0 ° C. to about 50 ° C., but in each case room temperature is the preferred temperature.

Mixtures of diastereoisomers and preparation of compounds of (I) as separated diastereoisomers are described in U.S. Pat.
29,449.

Alternatively, the compounds of the invention are (a) formula (II) By reducing the (+) or (-) enantiomer of glycidic acid or its derivative of formula (III) Cinnamyl alcohol-2,3-epoxide (+) or
(-) Enantiomer is obtained, and (b) the (+) or (-) enantiomer of formula (III) is replaced by formula (IV) (Wherein R is as defined above) is reacted with a phenol derivative to give formula (V) (Where R is as defined above)
(+) Or (-) enantiomer is obtained and (c) the (+) or (-) enantiomer of formula (V) is esterified with a carboxylic acid or a reactive derivative thereof to give formula (VI) (Wherein R is as defined above and R ₁ is the residue of a carboxylic acid) to give the (+) or (−) enantiomer of (d) of formula (VI) The (+) or (-) enantiomer is esterified with sulfonic acid or its reactive derivative to give the compound of formula (VII) Where R and R ₁ are as defined above and R ₂ is the residue of a sulfonic acid, and the (+) or (−) enantiomer of the formula (e) VII) (+) or (-) enantiomers of the formula (VIII) (Where R is as defined above)
(+) Or (-) enantiomer is obtained and (f) the (+) or (-) enantiomer of formula (VIII) is reacted with ammonia to form formula (IX) (Where R is as defined above)
(+) Or (-) enantiomer is obtained, and (g) the (+) or (-) enantiomer of formula (IX) is converted into the formula (X) Y-CH ₂ -CO-Y (X) (where Where Y is a halogen) and react with a compound of formula (XI) (Wherein R and Y are as defined above) to obtain the (+) or (-) enantiomer, and (h) the (+) or (-) enantiomer of formula (XI) Is cyclized to formula (XII) (Where R is as defined above)
The (+) or (-) enantiomer is obtained, and (1) the (+) or (-) enantiomer of formula (XII) is reduced to formula (I)
Prepared by a method comprising obtaining the (+) or (-) enantiomer of and the optionally obtained 2S, 3S enantiomer of formula (I) is converted to its pharmaceutically acceptable salt. be able to.

The derivative of glycidic acid of formula (II) may be, for example, an acid anhydride, preferably a mixed acid anhydride. The carboxylic acids used in the esterification step (c) above are aliphatic, such as C ₂
It may be a C ₆ -aliphatic carboxylic acid such as acetic acid or propionic acid, or an aromatic such as benzoic acid or p-nitrobenzoic acid. In formulas (VI) and (VII) above, the carboxylic acid residue R ₁ is, for example, acetyl, propionyl, benzoyl or p-nitrobenzoyl. The sulfonic acid used in the esterification step (d) is, for example, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. The above formula (VI
The sulfonic acid residue R ₂ in I) is, for example, methanesulfonyl, ethanesulfonyl, benzenesulfonyl or p-
Trienesulfonyl, preferably methanesulfonyl. Halogen Y in the compounds of formula (X) and formula (XI) is preferably chlorine, bromine or iodine, most preferably chlorine.

The reduction step (a) is carried out in a known manner, preferably with BH ₃ or a mixed hydride such as NaBH ₄ in a suitable anhydrous inert solvent such as absolute ethanol, diethyl ether or tetrahydrofuran, eg with cooling to about 0 ° C. You can

The reaction of the enantiomer of formula (III) with the compound of formula (IV) is preferably for example in the presence of a base such as aqueous sodium or potassium hydroxide, preferably in the absence of another solvent, e.g.
It is carried out by heating at a temperature of 60 ° C to about 120 ° C.

The esterification of the enantiomer of formula (V) to obtain the compound of formula (VI) is preferably carried out in an anhydrous organic solvent such as benzene or toluene in the presence of a base such as an organic base such as triethylamine or pyridine, e.g. ~
It is carried out with cooling to 0 ° C. or at room temperature with a reactive derivative of a carboxylic acid, preferably a carboxylic acid halide, especially chloride, and according to a preferred procedure pyridine is used as solvent in the absence of other bases.

The esterification of the enantiomers of formula (VI) to give compounds of formula (VII) is preferably a reactive derivative of a sulfonic acid in the presence of an acid acceptor such as an organic base such as triethylamine or pyridine, preferably a sulfonic acid halide, especially It is carried out with chlorides such as methanesulphonyl chloride or p-toluenesulphonyl chloride. The reaction is preferably carried out in a suitable anhydrous solvent such as benzene, toluene, methylene chloride or pyridine, e.g.
It is performed while cooling to 10 ° to 5 ° C. When pyridine is used as a solvent it also acts as a base. The conversion of the compound of formula (VII) into the compound of formula (VIII) is carried out by reaction with a suitable base, preferably an inorganic base such as an alkali metal or alkaline earth metal hydroxide, preferably sodium or potassium hydroxide. Preferably the reaction is carried out at room temperature in an aqueous organic solvent such as dioxane or dimethylformamide.

Subsequent reaction of the epoxide of formula (VIII) with ammonia is preferably carried out using 30-32% aqueous ammonia in a suitable solvent such as dimethylacetamide or an aliphatic alcohol such as methanol or ethanol at room temperature. Reaction of the resulting enantiomer of formula (IX) with a compound of formula (X) is for example in the presence of a base such as an organic base such as triethylamine, preferably in an anhydrous inert solvent such as a halogenated hydrocarbon such as methylene chloride. For example, it can be performed while cooling to -10 ° C to 0 ° C.

The following cyclization of the enantiomer of formula (XI) is carried out, for example, according to known methods by treatment with a base, for example potassium tert-butoxide in tertiary butyl alcohol at room temperature.

Reduction of the resulting enantiomer of formula (VII) can be accomplished, for example, by anhydrous
Inert solvents such as diethyl ether, tetrahydrofuran
BH in orchid, dioxane or toluene₃Or mixed water
Oxides such as lithium aluminum hydride or hydrogen
A temperature of about 0 ° C. to the reflux temperature using sodium boride.
It is done by processing in degrees. Particularly suitable reduction method
It is used as a reducing agent in anhydrous toluene at room temperature.
[Red-Al (Vitride, Vitride )〕to use
Is included. The salt formation of the resulting enantiomer of formula (I) has not yet occurred.
It can be carried out in any conventional manner according to the known salt formation method.
Wear.

The glycidic acid enantiomers of formula (II) used as starting material in the above alternatives are known compounds or compounds which can be prepared from known compounds by known methods. For example, J.Org.Che by K. Harada
m. "Vol. 31, p. 1407 (1966).

The fact that the compounds of the invention are active on the central nervous system, in particular as antidepressants, increases their concentration, for example by blocking the uptake of physiologically active monoamines by the compounds of the invention. Have the potential and / or are indicated by blunting the alpha-2 presynaptic receptors.

As is known, an important property of antidepressants is their ability to block the uptake of neurotransmitters at cerebral synapses [Iversen LL, "J.Pharm.Pharmacol." Vol. 17, p. 42 (1965). ], And even more important property is α
-2 ability to block or blunt adrenoreceptors [Chapleo CB, "J. Med. Chem." Vol. 26, Vol. 8
23 (1983)].

The compounds of the present invention are also labeled in radioactivity in vitro {in that case eg according to the experimental method described by Snyder SH, "J. Pharmacol. Exp. Ther." Vol. 165, p. 76, (1969). It was found that the concentration of biogenic amine can be increased also in the adult body by various methods.

Physiologically active monoamines whose concentrations are increased by the compounds of the invention include serotonin, norepinephrine and dopamine.

The antidepressant activity of the compounds of the invention is also evidenced by the fact that they are active against reserpine-induced blepharospasm and hypothermia in mice.

The compounds of the invention can also be used, for example, in treating sleep disorders and as weak tranquilizers. The toxicity of the compounds of the present invention is negligible and thus they can be safely used in therapy.

The compounds of the invention may be administered in the usual manner, eg by injection or rectally, but are preferably administered orally. A suitable dose for the oral administration of the compound of the present invention to an adult is preferably 0.5 to 10 mg per administration and administered 2 to 4 times a day.

The pharmaceutical composition according to the invention comprises as active ingredient the 2S, 3S enantiomer of the compound having formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and / or diluent. To do. The composition can be manufactured by a conventional method using conventional components. For example, for oral administration, a pharmaceutical composition containing a compound of the invention is preferably a diluent such as lactose, dextrose, sucrose,
Tablets, pills or capsules containing the active substance together with mannitol, sorbitol, cellulose, lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycol. They are also binders such as starch, gelatin, methylcellulose, acacia, tragacanth, polyvinylpyrrolidone, disintegrants such as starch, alginic acid, alginates, effervescent mixtures, dyes, sweeteners, wetting agents such as lecithin, polysorbates, lauryl sulphates. And non-toxic pharmacologically inactive substances commonly used in pharmaceutical formulations.

Such pharmacological formulations may be prepared in known manner, for example by mixing,
It can be manufactured by granulation, powdering, sugar coating or coating coating operation. Other pharmaceutical formulations containing the compounds of the invention can also be prepared in a known manner, for example by syrups or drops for oral administration, sterile solutions for injection or suppositories. You can buy it.

The present invention is described below with reference to examples in order to better understand the present invention, but the present invention is not limited thereto. Unless otherwise specified, the [α] _D value is 95.
For a concentration of 1% in% ethanol.

Example 1 A solution of 2- [α- (2-ethoxy-phenoxy) -benzyl] -morpholine (±) RS, RS diastereoisomer (1.6 g) in absolute ethanol was added to methanesulfonic acid (0.33 m).
) Is added. A solid is precipitated by diluting with diethyl ether (200 m). When collected by filtration, 2- [α- (2-ethoxy-phenoxy) -benzyl] morpholine methanesulfonate [mp 146-1
47 ° C., UV (MeOH): λ _max = 275 nm, Is obtained as (±) RS, RS racemic form.

Example 2 (±) RS, RS2- [α- (2
An aqueous solution of -ethoxy-phenoxy) -benzyl] -morpholine methanesulfonate (mp 146-147 ° C, 40g) is extracted with ethyl acetate. The organic solution is washed with water, dried over sodium sulphate and evaporated to dryness under vacuum. The free base (31 g) was dissolved in absolute ethanol (140 m), and L (+) dissolved in absolute ethanol (140 m).
Mandelic acid (15.06 g) is added to the solution. If the precipitate is passed, mp134-151 ℃, ▲ [α] ²⁰ _D ▼ ＝ (+) 48.01 (80%
18.85 g of solids with 1% solution in ethanol) are obtained. 16.86 g of product (mandelate), mp 151-153 ° C, after crystallization from absolute ethanol (200 m)
Is obtained. [Α] ²⁰ _D ▼ = + 49.09 (1% solution in 80% ethanol) The mandelate salt is dissolved in water, the solution is made basic with potassium carbonate and the base is extracted with ethyl acetate. The organic solution is dried over sodium sulphate and evaporated to dryness under vacuum. (+) 2S, 3S-2- [α
The oily residue containing-(2-ethoxy-phenoxy) -benzyl] -morpholine (12.15g) is dissolved in ethanol and a solution of methanesulfonic acid (3.72g) in ethanol is added. A precipitate forms after dilution with diethyl ether, which is passed over to give (+) 2S, 3S-2- [α- (2-ethoxy-phenoxy) -benzyl] -morpholine methanesulfonate (13.05g). . mp100 ~ 102 ℃,
▲ [α] ²⁰ _D ▼ = + 21.89 ° (1% solution in 95% ethanol). Molar purity (DSC) = 98%.

NMR (CDCl ₃ ) δ: 1.42 (t, 3H, CH ₃ -CH ₂ ), 2.71 (s, 3H, CH ₃ SO ₃ ), 2.84 to 3.50 (m, 4H, CH ₂ -N-CH ₂ ), 3.85 ~ 4.40 (m, 3H, CH ₂ -O-CH), 4.05 (q, 2H, CH ₂ -O-Ar), 5.14 (d, 1H, O-CH-Ar), 6.64 ~ 6.92 (m, 4H, 7.33 (m, 5H, Ar-CH), 9.20 (ds, 2H, A similar method to that described above starts with the D (-) mandelic acid starting from the levo isomers (-) 2R, 3R-2- [α- (2-ethoxy-phenoxy) -benzyl] -morpholine and (-) 2R, 3R. -2-
[Α- (2-Ethoxyphenoxy) -benzyl] -morpholine used to produce methanesulfonate,
The latter compound has an mp of 100-102 ℃, ▲ [α] ²⁰ _D ▼ = -21.8
With 9 ° (1% solution in 95% ethanol).

The same operation produces the following enantiomers starting from the corresponding (±) RS, RS racemic form.

(+) 2- [α- (2-Methoxy-phenoxy) -benzyl] -morpholine, (-) 2- [α- (2-Methoxy-phenoxy) -benzyl] -morpholine, (+) 2- [α- (4-trifluoromethyl-phenoxy)
-Benzyl] -morpholine, (-) 2- [α- (4-trifluoromethyl-phenoxy)
-Benzyl] -morpholine, (+) 2- [α- (2-Methoxy-phenoxy) -benzyl] -morpholine methanesulfonate, (-) 2- [α- (2-Methoxy-phenoxy) -benzyl]- Morpholine methanesulfonate, (+) 2- [α- (4-trifluoromethyl-phenoxy)
-Benzyl] -morpholine methanesulfonate, (-) 2- [α- (4-trifluoromethyl-phenoxy)
-Benzyl] -morpholine methanesulfonate.

(+) 2S, 3S- and (-) obtained from (±) RS, RS racemic
The optical purity of 2R, 3R-2- [α- (2-ethoxy-phenoxy) -benzyl] -morpholine methanesulfonate is determined as follows.

(+) 2S, 3S-2- [α- (2
-Ethoxy-phenoxy) -benzyl] -morpholine base (1 g) (obtained from the corresponding (±) RS, RS diastereoisomer) and triethylamine (0.90 m) in water at 10 ° C with rapid stirring. L (-) Menthoxy-acetyl-chloride in toluene (10m)
(0.80m) is added dropwise. After stirring for 1 hour at room temperature, the reaction is complete. The reaction mixture is washed with water, dried over sodium sulfate and evaporated to dryness under vacuum.

A similar procedure was obtained from (±) RS, RS-2- [α- (2-ethoxy-phenoxy) -benzyl] -morpholine.
It also applies to the (-) 2R, 3R-enantiomer.

The two diastereoisomeric amides thus obtained were each subjected to high performance liquid chromatography (HPLC) technology [Partisil PXS 10/2
5, cyclohexane containing isopropylamine 0.15%:
When analyzed by ethyl acetate 93: 7], the retention times (RT) were 15, 13 minutes and 17, 23 minutes, respectively.

The result in both cases is And therefore for both the (+) and (-) enantiomers Can be estimated.

Example 3 (+) 2S, 3R-phenyl-glycidic acid D (+)-α-methyl-
Add a solution of 3.8 g (13.3 mmol) of phenethylamine salt to 2
Treat with 6.65 m (13.3 mmol) N hydrochloric acid. The organic acid is extracted with diethyl ether and dried over sodium sulfate and then the solvent is removed under vacuum. The residue was dissolved in 70 methylene chloride and triethylamine 2
m (14.3 mmol) is added. The solution is cooled to 0 ° C. and under stirring ethyl-chlorocarbonate 1.36 m
(14.3 mmol) is added dropwise over 1 hour. After 2 hours this solution is slowly added to a suspension of 2.26 g (59.7 mmol) of sodium borohydride in 17 m of absolute ethanol at 0 ° C. with stirring. After 0.5 hours, allow it to warm to room temperature and continue stirring overnight. The mixture is poured into water and the product is extracted with methylene chloride. Flash chromatography e-column (using chloroform: methanol 100: 2 as eluent)
After separation with (+) 2R, 3R-cinnamyl alcohol-2,3
-0.62 g (31%) of epoxide is obtained as a colorless oil. ▲ [α] ²⁰ _D ▼ = + 45.9 ° (C1.5, absolute ethanol).

(Example: calculated for C71.68H6.71C ₉ H ₁₀ O ₂ C71.9
7H6.71%) ¹ HN.MR (CDCl ₃ ) δ: 3.24 (1H, ddd, -CH-CH ₂ OH), 3.76 (1H, dd, -CH _A H _B -OH), 3.94 (1H, d, Ph-CH, J = 2.1Hz), 4.05 (1H, dd, CH _A H _B -OH), 7.35 (5H, s, Ph): IR (CHCl ₃ ) cm ^-1 : 3590-3450 (OH), 1600 , 1490 (Aromatic C
= C), 1220, 1060 (Alk-O-Alk, Alk-OH): (+)-(2S, 3R) phenylglycidic acid 0.33 as a starting material
g (15.3%) is recovered along with 0.92 g (36.5%) of its ethyl ester.

Example 4 To a solution of 1.77 g (44.3 mmol) of sodium hydroxide in 100 m of water was added 18.4 g (133 of 2-ethoxy-phenol).
Mmol) is added. The mixture is stirred under nitrogen at 70 ° until the solids are completely dissolved, then 6.7 g (44.3 mmol) of (+) 2R, 3R-cinnamyl alcohol-2,3-epoxide are added in 10 minutes. The solution was stirred at 70 ° C for 2.5 hours and then at 10-15 ° for 1N sodium hydroxide 200m.
Pour into. After extraction with methylene chloride, the organic solution is washed successively with 1N sodium hydroxide and brine. When the solvent is removed, (+) 2R, 3S-3- (2-ethoxy-
10.2 g of phenoxy) 1,2-dihydroxy-3-phenylpropane are obtained. ▲ 〔α〕 ²⁰ _D ▼ ＝ + 7.8 ° ； mp8
7-89 °; IR (KBr) cm ^-1 3440-3380 (OH), 1590, 1490 (aromatic C =
C), 1240 (Ar-O-Alk).

Example 5 To a solution of 10 g (34.6 mmol) of (+) 2R, 3S-3- (2-ethoxy-phenoxy) -1,2-dihydroxy-3-phenylpropane in 100 m of pyridine 4-nitro-in 100 m of pyridine. 6.44 g (34.0 mmol) of benzoyl chloride are added at -10 ° over 1.5 hours. After 0.5 hours the solution is poured into a mixture of 2N hydrochloric acid 2 and 1300 g of ice and the oily precipitate is extracted with ethyl acetate. After the usual post-treatment, the compound (+) 2R, 3S-3- (2-ethoxy-phenoxy) -2-hydroxy-1- (4-nitro-benzoyloxy) -3-phenylpropane (8.2 g) Obtained as an oil. ▲ [α] ²⁰ _D ▼ ＝ + 11.7 °.

Example 6 Methylene chloride 90m (+) 2R, 3S-3- (2-ethoxy-phenoxy) -2-hydroxy-1- (4-nitro-benzoyloxy) -3-phenylpropane 80g
(18.2 mmol) and triethylamine 3.86 m (2
(7.4 mmol) in a solution of methanesulfonyl chloride 1.54
m (20.0 mmol) is added dropwise at 0-5 ° and the solution is kept at that temperature for 0.5 h. After washing with 10% hydrochloric acid and 5% sodium hydrogen carbonate solution and water, the solution is dried over sodium sulfate and the solvent is evaporated to dryness. After the usual post treatment, the compound (+) 2R, 3S-3-
(2-Ethoxy-phenoxy) -2-mesyloxy-1
-(4-Nitrobenzoyloxy) -3-phenylpropane (7.5 g) is obtained as an oil (▲ [α] ²⁰ _D ▼ = + 33.6 °).

Example 7 Dioxane 40 m and 2N sodium hydroxide 16 m
Medium (+) 2R.3S-3- (2-ethoxy-phenoxy) -2
-Mesyloxy-1- (4-nitrobenzoyloxy)
A solution of 3.95 g (7.7 mmol) of 3-phenylpropane is stirred for 4 hours at room temperature. After diluting with 200 m of water, the solution is extracted with ethyl acetate and the organic phase is washed with a 5% aqueous solution of sodium hydrogen carbonate and then with water. After evaporation of the solvent under vacuum, the residual oily epoxide, namely (-) 2S, 3S-3- (2-ethoxy-phenoxy)-
The weight of 3-phenylpropane 1,2-epoxide is 2.05 g.
(100%), which is used as is in the next step. ▲ [α] ²⁰ _D ▼ = -3.1 °.

Example 8 Methanol 50 m and 2% ammonium hydroxide 30
m- (2), 3S-3- (2-ethoxy-phenoxy)-
A solution of 2.05 g (7.6 mmol) of 3-phenylpropane 1,2-epoxide is left for 6 hours in a sealed frass. After evaporation of the solvent the residue was dissolved in ethyl acetate and 0.52 m of methanesulphonic acid in 10 m of ethyl acetate.
(8 mmol) is added to the solution. After 16 hours, 2.13 g of crystalline product (+) 2S, 3S-1-amino-3- (2-ethoxy-phenoxy) -2-hydroxy-3-phenylpropane is collected. mp97-99 ℃, ▲ 〔α〕 ²⁰ _D ▼
= +34.4.

Example 9 (+) 2S, 3S-1-amino-3- (2-ethoxy-phenoxy) -2-hydroxy-3-phenylpropane 2.13 which is the above amino alcohol in 70 m of methylene chloride.
g (7.4 mmol) and triethylamine 2.27 m (1
To a solution of 6.2 mmol) held at -5 to 10 °, 0.64 m (8.0 mmol) of chloroacetyl chloride dissolved in 20 m of methylene chloride is added dropwise. After 0.5 hours the solution is washed with water, dried over sodium sulphate and evaporated to dryness. Residue after normal post treatment (+) 2
S, 3S-1-chloroacetylamino-3- (2-ethoxy-phenoxy) -2-hydroxy-3-phenylpropane (2.6 g) was obtained as an oil ▲ [α] ²⁰ _D ▼ = 1 + 18.6 °. To be

Example 10 Potassium tertiary butoxide in 15 m of tertiary butanol
40 g of tertiary butanol was added to 2.0 g (18.0 mmol) of solution.
(+) 2S, 3S-1-chloroacetylamino-3- (2 in m
3.3 g (9.0 mmol) of -ethoxy-phenoxy) -2-hydroxy-3-phenylpropane are added over 2 hours at room temperature. After 1 hour 8% hydrochloric acid is added until pH 4-5 and the solution is evaporated to dryness under vacuum. The residue is dissolved in water, the solution is neutralized with solid sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase is washed thoroughly with water, dried over sodium sulphate and the solvent is distilled off under vacuum. (-) 2S, 3S-6- [α- (2-Ethoxy-phenoxy) -benzyl] -morpholine-3-, which is an oily residue.
ON (2.6 g, ▲ [α] ²⁰ _D ▼ = -21.2 °) is obtained.

Example 11 (-) 2S, 3S-6- [α- (2-E
Toxy-phenoxy) -benzyl] -morpholine-3-
A solution of 5.0 g (15.3 mmol) on
-AL (Vitride )] In 70% toluene solution 12.7 m (45.
4 mmol) diluted with 40 m of anhydrous toluene
Add at room temperature over 15 minutes. Excessive redness after 4 hours
-Decompose RED-AL with 2m sodium hydroxide 20m
It The organic phase is separated, washed with water, dried and evaporated to dryness.
To do. Dissolve the residue in ethyl acetate and add methanesulfonic acid.
1.0 m (15.4 mmol) is added to the solution. At room temperature
After left overnight, solid content, namely (+) 2S, 3S-2- [α-
(2-Ethoxy-phenoxy) -benzyl] -morpholin
The methanesulfonate. m.p. 100 to 102 ℃
4.9 g of compound are obtained. IR (KBr) cm^-1:1590 ~ 1495 (Aromatic C = C), 1250 (Ar-O-Alk), 1205 (Al
k-O-Alk), 1190, 1040 (SO₃H); ▼ [α]²⁰ _D▼ = ＋ 21.81
°.

Example 12 (+) 2S, 3S-2- [α- (2-ethoxy-phenoxy)-
Benzyl] -morpholine (3.2 g) was added to absolute ethanol (5
0m) and then add a small excess of hydrochloric acid in ethanol. The solvent is evaporated to dryness under vacuum and diethyl ether is added to the oily residue. When the solid content obtained after milling was passed over, (+) 2S, 3S-2- [α- (2
-Ethoxy-phenoxy) -benzyl] -morpholine hydrochloride (3.3 g, mp 138-140 ° C) is obtained.

By the same operation, the following hydrochloride salts of (+) and (-) enantiomers can be obtained.

(-) 2R, 3R-2- [α- (2-ethoxy-phenoxy)-
Benzyl] -morpholine hydrochloride, mp 138-140 ° C, (+) 2- [α- (2-methoxy-phenoxy) -benzyl] -morpholine hydrochloride, (-) 2- [α- (2-methoxy-phenoxy) -Benzyl] -morpholine hydrochloride, (+) 2- [α- (4-trifluoromethyl-phenoxy)
-Benzyl] -morpholine hydrochloride and (-) 2- [α- (4-trifluoromethyl-phenoxy)
-Benzyl] -morpholine hydrochloride.

Example 13 Each having a weight of 200 mg and each having 5 m of active ingredient
A tablet containing g is manufactured by the following method.

Composition (per 10,000 tablets) (+) 2S, 3S-2- [α- (2-Ethoxy-phenoxy) -benzyl] -morpholine methanesulfonate, 50g (±) RS, RS derived from racemic form Dextro (+) enantiomer Lactose 1,430 g Corn starch 450 g Talc (powder) 50 g Magnesium stearate 20 g (+) 2S, 3S-2- [α- (2-ethoxy-phenoxy)-
Benzyl] -morpholine methanesulfonate, lactose and half the amount of corn starch are mixed and sieved with a mesh of 0.55 mm. Disperse 30g of corn starch in 300m of boiling water. The above powder mixture is granulated using the obtained starch demulcent. The granules are dried and passed through a 1.4 mm mesh screen. Add the rest of the starch and talc and magnesium stearate. Mix carefully and compress the material using a punch with a diameter of 8 mm to produce tablets.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Alessandro Rocci Milan, Italy. Via Bartuini 7

Claims (7)

[Claims] 1. A formula (I) The (+) 2S, 3S enantiomer of the compound of the formula (wherein R is a C ₁ -C ₆ alkoxy group or a trihalomethyl group) and a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R is methoxy, ethoxy or trifluoromethyl. 3. (+) 2- [α- (2-Methoxy-phenoxy) -benzyl] -morpholine, (+) 2- [α- (2-ethoxy-phenoxy) -benzyl] -morpholine, (+) A compound according to claim 1 selected from the group consisting of 2- [α- (4-trifluoromethyl-phenoxy) -benzyl] -morpholine, and a pharmaceutically acceptable salt thereof. 4. The compound according to any one of claims 1 to 3, which is a hydrochloride. 5. The compound according to any one of claims 1 to 3, which is a methanesulfonate. 6. (a) (±) RS as a free base, RS racemic formula (I) (However Shikichu, R represents C ₁ -C ₆ alkoxy or trihalomethyl group is a) to give a mixture of compounds having reacted with optically active acids two diastereoisomeric salts, (b) to give The separated salts are separated by crystallization, and (c) each of the separated salts is extracted with dextro.
Liberating the (+) enantiomer base, and (d) optionally forming a salt of the resulting dextro (+) enantiomer base with a pharmaceutically acceptable acid, wherein A method for producing the (+) 2S, 3S enantiomer of the compound (1) and a pharmaceutically acceptable salt thereof. 7. Formula (I) (Wherein R is a C ₁ -C ₆ alkoxy group or a trihalomethyl group), in producing the (+) 2S, 3S enantiomer of the compound and a pharmaceutically acceptable salt thereof, (a) Formula (II) By reducing the (+) or (-) enantiomer or derivative thereof of glycidic acid having the formula (III) Of cinnamyl alcohol-2,3-epoxide having (+)
Alternatively, the (-) enantiomer is obtained, and (b) the (+) or (-) enantiomer of the formula (III) is replaced by the formula (IV) (Wherein R is as defined above) is reacted with a phenol derivative of formula (V) (Where R is as defined above)
(+) Or (-) enantiomer is obtained and (c) the (+) or (-) enantiomer of formula (V) is esterified with a carboxylic acid or a reactive derivative thereof to give formula (VI) (Wherein R is as defined above and R ₁ is the residue of a carboxylic acid) to give the (+) or (−) enantiomer of (d) of formula (VI) The (+) or (-) enantiomer is esterified with sulfonic acid or a reactive derivative thereof to give the compound of formula (VII) Where (+) or (-) enantiomer of (wherein R and R ₁ are as defined above and R ₂ is the residue of a sulfonic acid), and (e) (VII ) To produce an epoxide from the (+) or (-) enantiomer of formula (VIII) (Where R is as defined above)
The (+) or (-) enantiomer is obtained and the (+) or (-) enantiomer of (f) (VIII) is reacted with ammonia to give the compound of formula (IX) (Where R is as defined above)
(+) Or (-) enantiomer is obtained, and (g) the (+) or (-) enantiomer of formula (IX) is converted into formula (X) Y-CH ₂ -CO-Y (X) (where Where Y is a halogen) and react with a compound of formula (XI) (Wherein R and Y are as defined above) to obtain the (+) or (-) enantiomer, and (h) the (+) or (-) enantiomer of formula (XI) Is cyclized to formula (XII) (Where R is as defined above)
(+) Or (-) enantiomer is obtained, and (i) the (+) or (-) enantiomer of formula (XII) is reduced to formula (I)
A process for the preparation of the above compounds, which comprises obtaining the (+) enantiomer of and the optionally obtained 2S, 3S enantiomer of formula (I) is converted into its pharmaceutically acceptable salt.