JPS61129174A - Enantiomer of phenoxy derivative of benzylmorpholine and salts thereof - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides RR of phenoxy derivatives of benzylmorpholine.
and SS enantiomers and salts thereof, processes for their production and systematic compositions containing them. U.S. Pat. No. 4,229,449 specifically describes the following formula (
I) 2-(α-phenoxy-benzyl)-7ulfoline derivatives (wherein R is an o 1-o 6 alkoxy group and 9 is a trihalomethyl group) and systematically acceptable salts thereof is listed.

Due to the presence of two chiral centers at carbon atoms 2 and O in the above formula ((), two sets of enantiomers exist for the compound of formula (), respectively).

These two pairs, which have a diastereoisomeric relationship with each other, are called rupic, No.
ugNcr, *Tuy OF 0RGANICcamx
sTRy) 1979 edition, section J489 with the symbols (nR8, R8 and (:f=l R8,
Made to wear by SR.

In the formula (I1 and Ike's formula in the present specification).

The two chiral centers are conventionally numbered 2 and 6 to clearly indicate the absolute configuration of each center when known.

However, such conventional numbering is independent of the numbering required by, for example, the IUPAO nomenclature for the precise names of the compounds described herein.

U.S. Pat. No. 4.229 for a particular diastereoisomer or set of enantiomers having formula f1) above.
．． No. 449, however, there is no specific mention of the single enantiomer derived therefrom.

According to the invention, 2R, 3R or 28 of the compound of formula (I)
, 3S enantiomer and its systemically acceptable salts are provided. Therefore, the enantiomer of the present invention is dextro f+
) or levo←) exist as enantiomers. Preferred compounds of the invention are those where R is methoxy, ethoxy or trifluoromethyl.

The present invention also includes 2R, 3R or 28, 3 of formula (I).
Also included are the metabolites of the eight enantiomers, the biological IW=forms and the pharmaceutically acceptable salts already mentioned, as well as systematic compositions containing the enantiomers mentioned above or their salts. Examples of systematically acceptable salts of the enantiomers of the present invention are a!
Organic acids, including salts with acids such as hydrochloric acid, hydrochloric acid, sulfuric acid, and optically active acids, both salts with citric acid, tartaric acid, methanesulfonic acid, 7-maric acid, maleic acid, and mandelic acid. It is. Preferred salts are those with hydrochloric acid and methanesulfonic acid, and even more preferred are those with methanesulfonic acid. Examples of particularly preferred compounds of the invention are the following (+) and (→ enantiomers).

(+32- [α-(2-Methoxy-phenoxynobenzyl-co-morpholine.

(→2-[α-(2-methoxy-phenoxy)-benzylcoumorpholine, (+12-(α-(2-ethoxy-phenoxy)-benzylcoumorpholine).

(-12-(α-(2-ethoxy-phenoxy)-benzylcoumorpholine, (+12-[α-(4-trifluoromethyl-phenoxy)-benzylcoumorpholine, R2-[α-(4-trifluoromethyl -phenoxy)-benzylcoumorpholines and their chemically acceptable salts, especially with hydrochloric acid or methanesulfonic acid.

The compounds of the present invention include (a) (:l) of a compound of formula (I) as the radical
:lRe, RSS racemic all-optically active enemy 2
Obtain a mixture of diastereoisomeric salts of the species.

(I) 1 The obtained n-fc term was separated by crystallization, and (
0) liberating the dextro (± or levo (c)) enantiomeric base from the respective salts, optionally separated;
and (dl) may be prepared by a process consisting of forming a chemically acceptable salt of the optionally obtained dextro(+l or levoH enantiomeric base).

(to) R8, R8 of the compound of formula (I) as a free base
, 7 semiform and the optically active acid can be carried out using any suitable optically active acid, such as D(-)mandelic acid, D(-)mandelt&.

10(+)camphorsulfone rR,L, (+)dibenzoyltartaric acid, L(-)pyrrolidone-carboxylic acid, L+
+1? i! It may be molten acid or of-+ bitaric acid. This salt-forming reaction is preferably carried out in an organic, preferably anhydrous solvent, such as methanol.

It may be ethanol, dioxane or dimethylformamide.

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

Liberation of the corresponding dextro (+) or levo H enantiomeric base from the separated salt can be accomplished by treatment with a small excess of the appropriate base. Preferably, non-mold bases are used, such as alkali metal or alkaline earth metal hydroxides or carbonates tfcri bicarbonate. Sodium or potassium carbonates or bicarbonates are particularly preferred J1 groups.

Salt formation of the resulting dextro(+) or levo f-)LIM image isomer 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 Xiangge can be treated with anhydrous gaseous hydrochloric acid in an anhydrous solvent such as diethyl ether, toluene, ethanol or with an anhydrous alcoholic solution of hydrochloric acid and subjected to filtration or evaporation of the solvent. It is obtained by isolating the hydrochloride salt. Salts with methanesulfonic acid are likewise obtained, for example, by adding an ethanolic solution of methanesulfonic acid to an ethanolic mixture of the enantiomeric bases. Precipitation of the methanesulfonate salt can be carried out, if necessary, in an anhydrous, non-toxic bath medium such as diethyl ether, n.
- Conveniently carried out by adding hexane or cyclohexane.

All reaction steps described in a)-d) above are f
Although it can be carried out at temperatures from JO°C to about 50°C,
In either case, the temperature is a preferable temperature.

The preparation of compounds of formula (I1) as mixtures of diastereoisomers and as separated diastereoisomers is described in U.S. Pat. No. 4,229,449.

Alternatively, the compounds of the invention can be prepared by reducing the (-+J or ←) enantiomer of glycicic acid of formula (II) or its derivatives to the or (-obtain the enantiomer.

(b) Formula (assistant (+1 or H theory isomer is expressed as □□□(
However, in the formula, R is 7 as shown above.
Formula (V) (wherein, R
is p as determined above) to obtain the (+l or H enantiomer of (0) formula fV) (± or (-)
The enantiomer is esterified with a carboxylic acid or a reactive derivative thereof to obtain the formula (VD (fc), where R is as defined above, and R1 is the residue of a carboxylic acid) (-1-1 or (obtaining the isomer of (-1-1), (d)
The [+H or (c) modest isomer of formula (VD) is esterified with a sulfonic acid or a reactive derivative thereof to form a compound of formula (■, where R and R1 are as defined above, and R2 is the residue of a sulfonic acid) to obtain the (+1 or H enantiomer).

(eJ Formation of epoxide from the (+l or H enantiomer of formula (■)) of formula (■) (where R is as defined above)) or ← (enantiomer Get a body.

(f) reacting the (-1-1 or H enantiomer of formula '16D with ammonia to produce formula (IX), where R is as defined above) (c) is the enantiomer, (g) is (-1 in the formula diagram)
-1 or ←) enantiomer with the formula (to) r-aH2-co
-r QO in which Y is a halogen to form the (+) or H enantiomer of cyclize the (+) or H enantiomer of formula JD to obtain the (+) of formula JD, where R is as defined above. (I) gives the enantiomer of formula (X
The (+) or ←) enantiomer of ll) is reduced to form the formula +1
+ (+) or (-) * 11 isomer is obtained and optionally the obtained 2R, 3R or zs of formula (I),
It can be prepared by a process consisting of converting the 38m enantiomer into its optically acceptable salt.

The glycissinated derivative of formula (I[) is, for example, an acid anhydride, or preferably a mixture! It may also be an R anhydride.

The carboxylic acids used in the above esterification step (C1) may be aliphatic, such as 02-C6 aliphatic carboxylic acids, such as 02-C6 aliphatic carboxylic acids, such as propionic acid, or aromatic acids, such as benzoic acid or p-nitrobenzoic acid. Good. In the above formulas (VD and (Vll), carboxylic acid residue R1
is, for example, acetyl, propionyl, benzoyl or p-nitrobenzoyl. Esterification step ((Ll
The sulfonic acids used in U, t, methanesulfonic acid, ethanesulfonic acid, <benzenesulfonic acid or p-)
It is luenesulfonic acid. The sulfonic residue R2 in the above formula (■) is, for example, methanesulfonyl, ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl + tt, < hamethanesulfonyl.Formula (X
)′J? The halogen Y in the compounds of formula (2) and (2) is preferably halogen, iodine or iodine, most preferably halogen.

The reduction step (a) is carried out in a known manner, preferably in a suitable anhydrous inert solvent such as anhydrous ethanol, diethyl ether or dihydrofuran, for example before cooling to about 0° C. For example, NaBH
4t- can be used.

The reaction of the am isomer of formula M with a compound of formula M is preferably carried out in the presence of a base such as aqueous sodium or potassium hydroxide, preferably in the absence of other solvents, e.g.
It is carried out by heating at a temperature of 120°C to about 120°C.

Esterification of enantiomers of formula (V) to obtain compounds of formula (Vl) is preferably carried out in the presence of a base such as an organic base such as triethylamine or pyridine in an anhydrous organic solvent such as benzene or toluene, e.g. Reactive derivatives of carboxylic acids are prepared with cooling to about -10°C to 0°C or at room temperature! The reaction is carried out with a carboxylic acid halide, especially a chloride, and according to a preferred procedure pyridine is conveniently used as a solvent in the absence of other bases.

Esterification of enantiomers of the formula (4) to give compounds of the formula (4) is preferably carried out in the presence of an acid acceptor such as an organic base such as triethylamine or pyridine to form a reactive derivative of a sulfonic acid, preferably a sulfonic acid halide, especially a sulfonic acid halide. The reaction is preferably carried out using a chloride such as methanesulfonyl chloride or p-toluenesulfonyl chloride.
This is carried out while cooling to 0° to 5°C. When pyridine is used as a solvent it also acts as a base. The conversion of a compound of formula (VIA) into a compound of formula (■) is carried out by reaction with a suitable base, preferably an inorganic base, such as an alkali metal or alkaline earth metal hydroxide, preferably aqueous sodium or potassium. . Preferably the reaction is carried out in an aqueous solvent such as dioxane or dimethylformamide at room temperature.

The subsequent reaction of the epoxide of formula (■) with ammonia is preferably carried out using 30-32% aqueous ammonia at room temperature in a suitable solvent such as dimethylacetamide or an aliphatic alcohol such as methanol or ethanol. The enantiomer of the resulting formula and the reaction with a compound of the formula (sword) is carried out in a preferably anhydrous inert solvent such as a halogenated hydrocarbon such as methylene chloride in the presence of a base such as an organic base such as triethylamine. It can be carried out while cooling to 0°C to 0°C.

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

The resulting enantiomer of formula CM) can be reduced, for example, using an anhydrous, non-phosphorescent polymer such as diethyl ether.

Tetrahydro7ran, dioxane Ma9 is B in toluene
Reflux from about 0°C using H5 or mixed hydrides such as lithium aluminum hydride or sodium borohydride! This is done by processing at temperatures up to 30°F. A particularly suitable reduction method involves the use of Red-Am (Vitride) as the reducing agent in anhydrous toluene at room temperature.
This includes using the "ride" button.

Salt formation of the resulting enantiomer of formula (I) can be carried out in any conventional manner according to known salt formation methods.

Formula 1ll used as starting material in the above alternative method
) is the glycicic acid enantiomer a known compound or
Or, it is a compound that can be produced by a known method from the above-mentioned compounds.

For example, Harada arrival gJ, Org, ckxem
, J Vol. 31, No. 1407 Kai (I966) t-See.

The compound of the present invention is active on the central nervous system,
Particularly active as antidepressants, for example, the compounds of the invention have the ability to increase the concentration of physiologically active monoamines by blocking their uptake and/or It is shown by blunting α-2 presynaptic receptors.

As noted, an important property of antidepressants is their ability to block neurotransmitter uptake at cerebral synapses (F) (Iversen L, L, J.

Pharm, Pharmacol, J Vol. 17 No. 42
Sada C 1965)], and an even more important characteristic is α
-2 adreceptor (Chapleo C.B., J. Med.
, Ohem, J Vol. 26, p. 826 (I983)]
.

The compounds of the invention can also be tested in vitro (for example, in 5nyder S, H., J. Pharmaco.
LJ! ! xp.

The activity was determined using radioactively labeled compounds according to the experimental methods described in J. It has been found that the concentration of biogenic amines can be increased.

Physiologically active monoamines whose concentrations can be determined by the uninvented compounds include serotonin, norepinephrine, and dopamine.

The anti-itch activity of the compounds of the invention is also evidenced by the fact that they are active in suppressing 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 invention may be negligible and therefore they can be safely used in therapy.

Although the compounds of the invention may be administered in the usual manner, such as by injection or rectally, they are preferably administered orally. Suitable dosages for oral administration of the compounds of this invention to adults are preferably 0.5 to 10 cm per dose administered 2 to 4 times per 91 days.

The music composition according to the invention has the formula (I) as active ingredient
2R, 3R or 28,38 enantiomers of the compound having or musically acceptable salts thereof and systematic K1
ff Contains a compatible carrier and/or diluent. The compositions can be manufactured using conventional ingredients and conventional methods. For example, for oral administration, acid compounds containing compounds of the invention are preferably prepared using diluents such as lactose, textulose, lactose, mannitol, lactose, cellulose, etc. tablets, pills or capsules containing the active substance together with, for example, silica, Merck, stearic acid, magnesium or calcium stearate and/or polyethylene glycol. They are also sizing agents such as starch, gelatin, methylcellulose, gum arabic, tragacanth, polyvinylpyrrolidone, disintegrants such as twill powder, alginic acid, alginates, foaming mixtures, dyes.

Sweetening agents, humectants such as lecithin, borinurbate, lauryl sulfate and non-toxic pharmacologically inert substances commonly used in medicinal formulations may also be included.

Such therapeutic preparations can be prepared in known manner, e.g. by mixing,
They can be manufactured by granulation, tableting, shielding or coating operations. Ikegaku formulations containing the compounds of the invention can also be prepared by conventional methods, such as syrups or drops for oral administration, sterile solutions or base formulations for injection. It may be.

EXAMPLES In order to better understand the present invention, examples will be described below, but the present invention is not limited thereto. If not specified, [α]9 value is 95
% in ethanol.

Example 1 Methanesulfone # (0
, 33ml). Diethyl ether (20011
111), the solids precipitate. If you pick this t-fruit, it will be 2-[α-(2-ethoxy-
Phenoxine-henzyl comorpholine methanesulfone modified 4 (m, p, 146-147℃, U, V, (M
eOH): λmax=275nm, z”A
= 50) 1Q stomach is obtained as (to) R8,RS racemic form.

Example 2 R8, R82-(α-(
2-Ethoxy-phenokidine-benzylco-morpholine methanesulfonate (m, p, 146~, 147℃s
The aqueous solution of 4o p ) is extracted with ethyl acetate. The solution is washed with water, dried over sodium sulfate and evaporated to dryness under vacuum. Mandelic acid (J
Pour 9 mouthfuls of 5.06JI) into the solution. Precipitation t-filtered m, p, 164-151℃ (<0=(-1-)
48.01 (80% zri/-h) 1% ft1K
) A solids content of 18.85 jl with k is obtained. After crystallization from anhydrous ethanol (200 ml), m-pis
The product rostrum (mandelate salt) 16.86F is obtained at i~156°C. [α] - +49.09 (1% solution in 80% ethanol/it) Dissolve the mandelate salt in water, make the solution basic with potassium carbonate, and extract the No. 70 group with ethyl acetate. do. The organic solution is dried over sodium sulfate and evaporated to dryness under vacuum. (+) 28
．． 38-2- (α-(2-ethoxy-phenoxy)-
The oily residue containing benzyl co-morpholine C12,159) was dissolved in ethanol and methanesulfonic acid (C12,159) was dissolved in ethanol.
3,72jl) of ethanol dissolved in Toguchi. After dilution with diethyl ether, the precipitate was reformed and filtered to yield @-)2S,68-2-(α-(2-ethoxy-phenoxy)-benzylco-morpholine methanesulfonate (Ii5,9). m, p, 1(I0
˜102° C., [α)i′=+zta9° (1% melt in 951% ethanol).

Molar fineness (D, S, C,) = 98 chi.

N, M, R, (CDOJ13) δ: 1.42 (t,
3) (, CH3-0H2), 2.71 (S, 6H, 0H
5SOi).

2.84-5.50 (m, 4H, CH2-N-CH2)
.

5.85-4.40 Cm, 6H, 0H2-0-OH).

4.05 (q, 2H, CH2-0-Ar), 5.14 (
d, IH, OCtan-Ar), 6.64-6.92 (m
, 4H, Ar1°), 755Cm, 5H, Ar-0H)
, 9.20 (bs, 2H, NH2).

A method similar to that described above starts from DH mandelic acid and the levoisomers H2R,5R-2-(α-(2-ethoxy-phenoxy)-benzylco-morpholine and (-12R,,
5R-2-(α-(2-ethoxyphenoxy)-benzylco-morpholine methanesulfonate), the latter compound m, I), 100-102
°C, [α] also has '=-21,89° (Ichi solution in 95% ethanol).

By analogous manipulation the next enantiomer is prepared starting from the corresponding JR8, RS racemic form.

(-)) 2-(α-(2-methoxy-phenoxy)-benzylco-morpholine, R2-[α-(2-methoxy-phenoxy7]-benzylco-morpholine).

(-)12-(α-(4-trifluoromethyl-phenoxy)-benzylco-morpholine.

(-12-(α-(4-trifluoromethyl-phenoxy)-benzylco-morpholine.

(+l 2- (α-(2-methoxy-phenoxy)-
Hensyltumorpholine methanesulfonate, ←) 2-
(α-(2-Methoxy-phenoxy)-benzylco-morpholine methanesulfonate.

(±2-[α-[4-trifluoromethyl-72-benzyl]-morpholine methanesulfone rIR salt, (→2-[α-(4-trifluoromethyl-phenoxy)-benzyl-morpholine methanesulfone acid salt.

(to) R8, obtained from RS racemic form &(+)2S,,
The optical purity of 5B- and H2R,3R-2-(α-(2-ethoxy-phenoxine-benzyl)-morpholine methanesulfone #R salts is determined as follows.

(+) 28,6S −2 in anhydrous toluene (4Qmi)
-[a-(2-Ethoxy-phenoxy)-benzylcoumorpholine salt MCjpn (corresponding ωFIS, obtained from the RS diastereoisomer) and triethylamine (0,90 fine) were added to a 1w solution at a temperature of 10°C rapidly. L H menthoxy-acetyl-chloride (0.80 ml) in anhydrous toluene (jQmffi) is added dropwise with stirring. The reaction is complete after stirring for 1 hour at room temperature. The reaction mixture is washed with water and treated with sodium sulfate. Dry and evaporate to dryness under vacuum.

Similar operations apply to the (-12R,3R-enantiomer obtained from (t)R8,Re -2-[α-(2-ethoxy-phenoxy)-benzylco-morpholine).

The two diastereoisomeric amides thus obtained were analyzed by high performance liquid chromatography (HPLC).
Technology [Partia
il PXS) 10/25, isopropylamine 0
．． Cyclohexane to say 15%: Ethyl acetate 95%
), the retention times (R, T, ) are each 1
They were 5.15 minutes and 17.23 minutes.

In both cases the result is a relative purity of 98.5%. From this it can be assumed that the optical purity is >97% for the (g) and h) enantiomers.

Example 3 (±28.SR-phenylglycisic acid D(+)-α
-Methyl-7enetelamine salt 3.83' (I3,,5
solution of t-2N salt tR6,65ml (I3
, 3 mmol). After extracting the M-chloride with diethyl ether and diluting it with sodium sulfate, the solvent is removed. Dissolve the residue in 70ml of methylene chloride and 2ml of triethylamine! (I4.3 mmol) is added. This solution was cooled to t-0°C and, under stirring, 1.56 mQ of ethyl-chlorocarbonate (
I4.5 mmol) was added over t-1 hours. After 2 hours, the solution was added to a suspension of 2.269 (59.7 mmol) of sodium chloride in absolute ethanol at 0°C.
Add while stirring constantly. After 0.5 hours, allow the temperature to rise to room temperature and continue stirring. Pour this mixed vlJ into water.

The product is then extracted with methylene chloride.

After separation using a flash chromatography column (using an eluent of chloroform:methanol 100:2), (+)2R,6R-cinnamyl alcohol-2,6
- Eboxide 0.62jliI) is obtained as a colorless oil. [α) fi' = + 45.9° (C
1,5, absolute ethanol).

(Example: 0 71.68H6,71c9a1oo2
Calculated value for 0 71.97 H6, 71%) IH
-N, M, R, (ODObu3) δ: 3.24 (IH
,ddd,-0H-C! H20Hn, 3.76 (IH
, da, Odan□HB-OH).

5.94 (IH, d, Ph-C@, J=2.17)
.

4.05 (IH, dd, CH, DanB-OH), 7.35
(5H, s, Ph); IR (CHCJ25) cm, 5590-3450 (
OH), 1600.1490 (aromatic 0=C),
1220.1060 (Alk-0-Alk, Alf-O
H): The starting material (+l -(28,3R)phenylglycidine rRO,36p (I5,3%) is recovered together with its ethyl ester 0,929 (56,5%).

Example 4 1.77jl of sodium hydroxide in 100mt of water (44
, 5 mmol) in a solution of 2-nitoxy-phenol 18
．． Add 66 mmol of 2R,3R-cinnamyl alcohol-2,6-epoxide and stir the mixture at 70 °C until the solids are completely dissolved. (44.3 mmol) is added in 10 minutes. The solution is stirred for 2.5 hours at -70°C and then poured into 200 ml of 1N sodium hydroxide at 10-15°. After extraction with methylene chloride, the The solution is washed sequentially with INtC sodium oxide and saline. Upon removal of the solvent, (2R, 38-3-(2-ethoxy-phenoxy)1.2-:/'Hydroxy-6-phenylpropane 10.29 , is obtained. [α几=+7.
8°;, m, p, 87-89°; IR(KBr)c! n5440-5580COH), 1
590.1490 (aromatic 0=0), 1240 (A
r-0-Alk).

Example 5 In 100 mff1 of pyridine (-1-+2R, 38-5-
(2-ethoxy-phenoxy)-1,2-dihydroxy-6-phenylpropane 6.449 (34.0 mmol) in a bath of 109 (34.6 mmol) of 4-nitro-benzoyl chloride in 100 mt of pyridine. 1-
Roast at -10° for 1.5 hours. After 0.5 hours, the bath solution is poured into a mixture of t-2N hydrochloric acid and ice 15009, and the oily precipitate is extracted with ethyl acetate. Compound juice) 2R93B-3-(,
2-ethoxy-phenoxy)-2-hydroxy-1-(
4-Nitro-benzoyloxy)-3-phenylpropane (8,1) Obtained as an oil. [α), =+
11.7°.

Example 6 f+J 2R,,5S in 90ml methylene chloride
A solution of -3-(2-ethoxy-phenoxy)-2-hydroxy-1-(4-nitro-benzoyloxy)-3-phenylpropane 809 (I8.2 mmol) and triethylamine 3.86 mQ (27.4 mmol) 1.541 d (20.0 mmol) of methanesulfonyl chloride was added dropwise at t-0 to 5° and the bath was kept at that temperature for 0.5 hour. After washing with 10% hydrochloric acid and 5% sodium bicarbonate solution and water, the solution is dried over sodium sulfate and the solvent is evaporated to dryness.

After general post-treatment, the compound (+l 2R, 38-
6-(2-ethoxy-phenoxy)-2-mesyloxy-1-(4-nitrobenzoyloxy)-3-phenylbropane (7,57)? Mountain @ ([α]'i0=+5
5.6°).

Example 7 Dioxane 40 rn and 2N sodium hydroxide 16 rn
i (-+l 2R,5B -6-(2-ethoxy-phenoquine)-2-mesyloxy-1-(4-nitrohensoyloxy)-5-phenylpropazone 3.95jl
Stir warm for 4 hours. After diluting with 2 aamt of water, the solution is extracted with ethyl acetate and the organic phase is diluted with 500 ml of sodium bicarbonate. % aqueous solution and then with water. After evaporation of the solvent under vacuum, the remaining trumpet oil-like epoxide, i.e. (-)28.38-5<2-ethoxyphenoxy)-3-phenylpropane, , 2-epoxide weighs 2.05jl (I00ch), which is used in the stitching stage.

Example 8 50 ml methanol and 32% ammonium hydroxide 6
A solution of 2.05 jl (7.6 mmol) of pan-1,2-epoxide is left in a sealed flask for 6 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate and 0.52 μm (8 mmol) of methanesulfonic acid in 10 μm of ethyl acetate was added to the solution. After 16 hours, a crystalline product formed. Yes (+32
8,3B -1-amino-3-(2-ethoxyphenoxy)-2-hydroxy-3-phenylpropane 2.1
3Jl t” Pick the fruit. m, p, 97-99℃, [α
Example 9 Methylene chloride 70 is the above amino alcohol (+) 28.5B -1-amino-3-(2-ethoxy-phenoxy)-2-hydroxy-3-7x= + Propa/2.13jl (74 mmol and 2.27 mJ of triethylamine! (I6.2 mmol))
Methylene chloride 2 (Im
0.64 mQ of chloroacetyl chloride dissolved in 1 (
8.0 mmol) f:, m added. After O,S hours, the solution 'e' is washed with water, dried over sodium sulfate and evaporated to dryness. It is a residue after normal post-treatment (+
l 28,68-1-chloroacetyl 7mi/-3-(2
-ethoxy-phenoxy)-2-human a:If-cy3
-Phenylpropa;/(2,6)) is an oily substance [α 0=
+18.6°.

Example 10 A solution of 2.0 jl (I8,0 mmol) of potassium 6-butoxide in 15 ml of tertiary-butanol (+) 2s, 6s -1-ria in 4QmQ of tertiary-butanol.

Acetylamino-6-(2-ethoxy-phenoxy)-
2-Hydroquine-6-phenylpropane 55 jl (
9,Q mol) was added over 2 hours at room temperature. 1
8T salt rR is added until the time is -4 to 5, and the solution is evaporated to dryness under a sanitary sieve. The residue is dissolved in water, the solution is neutralized with solid sodium bicarbonate and extracted with ethyl acetate. The sentient phase is thoroughly washed with water, dried over sodium sulfate, and the solvent is distilled off in vacuo.

The oily residue @2S,5B -6-(α-(2-ethoxy-phenoxy)-hensile-morpholine-6-
On(2,6 degrees, [α几'=-21,2 degrees is obtained.

Example 11 Anhydrous toluene 200ml tcF'H2B, 5B -6-
(ct-(2-ethoxy-phenol-benzyl)
-morpholin-6-one5. Red-Al CRJlcD-AL (Vitr
ide■)] 770% toluene solution 12.7 mj!
A solution of 45.4 mmol diluted in 40 g of anhydrous toluene is added over 15 minutes at room temperature. After 4 hours, the excess RID-AL is decomposed to 2N7 with 20 g of sodium saponide. Separate, wash with water, dry and evaporate to dryness. Dissolve the residue in ethyl acetate and
Methanesulfonic acid 1.0 mff1 (I5.4 mmol)
Add to the solution. After standing overnight at room temperature, the solid component, ie (-1-128,,5S-2-(α-(2-ethoxy-phenoxy)-hensyl)-morpholine methanesulfone fi salt t-F, was removed.

m, p. 4.9 compounds are obtained with a temperature of 100-102°C.

Engineering R (KBr) crn, 6000~2400 (NH2
), 1590-1495 (aromatic a=C)
, 1250 (Ar-0-Alk) , 120
5 (Alk-0-Alk), 1190.1040C8
O, H): (α〕=+21.81°.

Example 12 (+1 zs, 6s -2-[:α-(2-ethoxy-
phenoxy)-benzylcoumorpholine<! 1.2p)
was added to absolute ethanol (50111+1), and then a small excess of hydrochloric acid in ethanol was added. The solvent is evaporated to dryness under vacuum and diethyl ether is poured into the oily residue. When the solid obtained after grinding is t-filtered (2S,3S-2-[α-(2-ethoxy-
(phenoxy)-benzyl two morpholine salt Shunshio <5. s
p, m, p, 138-140°C) are obtained.

The following hydrochloride salts of the H and H enantiomers can be obtained in the same manner.

(-32R,3R-2-(α-(2-ethoxy-phenoxy)-benzylco-morpholine tetraacid, m, p, 13
8 to 140°C, (g) 2-[α-(2-methoxy-phenoquidine-inzylco-morpholine hydrochloride), (c) 2-[α-(2-methoxy-7-benzylco-morpholine salt c) salts, (±2-[α-(4-trifluoromethyl-7dinoquine)-benzylco-morpholine hydrochloride and (→2-[α-(4-trifluoromethyl-phenoxy)-benzylco-morpholine salt) .

Example 16 Tablets each having a weight of 200j+9 and each containing 5Tn9 of active ingredient are manufactured in the following manner.

Composition (I0,0: for 10 tablets) Lactose 1.4
30 Meat Corn Starch 4502 Talc (Powder) 50 Magnesium Nostearate 20p
(±28.68-2-(α-(2-ethoxy-phenoxy)-(ndyl)-morpholine methanesulfonic acid weir,
Mix lactose and half the amount of sorghum starch, and make a mesh of 0.
Pass through a 55M sieve. 30 pieces of corn starch - 300 pieces of boiling water. The above powder mixture is granulated using the obtained powder demulcent. The granules are dried and passed through a 1.4-mesh sieve. Trim any leaks from the starch and add talc and magnesium stearate. Mix carefully and compress the material using an 8 inch diameter punch to produce 1c tablets.

Patent applicant: Ichiji Farmitalia Calguchi Elpa Società sul Azzio and two others

Claims (1)

[Claims] 1) 2R, 3R of the compound of formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (wherein R is a C_1 to C_6 alkoxy group or trihalomethyl group) or 2S, 3S enantiomers and pharmaceutically acceptable salts thereof. 2) The compound according to claim 1, wherein R is methoxy, ethoxy or trifluoromethyl. 3) The compound according to claim 1 or 2, wherein the enantiomer is the dextro (+) enantiomer. 4) The compound according to claim 1 or 2, whose enantiomer is the levo (-) enantiomer. 5) (+)2-[α-(2-methoxy-phenoxy)-
benzyl]-morpholine, (+)2-[α-(2-ethoxy-phenoxy)-benzyl]-morpholine, (+)2-[α-(4-trifluoromethyl-phenoxy)-benzyl]-morpholine, from A compound according to claim 3 selected from the group consisting of: and a pharmaceutically acceptable salt thereof. 6)(-)2-[α-(2-methoxy-phenoxy)-
benzyl]-morpholine, (-)2-[α-(2-ethoxy-phenoxy)-benzyl]-morpholine, (-)2-[α-(4-trifluoromethyl-phenoxy)-benzyl]-morpholine, from A compound according to claim 4 selected from the group consisting of: and a pharmaceutically acceptable salt thereof. 7) The compound according to any one of claims 1 to 6, which is a hydrochloride. 8) Claims 1 to 6 which are methanesulfonate salts
A compound according to any of the paragraphs. 9)(+)2-[α-(2-ethoxy-phenoxy)-
6. The compound according to claim 5, which is [benzyl]-morpholine or a pharmaceutically acceptable salt thereof. 10) The compound according to claim 9, which is a hydrochloride. 11) The compound according to claim 9, which is a methanesulfonate. 12) (a) (+)RS as the free base, reacting a compound of formula (I) in RS racemic form with an optically active acid to obtain a mixture of two diastereoisomeric salts; (b)
separating the resulting salts by crystallization; (c) optionally liberating the dextro (+) or levo (-) enantiomeric base from each separated salt; and (d) optionally releasing a pharmaceutically acceptable base. Claims 1 to 11 consist of forming a salt of the dextro(+) or levo(-) enantiomeric base obtained using a diluent acid.
A method for producing a compound according to any of paragraphs. 13) (a) Formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) By reducing the (+) or (-) enantiomer of glycidic acid or its derivatives having formula (III) ▲ Formula , chemical formulas, tables, etc. ▼(III) Obtain the (+) or (-) enantiomer of cinnamyl alcohol-2,3-epoxide with (b) formula (III)
The (+) or (-) enantiomer of the formula (IV) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) (wherein R is as defined in claim 1) ) is reacted with a phenol derivative of formula (V
) ▲Mathematical formulas, chemical formulas, tables, etc.▼ Obtain the (+) or (-) enantiomer of (V) (where R is as defined above), and (c) the formula (V ) by esterifying the (+) or (-) enantiomer of ) with a carboxylic acid or its reactive derivative to form the formula (VI). as defined above and R_1 is the residue of a carboxylic acid); (d) the (+) or (-) mirror image of formula (VI); The isomer is esterified with sulfonic acid or its reactive derivative to form the formula (VII) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VII) (However, in the formula, R and R_1 are as defined above. , and R_2 is the residue of a sulfonic acid) to obtain the (+) or (-) enantiomer of (e) (VII) to form the epoxide from the (+) or (-) enantiomer of the formula (VIII) ▲Mathematical formulas, chemical formulas, tables, etc.▼(VIII) Obtain the (+) or (-) enantiomer of (where R is as defined above), and (f) ( The (+) or (-) enantiomer of VIII) is reacted with ammonia to form the formula (IX) ▲Mathematical formulas, chemical formulas, tables, etc.▼(IX) (g) to obtain the (+) or (-) enantiomer of formula (IX) as formula (X) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( X) (wherein, Y is a halogen) by reacting with a compound of formula (X I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (X I) (wherein R and Y are defined above) (h) cyclize the (+) or (-) enantiomer of formula (X I ) to obtain formula (XII) ▲ Formula, Chemical formulas, tables, etc. ▼ Obtain the (+) or (-) enantiomer of (XII) (wherein R is as defined above), and (i) ( +) or (-) enantiomer is reduced to give the (+) or (-) enantiomer of formula (I) and optionally the resulting 2R, 3R or 2S, 3S mirror image of formula (I). 12. A process for producing a compound according to any of claims 1 to 11, which comprises converting the isomer into its pharmaceutically acceptable salt. 14) A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 as an active ingredient and a pharmaceutically acceptable carrier and/or diluent.